Vancomycin AUC/MIC Ratio and 30-Day Mortality in Patients with Staphylococcus aureus Bacteremia

PubMed Central

Turnidge, John D.; Munckhof, Wendy J.; Robinson, J. Owen; Korman, Tony M.; O'Sullivan, Matthew V. N.; Anderson, Tara L.; Roberts, Sally A.; Warren, Sanchia J. C.; Gao, Wei; Howden, Benjamin P.; Johnson, Paul D. R.

2013-01-01

A ratio of the vancomycin area under the concentration-time curve to the MIC (AUC/MIC) of ≥400 has been associated with clinical success when treating Staphylococcus aureus pneumonia, and this target was recommended by recently published vancomycin therapeutic monitoring consensus guidelines for treating all serious S. aureus infections. Here, vancomycin serum trough levels and vancomycin AUC/MIC were evaluated in a “real-world” context by following a cohort of 182 patients with S. aureus bacteremia (SAB) and analyzing these parameters within the critical first 96 h of vancomycin therapy. The median vancomycin trough level at this time point was 19.5 mg/liter. There was a significant difference in vancomycin AUC/MIC when using broth microdilution (BMD) compared with Etest MIC (medians of 436.1 and 271.5, respectively; P < 0.001). Obtaining the recommended vancomycin target AUC/MIC of ≥400 using BMD was not associated with lower 30-day all-cause or attributable mortality from SAB (P = 0.132 and P = 0.273, respectively). However, an alternative vancomycin AUC/MIC of >373, derived using classification and regression tree analysis, was associated with reduced mortality (P = 0.043) and remained significant in a multivariable model. This study demonstrated that we obtained vancomycin trough levels in the target therapeutic range early during the course of therapy and that obtaining a higher vancomycin AUC/MIC (in this case, >373) within 96 h was associated with reduced mortality. The MIC test method has a significant impact on vancomycin AUC/MIC estimation. Clinicians should be aware that the current target AUC/MIC of ≥400 was derived using the reference BMD method, so adjustments to this target need to be made when calculating AUC/MIC ratio using other MIC testing methods. PMID:23335735

Healthcare-associated Staphylococcus aureus Bacteremia in Children: Evidence for Reverse Vancomycin Creep and Impact of Vancomycin Trough Values on Outcome.

PubMed

McNeil, J Chase; Kok, Eric Y; Forbes, Andrea R; Lamberth, Linda; Hulten, Kristina G; Vallejo, Jesus G; Mason, Edward O; Kaplan, Sheldon L

2016-03-01

Elevated vancomycin minimum inhibitory concentrations (MICs) in Staphylococcus aureus have been associated with worse clinical outcomes in adults. For invasive meticillin-resistant S. aureus (MRSA) infections in adults, the Infectious Diseases Society of America recommends targeting vancomycin serum trough concentrations between 15 and 20 μg/mL. We evaluated trends in vancomycin MICs from healthcare-associated (HCA) S. aureus bacteremia isolates in children in addition to correlating vancomycin serum trough levels with clinical outcomes. Patients and isolates were identified from a prospective S. aureus surveillance study at Texas Children's Hospital (TCH). HCA S. aureus bacteremia isolates from 2003 to 2013 were selected. Vancomycin MICs by E-test were determined and medical records were reviewed. Acute kidney injury (AKI) was defined as doubling of the baseline serum creatinine. Three hundred forty-one isolates met inclusion criteria. We observed a reverse vancomycin creep among MRSA isolates in the study period with a decline in the proportion of isolates with vancomycin MIC ≥ 2 μg/mL (from 32.7% to 5.6%; P < 0.001). However, the proportion of MSSA isolates with MIC ≥ 2 μg/mL increased (from 2.9% to 9%; P = 0.04). Among patients who had vancomycin troughs performed, there was no difference in duration of bacteremia or fever with vancomycin trough >15 versus <15 μg/mL. A vancomycin trough >15 μg/mL was, however, an independent risk factor for AKI. Vancomycin MICs are shifting among HCA S. aureus bacteremia isolates with significant differences between MRSA and MSSA at TCH. Higher vancomycin troughs did not improve outcomes in pediatric HCA S. aureus bacteremia but were associated with increased nephrotoxicity. Further studies are needed to better understand optimal management of children with S. aureus bacteremia.

Determination of the Feasibility of Preparing Vancomycin Microparticles

DTIC Science & Technology

1997-01-01

Maryland 21702-5012. 13. ABSTRACT (Maximum 200 The main objective of this project was to develop, prepare, and deliver 25 g of vancomycin microcapsules ...demonstrated that the BIOTEK vancomycin microcapsules met all the criteria stipulated in the contract. The microcapsules maintained a sustained release of...therapeutic levels of vancomycin and inhibited bacterial growth of Staphylococcus aureus for 19 days. The preparation of these vancomycin microcapsules

The Effect of Age and Weight on Vancomycin Serum Trough Concentrations in Pediatric Patients

PubMed Central

Madigan, Theresa; Sieve, Ronald M.; Graner, Kevin K.; Banerjee, Ritu

2013-01-01

Background Vancomycin treatment failure has been associated with low serum vancomycin trough concentrations, prompting recommendations to increase the daily doses in adults and children. Despite more aggressive vancomycin dosing, there continues to be significant variability in vancomycin trough concentrations in pediatric patients. Methods To determine if vancomycin trough concentrations in pediatric patients differ by age and weight, we reviewed records of hospitalized patients who received vancomycin between 2008 and 2012. Patients were divided into groups that received vancomycin 40 mg/kg/day (2008 to 2009) or 60 mg/kg/day (2010 to 2012). Vancomycin trough concentrations were compared between groups and within the 60-mg/kg/day group, stratified by patient age and weight. Results After increasing the vancomycin dose from 40 mg/kg/day to 60 mg/kg/day, initial trough concentrations increased significantly in patients younger than 2 and greater than 6 years of age, but not in patients between the ages of 2 and 5 years. In the 60-mg/kg/day group, only 16.7% of patients between 2 and 5 years of age had initial trough concentrations in the therapeutic range (10 mcg/mL to 20 mcg/mL). Initial trough concentrations were therapeutic in a greater proportion of patients ages 6 years to 12 years (38.7%) and 13 years to 18 years (63.0%). Patients between the ages of 13 and 18 had the highest proportion of supratherapeutic initial vancomycin trough concentrations (14.8%). Patients weighing > 50 kg had significantly higher trough concentrations than patients ≤ 50 kg (17.1 mcg/mL vs. 9.3 mcg/mL; p<0.001). Conclusion Although increasing the vancomycin dose from 40 mg/kg/day to 60 mg/kg/day led to a significant increase in vancomycin trough concentrations, a large proportion of patients receiving 60 mg/kg/day of vancomycin had trough concentrations outside of the therapeutic range. Specifically, patients younger than 6 years tend to have low trough concentrations, while adolescents and children > 50 kg are more likely to have elevated trough concentrations. Vancomycin dosing strategies in pediatric patients should consider age and weight as well as renal function and indication. PMID:23864541

Combination of cephalosporins with vancomycin or teicoplanin enhances antibacterial effect of glycopeptides against heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) and VISA

PubMed Central

Lai, Chih-Cheng; Chen, Chi-Chung; Chuang, Yin-Ching; Tang, Hung-Jen

2017-01-01

Eight heterogeneous vancomycin-intermediate S. aureus (h-VISA) and seven VISA clinical isolates confirmed by the population analysis profile/area under the curve ratio (PAP/AUC) were collected. We further performed the PAP/AUC, time-killing methods and MIC tests using vancomycin/teicoplanin alone or combination with susceptible breakpoint concentrations of cefazolin, cefmetazole, cefotaxime, and cefepime for these isolates. The PAP/AUC MIC curve shifted left after addition of cephalosporins with vancomycin or teicoplanin for both h-VISA and VISA isolates. With the combination of different cephalosporins with vancomycin or teicoplanin, the AUC/Mu3 AUC ratio decreased to <0.9 for the standard Mu3 isolate which are compatible with the definition of vancomycin susceptible S. aureus. These decreases ranged between 1.81–2.02 and 2.37–2.85-fold for h-VISA treated with cephalosporins and vancomycin or teicoplanin, and 2.05–4.59, and 2.93–4,89-fold for VISA treated with cephalosporins with vancomycin or teicoplanin. As measured by time-killing assays, the combinations of different cephalosporins with vancomycin concentrations at 1/2 and 1/4 MIC, exhibited a bactericidal and bacteriostatic effect in VISA. The mean fold of MIC decline for vancomycin base combinations ranged from 1.81–3.83 and 2.71–9.33 for h-VISA and VISA, respectively. Overall, this study demonstrated the enhanced antibacterial activity of vancomycin/teicoplanin after adding cephalosporins against clinical h-VISA/VISA isolates. PMID:28139739

Impact of a clinical pathway on appropriate empiric vancomycin use in cancer patients with febrile neutropenia.

PubMed

Vicente, Mildred; Al-Nahedh, Mohammad; Parsad, Sandeep; Knoebel, Randall W; Pisano, Jennifer; Pettit, Natasha N

2017-12-01

Objectives Febrile neutropenia management guidelines recommend the use of vancomycin as part of an empiric antimicrobial regimen when specific criteria are met. Often, vancomycin use among patients with febrile neutropenia is not indicated and may be over utilized for this indication. We sought to evaluate the impact of implementing a febrile neutropenia clinical pathway on empiric vancomycin use for febrile neutropenia and to identify predictors of vancomycin use when not indicated. Methods Adult febrile neutropenia patients who received initial therapy with an anti-pseudomonal beta-lactam with or without vancomycin were identified before (June 2008 to November 2010) and after (June 2012 to June 2013) pathway implementation. Patients were assessed for appropriateness of therapy based on whether the patient received vancomycin consistent with guideline recommendations. Using a comorbidity index used for risk assessment in high risk hematology/oncology patients, we evaluated whether specific comorbidities are associated with inappropriate vancomycin use in the setting of febrile neutropenia. Results A total of 206 patients were included in the pre-pathway time period with 35.9% of patients receiving vancomycin therapy that was inconsistent with the pathway. A total of 131 patients were included in the post-pathway time period with 11.4% of patients receiving vancomycin inconsistent with the pathway ( p = 0.001). None of the comorbidities assessed, nor the comorbidity index score were found to be predictors of vancomycin use inconsistent with guideline recommendations. Conclusion Our study has demonstrated that implementation of a febrile neutropenia pathway can significantly improve adherence to national guideline recommendations with respect to empiric vancomycin utilization for febrile neutropenia.

Mycobacterium tuberculosis Rv1152 is a Novel GntR Family Transcriptional Regulator Involved in Intrinsic Vancomycin Resistance and is a Potential Vancomycin Adjuvant Target

PubMed Central

Zeng, Jie; Deng, Wanyan; Yang, Wenmin; Luo, Hongping; Duan, Xiangke; Xie, Longxiang; Li, Ping; Wang, Rui; Fu, Tiwei; Abdalla, Abualgasim Elgaili; Xie, Jianping

2016-01-01

Novel factors involved in Mycobacteria antibiotics resistance are crucial for better targets to combat the ever-increasing drug resistant strains. Mycobacterium tuberculosis Rv1152, a novel GntR family transcriptional regulator and a promising vancomycin adjuvant target, was firstly characterized in our study. Overexpression of Rv1152 in Mycobacterium smegmatis decreased bacterial susceptibility to vancomycin. Moreover, a deficiency in MSMEG_5174, an Rv1152 homolog made M. smegmatis more sensitive to vancomycin, which was reverted by complementing the MSMEG_5174 deficiency with Rv1152 of M. tuberculosis. Rv1152 negatively regulated four vancomycin responsive genes, namely genes encoding the ribosome binding protein Hsp, small unit of sulfate adenylyltransferase CysD, L-lysine-epsilon aminotransferase Lat, and protease HtpX. Taken together, Rv1152 controls the expression of genes required for the susceptibility to vancomycin. This is the first report that links the GntR family transcriptional factor with vancomycin susceptibility. Inhibitors of Rv1152 might be ideal vancomycin adjuvants for controlling multi-drug resistant Mycobacterial infections. PMID:27349953

Tapering Courses of Oral Vancomycin Induce Persistent Disruption of the Microbiota That Provide Colonization Resistance to Clostridium difficile and Vancomycin-Resistant Enterococci in Mice.

PubMed

Tomas, Myreen E; Mana, Thriveen S C; Wilson, Brigid M; Nerandzic, Michelle M; Joussef-Piña, Samira; Quiñones-Mateu, Miguel E; Donskey, Curtis J

2018-05-01

Vancomycin taper regimens are commonly used for the treatment of recurrent Clostridium difficile infections. One rationale for tapering and pulsing of the dose at the end of therapy is to reduce the selective pressure of vancomycin on the indigenous intestinal microbiota. Here, we used a mouse model to test the hypothesis that the indigenous microbiota that provide colonization resistance against C. difficile and vancomycin-resistant enterococci (VRE) is repopulated during tapering courses of vancomycin. Mice were treated orally with vancomycin daily for 10 days, vancomycin in a tapering dose for 42 days, fidaxomicin for 10 days, or saline. To assess colonization resistance, subsets of mice were challenged with 10 4 CFU of C. difficile or VRE at multiple time points during and after completion of treatment. The impact of the treatments on the microbiome was measured by cultures, real-time PCR for selected anaerobic bacteria, and deep sequencing. Vancomycin taper-treated mice developed alterations of the microbiota and disruption of colonization resistance that was persistent 18 days after treatment. In contrast, mice treated with a 10-day course of vancomycin exhibited recovery of the microbiota and of colonization resistance by 15 days after treatment, and fidaxomicin-treated mice maintained intact colonization resistance. These findings demonstrate that alteration of the indigenous microbiota responsible for colonization resistance to C. difficile and VRE persist during and after completion of tapering courses of vancomycin. Copyright © 2018 American Society for Microbiology.

Population Pharmacokinetics of Vancomycin in Patients Undergoing Allogeneic Hematopoietic Stem-Cell Transplantation.

PubMed

Okada, Akira; Kariya, Misato; Irie, Kei; Okada, Yutaka; Hiramoto, Nobuhiro; Hashimoto, Hisako; Kajioka, Ryosuke; Maruyama, Chika; Kasai, Hidefumi; Hamori, Mami; Nishimura, Asako; Shibata, Nobuhito; Fukushima, Keizo; Sugioka, Nobuyuki

2018-05-15

Vancomycin is a commonly used antimicrobial agent for patients undergoing allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Vancomycin has large inter- and intraindividual pharmacokinetic variability, which is mainly described by renal function; various studies have indicated that vancomycin pharmacokinetics are altered in special populations. However, little is known regarding vancomycin pharmacokinetics in patients undergoing allo-HSCT. Therefore, we aimed to develop a population pharmacokinetic (PopPK) model of vancomycin in patients undergoing allo-HSCT for effective and safe antimicrobial therapy and to develop a vancomycin dosing nomogram for a vancomycin optimal-dosing strategy. In total, 285 observations from 95 patients undergoing allo-HSCT were available. The final PopPK parameter estimates were central volume of distribution (V1, L), 39.2; clearance (L/h), 4.25; peripheral volume of distribution (V2, L), 56.1; and intercompartmental clearance (L/h), 1.95. The developed vancomycin model revealed an increase in V1 and V2 compared with those in the general population that consisted of patients with methicillin-resistant Staphylococcus aureus. Moreover, serum creatinine was reduced because of an increase in the plasma fraction because of destruction of hematopoietic stem cells accompanying allo-HSCT pretreatment, suggesting that the Cockcroft-Gault equation-based creatinine clearance value was overestimated. To our knowledge, this is the first PopPK study to develop a dosing nomogram for vancomycin in patients undergoing allo-HSCT and was proven to be useful in optimizing the dosage and dosing interval of vancomycin in these patients. This strategy will provide more useful information for vancomycin therapy with an evidence-based dose adjustment. © 2018, The American College of Clinical Pharmacology.

Is vancomycin MIC creep a worldwide phenomenon? Assessment of S. aureus vancomycin MIC in a tertiary university hospital

PubMed Central

2013-01-01

Background Vancomycin is the primary treatment for infections caused by methicilin-resistant Staphylococcus aureus (MRSA). The association of vancomycin treatment failures with increased vancomycin minimum inhibitory concentration (MIC) is a well-recognized problem. A number of single-centre studies have identified progressive increases in glycopeptide MICs for S. aureus strains over recent years – a phenomenon known as vancomycin MIC creep. It is unknown if this is a worldwide phenomenon or if it is localized to specific centers. Methods The aim of this study was to evaluate the trend of vancomycin MIC for isolates of MRSA over a 3-year period in a tertiary university hospital in Portugal. MRSA isolates from samples of patients admitted from January 2007 to December 2009 were assessed. Etest method was used to determine the respective vancomycin MIC. Only one isolate per patient was included in the final analysis. Results A total of 93 MRSA isolates were studied. The vancomycin MICs were 0.75, 1, 1.5 and 2 mg/L for 1 (1.1%), 19 (20.4%), 38 (40.9%), 35 (37.6%) isolates, respectively. During the 3 year period, we observed a significant fluctuation in the rate of MRSA with a vancomycin MIC > 1 mg/L (2007: 86.2%; 2008: 93.3%; 2009: 58.8%, p = 0.002). No MRSA isolate presented a MIC > 2 mg/L. Conclusions We were unable to find in our institution data compatible to the presence of vancomycin MIC creep during the study period. This phenomenon seems not to be generalized; as a result each institution should systematically monitor MRSA vancomycin MIC over time. PMID:23422012

[Effects of restrictions on use of vancomycin in a German university hospital].

PubMed

Glück, T; Linde, H J; Wiegrebe, E; Lehn, N; Reng, M; Schölmerich, J

2000-02-15

Recently, increasing antibiotic resistance has been observed among gram-positive bacteria. However, only few isolates were found to be resistant against glycopeptides. Therefore, internationally accepted guidelines recommend a restricted use of vancomycin and other glycopeptide antibiotics in order to prevent the development of resistance against these clinically important antibiotics. In many countries, the hospital pharmacies play a key role in control and reinforcement of antibiotic formulary restrictions. In Germany, however, the hospital pharmacies usually do not take over such control functions, and most wards keep a stock of regularly used drugs including antibiotics, which makes reinforcement of restrictions difficult. In an attempt to achieve a restriction of vancomycin use, the pharmacy of our university hospital was advised to deliver vancomycin to the wards only on request with a special order form signed by an attending, individually for every patient who should receive vancomycin. The efficacy of this restriction measure was evaluated in 3-month periods before and after the restriction became effective. Hospitalwide, this led to a 20.1% reduction of i.v. vancomycin and an 85.7% reduction of oral vancomycin use per 1000 patient days. If the hematology/oncology units were not considered, the reduction of i.v. vancomycin use was 41.8%, and the total use after the restriction 24.2 g per 1000 patient days. Microbiology results which justified the use of vancomycin decreased by 8.3% (10.9% hematology/oncology units not considered) between the 2 observation periods. Assuming a 7-day mean course of i.v. vancomycin therapy, the empirical use of i.v. vancomycin decreased from 39.9% to 8% after the restriction had been instituted. Allowing only experienced physicians (attendings) to decide on the use of vancomycin therapy, proved in our experience to be an effective measure to reduce unnecessary vancomycin use.

Intraperitoneal Vancomycin Concentrations During Peritoneal Dialysis–Associated Peritonitis: Correlation with Serum Levels

PubMed Central

Fish, Richard; Nipah, Robert; Jones, Chris; Finney, Hazel; Fan, Stanley L.S.

2012-01-01

♦ Background: For the treatment of peritoneal dialysis–associated peritonitis (PDP), it has been suggested that serum concentrations of vancomycin be kept above 12 mg/L – 15 mg/L. However, studies correlating vancomycin concentrations in serum and peritoneal dialysate effluent (PDE) during active infection are sparse. We undertook the present study to investigate this issue and to determine whether achieving the recommended serum level of vancomycin results in therapeutic levels intraperitoneally. ♦ Methods: We studied patients treated with intraperitoneal (IP) vancomycin for non-gram-negative PDP. We gave a single dose (approximately 30 mg/kg) at presentation, and we subsequently measured vancomycin levels in PDE on day 5; we wanted to determine if efflux of vancomycin from serum to PDE during a 4-hour dwell was consistent and resulted in therapeutic levels. ♦ Results: Of the 48 episodes of PDP studied, serum vancomycin concentrations exceeding 12 mg/L were achieved in 98% of patients, but in 11 patients (23%), a PDE vancomycin level below 4 mg/L—the minimal inhibitory concentration (MIC) of many gram-positive organisms—was observed at the end of a 4-hour dwell on day 5. The correlation between the concentrations of vancomycin in serum and PDE (from efflux of antibiotic over 4 hours) was statistically significant, but poor (R2 = 0.18). ♦ Conclusions: Our data support the International Society for Peritoneal Dialysis statement that adequate serum vancomycin concentrations can be achieved with intermittent dosing (single dose every 5 days), but cannot guarantee therapeutic PDE levels in the treatment of PDP. Intermittent dosing of vancomycin may not consistently result in PDE concentrations markedly greater than MIC of many important pathogens. Although the clinical significance of this finding remains to be determined, it may be preferable to give smaller but more frequent doses of PDE vancomycin (continuous dosing) for adults with PDP (as is currently recommended for children). PMID:22045102

Loss of Microbiota-Mediated Colonization Resistance to Clostridium difficile Infection With Oral Vancomycin Compared With Metronidazole

PubMed Central

Lewis, Brittany B.; Buffie, Charlie G.; Carter, Rebecca A.; Leiner, Ingrid; Toussaint, Nora C.; Miller, Liza C.; Gobourne, Asia; Ling, Lilan; Pamer, Eric G.

2015-01-01

Antibiotic administration disrupts the intestinal microbiota, increasing susceptibility to pathogens such as Clostridium difficile. Metronidazole or oral vancomycin can cure C. difficile infection, and administration of these agents to prevent C. difficile infection in high-risk patients, although not sanctioned by Infectious Disease Society of America guidelines, has been considered. The relative impacts of metronidazole and vancomycin on the intestinal microbiota and colonization resistance are unknown. We investigated the effect of brief treatment with metronidazole and/or oral vancomycin on susceptibility to C. difficile, vancomycin-resistant Enterococcus, carbapenem-resistant Klebsiella pneumoniae, and Escherichia coli infection in mice. Although metronidazole resulted in transient loss of colonization resistance, oral vancomycin markedly disrupted the microbiota, leading to prolonged loss of colonization resistance to C. difficile infection and dense colonization by vancomycin-resistant Enterococcus, K. pneumoniae, and E. coli. Our results demonstrate that vancomycin, and to a lesser extent metronidazole, are associated with marked intestinal microbiota destruction and greater risk of colonization by nosocomial pathogens. PMID:25920320

Nanoconjugated vancomycin: new opportunities for the development of anti-VRSA agents

NASA Astrophysics Data System (ADS)

Prasad Chakraborty, Subhankari; Sahu, Sumanta Kumar; Mahapatra, Santanu Kar; Santra, Susmita; Bal, Manjusri; Roy, Somenath; Pramanik, Panchanan

2010-03-01

More than 90% of Staphylococcus strains are resistant to penicillin. In 1961 S. aureus developed resistance to methicillin (MRSA), invalidating almost all antibiotics, including the most potent β-lactams. Vancomycin, a glycopeptide antibiotic, was used for the treatment of MRSA in 1980. Vancomycin inhibits the bio-synthesis of peptidoglycan and the assembly of NAM-NAG-polypeptide into the growing peptidoglycan chain. Vancomycin resistant S. aureus (VRSA) first appeared in the USA in 2002. Folic acid tagged chitosan nanoparticles are used as Trojan horses to deliver vancomycin into bacterial cells. These nanoparticles are biocompatible and biodegradable semisynthetic polymers. These nanosized vehicles enhance the transport of vancomycin across epithelial surfaces and show its efficient drug action, which has been understood from studies of the minimum inhibitory concentration and minimum bactericidal concentration of nanoparticles of a chitosan derivative loaded with vancomycin. Tolerance values distinctly show that vancomycin loaded into nanoconjugate is very effective and has a strong bactericidal effect on VRSA.

Pharmacodynamic activity of ceftobiprole compared with vancomycin versus methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate Staphylococcus aureus (VISA) and vancomycin-resistant Staphylococcus aureus (VRSA) using an in vitro model.

PubMed

Zhanel, George G; Voth, Dylan; Nichol, Kim; Karlowsky, James A; Noreddin, Ayman M; Hoban, Daryl J

2009-08-01

This study compared the pharmacodynamics of ceftobiprole and vancomycin against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA) using an in vitro model. Two methicillin-susceptible S. aureus (MSSA), two community-associated (CA)-MRSA, one healthcare-associated (HA)-MRSA, three VISA and two VRSA were studied. The pharmacodynamic model was inoculated with a concentration of 1 x 10(6) cfu/mL and ceftobiprole dosed every 8 h (at 0, 8 and 16 h) to simulate the fC(max) and t(1/2) obtained after 500 mg intravenous (iv) every 8 h dosing (fC(max,) 30 mg/L; t(1/2,) 3.5 h). Vancomycin was dosed every 12 h (at 0 and 12 h) to simulate fC(max) and t(1/2) obtained after 1 g iv every 12 h dosing (fC(max), 20 mg/L; t(1/2), 8 h). Samples were collected over 24 h to assess viable growth. Ceftobiprole T > MIC of > or =100% (ceftobiprole MICs, < or =2 mg/L) was bactericidal (> or =3 log(10) killing) against MSSA, CA-MRSA, HA-MRSA, VISA and VRSA at 16 and 24 h. Vancomycin fAUC(24)/MIC of 340 (vancomycin MIC, 1 mg/L for MSSA and MRSA) resulted in a 1.8-2.6 log(10) reduction in colony count at 24 h. Vancomycin fAUC(24)/MIC of 85-170 (vancomycin MIC, 2-4 mg/L for VISA) resulted in a 0.4-0.7 log(10) reduction at 24 h. Vancomycin fAUC(24)/MIC of 5.3 (vancomycin MIC, 64 mg/L for VRSA) resulted in a limited effect. Ceftobiprole T > MIC of > or =100% (ceftobiprole MICs, < or =2 mg/L) was bactericidal (> or =3 log(10) killing) against MSSA, CA-MRSA, HA-MRSA, VISA and VRSA at 16 and 24 h. Vancomycin was bacteriostatic against MSSA, MRSA and VISA, while demonstrating no activity against VRSA.

Vancomycin-induced thrombocytopenia in a 60-year-old man: a case report.

PubMed

Shah, Ravish A; Musthaq, Adnan; Khardori, Nancy

2009-06-26

Vancomycin, a glycopeptide antibiotic, is used to treat resistant gram-positive infections. There has been a 10- to 20-fold increase in its use over the past 25 years. Although ototoxicity and nephrotoxicity are well known side effects of vancomycin, it can also induce platelet reactive antibodies leading to life-threatening thrombocytopenia. Vancomycin is often clinically overlooked as a cause of thrombocytopenia, especially in a scenario of sepsis or when there is use of heparin. We report a proven case of vancomycin-induced thrombocytopenia and its reversal after discontinuation of vancomycin. A 60-year-old man with a history of hypertension, congestive heart failure and dyslipidemia was admitted for a right shoulder rotator cuff tear. He underwent right-shoulder arthroscopy and rotator cuff repair. About three weeks later, he developed pain, swelling and purulent drainage from his right shoulder. Arthroscopic irrigation and drainage was then performed. Intraoperative fluid revealed the presence of Methicillin susceptible Staphylococcus aureus, vancomycin-sensitive Enterococcus spp. and Serratia marcescens. The patient had no known allergies. After reviewing his antimicrobial susceptibility, he was started on vancomycin 1500 mgs intravenously every 12 hours (to treat both Staphylococcus aureus and Enterococcus spp) and ciprofloxacin 750 mgs by oral induction every 12 hours. The patient's condition improved following antibiotic treatment. He was discharged and allowed to go home on IV vancomycin and oral ciprofloxacin. The patient's platelet count on the day of starting vancomycin therapy was 253 x 10(3)/mm(3). At weeks one, two and three, the counts were 231 x 10(3)/mm(3), 272 x 10(3)/mm and 6 x 103/mm(3), respectively. The patient was admitted for further work-up of the thrombocytopenia. He was later shown to have vancomycin-induced platelet-reactive antibodies, causing significant thrombocytopenia, and then reversal after his vancomycin medication was discontinued. Thrombocytopenia is a potentially life-threatening condition. Vancomycin is often clinically overlooked as a cause of thrombocytopenia, especially in a scenario of sepsis or when there is use of heparin. Simple laboratory testing with drug-dependent antibodies can be helpful in identifying vancomycin as a cause of thrombocytopenia.

Randomized prospective study comparing vancomycin with teicoplanin in the treatment of infections associated with Hickman catheters.

PubMed Central

Smith, S R; Cheesbrough, J; Spearing, R; Davies, J M

1989-01-01

In 72 episodes of suspected or proven Hickman-catheter-associated infection occurring in 59 patients with various hematological disorders, patients were assigned to treatment with either vancomycin or teicoplanin in a randomized nonblinded prospective study. Of 60 episodes evaluable for response, 28 were treated with vancomycin and 32 were treated with teicoplanin. Sixteen infective episodes were microbiologically documented in the vancomycin group, and twenty-one were microbiologically documented in the teicoplanin group. Microbiologically and clinically documented infections treated with vancomycin had an 80% response rate, compared with a 69% response rate for those treated with teicoplanin (P = 0.316). Adverse events occurred in nine (25%) of the episodes in the vancomycin group, compared with three (8%) in the teicoplanin group (P = 0.044). Teicoplanin may provide an effective alternative to vancomycin in the treatment of Hickman-catheter-associated infection in patients with hematological malignancies. PMID:2529814

Randomized prospective study comparing vancomycin with teicoplanin in the treatment of infections associated with Hickman catheters.

PubMed

Smith, S R; Cheesbrough, J; Spearing, R; Davies, J M

1989-08-01

In 72 episodes of suspected or proven Hickman-catheter-associated infection occurring in 59 patients with various hematological disorders, patients were assigned to treatment with either vancomycin or teicoplanin in a randomized nonblinded prospective study. Of 60 episodes evaluable for response, 28 were treated with vancomycin and 32 were treated with teicoplanin. Sixteen infective episodes were microbiologically documented in the vancomycin group, and twenty-one were microbiologically documented in the teicoplanin group. Microbiologically and clinically documented infections treated with vancomycin had an 80% response rate, compared with a 69% response rate for those treated with teicoplanin (P = 0.316). Adverse events occurred in nine (25%) of the episodes in the vancomycin group, compared with three (8%) in the teicoplanin group (P = 0.044). Teicoplanin may provide an effective alternative to vancomycin in the treatment of Hickman-catheter-associated infection in patients with hematological malignancies.

Ceftaroline fosamil salvage therapy: an option for reduced-vancomycin-susceptible MRSA bacteraemia.

PubMed

Espedido, Björn A; Jensen, Slade O; van Hal, Sebastiaan J

2015-03-01

To examine the activity of ceftaroline against reduced-vancomycin-susceptible MRSA isolates. One-hundred and three MRSA blood culture isolates (predominantly ST239-MRSA-III), with varying vancomycin phenotypes, had their ceftaroline MICs determined by broth microdilution and MIC Evaluator strip (Oxoid-Thermo Fisher). Statistical analyses were performed that examined relationships with vancomycin and daptomycin MICs. Mutations in mecA were also examined. All 103 isolates (including 60 heteroresistant vancomycin-intermediate Staphylococcus aureus/vancomycin-intermediate S. aureus) were susceptible to ceftaroline, with one isolate displaying heteroresistance that may be related to a mecA mutation. Higher ceftaroline MICs were associated with vancomycin-susceptible S. aureus isolates. This study highlights that ceftaroline fosamil is an option for salvage therapy based on in vitro activity. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Effect of vancomycin, tylosin, and chlortetracycline on vancomycin-resistant Enterococcus faecium colonization of broiler chickens during grow-out

USDA-ARS?s Scientific Manuscript database

Broiler chickens may serve as reservoirs for human colonization by vancomycin-resistant Enterococcus (VRE). We examined the effects of vancomycin and two commonly-used antimicrobial feed additives on VRE colonization in broiler chickens during grow-out. Chicks received unsupplemented feed or feed ...

Staphylococcus aureus ventriculitis treated with single-dose intraventricular vancomycin or daptomycin (LY146032): bacterial and antibiotic kinetics in hydrocephalic rabbits.

PubMed Central

Haworth, C S; Sobieski, M W; Scheld, W M; Park, T S

1990-01-01

Vancomycin and a new antibiotic, daptomycin (LY146032), were tested in vitro and in vivo against Staphylococcus aureus. In vivo tests were performed with rabbits with kaolin-induced hydrocephalus. Five groups of rabbits were studied: untreated ventriculitis, intraventricular vancomycin only, and ventriculitis treated with intraventricular vancomycin (30 micrograms or 120 micrograms) or daptomycin (7.5 micrograms). Results of this study were as follows. (i) S. aureus demonstrated static growth in cerebrospinal fluid in vitro and in ventriculitis at a maximum titer of 10(5) to 10(6) CFU/ml. (ii) In vitro time kill curves in cerebrospinal fluid matched those in vivo. (iii) Single-dose intraventricular vancomycin did not lower S. aureus concentrations over 8 h, whereas daptomycin did. (iv) Ventriculitis did not significantly alter the clearance of intraventricular vancomycin. (v) Intraventricular half-lives were approximately 2.8 h (maximum) for vancomycin and 4.5 h for daptomycin. (vi) Vancomycin was detectable in the periventricular white matter only in the presence of ventriculitis. Daptomycin was also detectable in the periventricular white matter of rabbits with ventriculitis, but in amounts too small to quantitate. We concluded that daptomycin achieved greater bactericidal activity, more rapid killing kinetics, and a longer half-life in the ventricle than vancomycin did in this model. PMID:2158276

Evaluating guideline adherence regarding empirical vancomycin use in patients with neutropenic fever.

PubMed

Chastain, Daniel B; Wheeler, Sarah; Franco-Paredes, Carlos; Olubajo, Babatunde; Hawkins, W Anthony

2018-04-01

The purpose of this study was to evaluate the use of empirical vancomycin for patients with neutropenic fever (NF) with regard to adherence to treatment guidelines. Adult patients with a diagnosis of neutropenia, who met the definition of NF as per treatment guidelines, were identified. Use of vancomycin was evaluated as part of empirical therapy and again after 72h. Outcomes were assessed using descriptive statistics, the Chi-square or Fisher's exact test, and univariate exact logistic regression analyses. Sixty-four patients were included. Overall, inappropriate empirical vancomycin use was observed in more than 30% of patients. Of 35 patients with indications for empirical vancomycin, only 68% received it. At 72h, appropriate vancomycin continuation, de-escalation, or discontinuation occurred in 21 of 33 patients. On univariate regression, hematological malignancy was associated with appropriate empirical vancomycin prescribing, whether initiating or withholding (odds ratio 4.0, 95% confidence interval 1.31-12.1). No variable was independently associated with inappropriate continuation at 72h. There is poor guideline adherence to vancomycin prescribing as empirical therapy and at 72-h reassessment in patients with NF. Further efforts are needed to foster a more rational use of vancomycin in patients with NF. Copyright © 2018. Published by Elsevier Ltd.

Comparison of telavancin and vancomycin lock solutions in eradication of biofilm-producing staphylococci and enterococci from central venous catheters.

PubMed

Luther, Megan K; Mermel, Leonard A; LaPlante, Kerry L

2016-03-01

Results of a study of the activity of antibiotic lock solutions of vancomycin and telavancin against biofilm-forming strains of Staphylococcus epidermidis, Enterococcus faecalis, and Staphylococcus aureus are reported. An established in vitro central venous catheter model was used to evaluate lock solutions containing vancomycin (5 mg/mL) or telavancin (5 mg/mL), with and without preservative-containing heparin sodium (with 0.45% benzyl alcohol) 2500 units/mL, heparin, and 0.9% sodium chloride solution. Lock solutions were introduced after 24-hour bacterial growth in catheters incubated at 35 °C. After 72 hours of exposure to the lock solutions, catheters were drained, flushed, and cut into segments for quantification of colony-forming units. Against S. epidermidis, vancomycin and telavancin (with or without heparin) had similar activity. Against E. faecalis, vancomycin alone was more active than telavancin alone (p < 0.01). Against S. aureus, vancomycin plus heparin had activity similar to that of vancomycin alone; both lock agents had greater activity than telavancin (p < 0.02). The addition of heparin was associated with reduced activity of the vancomycin lock solution against S. epidermidis and E. faecalis (p < 0.01). Telavancin activity was not significantly changed with the addition of heparin. In a central venous catheter model, vancomycin and telavancin activity was similar in reducing biofilm-producing S. epidermidis. However, vancomycin was more active than telavancin against E. faecalis and S. aureus. None of the tested agents eradicated biofilm-forming strains. The addition of preservative-containing heparin sodium 2500 units/mL to vancomycin was associated with reduced activity against S. epidermidis and E. faecalis. Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Vancomycin Powder Regimen for Prevention of Surgical Site Infection in Complex Spine Surgeries.

PubMed

Van Hal, Michael; Lee, Joon; Laudermilch, Dann; Nwasike, Chinedu; Kang, James

2017-10-01

In total, 496 patients of a single surgeon cohort examining the surgical-site infection (SSI) rates with the addition of vancomycin powder in both diabetic and revision spine surgery cases. A historical control group of 652 patients were compared from the same surgeon over an earlier time period before the inception of using vancomycin powder prophylaxis. The objective of this study was to describe and compare the rates of infection in high-risk patient populations while using vancomycin powder. Vancomycin powder may not decrease an already low rate of infection. Therefore, use of vancomycin powder in high-risk patients with a higher rate of infection would potentially show benefit of vancomycin powder. In total, 496 patient charts were collected from a database of cases. Patients were included in the cohort if they had revision spinal operation or if they were diabetic. Patients in the time period July 2010 to August 2013 were included in the vancomycin protocol where 1 g of vancomycin powder was added to the wound before wound closure. Cases were considered positive if there was a positive culture or if there was sufficient clinical suspicion to treat. As a control to this cohort, 692 charts were reviewed from a earlier time period of the same surgeon and institution. In total, 28 patients of 496 (5.6%) patients in the cohort returned to the operating room for seroma, hematoma, draining wound, or infection. Sixteen of these patients (16/496, 3.2%) had a culture positive infection or were treated as an infection. This rate was significantly lower than the historical rate before the protocol. Although vancomycin does seem to be useful in decreasing SSIs, it is not a panacea. SSIs in high-risk patients were not completely eliminated by the vancomycin protocol.

Evaluation of risk factors for vancomycin-induced nephrotoxicity.

PubMed

Park, So Jin; Lim, Na Ri; Park, Hyo Jung; Yang, Jae Wook; Kim, Min-Ji; Kim, Kyunga; In, Yong Won; Lee, Young Mee

2018-05-09

Background Vancomycin is a glycopeptide antibiotic of choice for the treatment of serious infections caused by multi-resistant Gram-positive bacteria. However, vancomycin-associated nephrotoxicity (VAN) often limits its use. Previous data suggested a few risk factors of VAN, including higher mean vancomycin trough level, higher daily doses, old age, long duration of vancomycin therapy, and concomitant nephrotoxins. Objective To evaluate the incidence and risk factors of VAN and determine whether higher vancomycin trough concentrations were associated with a greater risk for VAN. Settings A retrospective, observational, single-center study at the 1960-bed university-affiliated tertiary care hospital (Samsung Medical Center), Seoul, Korea. Method A retrospective analysis of adult patients who received vancomycin parenterally in a tertiary care medical center from March 1, 2013 to June 30, 2013 was performed. We excluded patients with a baseline serum creatinine level > 2 mg/dL and those who had a history of end-stage renal disease and dialysis at baseline. The clinical characteristics were compared between patients with nephrotoxicity and those without nephrotoxicity to identify the risk factors associated with VAN. Main outcome measure Incidence of VAN and VAN-associated risk factors were analyzed. Results Of the 315 vancomycin-treated patients, nephrotoxicity occurred in 15.2% of the patients. In multivariate analysis, higher vancomycin trough concentrations of > 20 mg∕L (OR 9.57, 95% CI 2.49-36.83, p < 0.01) and intensive care unit (ICU) residence (OR 2.86, 95% CI 1.41-5.82, p < 0.01) were independently associated with VAN. Conclusion Our findings suggest that higher vancomycin trough levels and ICU residence might be associated with a greater risk for VAN. More careful monitoring of vancomycin serum trough levels and patient status might facilitate the timely prevention of VAN.

pHEMA-nHA encapsulation and delivery of vancomycin and rhBMP-2 enhances its role as a bone graft substitute.

PubMed

Li, Xinning; Xu, Jianwen; Filion, Tera M; Ayers, David C; Song, Jie

2013-08-01

Bone grafts are widely used in orthopaedic procedures. Autografts are limited by donor site morbidity while allografts are known for considerable infection and failure rates. A synthetic composite bone graft substitute poly(2-hydroxyethyl methacrylate)-nanocrystalline hydroxyapatite (pHEMA-nHA) was previously developed to stably press-fit in and functionally repair critical-sized rat femoral segmental defects when it was preabsorbed with a single low dose of 300 ng recombinant human bone morphogenetic protein-2/7 (rhBMP-2/7). To facilitate clinical translation of pHEMA-nHA as a synthetic structural bone graft substitute, we examined its ability to encapsulate and release rhBMP-2 and the antibiotic vancomycin. We analyzed the compressive behavior and microstructure of pHEMA-nHA as a function of vancomycin incorporation doses using a dynamic mechanical analyzer and a scanning electron microscope. In vitro release of vancomycin was monitored by ultraviolet-visible spectroscopy. Release of rhBMP-2 from pHEMA-nHA-vancomycin was determined by ELISA. Bioactivity of the released vancomycin and rhBMP-2 was examined by bacterial inhibition and osteogenic transdifferentiation capabilities in cell culture, respectively. Up to 4.8 wt% of vancomycin was incorporated into pHEMA-nHA without compromising its structural integrity and compressive modulus. Encapsulated vancomycin was released in a dose-dependent and sustained manner in phosphate-buffered saline over 2 weeks, and the released vancomycin inhibited Escherichia coli culture. The pHEMA-nHA-vancomycin composite released preabsorbed rhBMP-2 in a sustained manner over 8 days and locally induced osteogenic transdifferentiation of C2C12 cells in culture. pHEMA-nHA can encapsulate and deliver vancomycin and rhBMP-2 in a sustained and localized manner with reduced loading doses. The elasticity, osteoconductivity, and rhBMP-2/vancomycin delivery characteristics of pHEMA-nHA may benefit orthopaedic reconstructions or fusions with enhanced safety and efficiency and reduced infection risk.

Vancomycin heteroresistance in coagulase negative Staphylococcus blood stream infections from patients of intensive care units in Mansoura University Hospitals, Egypt.

PubMed

Mashaly, Ghada El-Saeed; El-Mahdy, Rasha Hassan

2017-09-19

Vancomycin heteroresistance in coagulase negative Staphylococci (CoNS) is a recent health concern especially in serious infections like bloodstream infections as it may lead to failure of therapy. Little information is available about the prevalence vancomycin heteroresistance in CoNS causing bloodstream infections in intensive care units (ICUs) patients of Mansoura University Hospitals (MUHs). This prospective study enrolled 743 blood samples collected from ICUs patients presented with clinical manifestations of bloodstream infections over the period extending from January 2014 to March 2016. Samples were processed, coagulase negative Staphylococci were identified by routine microbiological methods and the absence of coagulase activity. Species were identified by API Staph 32. Oxacillin resistant CoNS were identified by cefoxitin disc diffusion method. Susceptibility testing of isolated CoNS to vancomycin was carried out using vancomycin agar dilution method. Mec A gene detection by PCR was done for oxacillin resistant isolates. Screening for vancomycin heteroresistance was done on brain heart infusion (BHI) agar containing 4 μg/mL vancomycin. Confirmation of vancomycin heteroresistance was carried out by population analysis profile (PAP). A total of 58 isolates were identified as CoNS from patients of clinically suspected bloodstream infections. The identified species were 33 (56.9%) Staphylococcus epidermidis, 12 (20.7%) Staphylococcus capitis, 7 (12.1%) Staphylococcus haemolyticus, and 3 isolates (5.2%) Staphylococcus lugdunesis. Three isolates were unidentified by API Staph 32. Forty-four (75.9%) isolates were oxacillin resistant. Mec A gene was detected in all oxacillin resistant isolates. All isolates had susceptible vancomycin MICs by agar dilution. Nine isolates (15.5%) could grow on BHI agar containing 4 μg/mL vancomycin. These isolates showed heterogeneous profile of resistance to vancomycin by population analysis profile. Vancomycin heteroresistant CoNS causing bloodstream infections is growing unrecognized health hazard in ICUs patients. These isolates have susceptible vancomycin MICs. Screening methods are recommended and should be considered to improve clinical outcome in these high risk patients.

In vitro pharmacodynamics of human simulated exposures of ceftaroline and daptomycin against MRSA, hVISA, and VISA with and without prior vancomycin exposure.

PubMed

Bhalodi, Amira A; Hagihara, Mao; Nicolau, David P; Kuti, Joseph L

2014-01-01

The effects of prior vancomycin exposure on ceftaroline and daptomycin therapy against methicillin-resistant Staphylococcus aureus (MRSA) have not been widely studied. Humanized free-drug exposures of vancomycin at 1 g every 12 h (q12h), ceftaroline at 600 mg q12h, and daptomycin at 10 mg/kg of body weight q24h were simulated in a 96-h in vitro pharmacodynamic model against three MRSA isolates, including one heteroresistant vancomycin-intermediate S. aureus (hVISA) isolate and one VISA isolate. A total of five regimens were tested: vancomycin, ceftaroline, and daptomycin alone for the entire 96 h, and then sequential therapy with vancomycin for 48 h followed by ceftaroline or daptomycin for 48 h. Microbiological responses were measured by the changes in log10 CFU during 96 h from baseline. Control isolates grew to 9.16 ± 0.32, 9.13 ± 0.14, and 8.69 ± 0.28 log10 CFU for MRSA, hVISA, and VISA, respectively. Vancomycin initially achieved ≥3 log10 CFU reductions against the MRSA and hVISA isolates, followed by regrowth beginning at 48 h; minimal activity was observed against VISA. The change in 96-h log10 CFU was largest for sequential therapy with vancomycin followed by ceftaroline (-5.22 ± 1.2, P = 0.010 versus ceftaroline) and for sequential therapy with vancomycin followed by ceftaroline (-3.60 ± 0.6, P = 0.037 versus daptomycin), compared with daptomycin (-2.24 ± 1.0), vancomycin (-1.40 ± 1.8), and sequential therapy with vancomycin followed by daptomycin (-1.32 ± 1.0, P > 0.5 for the last three regimens). Prior exposure of vancomycin at 1 g q12h reduced the initial microbiological response of daptomycin, particularly for hVISA and VISA isolates, but did not affect the response of ceftaroline. In the scenario of poor vancomycin response for high-inoculum MRSA infection, a ceftaroline-containing regimen may be preferred.

Modulating activity of vancomycin and daptomycin on the expression of autolysis cell-wall turnover and membrane charge genes in hVISA and VISA strains.

PubMed

Cafiso, Viviana; Bertuccio, Taschia; Spina, Daniela; Purrello, Simona; Campanile, Floriana; Di Pietro, Cinzia; Purrello, Michele; Stefani, Stefania

2012-01-01

Glycopeptides are still the gold standard to treat MRSA (Methicillin Resistant Staphylococcus aureus) infections, but their widespread use has led to vancomycin-reduced susceptibility [heterogeneous Vancomycin-Intermediate-Staphylococcus aureus (hVISA) and Vancomycin-Intermediate-Staphylococcus aureus (VISA)], in which different genetic loci (regulatory, autolytic, cell-wall turnover and cell-envelope positive charge genes) are involved. In addition, reduced susceptibility to vancomycin can influence the development of resistance to daptomycin. Although the phenotypic and molecular changes of hVISA/VISA have been the focus of different papers, the molecular mechanisms responsible for these different phenotypes and for the vancomycin and daptomycin cross-resistance are not clearly understood. The aim of our study was to investigate, by real time RT-PCR, the relative quantitative expression of genes involved in autolysis (atl-lytM), cell-wall turnover (sceD), membrane charges (mprF-dltA) and regulatory mechanisms (agr-locus-graRS-walKR), in hVISA and VISA cultured with or without vancomycin and daptomycin, in order to better understand the molecular basis of vancomycin-reduced susceptibility and the modulating activity of vancomycin and daptomycin on the expression of genes implicated in their reduced susceptibility mechanisms. Our results show that hVISA and VISA present common features that distinguish them from Vancomycin-Susceptible Staphylococcus aureus (VSSA), responsible for the intermediate glycopeptide resistance i.e. an increased cell-wall turnover, an increased positive cell-wall charge responsible for a repulsion mechanism towards vancomycin and daptomycin, and reduced agr-functionality. Indeed, VISA emerges from hVISA when VISA acquires a reduced autolysis caused by a down-regulation of autolysin genes, atl/lytM, and a reduction of the net negative cell-envelope charge via dltA over-expression. Vancomycin and daptomycin, acting in a similar manner in hVISA and VISA, can influence their cross-resistance mechanisms promoting VISA behavior in hVISA and enhancing the cell-wall pathways responsible for the intermediate vancomycin resistance in VISA. Daptomycin can also induce a charge repulsion mechanism both in hVISA and VISA increasing the activity of the mprF.

Long-term Conventionally Dosed Vancomycin Therapy In Patients With Orthopaedic Implant-related Infections Seems As Effective And Safe As Long-term Penicillin Or Clindamycin Therapy. A Retrospective Cohort Study Of 103 Patients.

PubMed

Aleman, Jacomien; Moojen, Dirk Jan F; van Ogtrop, Marc L; Poolman, Rudolf W; Franssen, Eric J F

2018-01-01

Objectives : Antimicrobial therapy is one of the cornerstones of orthopaedic implant-related infections (OIRI) treatment. Infections with Gram-positive bacteria are often treated with vancomycin, penicillin or clindamycin. A recent IDSA guideline suggests increasing the dose of vancomycin to increase the trough vancomycin target serum concentrations. This is deemed necessary because of an observed decrease in vancomycin susceptibility among Gram-positive bacteria. However, elevated vancomycin concentrations are correlated with the risk of nephrotoxicity, especially with prolonged therapy. Compared to most countries, rates of resistance against antibiotics among bacteria in the Netherlands are lower for currently available antibiotics, therefore lower target concentrations of vancomycin are probably efficacious for the treatment of infections. In this study we evaluated the efficacy and safety of long-term conventionally dosed vancomycin therapy, as an initial therapy for OIRI, and compared this with long-term penicillin and clindamycin therapy, as initial therapy, in patients with Gram-positive orthopaedic implant-related infections. Methods : A retrospective, observational study was conducted in 103 adult patients treated for OIRI, with vancomycin, penicillin or clindamycin for at least 10 days. The target trough serum concentration of vancomycin was 10-15 mg/l. Results : 74% of our patients were treated successfully with vancomycin, as initial therapy, (no reinfection within 1 year) versus 55% of our patients treated with either an antibiotic of the penicillin class (mostly flucloxacillin) or clindamycin (p=0.08), as initial therapy. For patients treated with vancomycin we observed a serum creatinine increase of 6 μmol/l, for patients treated with either an antibiotic of the penicillin class or clindamycin the serum creatinine increase was 4 μmol/l (p=0.395). Conclusions : In our population of patients with OIRI long-term treatment with conventionally dosed vancomycin, as initial therapy, was not significantly less effective and safe as long-term treatment with an antibiotic of the penicillin class or clindamycin, as initial therapy.

Long-term Conventionally Dosed Vancomycin Therapy In Patients With Orthopaedic Implant-related Infections Seems As Effective And Safe As Long-term Penicillin Or Clindamycin Therapy. A Retrospective Cohort Study Of 103 Patients

PubMed Central

Aleman, Jacomien; Moojen, Dirk Jan F.; van Ogtrop, Marc L.; Poolman, Rudolf W.; Franssen, Eric J.F.

2018-01-01

Objectives: Antimicrobial therapy is one of the cornerstones of orthopaedic implant-related infections (OIRI) treatment. Infections with Gram-positive bacteria are often treated with vancomycin, penicillin or clindamycin. A recent IDSA guideline suggests increasing the dose of vancomycin to increase the trough vancomycin target serum concentrations. This is deemed necessary because of an observed decrease in vancomycin susceptibility among Gram-positive bacteria. However, elevated vancomycin concentrations are correlated with the risk of nephrotoxicity, especially with prolonged therapy. Compared to most countries, rates of resistance against antibiotics among bacteria in the Netherlands are lower for currently available antibiotics, therefore lower target concentrations of vancomycin are probably efficacious for the treatment of infections. In this study we evaluated the efficacy and safety of long-term conventionally dosed vancomycin therapy, as an initial therapy for OIRI, and compared this with long-term penicillin and clindamycin therapy, as initial therapy, in patients with Gram-positive orthopaedic implant-related infections. Methods: A retrospective, observational study was conducted in 103 adult patients treated for OIRI, with vancomycin, penicillin or clindamycin for at least 10 days. The target trough serum concentration of vancomycin was 10-15 mg/l. Results: 74% of our patients were treated successfully with vancomycin, as initial therapy, (no reinfection within 1 year) versus 55% of our patients treated with either an antibiotic of the penicillin class (mostly flucloxacillin) or clindamycin (p=0.08), as initial therapy. For patients treated with vancomycin we observed a serum creatinine increase of 6 μmol/l, for patients treated with either an antibiotic of the penicillin class or clindamycin the serum creatinine increase was 4 μmol/l (p=0.395). Conclusions: In our population of patients with OIRI long-term treatment with conventionally dosed vancomycin, as initial therapy, was not significantly less effective and safe as long-term treatment with an antibiotic of the penicillin class or clindamycin, as initial therapy. PMID:29761071

Comparative Effectiveness of Vancomycin Versus Daptomycin for MRSA Bacteremia With Vancomycin MIC >1 mg/L: A Multicenter Evaluation.

PubMed

Moise, Pamela A; Culshaw, Darren L; Wong-Beringer, Annie; Bensman, Joyce; Lamp, Kenneth C; Smith, Winter J; Bauer, Karri; Goff, Debra A; Adamson, Robert; Leuthner, Kimberly; Virata, Michael D; McKinnell, James A; Chaudhry, Saira B; Eskandarian, Romic; Lodise, Thomas; Reyes, Katherine; Zervos, Marcus J

2016-01-01

Clinical studies comparing vancomycin with alternative therapy for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia are limited. The objective of this study was to compare outcomes of early daptomycin versus vancomycin treatment for MRSA bacteremia with high vancomycin MICs in a geographically diverse multicenter evaluation. This nationwide, retrospective, multicenter (N = 11), matched, cohort study compared outcomes of early daptomycin with vancomycin for MRSA bloodstream infection (BSI) with vancomycin MICs 1.5 to 2 µg/mL. Matching variables, based on propensity regression analysis, included age, intensive care unit (ICU), and type of BSI. Outcomes were as follows: (1) composite failure (60-day all-cause mortality, 7-day clinical or microbiologic failure, 30-day BSI relapse, or end-of-treatment failure (EOT; discontinue/change daptomycin or vancomycin because of treatment failure or adverse event]); (2) nephrotoxicity; and (2) day 4 BSI clearance. A total of 170 patients were included. The median (interquartile range) age was 60 years (50-74); the median (range) Acute Physiology and Chronic Health Evaluation II score was 15 (10-18); 31% were in an ICU; and 92% had an infectious disease consultation. BSI types included endocarditis/endovascular (39%), extravascular (55%), and central catheter (6%). The median daptomycin dose was 6 mg/kg, and the vancomycin trough level was 17 mg/L. Overall composite failure was 35% (59 of 170): 15% due to 60-day all-cause mortality, 14% for lack of clinical or microbiologic response by 7 days, and 17% due to failure at end of therapy (discontinue/change because of treatment failure or adverse event). Predictors of composite failure according to multivariate analysis were age >60 years (odds ratio, 3.7; P < 0.01) and ICU stay (odds ratio, 2.64; P = 0.03). Notable differences between treatment groups were seen with: (1) end of therapy failure rates (11% vs 24% for daptomycin vs vancomycin; P = 0.025); (2) acute kidney injury rates (9% vs 23% for daptomycin vs vancomycin; P = 0.043); and (3) day 4 bacteremia clearance rates for immunocompromised patients (n = 26) (94% vs 56% for daptomycin vs vancomycin; P = 0.035). Results from this multicenter study provide, for the first time, a geographically diverse evaluation of daptomycin versus vancomycin for patients with vancomycin-susceptible MRSA bacteremia with vancomycin MIC values >1 µg/mL. Although the overall composite failure rates did not differ between the vancomycin and daptomycin groups when intensively matched according to risks for failure, the rates of acute kidney injury were significantly lower in the daptomycin group. These findings suggest that daptomycin is a useful therapy for clinicians treating patients who have MRSA bacteremia. Prospective, randomized trials should be conducted to better assess the potential significance of elevated vancomycin MIC. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

Derivatives of a Vancomycin-Resistant Staphylococcus aureus Strain Isolated at Hershey Medical Center

PubMed Central

Bozdogan, Bülent; Ednie, Lois; Credito, Kim; Kosowska, Klaudia; Appelbaum, Peter C.

2004-01-01

Antimicrobial susceptibilities and genetic relatedness of the vancomycin-resistant Staphylococcus aureus strain (VRSA) isolated at Hershey, Pa. (VRSA Hershey), and its vancomycin-susceptible and high-level-resistant derivatives were studied and compared to 32 methicillin-resistant S. aureus strains (MRSA) isolated from patients and medical staff in contact with the VRSA patient. Derivatives of VRSA were obtained by subculturing six VRSA colonies from the original culture with or without vancomycin. Ten days of drug-free subculture caused the loss of vanA in two vancomycin-susceptible derivatives for which vancomycin MICs were 1 to 4 μg/ml. Multistep selection of three VRSA clones with vancomycin for 10 days increased vancomycin MICs from 32 to 1,024 to 2,048 μg/ml. MICs of teicoplanin, dalbavancin, and oritavancin were also increased from 4, 0.5, and 0.12 to 64, 1, and 32 μg/ml, respectively. Pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing analysis indicated that VRSA Hershey was the vanA-acquired variety of a common MRSA clone in our hospital with sequence type 5 (ST5). Three of five vancomycin-intermediate S. aureus strains tested from geographically different areas were also ST5, and the Michigan VRSA was ST371, a one-allele variant of ST5. Derivatives of VRSA Hershey had differences in PFGE profiles and the size of SmaI fragment that carries the vanA gene cluster, indicating instability of this cluster in VRSA Hershey. However induction with vancomycin increased glycopeptide MICs and stabilized the resistance. PMID:15561854

Derivatives of a vancomycin-resistant Staphylococcus aureus strain isolated at Hershey Medical Center.

PubMed

Bozdogan, Bülent; Ednie, Lois; Credito, Kim; Kosowska, Klaudia; Appelbaum, Peter C

2004-12-01

Antimicrobial susceptibilities and genetic relatedness of the vancomycin-resistant Staphylococcus aureus strain (VRSA) isolated at Hershey, Pa. (VRSA Hershey), and its vancomycin-susceptible and high-level-resistant derivatives were studied and compared to 32 methicillin-resistant S. aureus strains (MRSA) isolated from patients and medical staff in contact with the VRSA patient. Derivatives of VRSA were obtained by subculturing six VRSA colonies from the original culture with or without vancomycin. Ten days of drug-free subculture caused the loss of vanA in two vancomycin-susceptible derivatives for which vancomycin MICs were 1 to 4 microg/ml. Multistep selection of three VRSA clones with vancomycin for 10 days increased vancomycin MICs from 32 to 1,024 to 2,048 microg/ml. MICs of teicoplanin, dalbavancin, and oritavancin were also increased from 4, 0.5, and 0.12 to 64, 1, and 32 microg/ml, respectively. Pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing analysis indicated that VRSA Hershey was the vanA-acquired variety of a common MRSA clone in our hospital with sequence type 5 (ST5). Three of five vancomycin-intermediate S. aureus strains tested from geographically different areas were also ST5, and the Michigan VRSA was ST371, a one-allele variant of ST5. Derivatives of VRSA Hershey had differences in PFGE profiles and the size of SmaI fragment that carries the vanA gene cluster, indicating instability of this cluster in VRSA Hershey. However induction with vancomycin increased glycopeptide MICs and stabilized the resistance.

Screening municipal wastewater effluent and surface water used for drinking water production for the presence of ampicillin and vancomycin resistant enterococci.

PubMed

Taučer-Kapteijn, Maja; Hoogenboezem, Wim; Heiliegers, Laura; de Bolster, Danny; Medema, Gertjan

2016-07-01

The emergence of clinical enterococcal isolates that are resistant to both ampicillin and vancomycin is a cause of great concern, as therapeutic alternatives for the treatment of infections caused by such organisms are becoming limited. Aquatic environments could play a role in the dissemination of antibiotic resistant enterococci. This study investigated the presence of ampicillin and vancomycin resistant enterococci in the treated effluent of six wastewater treatment plants (WWTPs) and in surface water used as a source for drinking water production in the Netherlands. Membrane filtration in combination with selective media with ampicillin or vancomycin was applied to determine the presence of ampicillin resistant Enterococcus (ARE) and vancomycin resistant Enterococcus (VRE) species. Ampicillin resistant Enterococcus faecium (minimal inhibitory concentration (MIC) >16μg/mL; n=1033) was observed in all studied WWTP effluents. In surface water used for drinking water production (intake locations), no ARE or VRE were observed. At both types of location, intrinsic vancomycin resistant Pediococcus spp., Leuconostoc spp. and Lactobacillus spp. were isolated with the vancomycin medium. The ampicillin resistant E. faecium (AREfm) isolates (n=113) did not contain the vanA or vanB gene, but MIC testing for vancomycin showed intermediate vancomycin resistance (2-8μgmL(-1)) to occur in these AREfm strains. This study documents the discharge of ampicillin resistant E. faecium strains with intermediate vancomycin resistance by the WWTPs into the surface water, but no presence of these strains downstream at intake locations for drinking water production. Copyright © 2016 Elsevier GmbH. All rights reserved.

Antimicrobial susceptibility testing of a clinical isolate of vancomycin-dependent enterococcus using D-alanine-D-alanine as a growth supplement.

PubMed

Sng, L H; Cornish, N; Knapp, C C; Ludwig, M D; Hall, G S; Washington, J A

1998-04-01

Bacteremia due to a vancomycin-dependent enterococcus (VDE) occurred during long-term vancomycin therapy in a renal transplant recipient with underlying pancreatitis and a vancomycin-resistant enterococcal (VRE) wound infection and bacteremia. The VDE was isolated from blood during vancomycin therapy and grew only in the presence of vancomycin and D-alanine-D-alanine (DADA), a substance required for cell-wall synthesis. Colonies beyond the periphery of growth of the VDE around a vancomycin disk contained vancomycin-independent revertant mutants after 48 hours of incubation. Pulsed-field gel electrophoresis of the VDE, revertant mutant, the initial blood culture isolate of VRE, and an autopsy isolate showed that the four strains were identical. Antimicrobial susceptibility testing was performed using standard macrobroth and microbroth dilution methods. DADA was used as a growth supplement for macrobroth dilution susceptibility testing of the VDE isolate. Minimum inhibitory concentrations (MICs) were similar for the VRE isolate and the VDE revertant, which were both resistant to ampicillin, high-level gentamicin, ciprofloxacin, imipenem, vancomycin, and daptomycin, and were susceptible to fusidic acid, high-level streptomycin, rifampin, and a quinupristin-dalfopristin combination. The MICs of teicoplanin were 2 microg/mL or less and 16 microg/mL for the clinical VRE isolate and the VDE revertant, respectively. The autopsy isolate was resistant to all antimicrobials tested and showed a fourfold increase in MICs for quinupristin-dalfopristin compared with that of the original blood isolate. The VDE was susceptible to all drugs tested except vancomycin.

Outcomes with daptomycin in the treatment of Staphylococcus aureus infections with a range of vancomycin MICs

PubMed Central

Crompton, Jason A.; North, Donald S.; Yoon, MinJung; Steenbergen, Judith N.; Lamp, Kenneth C.; Forrest, Graeme N.

2010-01-01

Objectives Recent recommendations by the Infectious Diseases Society of America for the treatment of Staphylococcus aureus suggest the use of alternative agents when vancomycin MIC values are ≥2 mg/L. This study examines the outcome of patients treated with daptomycin for S. aureus infections with documented vancomycin MICs. Patients and methods All patients with skin, bacteraemia and endocarditis infections due to S. aureus with vancomycin MIC values in CORE 2005–08, a retrospective, multicentre, observational registry, were studied. The outcome (cure, improved, failure or non-evaluable) was the investigator assessment at the end of daptomycin therapy. Success was defined as cure or improved. Results Five hundred and forty-seven clinically evaluable patients were identified with discrete vancomycin MIC values [MIC <2 mg/L: 451 (82%); MIC ≥2 mg/L: 96 (18%)]. The vancomycin MIC groups were well matched for patient characteristics, types of infections, first-line daptomycin use (19%) and prior vancomycin use (58%). Clinical success was reported in 94% of patients. No differences were detected in the daptomycin success rate by the vancomycin MIC group overall or by the infection type. A multivariate logistic regression also failed to identify vancomycin MIC as a predictor of daptomycin failure. Adverse event (AE) rates were not different when analysed by MIC group; both groups had ∼17% of patients with one AE. Conclusions In this diverse population, daptomycin was associated with similar outcomes for patients, regardless of whether the vancomycin MIC was categorized as <2 or ≥2 mg/L. Further studies are warranted. PMID:20554570

Vancomycin

MedlinePlus

... colitis (inflammation of the intestine caused by certain bacteria) that may occur after antibiotic treatment. Vancomycin is ... medications called glycopeptide antibiotics. It works by killling bacteria in the intestines. Vancomycin will not kill bacteria ...

Persistent staphylococcal bacteremia in an intravenous drug abuser.

PubMed

Barg, N L; Supena, R B; Fekety, R

1986-02-01

A patient with methicillin-resistant Staphylococcus aureus bacteremia received vancomycin (MIC = 0.8 microgram/ml, MBC = 15 micrograms/ml) and heparin simultaneously through the same intravenous line to treat a septic deep venous thrombosis. Bacteremia persisted for 7 days. Bacteremia terminated when the simultaneous infusion of heparin and vancomycin through the same line was stopped. This suggested that an interaction between vancomycin and heparin may have occurred, which resulted in a reduction in vancomycin activity. To test for such an interaction, mixtures of heparin and vancomycin in various concentrations were made and tested for antimicrobial activity against the organisms in the patient. A precipitate formed at the concentrations achieved in the intravenous lines, and when the vancomycin concentrations were measured by bioassay, a 50 to 60% reduction in activity was noted. In contrast, when these solutions were prepared and mixed at microgram concentrations, a precipitate was no longer observed, and antimicrobial activity was not reduced. Heparin appeared to interact unfavorably with vancomycin at the concentrations in the intravenous lines when these drugs were administered simultaneously to patients. This may be the cause of poor therapeutic responses to vancomycin in some patients, especially those infected with tolerant organisms.

21 CFR 862.3950 - Vancomycin test system.

Code of Federal Regulations, 2010 CFR

2010-04-01

...) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862... diagnosis and treatment of vancomycin overdose and in monitoring the level of vancomycin to ensure...

Emergence in Asian Countries of Staphylococcus aureus with Reduced Susceptibility to Vancomycin

PubMed Central

Song, Jae-Hoon; Hiramatsu, Keiichi; Suh, Ji Yoeun; Ko, Kwan Soo; Ito, Teruyo; Kapi, Maria; Kiem, Sungmin; Kim, Yeon-Sook; Oh, Won Sup; Peck, Kyong Ran; Lee, Nam Yong

2004-01-01

To investigate the prevalence of Staphylococcus aureus with reduced susceptibility to vancomycin among methicillin-resistant S. aureus (MRSA) strains in Asian countries, a total of 1,357 clinical isolates of MRSA collected from 12 Asian countries were screened by using brain heart infusion agar plates containing 4 mg of vancomycin per liter. The presence of strains that were heterointermediately resistant to vancomycin (hVISA) was confirmed by population analysis. Of 347 (25.6%) MRSA isolates that grew on the screening agar plates, 58 isolates (4.3%) were hVISA. hVISA strains were found in India, South Korea, Japan, the Philippines, Singapore, Thailand, and Vietnam. However, neither vancomycin-intermediate S. aureus nor vancomycin-resistant S. aureus isolates were found among MRSA isolates from Asian countries in this survey. PMID:15561884

Development of a vancomycin dosing approach for critically ill patients receiving hybrid hemodialysis using Monte Carlo simulation.

PubMed

Lewis, Susan J; Mueller, Bruce A

2018-01-01

Prolonged intermittent renal replacement therapy is an increasingly popular treatment for acute kidney injury in critically ill patients that runs at different flow rates and durations than conventional hemodialysis or continuous renal replacement therapies. Pharmacokinetic studies conducted in patients receiving prolonged intermittent renal replacement therapy are scarce; consequently, clinicians are challenged to dose antibiotics effectively. The purpose of this study was to develop vancomycin dosing recommendations for patients receiving prolonged intermittent renal replacement therapy. Monte Carlo simulations were performed in thousands of virtual patients derived from previously published demographic, pharmacokinetic, and dialytic information derived from critically ill patients receiving vancomycin and other forms of renal replacement therapy. We conducted "in silico" vancomycin pharmacokinetic/pharmacodynamics analyses in these patients receiving prolonged intermittent renal replacement therapy to determine what vancomycin dose would achieve vancomycin 24-h area under the curve (AUC 24h ) of 400-700 mg·h/L, a target associated with positive clinical outcomes. Nine different vancomycin dosing regimens were tested using four different, commonly used prolonged intermittent renal replacement therapy modalities. A dosing nomogram based on serum concentration data achieved after the third dose was developed to individualize vancomycin therapy. An initial vancomycin dose of 15 or 20 mg/kg immediately followed by 15 mg/kg after subsequent prolonged intermittent renal replacement therapy treatments achieved AUC 24h of ≥400 mg·h/L for ≥90% of patients regardless of prolonged intermittent renal replacement therapy duration, modality, or time of vancomycin dose relative to prolonged intermittent renal replacement therapy. Many patients experienced AUC 24h of ≥700 mg·h/L, but once the dosing nomogram was applied to serum concentrations obtained after the third vancomycin dose, 67%-88% of patients achieved AUC 24h of 400-700 mg·h/L. An initial loading dose of 15-20 mg/kg followed by a maintenance regimen of 15 mg/kg after every prolonged intermittent renal replacement therapy session coupled with serum concentration monitoring should be used to individualize vancomycin dosing. These predictions need clinical verification.

AUC versus peak-trough dosing of vancomycin: applying new pharmacokinetic paradigms to an old drug.

PubMed

Brown, Daniel L; Lalla, Christina D; Masselink, Andrew J

2013-08-01

To compare and contrast the pharmacokinetic/pharmacodynamic foundations of traditional "peak-trough" vancomycin dosing methods versus newer "area under the curve" (AUC) strategies. To propose a new AUC-based dosing chart for empirically determining an initial vancomycin dosing regimen designed to achieve a desired AUC24 using the minimum inhibitory concentration (MIC), creatinine clearance (CrCl), and vancomycin clearance (ClVanco). Peak-trough vancomycin dosing is designed to achieve a Cpeak of 20-40 mg/L and a Ctrough of 10-15 or 15-20 mg/L, depending on the severity of the infection and the nature of the pathogen. New treatment guidelines for vancomycin suggest that therapy should achieve an AUC24/MIC of ≥400. AUC-based vancomycin dosing derives the daily dose from ClVanco, MIC, and the desired AUC24/MIC, without consideration of the patient's weight. A vancomycin dosing chart is proposed that estimates ClVanco using the following formula developed by Matzke et al: ClVanco in L/h = [(CrClmL/min × 0.689) + 3.66] × 0.06, which simplifies to (CrClmL/min × 0.41) + 0.22. Two levels of dosing are included-high dose (Ctrough: 15-20 mg/L) and moderate dose (Ctrough: 10-15 mg/L). Although the chart has not been validated clinically, it represents the product of standard dosing equations that are used to determine a starting dosing regimen based on well-established vancomycin pharmacokinetic parameters. An understanding of pharmacokinetic and pharmacodynamic principles, including the relevance of AUC in relation to MIC, enables clinicians to make the best use of vancomycin dosing options. The proposed dosing chart is pharmacokinetically valid but has yet to be applied clinically. It provides a foundation for further study of how clinicians can determine an optimal AUC-based starting vancomycin dosing regimen without having to derive ClVanco or AUC24.

A Quasi-Experiment To Study the Impact of Vancomycin Area under the Concentration-Time Curve-Guided Dosing on Vancomycin-Associated Nephrotoxicity

PubMed Central

Finch, Natalie A.; Zasowski, Evan J.; Murray, Kyle P.; Mynatt, Ryan P.; Zhao, Jing J.; Yost, Raymond; Pogue, Jason M.

2017-01-01

ABSTRACT Evidence suggests that maintenance of vancomycin trough concentrations at between 15 and 20 mg/liter, as currently recommended, is frequently unnecessary to achieve the daily area under the concentration-time curve (AUC24) target of ≥400 mg · h/liter. Many patients with trough concentrations in this range have AUC24 values in excess of the therapeutic threshold and within the exposure range associated with nephrotoxicity. On the basis of this, the Detroit Medical Center switched from trough concentration-guided dosing to AUC-guided dosing to minimize potentially unnecessary vancomycin exposure. The primary objective of this analysis was to assess the impact of this intervention on vancomycin-associated nephrotoxicity in a single-center, retrospective quasi-experiment of hospitalized adult patients receiving intravenous vancomycin from 2014 to 2015. The primary analysis compared the incidence of nephrotoxicity between patients monitored by assessment of the AUC24 and those monitored by assessment of the trough concentration. Multivariable logistic and Cox proportional hazards regression examined the independent association between the monitoring strategy and nephrotoxicity. Secondary analysis compared vancomycin exposures (total daily dose, AUC, and trough concentrations) between monitoring strategies. Overall, 1,280 patients were included in the analysis. After adjusting for severity of illness, comorbidity, duration of vancomycin therapy, and concomitant receipt of nephrotoxins, AUC-guided dosing was independently associated with lower nephrotoxicity by both logistic regression (odds ratio, 0.52; 95% confidence interval [CI], 0.34 to 0.80; P = 0.003) and Cox proportional hazards regression (hazard ratio, 0.53; 95% CI, 0.35 to 0.78; P = 0.002). AUC-guided dosing was associated with lower total daily vancomycin doses, AUC values, and trough concentrations. Vancomycin AUC-guided dosing was associated with reduced nephrotoxicity, which appeared to be a result of reduced vancomycin exposure. PMID:28923869

Association of the clinical efficacy of vancomycin with the novel pharmacokinetic parameter area under the trough level (AUTL) in elderly patients with hospital-acquired pneumonia.

PubMed

Fukumori, S; Tsuji, Y; Mizoguchi, A; Kasai, H; Ishibashi, T; Iwamura, N; To, H

2016-08-01

The pharmacokinetic-pharmacodynamic parameter that best predicts the efficacy of vancomycin is the ratio of the area under the concentration versus time curve (AUC) to the minimum inhibitory concentration (MIC). A 24-h AUC (AUC24 )/MIC ratio ≥ 400 was recommended in an American consensus review, but vancomycin treatment occasionally fails despite maintenance of AUC24 /MIC ≥ 400. We evaluated the association between clinical efficacy of vancomycin and two novel pharmacokinetic parameters, the 'area under the trough level' (AUTL) and the 'area above the trough level' (AATL), in hospitalized elderly patients with methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. The subjects were hospitalized elderly patients who were administered vancomycin for treatment of MRSA pneumonia between 2006 and 2012 at Sasebo Chuo Hospital (Nagasaki, Japan). Pharmacokinetic parameters of vancomycin were estimated for each patient by Bayesian analysis using population pharmacokinetic parameters for Japanese patients. Based on the patient-specific parameters thus obtained, AUC24 values were calculated as the vancomycin dosage divided by vancomycin clearance. AUTL was calculated as the trough serum concentration multiplied by 24 h, whereas AATL was calculated by subtracting AUTL from AUC24 . Logistic regression analysis demonstrated that efficacy of vancomycin was more strongly associated with AUTL than AUC24 . The optimal cut-off value of AUTL was 331 μg∙h/mL, which means that the optimal cut-off value of the trough serum concentration was 13·8 μg/mL. Efficacy of vancomycin was associated with AUTL, a novel pharmacokinetic parameter. Determining the target AUTL or trough concentration may enhance the efficacy of vancomycin therapy in elderly patients with MRSA pneumonia. Given that nephrotoxicity may increase with a Ctrough in excess of 15 μg/mL, this level should ideally not be exceeded. © 2016 John Wiley & Sons Ltd.

The Prevalence of Vancomycin-Intermediate Staphylococcus aureus and Heterogeneous VISA Among Methicillin-Resistant Strains Isolated from Pediatric Population in a Turkish University Hospital.

PubMed

Mirza, Hasan Cenk; Sancak, Banu; Gür, Deniz

2015-10-01

There are limited data regarding the prevalence of vancomycin-intermediate Staphylococcus aureus (VISA)/heterogeneous VISA (hVISA) among pediatric population. Our objective was to determine the distribution of vancomycin and daptomycin minimum inhibitory concentrations (MICs) and explore the phenomenon of vancomycin MIC creep and the VISA/hVISA prevalence among the methicillin-resistant Staphylococcus aureus (MRSA) strains belonging to pediatric population by population analysis profile-area under the curve (PAP-AUC) and Etest macromethod. Vancomycin and daptomycin susceptibilities of 94 pediatric isolates of MRSA were tested by broth microdilution (BMD) and Etest methods. To determine the prevalence of VISA/hVISA, Etest macromethod and PAP-AUC was performed on all isolates. All isolates were susceptible to vancomycin and daptomycin by both BMD and Etest methods. Twenty-eight (29.8%) isolates had vancomycin MICs of 2 μg/ml by BMD. No increase in vancomycin MICs was observed over time. There were no VISA among 94 MRSA tested but 20 (21.3%) hVISA isolates were identified by PAP-AUC. Results of Etest macromethod were compared to PAP-AUC. Etest macromethod was 60.0% sensitive and 90.5% specific. The hVISA isolates represented 53.6% of isolates with vancomycin MICs of 2 μg/ml. Also, 75% of hVISA isolates had vancomycin MICs of 2 μg/ml. To our knowledge, this is the first study investigating the prevalence of VISA/hVISA among MRSA isolated from pediatric patients by PAP-AUC method. Based on our findings, MRSA isolates, which have vancomycin MIC of 2 μg/ml can be investigated for the presence of hVISA. In this study, daptomycin showed potent activity against all isolates and may represent a therapeutic option for MRSA infections.

Prevalence of vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous VISA among methicillin-resistant S. aureus with high vancomycin minimal inhibitory concentrations in Taiwan: A multicenter surveillance study, 2012-2013.

PubMed

Huang, Sung-Hsi; Chen, Yee-Chun; Chuang, Yin-Ching; Chiu, Sheng-Kang; Fung, Chang-Phone; Lu, Po-Liang; Wang, Lih-Shinn; Wu, Tsu-Lan; Wang, Jann-Tay

2016-10-01

Intermediate-resistance and heteroresistance to vancomycin in methicillin-resistant Staphylococcus aureus (MRSA) is reported worldwide. A surveillance study in 2003 showed that the prevalence rates of vancomycin-intermediate S. aureus (VISA) and heterogeneous VISA (hVISA) in Taiwan were 0.2% and 0.7%, respectively. This study aimed to investigate the updated prevalence of VISA and hVISA in Taiwan. MRSA isolates from sterile sites with minimal inhibitory concentrations (MICs) of 1 μg/mL or more to vancomycin were collected from 15 participating hospitals in Taiwan. Enrolled MRSA isolates were submitted to antimicrobial susceptibility testing, staphylococcal cassette chromosome mec (SCCmec) element typing, and multilocus sequence typing. Isolates with vancomycin MIC of 1 μg/mL or 2 μg/mL were screened for vancomycin heterogeneous resistance by Etest glycopeptide-resistance detection (GRD). Those with positive GRD screening results were then analyzed by modified population analysis profiling-area under the curve method for confirmation of vancomycin heteroresistance. Between 2012 and 2013, a total of 622 MRSA isolates from sterile sites with vancomycin MIC of 1 μg/mL or more were studied. The prevalence rates of hVISA and VISA among these isolates were 10.0% and 2.7%, respectively. The hVISA prevalence increased significantly compared to that in 2003. Compared with vancomycin-susceptible S. aureus, hVISA and VISA isolates were less susceptible to ciprofloxacin, clindamycin, daptomycin, gentamicin, rifampin, and trimethoprim/sulfamethoxazole, and are thus, more likely to have SCCmec II or III element. A twofold increase in either vancomycin or teicoplanin MIC doubled the probability of being hVISA. Growing hVISA prevalence was highly suspected. Longitudinal surveillance of this phenomenon and monitoring of its clinical impact are necessary. Copyright © 2015. Published by Elsevier B.V.

Reduction in surgical site infection with suprafascial intrawound application of vancomycin powder in instrumented posterior spinal fusion: a retrospective case-control study.

PubMed

Haimoto, Shoichi; Schär, Ralph T; Nishimura, Yusuke; Hara, Masahito; Wakabayashi, Toshihiko; Ginsberg, Howard J

2018-05-04

OBJECTIVE Recent studies have demonstrated the efficacy of subfascial intrawound application of vancomycin powder in spine surgery in reducing the rate of surgical site infections (SSIs). However, to date no study has evaluated the efficacy and safety of suprafascial application of vancomycin powder in spine surgery. The purpose of this study was to quantify the rate of SSIs after open instrumented posterior spinal fusion with and without application of suprafascial vancomycin powder and to evaluate the rate of vancomycin powder-related local adverse effects. METHODS The authors conducted a single-center retrospective case-control study of adult patients undergoing open instrumented posterior fusion of the cervical, thoracic, or lumbar spine performed by a single surgeon from January 2010 through December 2016. In March 2013, routine application of 1 g of suprafascial vancomycin powder was started for all cases in addition to standard systemic antibiotic prophylaxis. Baseline demographics and operative data as well as the SSI rates were compared between the study groups. The incidence of vancomycin powder-related adverse effects was analyzed. RESULTS A total of 515 patients (268 in the untreated group and 247 in the treated group) were included in the study. The mean age was significantly higher in the treated group than in the untreated group (58.4 vs 54.4 years, p < 0.01). Operative variables were similar between the study groups. Patients receiving vancomycin powder had a significantly lower infection rate (5.6% in the untreated group vs 0% in the treated group, p < 0.001). No vancomycin powder-related adverse effects were identified in the treated group. CONCLUSIONS Routine application of suprafascial intrawound vancomycin powder in addition to systemic antibiotic prophylaxis is an easy-to-use, safe, and effective strategy for preventing SSIs after instrumented posterior spinal fusion. Suprafascial application of vancomycin powder could be a valuable alternative to previously reported subfascial distribution, minimizing the risk of local adverse drug reactions.

A Quasi-Experiment To Study the Impact of Vancomycin Area under the Concentration-Time Curve-Guided Dosing on Vancomycin-Associated Nephrotoxicity.

PubMed

Finch, Natalie A; Zasowski, Evan J; Murray, Kyle P; Mynatt, Ryan P; Zhao, Jing J; Yost, Raymond; Pogue, Jason M; Rybak, Michael J

2017-12-01

Evidence suggests that maintenance of vancomycin trough concentrations at between 15 and 20 mg/liter, as currently recommended, is frequently unnecessary to achieve the daily area under the concentration-time curve (AUC 24 ) target of ≥400 mg · h/liter. Many patients with trough concentrations in this range have AUC 24 values in excess of the therapeutic threshold and within the exposure range associated with nephrotoxicity. On the basis of this, the Detroit Medical Center switched from trough concentration-guided dosing to AUC-guided dosing to minimize potentially unnecessary vancomycin exposure. The primary objective of this analysis was to assess the impact of this intervention on vancomycin-associated nephrotoxicity in a single-center, retrospective quasi-experiment of hospitalized adult patients receiving intravenous vancomycin from 2014 to 2015. The primary analysis compared the incidence of nephrotoxicity between patients monitored by assessment of the AUC 24 and those monitored by assessment of the trough concentration. Multivariable logistic and Cox proportional hazards regression examined the independent association between the monitoring strategy and nephrotoxicity. Secondary analysis compared vancomycin exposures (total daily dose, AUC, and trough concentrations) between monitoring strategies. Overall, 1,280 patients were included in the analysis. After adjusting for severity of illness, comorbidity, duration of vancomycin therapy, and concomitant receipt of nephrotoxins, AUC-guided dosing was independently associated with lower nephrotoxicity by both logistic regression (odds ratio, 0.52; 95% confidence interval [CI], 0.34 to 0.80; P = 0.003) and Cox proportional hazards regression (hazard ratio, 0.53; 95% CI, 0.35 to 0.78; P = 0.002). AUC-guided dosing was associated with lower total daily vancomycin doses, AUC values, and trough concentrations. Vancomycin AUC-guided dosing was associated with reduced nephrotoxicity, which appeared to be a result of reduced vancomycin exposure. Copyright © 2017 American Society for Microbiology.

The release kinetics, antimicrobial activity and cytocompatibility of differently prepared collagen/hydroxyapatite/vancomycin layers: Microstructure vs. nanostructure.

PubMed

Suchý, Tomáš; Šupová, Monika; Klapková, Eva; Adamková, Václava; Závora, Jan; Žaloudková, Margit; Rýglová, Šárka; Ballay, Rastislav; Denk, František; Pokorný, Marek; Sauerová, Pavla; Hubálek Kalbáčová, Marie; Horný, Lukáš; Veselý, Jan; Voňavková, Tereza; Průša, Richard

2017-03-30

The aim of this study was to develop an osteo-inductive resorbable layer allowing the controlled elution of antibiotics to be used as a bone/implant bioactive interface particularly in the case of prosthetic joint infections, or as a preventative procedure with respect to primary joint replacement at a potentially infected site. An evaluation was performed of the vancomycin release kinetics, antimicrobial efficiency and cytocompatibility of collagen/hydroxyapatite layers containing vancomycin prepared employing different hydroxyapatite concentrations. Collagen layers with various levels of porosity and structure were prepared using three different methods: by means of the lyophilisation and electrospinning of dispersions with 0, 5 and 15wt% of hydroxyapatite and 10wt% of vancomycin, and by means of the electrospinning of dispersions with 0, 5 and 15wt% of hydroxyapatite followed by impregnation with 10wt% of vancomycin. The maximum concentration of the released active form of vancomycin characterised by means of HPLC was achieved via the vancomycin impregnation of the electrospun layers, whereas the lowest concentration was determined for those layers electrospun directly from a collagen solution containing vancomycin. Agar diffusion testing revealed that the electrospun impregnated layers exhibited the highest level of activity. It was determined that modification using hydroxyapatite exerts no strong effect on vancomycin evolution. All the tested samples exhibited sufficient cytocompatibility with no indication of cytotoxic effects using human osteoblastic cells in direct contact with the layers or in 24-hour infusions thereof. The results herein suggest that nano-structured collagen-hydroxyapatite layers impregnated with vancomycin following cross-linking provide suitable candidates for use as local drug delivery carriers. Copyright © 2017 Elsevier B.V. All rights reserved.

Meta-Analysis

PubMed Central

Kale-Pradhan, Pramodini B.; Mariani, Nicholas P.; Wilhelm, Sheila M.; Johnson, Leonard B.

2015-01-01

Background: Vancomycin is used to treat serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA). It is unclear whether MRSA isolates with minimum inhibitory concentration (MIC) 1.5 to 2 µg/mL are successfully treated with vancomycin. Objective: Evaluate vancomycin failure rates in MRSA bacteremia with an MIC <1.5 versus ≥1.5 µg/mL, and MIC ≤1 versus ≥2 µg/mL. Methods: A literature search was conducted using MESH terms vancomycin, MRSA, bacteremia, MIC, treatment and vancomycin failure to identify human studies published in English. All studies of patients with MRSA bacteremia treated with vancomycin were included if they evaluated vancomycin failures, defined as mortality, and reported associated MICs determined by E-test. Study sample size, vancomycin failure rates, and corresponding MIC values were extracted and analyzed using RevMan 5.2.5. Results: Thirteen studies including 2955 patients met all criteria. Twelve studies including 2861 patients evaluated outcomes using an MIC cutoff of 1.5 µg/mL. A total of 413 of 1186 (34.8%) patients with an MIC <1.5 and 531 of 1675 (31.7%) patients with an MIC of ≥1.5 µg/mL experienced treatment failure (odds ratio = 0.72, 95% confidence interval = 0.49-1.04, P = .08). Six studies evaluated 728 patients using the cutoffs of ≤1 and ≥2 µg/mL. A total of 384 patients had isolates with MIC ≤1 µg/mL, 344 had an MIC ≥2 µg/mL. Therapeutic failure occurred in 87 and 102 patients, respectively (odds ratio = 0.61, 95% confidence interval = 0.34-1.10, P = .10). As heterogeneity between the studies was high, a random-effects model was used. Conclusion: Vancomycin MIC may not be an optimal sole indicator of vancomycin treatment failure in MRSA bacteremia.

A Novel Injectable Borate Bioactive Glass Cement as an Antibiotic Delivery Vehicle for Treating Osteomyelitis

PubMed Central

Cui, Xu; Gu, Yi-Fei; Jia, Wei-Tao; Rahaman, Mohamed N.; Wang, Yang; Huang, Wen-Hai; Zhang, Chang-Qing

2014-01-01

Background A novel injectable cement composed of chitosan-bonded borate bioactive glass (BG) particles was evaluated as a carrier for local delivery of vancomycin in the treatment of osteomyelitis in a rabbit tibial model. Materials and Methods The setting time, injectability, and compressive strength of the borate BG cement, and the release profile of vancomycin from the cement were measured in vitro. The capacity of the vancomycin-loaded BG cement to eradicate methicillin-resistant Staphylococcus aureus (MRSA)-induced osteomyelitis in rabbit tibiae in vivo was evaluated and compared with that for a vancomycin-loaded calcium sulfate (CS) cement and for intravenous injection of vancomycin. Results The BG cement had an injectability of >90% during the first 3 minutes after mixing, hardened within 30 minutes and, after hardening, had a compressive strength of 18±2 MPa. Vancomycin was released from the BG cement into phosphate-buffered saline for up to 36 days, and the cumulative amount of vancomycin released was 86% of the amount initially loaded into the cement. In comparison, vancomycin was released from the CS cement for up 28 days and the cumulative amount released was 89%. Two months post-surgery, radiography and microbiological tests showed that the BG and CS cements had a better ability to eradicate osteomyelitis when compared to intravenous injection of vancomycin, but there was no significant difference between the BG and CS cements in eradicating the infection. Histological examination showed that the BG cement was biocompatible and had a good capacity for regenerating bone in the tibial defects. Conclusions These results indicate that borate BG cement is a promising material both as an injectable carrier for vancomycin in the eradication of osteomyelitis and as an osteoconductive matrix to regenerate bone after the infection is cured. PMID:24427311

Comparison of routine prophylaxis with vancomycin or cefazolin for femoral neck fracture surgery: microbiological and clinical outcomes.

PubMed

Merrer, Jacques; Desbouchages, Laetitia; Serazin, Valérie; Razafimamonjy, Jimmy; Pauthier, François; Leneveu, Michel

2006-12-01

To assess the impact of antibiotic prophylaxis on the emergence of vancomycin-resistant strains of Enterococcus faecium, Enterococcus faecalis, and Staphylococcus aureus and the incidence of surgical site infection (SSI) after vancomycin or cefazolin prophylaxis for femoral neck fracture surgery. Prospective cohort study. A hospital with a high prevalence of methicillin-resistant S. aureus (MRSA) carriage. All patients admitted with a femoral neck fracture from March 1, 2004 through February 28, 2005 were prospectively identified and screened for MRSA and vancomycin-resistant (VRE) carriage at admission and at day 7. Deep incisional and organ/space SSIs were also recorded. Of 263 patients included in the study, 152 (58%) received cefazolin and 106 (40%) received vancomycin. At admission, the prevalence of MRSA carriage was 6.8%; it was 12% among patients with risk factors and 2.2% among patients with no risk factors (P=.002). At day 7 after surgery, there were 6 patients (2%) who had hospital-acquired MRSA, corresponding to 0.7% in the cefazolin group and 5% in the vancomycin group (P=.04); none of the MRSA isolates were resistant to glycopeptides. The rate of VRE carriage at admission was 0.4%. Three patients (1%) had acquired carriage of VRE (1 had E. faecium and 2 had E. faecalis); all 3 were in the cefazolin group (2% of patients) and none in the vancomycin group (P=.27). Eight SSIs (3%) occurred, 4% in the cefazolin group and 2% in the vancomycin group (P=.47). This preliminary study demonstrates that cefazolin and vancomycin prophylaxis have similar impacts on the emergence of glycopeptide-resistant pathogens. Neither MRSA infection nor increased rates of SSI with other bacteria were observed in the vancomycin group, suggesting that a larger multicenter study should be initiated.

Evaluation of body weight-based vancomycin therapy and the incidence of nephrotoxicity: a retrospective study in the northwest of China.

PubMed

Dong, Mo-Han; Wang, Jing-Wen; Wu, Yin; Chen, Bei-Yu; Yu, Min; Wen, Ai-Dong

2015-08-01

To identify specific risk factors of vancomycin-induced nephrotoxicity in China, as the relationship between vancomycin therapy (dosing and trough concentration monitoring) and nephrotoxicity has been the subject of critical debate. The cases of 90 critically ill patients who received vancomycin therapy in Xijing Hospital in the northwest of China between March 2014 and January 2015 were reviewed retrospectively. Vancomycin dosing, blood serum trough concentration, and other independent risk factors associated with nephrotoxicity were evaluated in a multivariable model. Among the 90 critically ill patients, 59 were males; mean age was 46.3 years. The indications for vancomycin use were methicillin-resistant Staphylococcus aureus-associated pneumonia, central nervous system infection, and bacteremia. Clinical pharmacists prescribed weight-based dosing, ranging from 20 to 45mg/kg/day. Fourteen (15.6%) patients developed nephrotoxicity, with serum creatinine elevated significantly from a mean (standard deviation) of 90.0 (18.8) μmol/l to 133.8 (63.2) μmol/l (p = 0.015). It was found that those with a vancomycin dosage >38mg/kg/day (50.0% vs. 11.3%, p = 0.004) and a vancomycin serum trough concentration >20mg/l (57.1% vs. 12.0%, p = 0.01) were more likely to develop nephrotoxicity. The data from this study indicate that a vancomycin dosage >38mg/kg/day and a serum trough level >20mg/l are both independent factors associated with the development of nephrotoxicity, suggesting that renal function should be monitored closely during vancomycin treatment. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

The cost effectiveness of vancomycin for preventing infections after shoulder arthroplasty: a break-even analysis.

PubMed

Hatch, M Daniel; Daniels, Stephen D; Glerum, Kimberly M; Higgins, Laurence D

2017-03-01

Increasing methicillin resistance and recognition of Propionibacterium acnes as a cause of infection in shoulder arthroplasty has led to the adoption of local vancomycin powder application as a more effective method to prevent expensive periprosthetic infections. However, no study has analyzed the cost effectiveness of vancomycin powder for preventing infection after shoulder replacement. Cost data for infection-related care of 16 patients treated for deep periprosthetic shoulder infection was collected from our institution for the break-even analysis. An equation was developed and applied to the data to determine how effective vancomycin powder would need to be at reducing a baseline infection rate to make prophylactic use cost effective. The efficacy of vancomycin (absolute risk reduction [ARR]) was evaluated at different unit costs, baseline infection rates, and average costs of treating infection. We determined vancomycin to be cost effective if the initial infection rate decreased by 0.04% (ARR). Using the current costs of vancomycin reported in the literature (range: $2.50/1000 mg to $44/1000 mg), we determined vancomycin to be cost effective with an ARR range of 0.01% at a cost of $2.50/1000 mg to 0.19% at $44/1000 mg. Baseline infection rate does not influence the ARR obtained at any specific cost of vancomycin or the cost of treating infection. We have derived and used a break-even equation to assess efficacy of prophylactic antibiotics during shoulder surgery. We further demonstrated the prophylactic administration of local vancomycin powder during shoulder arthroplasty to be a highly cost-effective practice. Copyright © 2017 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

Use of a Clinical Decision Support System Alert to Prevent Supratherapeutic Vancomycin Concentrations

PubMed Central

Ralph, Rachel; Patel, Jean A.; Postelnick, Michael; Ziauddin, Salma; Flis, Weronika; Galal, Audrey N.

2014-01-01

Background: Alerts issued by clinical decision support systems (CDSS) may be useful to identify and prevent the occurrence of acute kidney injury among patients on nephrotoxic drugs, particularly vancomycin. Objective: The purpose of this instructive study was to determine the effectiveness of using a pharmacist-run CDSS alert of early serum creatinine increases in patients receiving intravenous vancomycin to decrease the proportion of severely elevated vancomycin concentrations. Methods: This was a retrospective study of a prospectively reviewed CDSS alert that triggered in patients with an increase in serum creatinine by 25% from baseline within 24 hours. Severely elevated vancomycin concentrations were divided into a control group (before alert implementation) and a study group (after alert implementation) and considered for study inclusion. The proportion of severely elevated vancomycin concentrations (ie, >30 mg/L) were collected in the control and study groups. Results: There were 1290 and 1501 vancomycin concentrations in the control group and the study group, respectively. A total of 696 CDSS alerts triggered during the study period. The proportion of severely elevated vancomycin troughs decreased from 5.3% (n = 68, median = 36.6 mg/L, interquartile range = 33.75-43.2 mg/L) in the control group to 3.7% (n = 55, median = 34.7 mg/L, interquartile range = 31.3-39.3 mg/L) in the study group. This reflects a statistically significant decrease in the proportion of severely elevated vancomycin concentrations (P = .04). Conclusion: Overall, this instructive analysis on a novel use of CDSS software suggests that the implementation of an alert based on early detection of serum creatinine changes led to a significant decrease in the proportion of severely elevated serum vancomycin concentrations.

A novel injectable borate bioactive glass cement as an antibiotic delivery vehicle for treating osteomyelitis.

PubMed

Ding, Hao; Zhao, Cun-Ju; Cui, Xu; Gu, Yi-Fei; Jia, Wei-Tao; Rahaman, Mohamed N; Wang, Yang; Huang, Wen-Hai; Zhang, Chang-Qing

2014-01-01

A novel injectable cement composed of chitosan-bonded borate bioactive glass (BG) particles was evaluated as a carrier for local delivery of vancomycin in the treatment of osteomyelitis in a rabbit tibial model. The setting time, injectability, and compressive strength of the borate BG cement, and the release profile of vancomycin from the cement were measured in vitro. The capacity of the vancomycin-loaded BG cement to eradicate methicillin-resistant Staphylococcus aureus (MRSA)-induced osteomyelitis in rabbit tibiae in vivo was evaluated and compared with that for a vancomycin-loaded calcium sulfate (CS) cement and for intravenous injection of vancomycin. The BG cement had an injectability of >90% during the first 3 minutes after mixing, hardened within 30 minutes and, after hardening, had a compressive strength of 18 ± 2 MPa. Vancomycin was released from the BG cement into phosphate-buffered saline for up to 36 days, and the cumulative amount of vancomycin released was 86% of the amount initially loaded into the cement. In comparison, vancomycin was released from the CS cement for up 28 days and the cumulative amount released was 89%. Two months post-surgery, radiography and microbiological tests showed that the BG and CS cements had a better ability to eradicate osteomyelitis when compared to intravenous injection of vancomycin, but there was no significant difference between the BG and CS cements in eradicating the infection. Histological examination showed that the BG cement was biocompatible and had a good capacity for regenerating bone in the tibial defects. These results indicate that borate BG cement is a promising material both as an injectable carrier for vancomycin in the eradication of osteomyelitis and as an osteoconductive matrix to regenerate bone after the infection is cured.

Vancomycin resistant enterococci in urine cultures: Antibiotic susceptibility trends over a decade at a tertiary hospital in the United Kingdom.

PubMed

Toner, Liam; Papa, Nathan; Aliyu, Sani H; Dev, Harveer; Lawrentschuk, Nathan; Al-Hayek, Samih

2016-03-01

Enterococci are a common cause of urinary tract infection and vancomycin-resistant strains are more difficult to treat. The purpose of this surveillance program was to assess the prevalence of and determine the risk factors for vancomycin resistance in adults among urinary isolates of Enterococcus sp. and to detail the antibiotic susceptibility profile, which can be used to guide empirical treatment. From 2005 to 2014 we retrospectively reviewed 5,528 positive Enterococcus sp. urine cultures recorded in a computerized laboratory results database at a tertiary teaching hospital in Cambridge, United Kingdom. Of these cultures, 542 (9.8%) were vancomycin resistant. No longitudinal trend was observed in the proportion of vancomycin-resistant strains over the course of the study. We observed emerging resistance to nitrofurantoin with rates climbing from near zero to 40%. Ampicillin resistance fluctuated between 50% and 90%. Low resistance was observed for linezolid and quinupristin/dalfopristin. Female sex and inpatient status were identified as risk factors for vancomycin resistance. The incidence of vancomycin resistance among urinary isolates was stable over the last decade. Although resistance to nitrofurantoin has increased, it still serves as an appropriate first choice in uncomplicated urinary tract infection caused by vancomycin-resistant Enterococcus sp.

Probing the role of the vancomycin e-ring aryl chloride: selective divergent synthesis and evaluation of alternatively substituted E-ring analogues.

PubMed

Pinchman, Joseph R; Boger, Dale L

2013-05-23

The selective functionalization of vancomycin aglycon derivatives through conversion of the E-ring aryl chloride to a reactive boronic acid and its use in the synthesis of a systematic series of vancomycin E-ring analogues are described. The series was used to examine the E-ring chloride impact in binding d-Ala-d-Ala and on antimicrobial activity. In contrast to the reduced activity of the unsubstituted E-ring derivatives, hydrophobic and relatively nonpolar substituents approach or match the chloro-substituted vancomycin and were insensitive to the electronic character of the substituent (e.g., Cl vs CN/OMe), whereas highly polar substituents fail to provide the enhancements. Moreover, the active permethylated vancomycin aglycon derivatives exhibit VanB VRE antimicrobial activity at levels that approach (typically within 2-fold) their activity against sensitive bacteria. The robust borylation reaction also enabled the functionalization of a minimally protected vancomycin aglycon (N-Boc-vancomycin aglycon) and provides a direct method for the preparation of previously inaccessible analogues.

Reengineering Antibiotics to Combat Bacterial Resistance: Click Chemistry [1,2,3]-Triazole Vancomycin Dimers with Potent Activity against MRSA and VRE.

PubMed

Silverman, Steven M; Moses, John E; Sharpless, K Barry

2017-01-01

Vancomycin has long been considered a drug of last resort. Its efficiency in treating multiple drug-resistant bacterial infections, particularly methicillin-resistant Staphylococcus aureus (MRSA), has had a profound effect on the treatment of life-threatening infections. However, the emergence of resistance to vancomycin is a cause for significant worldwide concern, prompting the urgent development of new effective treatments for antibiotic resistant bacterial infections. Harnessing the benefits of multivalency and cooperativity against vancomycin-resistant strains, we report a Click Chemistry approach towards reengineered vancomycin derivatives and the synthesis of a number of dimers with increased potency against MRSA and vancomycin resistant Enterococci (VRE; VanB). These semi-synthetic dimeric ligands were linked together with great efficiency using the powerful CuAAC reaction, demonstrating high levels of selectivity and purity. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Balancing vancomycin efficacy and nephrotoxicity: should we be aiming for trough or AUC/MIC?

PubMed

Patel, Karisma; Crumby, Ashley S; Maples, Holly D

2015-04-01

Sixty years later, the question that still remains is how to appropriately utilize vancomycin in the pediatric population. The Infectious Diseases Society of America published guidelines in 2011 that provide guidance for dosing and monitoring of vancomycin in adults and pediatrics. However, goal vancomycin trough concentrations of 15-20 μg/mL for invasive infections caused by methicillin-resistant Staphylococcus aureus were based primarily on adult pharmacokinetic and pharmacodynamic data that achieved an area under the curve to minimum inhibitory concentration ratio (AUC/MIC) of ≥400. Recent pediatric literature shows that vancomycin trough concentrations needed to achieve the target AUC/MIC are different than the adult goal troughs cited in the guidelines. This paper addresses several thoughts, including the role of vancomycin AUC/MIC in dosing strategies and safety monitoring, consistency in laboratory reporting, and future directions for calculating AUC/MIC in pediatrics.

Evaluation of NVB302 versus vancomycin activity in an in vitro human gut model of Clostridium difficile infection.

PubMed

Crowther, Grace S; Baines, Simon D; Todhunter, Sharie L; Freeman, Jane; Chilton, Caroline H; Wilcox, Mark H

2013-01-01

First-line treatment options for Clostridium difficile infection (CDI) are limited. NVB302 is a novel type B lantibiotic under evaluation for the treatment of CDI. We compared the responses to NVB302 and vancomycin when used to treat simulated CDI in an in vitro gut model. We used ceftriaxone to elicit simulated CDI in an in vitro gut model primed with human faeces. Vancomycin and NVB302 were instilled into separate gut models and the indigenous gut microbiota and C. difficile total viable counts, spores and toxin levels were monitored throughout. Ceftriaxone instillation promoted C. difficile germination and high-level toxin production. Commencement of NVB302 and vancomycin instillation reduced C. difficile total viable counts rapidly with only C. difficile spores remaining within 3 and 4 days, respectively. Cytotoxin was reduced to undetectable levels 5 and 7 days after vancomycin and NVB302 instillation commenced in vessel 2 and 3, respectively, and remained undetectable for the remainder of the experiments. C. difficile spores were unaffected by the presence of vancomycin or NVB302. NVB302 treatment was associated with faster resolution of Bacteroides fragilis group. Both NVB302 and vancomycin were effective in treating simulated CDI in an in vitro gut model. C. difficile spore recrudescence was not observed following successful treatment with either NVB302 or vancomycin. NVB302 displayed non-inferiority to vancomycin in the treatment of simulated CDI, and had less deleterious effects against B. fragilis group. NVB302 warrants further clinical investigation as a potentially novel antimicrobial agent for the treatment of CDI.

Long-term Stability of Vancomycin Hydrochloride in Glucose 5% Polyolefin Bags: The Brand Name Versus a Generic Product.

PubMed

Huvelle, Sophie; Godet, Marie; Hecq, Jean-Daniel; Gillet, Patricia; Jamart, Jacques; Galanti, Laurence M

2016-01-01

The objectives of this study were to determine if the preparation of vancomycin hydrochloride in advance of infusion could improve the quality of the drug, time management of drug delivery, cost savings of drug delivery, and to investigate the long-term stability of vancomycin hydrochloride (brand name Vancocin®) infusion in glucose 5% polyolefin bags versus the generic (Vancomycine®) at 5°C ± 3°C. Five bags of each infusion 1 g/100 mL vancomycin hydrochloride in 5% glucose (Vancocin ® and Vancomycine®) were stored up to 57 days at 5°C ± 3°C. A visual inspection and pH measurement were performed periodically during the storage, and the concentrations were measured by high-performance liquid chromatography-diode array detection. No color change or precipitation in the solution was observed throughout the study period. As recommended by the U.S. Food and Drug Administration, the lower confidence limit at 95% of the concentration for the solutions remained superior to 90% of the initial concentration up to 43 days for the brand vancomycin (Vancocin®) infusion (96% ± 2%) and up to 57 days for the generic (Vancomycine®) (95% ± 4%). The solutions prepared either from brand or generic vancomycin hydrochloride were chemically stable more than one month (43 days for the brand and 57 days for the generic solution) and could be prepared in advance in a centralized intravenous additive service facility. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

Penicillin skin testing in cardiac surgery.

PubMed

Cook, David J; Barbara, David W; Singh, Karen E; Dearani, Joseph A

2014-06-01

Penicillin is the most commonly reported allergy in cardiac surgical patients and a history of penicillin allergy frequently results in the use of vancomycin for antibiotic prophylaxis. However, clinical history is unreliable and true allergy is rare. Penicillin allergy testing has the potential to reduce vancomycin use and indirectly the potential for selection of vancomycin-resistant organisms, a national priority. After the publication of the 2007 Society of Thoracic Surgeons practice guideline report, we initiated a penicillin allergy testing service for cardiac surgical patients in 2009. We sought to determine the true incidence of penicillin allergy in the tested population, whether testing availability reduced vancomycin use in those tested, and if vancomycin use was reduced in the entire cardiac surgical population as a whole. A total of 276 patients were skin tested for allergy to penicillin or cephalosporin. Testing recommended no penicillin use in 13.8% of those tested giving a true penicillin allergy incidence of 0.9%. Only 24 of the 276 patients tested (9%) received vancomycin. However, given the small percentage of the total population that underwent allergy testing, the overall use of vancomycin in the cardiac surgery practice was not reduced in the posttesting period. The true rate of contraindication to penicillin in a cardiac surgical population is very low. Penicillin allergy testing can reduce vancomycin use in the tested population, but better means of conducting the testing and making the results available are necessary to reduce unnecessary vancomycin use in a broader cardiac surgical population. Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Phenotypic changes of methicillin-resistant Staphylococcus aureus during vancomycin therapy for persistent bacteraemia and related clinical outcome.

PubMed

Kim, T; Kim, E S; Park, S Y; Sung, H; Kim, M-N; Kim, S-H; Lee, S-O; Choi, S-H; Jeong, J-Y; Woo, J H; Chong, Y P; Kim, Y S

2017-08-01

Persistent bacteraemia (PB) due to methicillin-resistant Staphylococcus aureus (MRSA) that fails to respond to glycopeptide therapy is a well-documented clinical problem. There are limited data on changes in agr functionality, vancomycin susceptibility and heteroresistance during MRSA PB. Thus, the frequency of these changes and their clinical significance remain unclear. Only patients with MRSA PB (≥7 days) from a prospective cohort of S. aureus bacteraemia were included. We collected isogenic paired strains and compared vancomycin MIC, vancomycin heteroresistance, and agr functionality between initial and final blood isolates. We also assessed the clinical outcome. A total of 49 patients had MRSA PB over 22 months. Bacteraemia persisted for a median of 13 days and most patients (98%) received glycopeptide as initial therapy. Among 49 isogenic pairs, only one pair showed a vancomycin MIC increase ≥2-fold by broth microdilution method, and only seven (14%) by E-test. Significant portions of initial isolates had vancomycin heteroresistance (49%) and agr dysfunction (76%). Development of vancomycin heteroresistance during PB occurred in four (16%) among 25 initial vancomycin-susceptible isolates, and acquisition of agr dysfunction occurred in two (16%) among 12 initial agr-functional isolates. Changes in the opposite direction occasionally occurred. These phenotypic changes during PB were not associated with mortality, whereas agr dysfunction of the initial isolates was significantly associated with mortality. During MRSA PB, phenotypic changes of MRSA isolates occurred occasionally under prolonged vancomycin exposure but were not significantly associated with clinical outcome. In contrast, initial agr dysfunction could be a predictor for mortality in MRSA PB.

[Microbiological and epidemiological characteristics of vancomycin-dependent enterococci].

PubMed

Hwang, Keumrock; Sung, Heungsup; Namgoong, Seung; Yoon, Nam Surp; Kim, Mi-Na

2009-08-01

Vancomycin-dependent enterococci (VDE) are clinically equivalent to vancomycin-resistant enterococci (VRE), but more difficult to detect. This study was purposed to characterize VDE microbiologically and epidemiologically. The patients from whom VDE were detected from April 2007 to March 2008 were investigated. For available isolates, minimal inhibitory concentrations (MICs) of and the levels of dependence on vancomycin and teicoplanin were measured by E test (AB Biodisk, Sweden), and a test for reversion of VDE to non-dependent VRE (NDVRE) and pulsed field gel electrophoresis (PFGE) were performed. Patients' demographic and clinical findings were reviewed via electronic medical records. VDE were recovered from 6 (2.2%) of 272 patients carrying VRE during this study period. All patients were already colonized or infected by VRE and treated with vancomycin for 13 to 107 days. VDE were isolated from pleural fluid (one), urine (four), and stool (one). All isolates carried vanA with vancomycin MICs of >256 microg/mL, but two of them had intermediate susceptibilities to teicoplanin. Because 4 VDE isolates were reverted to NDVRE with single passage, vancomycin dependence was measurable for only two isolates as equal and above 0.064 and 0.5 microg/mL respectively, and was reverted after 5 and 7 passages, respectively. Six VDE isolates showed no related clones in PFGE analysis, and 3 of 4 available pairs of initial VRE isolates and subsequent VDE isolates were identical clones. VDE were not rare and seemed to emerge independently from VRE with a prolonged use of vancomycin. Vancomycin-dependence was reverted within several passages.

Influence of low-level resistance to vancomycin on efficacy of teicoplanin and vancomycin for treatment of experimental endocarditis due to Enterococcus faecium.

PubMed Central

Fantin, B; Leclercq, R; Arthur, M; Duval, J; Carbon, C

1991-01-01

Emergence of vancomycin-resistant strains among enterococci raises a new clinical challenge. Rabbits with aortic endocarditis were infected with Enterococcus faecium BM4172, a clinical strain resistant to low levels of vancomycin (MIC, 16 micrograms/ml) and susceptible to teicoplanin (MIC, 1 micrograms/ml), and against its susceptible variant E. faecium BM4172S obtained in vitro by insertional mutagenesis (MICs, 2 and 0.5 micrograms/ml, respectively). Control animals retained 8 to 10.5 log10 CFU/g of vegetation. We evaluated in this model the efficacy of vancomycin (30 mg/kg of body weight; mean peak and trough serum levels, 27 and 5 micrograms/ml, respectively), teicoplanin (standard dose, 10 mg/kg; mean peak and trough levels, 23 and 9 micrograms/ml, respectively; and high dose, 20 mg/kg; mean peak and trough levels, 63 and 25 micrograms/ml, respectively), gentamicin (6 mg/kg; mean peak and trough levels, 8.6 and less than 0.1 micrograms/ml, respectively), alone or in combination, given every 12 h intramuscularly for 5 days. Teicoplanin standard dose was as active as vancomycin against both strains. Vancomycin was not effective against E. faecium BM4172 but was highly effective against E. faecium BM4172S (7.5 +/- 1.1 log10 CFU/g of vegetation versus 4.9 +/- 1.0 log10 CFU/g of vegetation for vancomycin against E. faecium BM4172 and E. faecium BM4172S, respectively; P = 0.0012). A high dose of teicoplanin was more effective than vancomycin against E. faecium BM4172 (4.4 +/- 1.8 log10 CFU/g of vegetation versus 7.5 +/- 1.1 log10 CFU/g of vegetation for teicoplanin high dose and vancomycin, respectively; P less than 0.05). Against E. faecium BM4172 glycopeptide-gentamicin combinations were the most effective regimens in vitro and in vivo (2.8 +/- 0.7 and 3.5 +/- 1.3 log10 CFU/g of vegetation for vancomycin plus gentamicin and teicoplanin standard dose plus gentamicin, respectively; P < 0.05 versus single-drug regimens). We concluded that high-dose teicoplanin or the combination of a glycopeptide antibiotic plus gentamicin was effective against experimental infection due to E. faecium with low-level resistance to vancomycin. PMID:1834013

Vancomycin-bearing synthetic bone graft delivers rhBMP-2 and promotes healing of critical rat femoral segmental defects.

PubMed

Skelly, Jordan D; Lange, Jeffrey; Filion, Tera M; Li, Xinning; Ayers, David C; Song, Jie

2014-12-01

Bone grafts simultaneously delivering therapeutic proteins and antibiotics may be valuable in orthopaedic trauma care. Previously, we developed a poly(2-hydroxyethyl methacrylate)-nanocrystalline hydroxyapatite (pHEMA-nHA) synthetic bone graft that, when preabsorbed with 400-ng rhBMP-2/7, facilitated the functional repair of critical-size rat femoral defects. Recently, we showed that pHEMA-nHA effectively retains/releases vancomycin and rhBMP-2 in vitro. The success of such a strategy requires that the incorporation of vancomycin does not compromise the structural integrity of the graft nor its ability to promote bone healing. (1) To evaluate the ability of pHEMA-nHA-vancomycin composites in combination with 3-µg rhBMP-2 to repair 5 mm rat femoral segmental defects, and (2) To determine if the encapsulated vancomycin impairs the graft/rhBMP-2-assisted bone repair. pHEMA-nHA-vancomycin, pHEMA-nHA, or collagen sponge control with/without 3-µg rhBMP-2 were press-fit in 5 mm femoral defects in SASCO-SD male rats (289-300 g). Histology, microcomputed tomography, and torsion testing were performed on 8- and 12-week explants to evaluate the extent and quality of repair. The effect of vancomycin on the temporal absorption of endogenous BMP-2 and stromal cell-derived factor-1 was evaluated by immunohistochemistry. These factors are important for bone healing initiation and stem cell recruitment, respectively. Partial bridging of the defect with bony callus by 12 weeks was observed with pHEMA-nHA-vancomycin without rhBMP-2 while full bridging with substantially mineralized callus and partial restoration of torsional strength was achieved with 3-µg rhBMP-2. The presence of vancomycin changed the absorption patterns of endogenous proteins on the grafts, but did not appear to substantially compromise graft healing. The composite pHEMA-nHA-vancomycin preabsorbed with 3-µg rhBMP-2 promoted repair of 5 mm rat femoral segmental defects. With the sample sizes applied, vancomycin encapsulation did not appear to have a negative effect on bone healing. pHEMA-nHA-vancomycin preabsorbed with rhBMP-2 may be useful in the repair of critical-size long bone defects prone to infections.

Genetic and molecular predictors of high vancomycin MIC in Staphylococcus aureus bacteremia isolates.

PubMed

Holmes, Natasha E; Turnidge, John D; Munckhof, Wendy J; Robinson, J Owen; Korman, Tony M; O'Sullivan, Matthew V N; Anderson, Tara L; Roberts, Sally A; Warren, Sanchia J C; Coombs, Geoffrey W; Tan, Hui-Leen; Gao, Wei; Johnson, Paul D R; Howden, Benjamin P

2014-09-01

An elevated vancomycin MIC is associated with poor outcomes in Staphylococcus aureus bacteremia (SAB) and is reported in patients with methicillin-susceptible S. aureus (MSSA) bacteremia in the absence of vancomycin treatment. Here, using DNA microarray and phenotype analysis, we investigated the genetic predictors and accessory gene regulator (agr) function and their relationship with elevated vancomycin MIC using blood culture isolates from a multicenter binational cohort of patients with SAB. Specific clonal complexes were associated with elevated (clonal complex 8 [CC8] [P < 0.001]) or low (CC22 [P < 0.001], CC88 [P < 0.001], and CC188 [P = 0.002]) vancomycin MIC. agr dysfunction (P = 0.014) or agr genotype II (P = 0.043) were also associated with an elevated vancomycin MIC. Specific resistance and virulence genes were also linked to an elevated vancomycin MIC, including blaZ (P = 0.002), sea (P < 0.001), clfA (P < 0.001), splA (P = 0.001), and the arginine catabolic mobile element (ACME) locus (P = 0.02). These data suggest that inherent organism characteristics may explain the link between elevated vancomycin MICs and poor outcomes in patients with SAB, regardless of the antibiotic treatment received. A consideration of clonal specificity should be included in future research when attempting to ascertain treatment effects or clinical outcomes. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Intrawound Vancomycin Decreases the Risk of Surgical Site Infection After Posterior Spine Surgery: A Multicenter Analysis.

PubMed

Devin, Clinton J; Chotai, Silky; McGirt, Matthew J; Vaccaro, Alexander R; Youssef, Jim A; Orndorff, Douglas G; Arnold, Paul M; Frempong-Boadu, Anthony K; Lieberman, Isador H; Branch, Charles; Hedayat, Hirad S; Liu, Ann; Wang, Jeffrey C; Isaacs, Robert E; Radcliff, Kris E; Patt, Joshua C; Archer, Kristin R

2018-01-01

Secondary analysis of data from a prospective multicenter observational study. The aim of this study was to evaluate the occurrence of surgical site infection (SSI) in patients with and without intrawound vancomycin application controlling for confounding factors associated with higher SSI after elective spine surgery. SSI is a morbid and expensive complication associated with spine surgery. The application of intrawound vancomycin is rapidly emerging as a solution to reduce SSI following spine surgery. The impact of intrawound vancomycin has not been systematically studied in a well-designed multicenter study. Patients undergoing elective spine surgery over a period of 4 years at seven spine surgery centers across the United States were included in the study. Patients were dichotomized on the basis of whether intrawound vancomycin was applied. Outcomes were occurrence of SSI within postoperative 30 days and SSI that required return to the operating room (OR). Multivariable random-effect log-binomial regression analyses were conducted to determine the relative risk of having an SSI and an SSI with return to OR. .: A total of 2056 patients were included in the analysis. Intrawound vancomycin was utilized in 47% (n = 966) of patients. The prevalence of SSI was higher in patients with no vancomycin use (5.1%) than those with use of intrawound vancomycin (2.2%). The risk of SSI was higher in patients in whom intrawound vancomycin was not used (relative risk (RR) -2.5, P < 0.001), increased number of levels exposed (RR -1.1, P = 0.01), and those admitted postoperatively to intensive care unit (ICU) (RR -2.1, P = 0.005). Patients in whom intrawound vancomycin was not used (RR -5.9, P < 0.001), increased number of levels were exposed (RR-1.1, P = 0.001), and postoperative ICU admission (RR -3.3, P < 0.001) were significant risk factors for SSI requiring a return to the OR. The intrawound application of vancomycin after posterior approach spine surgery was associated with a reduced risk of SSI and return to OR associated with SSI. 2.

Influence of vancomycin minimum inhibitory concentration on the outcome of methicillin-susceptible Staphylococcus aureus left-sided infective endocarditis treated with antistaphylococcal β-lactam antibiotics: a prospective cohort study by the International Collaboration on Endocarditis⋆

PubMed Central

Pericàs, J.M.; Messina, J.A.; Garcia-de-la-Mària, C.; Park, L.; Sharma-Kuinkel, B.K.; Marco, F.; Wray, D.; Kanafani, Z.A.; Carugati, M.; Durante-Mangoni, E.; Tattevin, P.; Chu, V.H.; Moreno, A.; Fowler, V.G.; Miró, J.M.

2018-01-01

Objectives Left-sided methicillin-susceptible Staphylococcus aureus (MSSA) endocarditis treated with cloxacillin has a poorer prognosis when the vancomycin minimum inhibitory concentration (MIC) is ≥1.5 mg/L. We aimed to validate this using the International Collaboration on Endocarditis cohort and to analyse whether specific genetic characteristics were associated with a high vancomycin MIC (≥1.5 mg/L) phenotype. Methods All patients with left-sided MSSA infective endocarditis treated with antistaphylococcal β-lactam antibiotics between 2000 and 2006 with available isolates were included. Vancomycin MIC was determined by Etest as either high (≥1.5 mg/L) or low (<1.5 mg/L). Isolates underwent spa typing to infer clonal complexes and multiplex PCR for identifying virulence genes. Univariate analysis was performed to evaluate the association between in-hospital and 1-year mortality, and vancomycin MIC phenotype. Results Sixty-two cases met the inclusion criteria. Vancomycin MIC was low in 28 cases (45%) and high in 34 cases (55%). No significant differences in patient demographic data or characteristics of infection were observed between patients with infective endocarditis due to high and low vancomycin MIC isolates. Isolates with high and low vancomycin MIC had similar distributions of virulence genes and clonal lineages. In-hospital and 1-year mortality did not differ significantly between the two groups (32% (9/28) vs. 27% (9/34), p 0.780; and 43% (12/28) vs. 29% (10/34), p 0.298, for low and high vancomycin MIC respectively). Conclusions In this international cohort of patients with left-sided MSSA endocarditis treated with antistaphylococcal β-lactams, vancomycin MIC phenotype was not associated with patient demographics, clinical outcome or virulence gene repertoire. PMID:28159672

Application of DNA probes for rRNA and vanA genes to investigation of a nosocomial cluster of vancomycin-resistant enterococci.

PubMed Central

Woodford, N; Morrison, D; Johnson, A P; Briant, V; George, R C; Cookson, B

1993-01-01

DNA probes specific for genes encoding rRNA and the glycopeptide resistance gene vanA were used to investigate a cluster of vancomycin-resistant (MICs, > 512 mg/liter) Enterococcus faecalis and Enterococcus faecium isolated from separate patients in a renal unit in a London hospital. When digested with BamHI, 12 of 13 vancomycin-resistant E. faecalis isolates exhibited a common restriction fragment length polymorphism pattern of rRNA genes (ribotype). A vanA probe hybridized with chromosomal DNA in these 12 isolates. The other isolate of vancomycin-resistant E. faecalis had a different ribotype and the vanA gene was located on plasmid DNA. These data suggest that cross-infection with a single strain of vancomycin-resistant E. faecalis occurred in most instances. In contrast, 23 vancomycin-resistant E. faecium isolates showed greater heterogeneity, comprising 8 ribotypes, suggesting that multiple strains were present in the unit. Twenty-one of these 23 isolates harbored a 24-MDa plasmid which hybridized with the vanA probe, implying that interstrain dissemination of a vancomycin resistance plasmid may have occurred among E. faecium isolates in the renal unit. Images PMID:8096216

Leuconostoc garlicum: an unusual pathogen in the era of vancomycin therapy.

PubMed

Kumar, Anil; Augustine, Deepthi; Mehta, Asmita; Dinesh, Kavitha R; Viswam, Darsana; Philip, Rosamma

2012-01-01

Leuconostoc garlicum, belonging to the family of Leuconostocaceae, is a catalase-negative, Gram-positive ovoid cocci, intrinsically resistant to vancomycin. Clinical infection by Leuconostoc garlicum is rare. We report a case of respiratory tract infection subsequent to vancomycin therapy.

Outcomes associated with initial versus later vancomycin use in patients with complicated skin and skin-structure infections.

PubMed

Itani, Kamal M F; Akhras, Kasem S; Stellhorn, Robert; Quintana, Alvaro; Budd, David; Merchant, Sanjay

2009-01-01

Delayed coverage of pathogens including meticillin-resistant Staphylococcus aureus (MRSA) in pneumonia and bacteraemia has been associated with increased mortality and length of hospital stay (LOS). However, less is known about the impact of delayed appropriate coverage in complicated skin and skin-structure infections (cSSSIs). To evaluate the clinical and economic outcomes associated with early versus late use of vancomycin in the management of patients hospitalized for cSSSIs. Retrospective analysis was performed using an inpatient claims database of >500 US hospitals in 2005. Using prescription claims, patients with primary or secondary cSSSI admissions were classified into three groups: 1 = early vancomycin monotherapy; 2 = early vancomycin combination therapy; 3 = late vancomycin therapy. Outcomes studied included LOS and inpatient hospital costs. One-way analysis of variance was used for unadjusted analysis and multivariate regression methods were used to control for co-variates. A total of 34,942 patients (27.78% of all patients with cSSSIs) were treated with vancomycin. Mean age was 54.7 years and 54.3% of the patients were males. Mean unadjusted total LOS was 8.46, 9.44 and 13.2 days, and hospital costs in 2005 values were USD10 211.94, USD12 361.94 and USD18 344.00 for groups 1, 2 and 3, respectively. In-hospital mortality rate was highest in group 3 (4.18%) and lowest in group 1 (1.75%). Generalized linear models used to control for potential confounding variables between early versus late vancomycin use suggest that among cSSSI patients late vancomycin use is an independent predictor of higher LOS and costs. In this large inpatient database, later vancomycin use in patients with cSSSIs appears to be significantly associated with higher LOS and total costs.

External evaluation of population pharmacokinetic models of vancomycin in neonates: the transferability of published models to different clinical settings

PubMed Central

Zhao, Wei; Kaguelidou, Florentia; Biran, Valérie; Zhang, Daolun; Allegaert, Karel; Capparelli, Edmund V; Holford, Nick; Kimura, Toshimi; Lo, Yoke-Lin; Peris, José-Esteban; Thomson, Alison; Anker, John N; Fakhoury, May; Jacqz-Aigrain, Evelyne

2013-01-01

Aims Vancomycin is one of the most evaluated antibiotics in neonates using modeling and simulation approaches. However no clear consensus on optimal dosing has been achieved. The objective of the present study was to perform an external evaluation of published models, in order to test their predictive performances in an independent dataset and to identify the possible study-related factors influencing the transferability of pharmacokinetic models to different clinical settings. Method Published neonatal vancomycin pharmacokinetic models were screened from the literature. The predictive performance of six models was evaluated using an independent dataset (112 concentrations from 78 neonates). The evaluation procedures used simulation-based diagnostics [visual predictive check (VPC) and normalized prediction distribution errors (NPDE)]. Results Differences in predictive performances of models for vancomycin pharmacokinetics in neonates were found. The mean of NPDE for six evaluated models were 1.35, −0.22, −0.36, 0.24, 0.66 and 0.48, respectively. These differences were explained, at least partly, by taking into account the method used to measure serum creatinine concentrations. The adult conversion factor of 1.3 (enzymatic to Jaffé) was tested with an improvement in the VPC and NPDE, but it still needs to be evaluated and validated in neonates. Differences were also identified between analytical methods for vancomycin. Conclusion The importance of analytical techniques for serum creatinine concentrations and vancomycin as predictors of vancomycin concentrations in neonates have been confirmed. Dosage individualization of vancomycin in neonates should consider not only patients' characteristics and clinical conditions, but also the methods used to measure serum creatinine and vancomycin. PMID:23148919

An investigation of vancomycin minimum inhibitory concentration creep among methicillin-resistant Staphylococcus aureus strains isolated from pediatric patients and healthy children in Northern Taiwan.

PubMed

Chang, Chia-Ning; Lo, Wen-Tsung; Chan, Ming-Chin; Yu, Ching-Mei; Wang, Chih-Chien

2017-06-01

The phenomenon of vancomycin minimum inhibitory concentration (MIC) creep is an increasingly serious problem in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. In this study, we investigated the vancomycin and daptomycin MIC values of MRSA strains isolated from pediatric patients and MRSA colonized healthy children. Then, we assessed whether there was evidence of clonal dissemination for strains with an MIC to vancomycin of ≥ 1.5 μg/mL. We collected clinical MRSA isolates from pediatric patients and from healthy children colonized with MRSA during 2008-2012 at a tertiary medical center in northern Taiwan and obtained vancomycin and daptomycin MIC values using the Etest method. Pulse-field gel electrophoresis (PFGE) and staphylococcal cassette chromosome (SCCmec) typing were used to assess clonal dissemination for strains with an MIC to vancomycin of ≥ 1.5 μg/mL. A total 195 MRSA strains were included in this study; 87 were isolated patients with a clinical MRSA infection, and the other 108 strains from nasally colonized healthy children. Vancomycin MIC≥1.5 μg/mL was seen in more clinical isolates (60/87, 69%) than colonized isolates (32/108, 29.6%), p < 0.001. The PFGE typing of both strains revealed multiple pulsotypes. Vancomycin MIC creeps existed in both clinical MRSA isolates and colonized MRSA strains. Great diversity of PFGE typing was in both strains collected. There was no association between the clinical and colonized MRSA isolates with vancomycin MIC creep. Copyright © 2016. Published by Elsevier B.V.

Inhibition of Staphylococcus epidermidis biofilms using polymerizable vancomycin derivatives.

PubMed

Lawson, McKinley C; Hoth, Kevin C; Deforest, Cole A; Bowman, Christopher N; Anseth, Kristi S

2010-08-01

Biofilm formation on indwelling medical devices is a ubiquitous problem causing considerable patient morbidity and mortality. In orthopaedic surgery, this problem is exacerbated by the large number and variety of material types that are implanted. Metallic hardware in conjunction with polymethylmethacrylate (PMMA) bone cement is commonly used. We asked whether polymerizable derivatives of vancomycin might be useful to (1) surface modify Ti-6Al-4V alloy and to surface/bulk modify PMMA bone cement to prevent Staphylococcus epidermidis biofilm formation and (2) whether the process altered the compressive modulus, yield strength, resilience, and/or fracture strength of cement copolymers. A Ti-6Al-4V alloy was silanized with methacryloxypropyltrimethoxysilane in preparation for subsequent polymer attachment. Surfaces were then coated with polymers formed from PEG(375)-acrylate or a vancomycin-PEG(3400)-PEG(375)-acrylate copolymer. PMMA was loaded with various species, including vancomycin and several polymerizable vancomycin derivatives. To assess antibiofilm properties of these materials, initial bacterial adherence to coated Ti-6Al-4V was determined by scanning electron microscopy (SEM). Biofilm dry mass was determined on PMMA coupons; the compressive mechanical properties were also determined. SEM showed the vancomycin-PEG(3400)-acrylate-type surface reduced adherent bacteria numbers by approximately fourfold when compared with PEG(375)-acrylate alone. Vancomycin-loading reduced all mechanical properties tested; in contrast, loading a vancomycin-acrylamide derivative restored these deficits but demonstrated no antibiofilm properties. A polymerizable, PEGylated vancomycin derivative reduced biofilm attachment but resulted in inferior cement mechanical properties. The approaches presented here may offer new strategies for developing biofilm-resistant orthopaedic materials. Specifically, polymerizable derivatives of traditional antibiotics may allow for direct polymerization into existing materials such as PMMA bone cement while minimizing mechanical property compromise. Questions remain regarding ideal monomer structure(s) that confer biologic and mechanical benefits.

Effect of Surotomycin, a Novel Cyclic Lipopeptide Antibiotic, on Intestinal Colonization with Vancomycin-Resistant Enterococci and Klebsiella pneumoniae in Mice

PubMed Central

Deshpande, Abhishek; Hurless, Kelly; Cadnum, Jennifer L.; Chesnel, Laurent; Gao, Lihong; Chan, Luisa; Kundrapu, Sirisha; Polinkovsky, Alexander

2016-01-01

Surotomycin (formerly called CB-183,315) is a novel, orally administered cyclic lipopeptide antibacterial in development for the treatment of Clostridium difficile infection (CDI) that has potent activity against vancomycin-resistant enterococci (VRE) but limited activity against Gram-negative bacilli, including Bacteroides spp. We used a mouse model to investigate the impact of surotomycin exposure on the microbiome, and to test the consequences of the disruption on colonization by vancomycin-resistant enterococci (VRE) and extended-spectrum β-lactamase-producing Klebsiella pneumoniae (ESBL-KP), in comparison with the effects of oral vancomycin and metronidazole. Mice (8 per group) received saline, vancomycin, metronidazole, or surotomycin through an orogastric tube daily for 5 days and were challenged with 105 CFU of VRE or ESBL-KP administered through an orogastric tube on day 2 of treatment. The concentrations of the pathogens in stool were determined during and after treatment by plating on selective media. A second experiment was conducted to determine if the antibiotics would inhibit established VRE colonization. In comparison to controls, oral vancomycin promoted VRE and ESBL-KP overgrowth in stool (8 log10 to 10 log10 CFU/g; P < 0.001), whereas metronidazole did not (<4 log10 CFU/g; P > 0.5). Surotomycin promoted ESBL-KP overgrowth (>8 log10 CFU/g; P, <0.001 for comparison with saline controls) but not VRE overgrowth. Surotomycin suppressed preexisting VRE colonization, whereas metronidazole and vancomycin did not. These results suggest that treatment of CDI with surotomycin could reduce levels of VRE acquisition and overgrowth from those with agents such as vancomycin and metronidazole. However, surotomycin and vancomycin may promote colonization by antibiotic-resistant Gram-negative bacilli. PMID:26976870

OCCURRENCE OF VANCOMYCIN RESISTANT ENTEROCOCCI IN ANIMAL FECES

EPA Science Inventory

A survey was conducted to determine the occurrence of vancomycin resistant Enterococci (VRE) in animal and human fecal samples. A selective agar mEI, and mEI supplemented with 4 micrograms/ml vancomycin was used in a membrane filtration procedure to determine quantitative levels ...

Controlled release of vancomycin from thin sol-gel films on implant surfaces successfully controls osteomyelitis.

PubMed

Adams, Christopher S; Antoci, Valentin; Harrison, Gerald; Patal, Payal; Freeman, Terry A; Shapiro, Irving M; Parvizi, Javad; Hickok, Noreen J; Radin, Shula; Ducheyne, Paul

2009-06-01

Peri-prosthetic infection remains a serious complication of joint replacement surgery. Herein, we demonstrate that a vancomycin-containing sol-gel film on Ti alloy rods can successfully treat bacterial infections in an animal model. The vancomycin-containing sol-gel films exhibited predictable release kinetics, while significantly inhibiting S. aureus adhesion. When evaluated in a rat osteomyelitis model, microbiological analysis indicated that the vancomycin-containing sol-gel film caused a profound decrease in S. aureus number. Radiologically, while the control side showed extensive bone degradation, including abscesses and an extensive periosteal reaction, rods coated with the vancomycin-containing sol-gel film resulted in minimal signs of infection. MicroCT analysis confirmed the radiological results, while demonstrating that the vancomycin-containing sol-gel film significantly protected dense bone from resorption and minimized remodeling. These results clearly demonstrate that this novel thin sol-gel technology can be used for the targeted delivery of antibiotics for the treatment of periprosthetic as well as other bone infections. Copyright 2008 Orthopaedic Research Society

Is It Time to Replace Vancomycin in the Treatment of Methicillin-Resistant Staphylococcus aureus Infections?

PubMed Central

van Hal, Sebastiaan J.; Fowler, Vance G.

2013-01-01

For more than 4 decades, vancomycin has been the antibiotic of choice for methicillin-resistant Staphylococcus aureus (MRSA) infections. Recently, infections due to isolates with high but susceptible vancomycin minimum inhibitory concentrations have been associated with additional treatment failures and patient mortality. These poorer outcomes may in part be explained by the inability of attaining appropriate vancomycin levels in these patients. However, assumptions that these poor outcomes are solely due to failure to achieve optimal serum levels of vancomycin are premature. The availability of effective alternatives further erodes the position of vancomycin as first-line therapy. The emergence of resistance and cost considerations, however, favor a more measured approach when using alternative antimicrobials. Collectively, the current available data suggest that the optimal therapy for MRSA infections remains unclear. In the absence of further data, the Infectious Diseases Society of America guidelines remain relevant and inform clinicians of best practice for treating patients with MRSA infections. PMID:23511300

Two Synthetic Methods for Preparation of Chiral Stationary Phases Using Crystalline Degradation Products of Vancomycin: Column Performance for Enantioseparation of Acidic and Basic Drugs.

PubMed

Abdollahpour, Assem; Heydari, Rouhollah; Shamsipur, Mojtaba

2017-07-01

Two chiral stationary phases (CSPs) based on crystalline degradation products (CDPs) of vancomycin by using different synthetic methods were prepared and compared. Crystalline degradation products of vancomycin were produced by hydrolytic loss of ammonia from vancomycin molecules. Performances of two chiral columns prepared with these degradation products were investigated using several acidic and basic drugs as model analytes. Retention and resolution of these analytes on the prepared columns, as two main parameters, in enantioseparation were studied. The results demonstrated that the stationary phase preparation procedure has a significant effect on the column performance. The resolving powers of prepared columns for enantiomers resolution were changed with the variation in vancomycin-CDP coverage on the silica support. Elemental analysis was used to monitor the surface coverage of silica support by vancomycin-CDP. The results showed that both columns can be successfully applied to chiral separation studies.

The bactericidal effects of anti-MRSA agents with rifampicin and sulfamethoxazole-trimethoprim against intracellular phagocytized MRSA.

PubMed

Yamaoka, Toshimori

2007-06-01

We experienced therapeutic failure with vancomycin in patients with serious methicillin-resistant Staphylococcus aureus (MRSA) infections, in some of whom the bacteria were found to be alive in the leukocytes. We therefore evaluated the antimicrobial activity of several anti-MRSA agents (vancomycin, linezolid, quinupristin/dalfopristin, arbekacin) and co-administered agents (rifampicin, sulfamethoxazole-trimethoprim) against clinically isolated MRSA in phagocytized human polymorphonuclear leukocytes. After allowing the leukocytes to phagocytize the bacteria, the mixture was separated into leukocytes and supernatant, to which MRSA agents were added, and incubated for 24 h. After incubation, the leukocytes were crushed and the intracellular MRSA was cultured quantitatively. Vancomycin resulted in a less than 1% survival ratio of extracellular MRSA, but it was one of the highest ratios of intracellular MRSA with 33.8% compared with other agents. The survival ratios of intracellular MRSA with vancomycin plus rifampicin and with vancomycin plus rifampicin plus sulfamethoxazole-trimethoprim were 0.78% and 1.02%, respectively, which is significantly lower than that of vancomycin. For linezolid, quinupristin/dalfopristin, and arbekacin, there were no significant differences in the survival ratios between monotherapy and combination therapy against either extracellular or intracellular MRSA. The results suggest that the concomitant use of rifampicin or rifampicin plus sulfamethoxazole/trimethoprim with vancomycin is effective for MRSA phagocytized in leukocytes when vancomycin monotherapy is not sufficiently effective. Combination therapy showed no difference in efficacy in the case of linezolid, quinupristin/dalfopristin, and arbekacin.

Influence of Vancomycin Infusion Methods on Endothelial Cell Toxicity

PubMed Central

Drouet, Maryline; Chai, Feng; Barthélémy, Christine; Lebuffe, Gilles; Debaene, Bertrand; Odou, Pascal

2014-01-01

Peripheral intravenous therapy is frequently used in routine hospital practice and, due to various factors, its most common side effect is phlebitis. The infusion of vancomycin is particularly associated with phlebitis despite its widespread use. French guidelines recommend central intravenous infusion for high concentrations of vancomycin, but peripheral intravenous therapy is often preferred in intensive care units. Methods of vancomycin infusion are either intermittent infusion or continuous infusion. A comparison of these methods under in vitro conditions simulating clinical use could result in better infusion efficacy. Human umbilical vein endothelial cells (HUVECs) were therefore challenged with clinical doses of vancomycin over a 24- to 72-h period using these infusion methods. Cell death was measured with the alamarBlue test. Concentration-dependent and time-dependent vancomycin toxicity on HUVECs was noted with a 50% lethal dose at 5 mg/ml after 24 h, reaching 2.5 mg/ml after 72 h of infusion, simulating long-term infusion. This toxicity does not seem to be induced by acidic pH. In comparing infusion methods, we observed that continuous infusion induced greater cell toxicity than intermittent infusion at doses higher than 1 g/day. The increasing use of vancomycin means that new guidelines are required to avoid phlebitis. If peripheral intravenous therapy is used to reduce infusion time, along with intermittent infusion, vein irritation and localized phlebitis may be reduced. Further studies have to be carried out to explore the causes of vancomycin endothelial toxicity. PMID:25421476

Vancomycin Dosing in Obese Patients: Special Considerations and Novel Dosing Strategies.

PubMed

Durand, Cheryl; Bylo, Mary; Howard, Brian; Belliveau, Paul

2018-06-01

To review the literature regarding vancomycin pharmacokinetics in obese patients and strategies used to improve dosing in this population. PubMed, EMBASE (1974 to November 2017), and Google Scholar searches were conducted using the search terms vancomycin, obese, obesity, pharmacokinetics, strategy, and dosing. Additional articles were selected from reference lists of selected studies. Included articles were those published in English with a primary focus on vancomycin pharmacokinetic parameters in obese patients and practical vancomycin dosing strategies, clinical experiences, or challenges of dosing vancomycin in this population. Volume of distribution and clearance are the pharmacokinetic parameters that most often affect vancomycin dosing in obese patients; both are increased in this population. Challenges with dosing in obese patients include inconsistent and inadequate dosing, observations that the obese population may not be homogeneous, and reports of an increased likelihood of supratherapeutic trough concentrations. Investigators have revised and developed dosing and monitoring protocols to address these challenges. These approaches improved target trough attainment to varying degrees. Some of the vancomycin dosing approaches provided promising results in obese patients, but there were notable differences in methods used to develop these approaches, and sample sizes were small. Although some approaches can be considered for validation in individual institutions, further research is warranted. This may include validating approaches in larger populations with narrower obesity severity ranges, investigating target attainment in indication-specific target ranges, and evaluating the impact of different dosing weights and methods of creatinine clearance calculation.

Vancomycin Resistance in Staphylococcus aureus


PubMed Central

McGuinness, Will A.; Malachowa, Natalia; DeLeo, Frank R.

2017-01-01

The evolution of Staphylococcus aureus during the modern antibiotic era has been delineated by distinct strain emergence events, many of which include acquisition of antibiotic resistance. The relative high burden of methicillin-resistant S. aureus (MRSA) in healthcare and community settings is a major concern worldwide. Vancomycin, a glycopeptide antibiotic that inhibits cell wall biosynthesis, remains a drug of choice for treatment of severe MRSA infections. S. aureus strains exhibiting increased resistance to vancomycin, known as vancomycin intermediate-resistant S. aureus (VISA) (MIC = 4-8 µg/mL), were discovered in the 1990s. The molecular basis of resistance in VISA is polygenic and involves stepwise mutations in genes encoding molecules predominantly involved in cell envelope biosynthesis. S. aureus isolates with complete resistance to vancomycin (MIC ≥ 16 µg/mL) are termed vancomycin-resistant S. aureus (VRSA)—they were first reported in the U.S. in 2002. Resistance in VRSA is conferred by the vanA gene and operon, which is present on a plasmid. Although treatment of VRSA infections is challenging, the total number of human VRSA infections to date is limited (14 in the U.S.). By comparison, the burden of VISA is relatively high and the molecular mechanisms of resistance are less well-defined. VISA are associated with persistent infections, vancomycin treatment failure, and poor clinical outcomes. Here, we review in brief progress made toward understanding the acquisition of antibiotic resistance in S. aureus, with an emphasis on the molecular mechanisms underlying vancomycin resistance. PMID:28656013

Vancomycin Resistance in Staphylococcus aureus
.

PubMed

McGuinness, Will A; Malachowa, Natalia; DeLeo, Frank R

2017-06-01

The evolution of Staphylococcus aureus during the modern antibiotic era has been delineated by distinct strain emergence events, many of which include acquisition of antibiotic resistance. The relative high burden of methicillin-resistant S. aureus (MRSA) in healthcare and community settings is a major concern worldwide. Vancomycin, a glycopeptide antibiotic that inhibits cell wall biosynthesis, remains a drug of choice for treatment of severe MRSA infections. S. aureus strains exhibiting increased resistance to vancomycin, known as vancomycin intermediate-resistant S. aureus (VISA) (MIC = 4-8 µg/mL), were discovered in the 1990s. The molecular basis of resistance in VISA is polygenic and involves stepwise mutations in genes encoding molecules predominantly involved in cell envelope biosynthesis. S. aureus isolates with complete resistance to vancomycin (MIC ≥ 16 µg/mL) are termed vancomycin-resistant S. aureus (VRSA)-they were first reported in the U.S. in 2002. Resistance in VRSA is conferred by the vanA gene and operon, which is present on a plasmid. Although treatment of VRSA infections is challenging, the total number of human VRSA infections to date is limited (14 in the U.S.). By comparison, the burden of VISA is relatively high and the molecular mechanisms of resistance are less well-defined. VISA are associated with persistent infections, vancomycin treatment failure, and poor clinical outcomes. Here, we review in brief progress made toward understanding the acquisition of antibiotic resistance in S. aureus , with an emphasis on the molecular mechanisms underlying vancomycin resistance.

Health economic evaluation of patients treated for nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus: secondary analysis of a multicenter randomized clinical trial of vancomycin and linezolid.

PubMed

Niederman, Michael S; Chastre, Jean; Solem, Caitlyn T; Wan, Yin; Gao, Xin; Myers, Daniela E; Haider, Seema; Li, Jim Z; Stephens, Jennifer M

2014-09-01

Results from studies comparing health care resource use (HCRU), costs of treatment, and cost-effectiveness of linezolid compared with vancomycin therapy in the treatment of hospitalized patients with methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia are limited in the published literature. We therefore conducted an analysis to compare the HCRU, costs of treatment, and cost-effectiveness of linezolid compared with vancomycin in the treatment of hospitalized patients with MRSA nosocomial pneumonia using data from a Phase IV clinical trial. The economic effect of moderate to severe adverse events (MSAEs) and the development of renal failure were also evaluated. We performed a post hoc analysis of data from a Phase IV, double-blind, randomized, comparator-controlled, multicenter trial that compared linezolid and vancomycin treatment in patients with MRSA nosocomial pneumonia. HCRU and costs were compared based on treatment, development of MSAEs, and development of renal failure using data from the modified intent-to-treat population. Predictors of costs were evaluated using generalized linear models. A piggyback cost-effectiveness analysis was conducted to assess the incremental cost-effectiveness ratio of linezolid versus vancomycin, given the significantly higher clinical success of linezolid compared with vancomycin found in the trial. Overall, HCRU and costs were similar between the linezolid and vancomycin treatment groups; drug costs were significantly higher and dialysis costs significantly lower for linezolid- compared with vancomycin-treated patients. Total treatment costs were approximately $8000 higher (P = .046) for patients who developed renal failure compared with those who did not. Renal failure occurred more commonly in patients randomized to receive vancomycin (15%) compared with linezolid (4%; P < .001). Region, ventilator-associated pneumonia, clinical failure, and development of renal failure were associated with significantly higher total costs. The point estimate incremental cost-effectiveness ratio for linezolid compared with vancomycin was $16,516 per treatment success, with linezolid dominant in 24% and dominated in <2% of bootstrapped samples. This phase 4 clinical trial conducted in patients with MRSA-confirmed nosocomial pneumonia reveals that linezolid- compared with vancomycin-treated patients had similar HCRU and total overall costs. Fewer patients developed renal failure during the study while taking linezolid compared with vancomycin, and patients with a documented MSAE or renal failure had increased HCRU and costs. In summary, linezolid may be a cost-effective treatment strategy in MRSA-confirmed nosocomial pneumonia. Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.

Synergy of arbekacin-based combinations against vancomycin hetero-intermediate Staphylococcus aureus.

PubMed

Lee, Ji Young; Oh, Won Sup; Ko, Kwan Soo; Heo, Sang Taek; Moon, Chi Sook; Ki, Hyun Kyun; Kiem, Sungmin; Peck, Kyong Ran; Song, Jae Hoon

2006-04-01

This study was undertaken to evaluate the in vitro activities of arbekacin-based combination regimens against vancomycin hetero-intermediate Staphylococcus aureus (hetero-VISA). Combinations of arbekacin with vancomycin, rifampin, ampicillin-sulbactam, teicoplanin, or quinupristin-dalfopristin against seven hetero-VISA strains and two methicillin-resistant S. aureus strains were evaluated by the time-kill assay. The combinations of arbekacin with vancomycin, teicoplanin, or ampicillin-sulbactam showed the synergistic interaction against hetero-VISA strains. Data suggest that these arbekacin-based combination regimens may be useful candidates for treatment options of hetero-VISA infections.

Vancomycin: ligand recognition, dimerization and super-complex formation.

PubMed

Jia, ZhiGuang; O'Mara, Megan L; Zuegg, Johannes; Cooper, Matthew A; Mark, Alan E

2013-03-01

The antibiotic vancomycin targets lipid II, blocking cell wall synthesis in Gram-positive bacteria. Despite extensive study, questions remain regarding how it recognizes its primary ligand and what is the most biologically relevant form of vancomycin. In this study, molecular dynamics simulation techniques have been used to examine the process of ligand binding and dimerization of vancomycin. Starting from one or more vancomycin monomers in solution, together with different peptide ligands derived from lipid II, the simulations predict the structures of the ligated monomeric and dimeric complexes to within 0.1 nm rmsd of the structures determined experimentally. The simulations reproduce the conformation transitions observed by NMR and suggest that proposed differences between the crystal structure and the solution structure are an artifact of the way the NMR data has been interpreted in terms of a structural model. The spontaneous formation of both back-to-back and face-to-face dimers was observed in the simulations. This has allowed a detailed analysis of the origin of the cooperatively between ligand binding and dimerization and suggests that the formation of face-to-face dimers could be functionally significant. The work also highlights the possible role of structural water in stabilizing the vancomycin ligand complex and its role in the manifestation of vancomycin resistance. © 2013 The Authors Journal compilation © 2013 FEBS.

Effects of Vancomycin Versus Nafcillin in Enhancing Killing of Methicillin-Susceptible Staphylococcus aureus Causing Bacteremia by Human Cathelicidin LL37

PubMed Central

Le, Jennifer; Dam, Quang; Schweizer, Marin; Thienphrapa, Wdee; Nizet, Victor; Sakoulas, George

2016-01-01

Recent studies have demonstrated that anti-staphylococcal beta-lactam antibiotics, like nafcillin, render methicillin-resistant Staphylococcus aureus (MRSA) more susceptible to killing by innate host defense peptides (HDPs), such as cathelicidin LL-37. We compared the effects of growth in 1/4 minimum inhibitory concentration (MIC) of nafcillin or vancomycin on LL-37 killing of 92 methicillin-susceptible S. aureus (MSSA) isolates. For three randomly selected strains among these, we examined the effects of nafcillin, vancomycin, daptomycin, or linezolid on LL-37 killing and autolysis. Growth in the presence of sub-inhibitory nafcillin significantly enhanced LL-37 killing of MSSA compared to vancomycin and antibiotic-free controls. Nafcillin also reduced MSSA production of the golden staphylococcal pigment staphyloxanthin in 39% of pigmented strains vs. 14% for vancomycin. Among antibiotics tested, only nafcillin resulted in significantly increased MSSA autolysis. These studies point to additional mechanisms of anti-staphylococcal activity of nafcillin beyond direct bactericidal activity, properties that vancomycin and other antibiotic classes do not exhibit. The ability of nafcillin to enhance sensitivity to innate host defense peptides may contribute to its superior effectiveness against MSSA as suggested by studies comparing clinical outcomes to vancomycin treatment. PMID:27234592

Pharmacodynamic studies of vancomycin, metronidazole and fusidic acid against Clostridium difficile.

PubMed

Odenholt, Inga; Walder, Mats; Wullt, Marlene

2007-01-01

Pharmacodynamic studies of antibiotics have attracted great interest in recent years. However, studies on the pharmacodynamics of different antibiotics against Clostridium difficile are scarce. The postantibiotic effects (PAE) and the postantibiotic sub-minimum inhibitory concentration (MIC) effects (PA SME) of vancomycin, metronidazole and fusidic acid were investigated by viable counts against three different strains of C. difficile. The killing rate and extent of the three antibiotics against the same strains were also studied by adding 2, 4, 8, 16 and 32x MIC of the three antibiotics, respectively. Metronidazole exerted a very rapid bactericidal effect at concentrations of 8x MIC and above against all three strains investigated. Vancomycin gave overall less kill in comparison to metronidazole and was bacteriostatic against two of the three strains. Fusidic acid exerted a concentration-dependent killing against two of the strains. Vancomycin exerted short PAEs and PA SMEs against all three strains. Significantly longer PAEs and PA SMEs were noted for fusidic acid. Metronidazole gave similar short PAEs like vancomycin but longer PA SMEs were noted against two of the investigated strains. Metronidazole exerted the most prominent bactericidal effect greater than fusidic acid and greater than vancomycin. Fusidic acid gave overall the longest PAEs and PA SMEs greater than metronidazole and greater than vancomycin. Copyright 2007 S. Karger AG, Basel.

Antibiotic prophylaxis and risk of Clostridium difficile infection after coronary artery bypass graft surgery.

PubMed

Poeran, Jashvant; Mazumdar, Madhu; Rasul, Rehana; Meyer, Joanne; Sacks, Henry S; Koll, Brian S; Wallach, Frances R; Moskowitz, Alan; Gelijns, Annetine C

2016-02-01

Antibiotic use, particularly type and duration, is a crucial modifiable risk factor for Clostridium difficile. Cardiac surgery is of particular interest because prophylactic antibiotics are recommended for 48 hours or less (vs ≤24 hours for noncardiac surgery), with increasing vancomycin use. We aimed to study associations between antibiotic prophylaxis (duration/vancomycin use) and C difficile among patients undergoing coronary artery bypass grafting. We extracted data on coronary artery bypass grafting procedures from the national Premier Perspective claims database (2006-2013, n = 154,200, 233 hospitals). Multilevel multivariable logistic regressions measured associations between (1) duration (<2 days, "standard" vs ≥2 days, "extended") and (2) type of antibiotic used ("cephalosporin," "cephalosporin + vancomycin," "vancomycin") and C difficile as outcome. Overall C difficile prevalence was 0.21% (n = 329). Most patients (59.7%) received a cephalosporin only; in 33.1% vancomycin was added, whereas 7.2% received vancomycin only. Extended prophylaxis was used in 20.9%. In adjusted analyses, extended prophylaxis (vs standard) was associated with significantly increased C difficile risk (odds ratio, 1.43; confidence interval, 1.07-1.92), whereas no significant associations existed for vancomycin use as adjuvant or primary prophylactic compared with the use of cephalosporins (odds ratio, 1.21; confidence interval, 0.92-1.60, and odds ratio, 1.39; confidence interval, 0.94-2.05, respectively). Substantial inter-hospital variation exists in the percentage of extended antibiotic prophylaxis (interquartile range, 2.5-35.7), use of adjuvant vancomycin (interquartile range, 4.2-61.1), and vancomycin alone (interquartile range, 2.3-10.4). Although extended use of antibiotic prophylaxis was associated with increased C difficile risk after coronary artery bypass grafting, vancomycin use was not. The observed hospital variation in antibiotic prophylaxis practices suggests great potential for efforts aimed at standardizing practices that subsequently could reduce C difficile risk. Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

WalK(S221P), a naturally occurring mutation, confers vancomycin resistance in VISA strain XN108.

PubMed

Peng, Huagang; Hu, Qiwen; Shang, Weilong; Yuan, Jizhen; Zhang, Xiaopeng; Liu, Hui; Zheng, Ying; Hu, Zhen; Yang, Yi; Tan, Li; Li, Shu; Hu, Xiaomei; Li, Ming; Rao, Xiancai

2017-04-01

Vancomycin-intermediate Staphylococcus aureus (VISA) strains have spread globally. We previously isolated an ST239 VISA (XN108) with a vancomycin MIC of 12 mg/L. The mechanism for XN108 resistance to vancomycin was investigated in this study. Genome comparison was performed to characterize mutations that might contribute to the XN108 resistance phenotype. The novel mutation WalK(S221P) was identified and investigated using allelic replacement experiments. Vancomycin susceptibilities, autolytic activities and morphologies of the strains were examined. Autophosphorylation activities of WalK and the WalK(S221P) mutant were determined in vitro with [λ- 32 P]ATP, and binding activity of WalK(S221P)-activated WalR to the promoter region of its target gene lytM was determined by electrophoretic mobility shift assay. Genome comparison revealed three mutations, GraS(T136I), RpoB(H481N) and WalK(S221P), which might be responsible for vancomycin resistance in XN108. The introduction of WalK(S221P) to the vancomycin-susceptible strain N315 increased its vancomycin MIC from 1.5 to 8 mg/L, whereas the allelic replacement of WalK(S221P) with the native N315 WalK allele in XN108 decreased its vancomycin MIC from 12 to 4 mg/L. The VISA strains have thickened cell walls and decreased autolysis, consistent with observed changes in the expression of genes involved in cell wall metabolism and virulence regulation. WalK(S221P) exhibited reduced autophosphorylation, which may lead to reduced phosphorylation of WalR. WalK(S221P)-phosphorylated WalR also exhibited a reduced capacity to bind to the lytM promoter. The naturally occurring WalK(S221P) mutation plays a key role in vancomycin resistance in XN108. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Trimethoprim/sulfamethoxazole versus vancomycin in the treatment of healthcare/ventilator-associated MRSA pneumonia: a case-control study.

PubMed

Eliakim-Raz, Noa; Hellerman, Moran; Yahav, Dafna; Cohen, Jonathan; Margalit, Ili; Fisher, Sharon; Zusman, Oren; Shaked, Hila; Bishara, Jihad

2017-03-01

Therapeutic options available to treat MRSA pneumonia are limited. Trimethoprim/sulfamethoxazole is an attractive treatment because of its bactericidal anti-MRSA activity, oral and parenteral formulations and good penetration to the lung tissue. We aimed to compare the efficacy and safety of trimethoprim/sulfamethoxazole with vancomycin in the treatment of healthcare/ventilator-associated MRSA pneumonia. We carried out a retrospective case-control study of all consecutive hospitalized adult patients diagnosed with MRSA pneumonia at Beilinson Hospital during 2010-15 and treated with either vancomycin or trimethoprim/sulfamethoxazole. The primary outcomes were all-cause mortality at 30 days and clinical failure at the end of treatment. In order to reduce bias affecting the decision to use a specific antibiotic and as a sensitivity analysis, a propensity-score model for choosing between vancomycin and trimethoprim/sulfamethoxazole was used. We identified 42 patients with MRSA pneumonia treated with trimethoprim/sulfamethoxazole and 39 treated with vancomycin. There were no significant differences in the baseline characteristics between the groups. Vancomycin-treated patients showed significantly higher 30 day mortality on both multivariate analysis (HR = 5.28; 95% CI = 1.50-18.60; P  < 0.05) and sensitivity analysis with propensity score [vancomycin 13/24 (54.1%) versus trimethoprim/sulfamethoxazole 4/24 (16.7%); P  < 0.05], and higher clinical failure rates [vancomycin 23/39 (59%) versus trimethoprim/sulfamethoxazole 15/42 (35.7%); P  < 0.05], also in the sensitivity analysis with propensity score [vancomycin 14/24 (58.3%) versus trimethoprim/sulfamethoxazole 6/24 (25%); P  < 0.05]. The rates of side effects in both arms were comparable. Trimethoprim/sulfamethoxazole appears to be superior to vancomycin in the treatment of MRSA pneumonia. A large-scale randomized controlled trial is needed to evaluate these findings. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Population Pharmacokinetic Model for Vancomycin Used in Open Heart Surgery: Model-Based Evaluation of Standard Dosing Regimens.

PubMed

Alqahtani, Saeed A; Alsultan, Abdullah S; Alqattan, Hussain M; Eldemerdash, Ahmed; Albacker, Turki B

2018-04-23

The purpose of this study was to investigate the population pharmacokinetics of vancomycin in patients undergoing open heart surgery. In this observational pharmacokinetic study, multiple blood samples were drawn over a 48-h period of intravenous vancomycin in patients who were undergoing open heart surgery. Blood samples were analysed using the Architect i4000SR Immunoassay Analyzer. Population pharmacokinetic models were developed using Monolix 4.4 software. Pharmacokinetic-pharmacodynamic (PK-PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets. One-hundred and sixty-eight blood samples were analysed from 28 patients. The pharmacokinetics of vancomycin was best described by a two-compartment model with between-subject variability in CL, V of the central compartment, and V of the peripheral compartment. CL and central compartment V of vancomycin were related to CL CR , body weight, and albumin concentration. Dosing simulations showed that standard dosing regimens of 1 and 1.5 g failed to achieve the PK-PD target of AUC 0--24 /MIC > 400 for an MIC of 1 mg/L, while high weight-based dosing regimens were able to achieve the PK-PD target. In summary, administration of standard doses of 1 and 1.5 g of vancomycin two times daily provided inadequate antibiotic prophylaxis in patients undergoing open heart surgery. The same findings were obtained when 15 mg/kg and 20 mg/kg doses of vancomycin were administered. Achieving the PK-PD target required higher doses (25 mg/kg and 30 mg/kg) of vancomycin. Copyright © 2018 American Society for Microbiology.

Evolutionary dynamics of Enterococcus faecium reveals complex genomic relationships between isolates with independent emergence of vancomycin resistance

PubMed Central

Ip, Camilla L. C.; Ansari, M. Azim; Wilson, Daniel J.; Espedido, Bjorn A.; Jensen, Slade O.; Bowden, Rory

2016-01-01

Enterococcus faecium, a major cause of hospital-acquired infections, remains problematic because of its propensity to acquire resistance to vancomycin, which currently is considered first-line therapy. Here, we assess the evolution and resistance acquisition dynamics of E. faecium in a clinical context using a series of 132 bloodstream infection isolates from a single hospital. All isolates, of which 49 (37 %) were vancomycin-resistant, underwent whole-genome sequencing. E. faecium was found to be subject to high rates of recombination with little evidence of sequence importation from outside the local E. faecium population. Apart from disrupting phylogenetic reconstruction, recombination was frequent enough to invalidate MLST typing in the identification of clonal expansion and transmission events, suggesting that, where available, whole-genome sequencing should be used in tracing the epidemiology of E. faecium nosocomial infections and establishing routes of transmission. Several forms of the Tn1549-like element–vanB gene cluster, which was exclusively responsible for vancomycin resistance, appeared and spread within the hospital during the study period. Several transposon gains and losses and instances of in situ evolution were inferred and, although usually chromosomal, the resistance element was also observed on a plasmid background. There was qualitative evidence for clonal expansions of both vancomycin-resistant and vancomycin-susceptible E. faecium with evidence of hospital-specific subclonal expansion. Our data are consistent with continuing evolution of this established hospital pathogen and confirm hospital vancomycin-susceptible and vancomycin-resistant E. faecium patient transmission events, underlining the need for careful consideration before modifying current E. faecium infection control strategies. PMID:27713836

Evolutionary dynamics of Enterococcus faecium reveals complex genomic relationships between isolates with independent emergence of vancomycin resistance.

PubMed

van Hal, Sebastiaan J; Ip, Camilla L C; Ansari, M Azim; Wilson, Daniel J; Espedido, Bjorn A; Jensen, Slade O; Bowden, Rory

2016-01-19

Enterococcus faecium , a major cause of hospital-acquired infections, remains problematic because of its propensity to acquire resistance to vancomycin, which currently is considered first-line therapy. Here, we assess the evolution and resistance acquisition dynamics of E. faecium in a clinical context using a series of 132 bloodstream infection isolates from a single hospital. All isolates, of which 49 (37 %) were vancomycin-resistant, underwent whole-genome sequencing. E. faecium was found to be subject to high rates of recombination with little evidence of sequence importation from outside the local E. faecium population. Apart from disrupting phylogenetic reconstruction, recombination was frequent enough to invalidate MLST typing in the identification of clonal expansion and transmission events, suggesting that, where available, whole-genome sequencing should be used in tracing the epidemiology of E. faecium nosocomial infections and establishing routes of transmission. Several forms of the Tn 1549 -like element- vanB gene cluster, which was exclusively responsible for vancomycin resistance, appeared and spread within the hospital during the study period. Several transposon gains and losses and instances of in situ evolution were inferred and, although usually chromosomal, the resistance element was also observed on a plasmid background. There was qualitative evidence for clonal expansions of both vancomycin-resistant and vancomycin-susceptible E. faecium with evidence of hospital-specific subclonal expansion. Our data are consistent with continuing evolution of this established hospital pathogen and confirm hospital vancomycin-susceptible and vancomycin-resistant E. faecium patient transmission events, underlining the need for careful consideration before modifying current E. faecium infection control strategies.

Impact of Pharmacy Practice Model Expansion on Pharmacokinetic Services: Optimization of Vancomycin Dosing and Improved Patient Safety.

PubMed

Han, Zhe; Pettit, Natasha N; Landon, Emily M; Brielmaier, Benjamin D

2017-04-01

Background: The impact of pharmacy interventions on optimizing vancomycin therapy has been described, however interventions vary among studies and the most optimal pharmacy practice model (PPM) for pharmacokinetic (PK) services has not been established. Objective: The purpose of this study is to demonstrate the value of 24 hours a day, 7 days a week (24/7) PK services. Methods: New PK services were implemented in 2 phases with institutional PPM expansion. Phase 1 included universal monitoring by pharmacists with recommendations made to prescribers during business hours. Phase 2 expanded clinical pharmacists' coverage to 24/7 and provided an optional 24/7 pharmacist-managed PK consult service. We compared vancomycin therapeutic trough attainment, dosing, and clinical and safety outcomes between phases 1 and 2 in adult inpatients receiving therapeutic intravenous vancomycin. Results. One hundred and fifty patients were included in each phase. Phase 2 had a greater proportion of vancomycin courses with therapeutic initial trough concentrations (27.5% vs 46.1%; p = 0.002), higher initial trough concentrations (10.9 mcg/mL vs 16.4 mcg/mL; p < 0.001), and optimized initial vancomycin dosing (13.5 mg/kg vs 16.2 mg/kg; p < 0.001). Phase 2 also saw significant reduction in the incidence of vancomycin-associated nephrotoxicity (21.1% vs 11.7%; p = 0.038). Dose optimization and improvement in initial target trough attainment were most notable among intensive care unit (ICU) patients. Conclusions. Our study demonstrated that 24/7 PK services implemented with institutional PPM expansion optimized vancomycin target trough attainment and improved patient safety.

VraR Binding to the Promoter Region of agr Inhibits Its Function in Vancomycin-Intermediate Staphylococcus aureus (VISA) and Heterogeneous VISA.

PubMed

Dai, Yuanyuan; Chang, Wenjiao; Zhao, Changcheng; Peng, Jing; Xu, Liangfei; Lu, Huaiwei; Zhou, Shusheng; Ma, Xiaoling

2017-05-01

Acquisition of vancomycin resistance in Staphylococcus aureus is often accompanied by a reduction in virulence, but the mechanisms underlying this change remain unclear. The present study was undertaken to investigate this process in a clinical heterogeneous vancomycin-intermediate S. aureus (hVISA) strain, 10827; an hVISA reference strain, Mu3; and a VISA reference strain, Mu50, along with their respective series of vancomycin-induced resistant strains. In these strains, increasing MICs of vancomycin were associated with increased expression of the vancomycin resistance-associated regulator gene ( vraR ) and decreased expression of virulence genes ( hla , hlb , and coa ) and virulence-regulated genes (RNAIII, agrA , and saeR ). These results suggested that VraR might have a direct or indirect effect on virulence in S. aureus In electrophoretic mobility shift assays, VraR did not bind to promoter sequences of hla , hlb , and coa genes, but it did bind to the agr promoter region. In DNase I footprinting assays, VraR protected a 15-nucleotide (nt) sequence in the intergenic region between the agr P2 and P3 promoters. These results indicated that when S. aureus is subject to induction by vancomycin, expression of vraR is upregulated, and VraR binding inhibits the function of the Agr quorum-sensing system, causing reductions in the virulence of VISA/hVISA strains. Our results suggested that VraR in S. aureus is involved not only in the regulation of vancomycin resistance but also in the regulation of virulence. Copyright © 2017 American Society for Microbiology.

Activity of vancomycin release from bioinspired coatings of hydroxyapatite or TiO2 nanotubes.

PubMed

Ionita, Daniela; Bajenaru-Georgescu, Daniela; Totea, Georgeta; Mazare, Anca; Schmuki, Patrik; Demetrescu, Ioana

2017-01-30

Herein we investigate the efficiency of various biomimetic coatings for localized drug delivery, using vancomycin as key therapeutic drug, which is a widely used antibiotic for the treatment of strong infections caused by positive Gram bacteria. We evaluate classical hydroxyapatite and biomimetic hydroxyapatite-collagen coatings obtained by electrochemical deposition as well as TiO 2 nanotubes arrays obtained by electrochemical anodization. Surface morphology, compositional and structural data confirm the incorporation of vancomycin into the layers and drug release profiles for vancomycin evaluate their release ability. Namely, hydroxyapatite coatings lead to a ≈92% vancomycin release after 30h and hydroxyapatite-collagen to 85%, while the TiO 2 nanotubes layers lead to 78% release. The antibacterial effect of such drug loaded coatings is evaluated against S. aureus (Gram-positive bacteria). Our study shows that the vancomycin incorporated hydroxyapatite coatings lead to a faster release, while the nanotubular coatings may lead to longer time release and additionally both types of coatings ensure a good antibacterial inhibition. Copyright © 2016 Elsevier B.V. All rights reserved.

Enterococcus in surface waters from the Des Moines River (Iowa) watershed: location, persistence and vancomycin resistance.

PubMed

Larsen, Bryan; Essmann, Michael K; Geletta, Simon; Duff, Barbara

2012-01-01

The object of this study was to quantify vancomycin-resistant enterococci in surface water from Central Iowa obtained from April 2007 to August 2007. Water from established sampling sites in four watersheds was plated on bile-esculin agar. Presumptively identified enterococci were categorized as "above the level of concern" if the sample contained ≥ 107 CFU per 100 ml. Confirmation of isolates as enterococci was based on growth at elevated temperature in high salt and on Enterococcus agar. Isolates that grew on 6 μg/ml vancomycin agar were deemed resistant. PCR analysis of resistant strains characterized vancomycin resistance genes. 77.2% of surface water samples from Central Iowa contained enterococci. Among enterococcal isolates, 10.4% grew on media containing 6 μg/ml vancomycin. PCR analysis of resistance genes showed a preponderance of VanC2/C3 in the area studied and VanB was not detected. Vancomycin-resistant Enterococcus is present in Central Iowa surface waters but resistance rarely involved VanA genotypes. Nevertheless, the potential for community-acquired infections remains a risk.

Daptomycin non-susceptibility in vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous-VISA (hVISA): implications for therapy after vancomycin treatment failure.

PubMed

Kelley, Peter G; Gao, Wei; Ward, Peter B; Howden, Benjamin P

2011-05-01

The aim of this study was to establish the relationship between reduced vancomycin and daptomycin susceptibility among Australasian vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous-VISA (hVISA) isolates from patients never exposed to daptomycin. Forty-seven stored clinical isolates of hVISA/VISA collected before November 2008 from around Australia and New Zealand were selected. Daptomycin and vancomycin MIC testing was performed using broth microdilution (BMD) and Etest methods. Daptomycin population analysis was performed on a subset of isolates. The percentage of daptomycin non-susceptible isolates was 0% for vancomycin-susceptible S. aureus (VSSA) (Etest and BMD), for hVISA it was 26% by Etest and 15% by BMD, and for VISA 62% by Etest and 38% by BMD. Population analysis profile testing demonstrated daptomycin heteroresistance among the hVISA and VISA strains tested. This is the highest rate of daptomycin non-susceptibility reported among hVISA isolates to date. Clinicians should exhibit caution when using daptomycin in situations where serious hVISA or VISA infection is a possibility.

Cell Wall Remodeling by a Synthetic Analog Reveals Metabolic Adaptation in Vancomycin Resistant Enterococci.

PubMed

Pidgeon, Sean E; Pires, Marcos M

2017-07-21

Drug-resistant bacterial infections threaten to overburden our healthcare system and disrupt modern medicine. A large class of potent antibiotics, including vancomycin, operate by interfering with bacterial cell wall biosynthesis. Vancomycin-resistant enterococci (VRE) evade the blockage of cell wall biosynthesis by altering cell wall precursors, rendering them drug insensitive. Herein, we reveal the phenotypic plasticity and cell wall remodeling of VRE in response to vancomycin in live bacterial cells via a metabolic probe. A synthetic cell wall analog was designed and constructed to monitor cell wall structural alterations. Our results demonstrate that the biosynthetic pathway for vancomycin-resistant precursors can be hijacked by synthetic analogs to track the kinetics of phenotype induction. In addition, we leveraged this probe to interrogate the response of VRE cells to vancomycin analogs and a series of cell wall-targeted antibiotics. Finally, we describe a proof-of-principle strategy to visually inspect drug resistance induction. Based on our findings, we anticipate that our metabolic probe will play an important role in further elucidating the interplay among the enzymes involved in the VRE biosynthetic rewiring.

Daptomycin versus vancomycin for complicated skin and skin structure infections: clinical and economic outcomes.

PubMed

Davis, Susan L; McKinnon, Peggy S; Hall, Levi M; Delgado, George; Rose, Warren; Wilson, Robert F; Rybak, Michael J

2007-12-01

To assess the effect of daptomycin compared with vancomycin on the clinical and economic outcomes in patients with complicated skin and skin structure infections. Prospective, open-label study. Level 1 trauma center in Detroit, Michigan. Fifty-three adult patients with complicated skin and skin structure infections at risk for methicillin-resistant Staphylococcus aureus (MRSA) infection who were treated with daptomycin and a matched cohort of 212 patients treated with vancomycin. Patients in the prospective arm received intravenous daptomycin 4 mg/kg every 24 hours for at least 3 days but not more than 14 days. Historical controls received at least 3 days of vancomycin dosed to achieve trough concentrations of 5-20 microg/ml. Outcomes evaluated included blinded assessments of clinical resolution, duration of therapy, and costs. The most common diagnoses were cellulitis (31%), abscess (22%), and both cellulitis with abscess (37%). Microbiology differed significantly between groups, with S. aureus found in 27 patients (51%) in the daptomycin group and 167 patients (79%) in the vancomycin group and MRSA in 22 (42%) and 159 (75%), respectively (p<0.001). The proportions of patients with clinical improvement or resolution of their infections on days 3 and 5 were 90% versus 70% and 98% versus 81% in the daptomycin versus vancomycin groups, respectively (p<0.01 for both comparisons), and 100% at the end of therapy in both groups. Among patients with complete resolution of their infections (41 patients [77%] with daptomycin vs 89 patients [42%] with vancomycin, p<0.05), median duration of intravenous therapy was 4 and 7 days, respectively, (p<0.001), and hospital costs were $5027 and $7552 (p<0.001). Patients receiving daptomycin achieved more rapid resolution of symptoms and clinical cure and had a decreased duration of inpatient therapy compared with those receiving vancomycin. This study suggests that daptomycin is a cost-effective alternative to vancomycin for complicated skin and skin structure infections.

Use of daptomycin in the treatment of vancomycin-resistant enterococcal urinary tract infections: a short case series.

PubMed

Ramaswamy, Divya Pradeep; Amodio-Groton, Maria; Scholand, Stephen J

2013-07-16

Vancomycin-resistant enterococci are a leading cause of hospital-acquired urinary tract infection and a growing concern for the clinician. The aim of this study was to evaluate the effectiveness of daptomycin in the treatment of patients with vancomycin-resistant enterococcal urinary tract infection treated in our 200-bed community-based institution. Patients with confirmed symptomatic vancomycin-resistant enterococcal urinary tract infection identified by infectious disease consultation between January 1, 2007, and December 8, 2009, vancomycin-resistant enterococci-positive urine culture, and urinary symptoms and/or pyuria on urinalysis, and treated with daptomycin, were included in this case series. Daptomycin was generally administered at a planned dosage regimen of ≥ 5 mg/kg every 24 hours in patients with normal to moderately impaired kidney function or every 48 hours in patients with severe kidney disease. Microbiologic cure was defined as eradication of vancomycin-resistant enterococci in urine cultures taken after the completion of daptomycin treatment. Clinical cure was defined by symptom resolution, as assessed by the infectious disease clinician caring for the patient. Included in this case series are 10 patients who received daptomycin for confirmed vancomycin-resistant enterococcal urinary tract infection. Patients had a history of extensive hospital stays. Chart review revealed that all levels of kidney function (3, 2, 3, and 2 patients with kidney disease classified as normal, mild, moderate, and severe/kidney failure, respectively) were represented in the sample and that patients with (n = 5) or without (n = 5) previous urinary tract infection and with (n = 3) or without (n = 7) Foley catheters were included. Treatment with daptomycin achieved clinical cure and vancomycin-resistant enterococcal eradication in all cases in this series. Treatment with daptomycin was well tolerated and effective in all patients in this series, regardless of renal function, history of urinary tract infection, or Foley catheter use. This study adds to emerging clinical evidence that daptomycin is a valuable treatment for vancomycin-resistant enterococcal urinary tract infection.

A Pooled Analysis of the Phase 3 REVIVE Trials: Randomized, Double-blind Studies to EValuate the Safety and Efficacy of Iclaprim Versus Vancomycin for trEatment of Acute Bacterial Skin and Skin Structure Infections.

PubMed

Huang, David B; Corey, G Ralph; Holland, Thomas L; Lodise, Thomas; O'Riordan, William; Wilcox, Mark H; File, Thomas M; Dryden, Matthew; Balser, Barbara; Desplats, Eve; Torres, Antoni

2018-05-18

Iclaprim, a diaminopyrimidine antibiotic, was compared with vancomycin for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSIs) in two studies (REVIVE-1 and REVIVE-2). We explored the efficacy and tolerability of iclaprim in a pooled analysis of results from both studies. REVIVE-1 and REVIVE-2 were Phase 3, double-blind, randomized (1:1), multicenter, active-controlled, non-inferiority (margin of 10%) trials, each designed to enroll 600 patients a piece with ABSSSI. The studies used identical study protocols. Iclaprim 80 mg and vancomycin 15 mg/kg were administered IV every 12 hours for 5-14 days. The primary endpoint was a ≥20% reduction from baseline in lesion size (early clinical response [ECR]) at the early time point (48 to 72 hours after the start of study drug) in the intent-to-treat population. In REVIVE-1, ECR at the early time point was 80.9% with iclaprim vs. 81.0% with vancomycin (treatment difference, -0.13%; 95% confidence interval, -6.42% to 6.17%). In REVIVE-2, ECR was 78.3% with iclaprim vs. 76.7% with vancomycin (treatment difference: 1.58%, 95% CI: -5.10% to 8.26%). The pooled ECR was 79.6% with iclaprim vs. 78.8% with vancomycin (treatment difference: 0.75%, 95% CI: -3.84 to 5.35%). Iclaprim and vancomycin were comparable for the incidence of mostly mild adverse events, except for a higher incidence of elevated serum creatinine with vancomycin (n=7) compared with iclaprim (n=0). Iclaprim achieved noninferiority compared with vancomycin for early clinical response at the early time point and secondary endpoints with a similar safety profile in two Phase 3 studies for the treatment of ABSSSI suspected or confirmed to be caused by Gram-positive pathogens. NCT02600611 and NCT02607618. Copyright © 2018. Published by Elsevier B.V.

Relationship between day 1 and day 2 Vancomycin area under the curve values and emergence of heterogeneous Vancomycin-intermediate Staphylococcus aureus (hVISA) by Etest® macromethod among patients with MRSA bloodstream infections: a pilot study.

PubMed

Martirosov, Dmitriy M; Bidell, Monique R; Pai, Manjunath P; Scheetz, Marc H; Rosenkranz, Susan L; Faragon, Corey; Malik, M; Mendes, R E; Jones, R N; McNutt, Louise-Anne; Lodise, Thomas P

2017-08-02

In vitro data suggests that suboptimal initial vancomycin exposure may select for heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) infections. However, no clinical studies have evaluated the relationship between initial vancomycin exposure and emergence of hVISA. This pilot study seeks to assess the relationship between day 1 and day 2 vancomycin area under the curve (AUC) and emergence of hVISA bloodstream infections (BSIs) by Etest® macromethod among patients with a non-hVISA BSI at baseline. This was a retrospective cohort study of patients with methicillin-resistant Staphylococcus aureus (MRSA) BSIs at Albany Medical Center Hospital (AMCH) between January 2005 and June 2009. The vancomycin AUC exposure variables on day 1 (AUC 0-24h ) and day 2 (AUC 24-48h ) were estimated using the maximal a posteriori probability (MAP) procedure in ADAPT 5. There were 238 unique episodes of MRSA BSIs during the study period, 119 of which met inclusion criteria. Overall, hVISA emerged in 7/119 (5.9%) of patients. All 7 cases of hVISA involved patients who did not achieve area under the curve over broth microdilution minimum inhibitory concentration (AUC 0-24h /MIC BMD ) ratio of 521 or an AUC 24-48h /MIC BMD ratio of 650. No associations between other day 1 and day 2 AUC variables and emergence of hVISA were noted. Although more data are needed to draw definitive conclusions, these findings suggest that hVISA emergence among patients with non-hVISA MRSA BSIs at baseline may be partially explained by suboptimal exposure to vancomycin in the first 1 to 2 days of therapy. At a minimum, these findings support further study of the relationship between initial vancomycin exposure and hVISA emergence among patients with MRSA BSIs in a well-powered, multi-center, prospective trial.

Intraoperative vancomycin use in spinal surgery: single institution experience and microbial trends.

PubMed

Ghobrial, George M; Thakkar, Vismay; Andrews, Edward; Lang, Michael; Chitale, Ameet; Oppenlander, Mark E; Maulucci, Christopher M; Sharan, Ashwini D; Heller, Joshua; Harrop, James S; Jallo, Jack; Prasad, Srinivas

2014-04-01

Retrospective case series. To demonstrate the microbial trends of spinal surgical site infections in patients who had previously received crystallized vancomycin in the operative bed. Prior large, case control series demonstrate the significant decrease in surgical site infection with the administration of vancomycin in the wound bed. A single institution, electronic database search was conducted for all patients who underwent spinal surgery who had received prophylactic crystalline vancomycin powder in the wound bed. Patients with a prior history of wound infection, intrathecal pumps, or spinal stimulators were excluded. A total of 981 consecutive patients (494 males, 487 females; mean age, 59.4 yr; range, 16-95 yr) were identified from January 2011 to June 2013. The average dose of vancomycin powder was 1.13 g (range, 1-6 g). Sixty-six patients (6.71%) were diagnosed with a surgical site infection, of which 51 patients had positive wound cultures (5.2%). Of the 51 positive cultures, the most common organism was Staphylococcus aureus. The average dose of vancomycin was 1.3 g in the 38 cases where a gram-positive organism was cultured. A number of gram-negative infections were encountered such as Serratia marcescens, Enterobacter aerogenes, Bacteroides fragilis, Enterobacter cloacae, Citrobacter koseri, and Pseudomonas aeruginosa. The average dose of vancomycin was 1.2 g in 23 cases where a gram-negative infection was cultured. Fifteen of the 51 positive cultures (29.4%) were polymicrobial. Eight (53%) of these 15 polymicrobial cultures contained 3 or more distinct organisms. Prophylactic intraoperative vancomycin use in the wound bed in spinal surgery may increase the incidence of gram-negative or polymicrobial spinal infections. The use of intraoperative vancomycin may correlate with postoperative seromas, due to the high incidence of nonpositive cultures. Large, randomized, prospective trials are needed to demonstrate causation and dose-response relationship.

Synergy of Arbekacin-based Combinations Against Vancomycin Hetero-intermediate Staphylococcus aureus

PubMed Central

Lee, Ji-Young; Oh, Won Sup; Ko, Kwan Soo; Heo, Sang Taek; Moon, Chi Sook; Ki, Hyun Kyun; Kiem, Sungmin; Peck, Kyong Ran

2006-01-01

This study was undertaken to evaluate the in vitro activities of arbekacin-based combination regimens against vancomycin hetero-intermediate Staphylococcus aureus (hetero-VISA). Combinations of arbekacin with vancomycin, rifampin, ampicillin-sulbactam, teicoplanin, or quinipristin-dalfopristin against seven hetero-VISA strains and two methicillin-resistant S. aureus strains were evaluated by the time-kill assay. The combinations of arbekacin with vancomycin, teicoplanin, or ampicillin-sulbactam showed the synergistic interaction against hetero-VISA strains. Data suggest that these arbekacin-based combination regimens may be useful candidates for treatment options of hetero-VISA infections. PMID:16614499

Identification of VanN-type vancomycin resistance in an Enterococcus faecium isolate from chicken meat in Japan.

PubMed

Nomura, Takahiro; Tanimoto, Koichi; Shibayama, Keigo; Arakawa, Yoshichika; Fujimoto, Shuhei; Ike, Yasuyoshi; Tomita, Haruyoshi

2012-12-01

Five VanN-type vancomycin-resistant Enterococcus faecium strains were isolated from a sample of domestic chicken meat in Japan. All isolates showed low-level resistance to vancomycin (MIC, 12 mg/liter) and had the same pulsed-field gel electrophoresis profile. The vancomycin resistance was encoded on a large plasmid (160 kbp) and was expressed constitutively. The VanN-type resistance operon was identical to the first resistance operon to be reported, with the exception of a 1-bp deletion in vanT(N) and a 1-bp substitution in vanS(N).

Characterisation of the selective binding of antibiotics vancomycin and teicoplanin by the VanS receptor regulating type A vancomycin resistance in the enterococci.

PubMed

Hughes, C S; Longo, E; Phillips-Jones, M K; Hussain, R

2017-08-01

A-type resistance towards "last-line" glycopeptide antibiotic vancomycin in the leading hospital acquired infectious agent, the enterococci, is the most common in the UK. Resistance is regulated by the VanR A S A two-component system, comprising the histidine sensor kinase VanS A and the partner response regulator VanR A . The nature of the activating ligand for VanS A has not been identified, therefore this work sought to identify and characterise ligand(s) for VanS A . In vitro approaches were used to screen the structural and activity effects of a range of potential ligands with purified VanS A protein. Of the screened ligands (glycopeptide antibiotics vancomycin and teicoplanin, and peptidoglycan components N-acetylmuramic acid, D-Ala-D-Ala and Ala-D-y-Glu-Lys-D-Ala-D-Ala) only glycopeptide antibiotics vancomycin and teicoplanin were found to bind VanS A with different affinities (vancomycin 70μM; teicoplanin 30 and 170μM), and were proposed to bind via exposed aromatic residues tryptophan and tyrosine. Furthermore, binding of the antibiotics induced quicker, longer-lived phosphorylation states for VanS A , proposing them as activators of type A vancomycin resistance in the enterococci. Copyright © 2017 Diamond Light Source Ltd. Published by Elsevier B.V. All rights reserved.

Survey of Virulence Determinants among Vancomycin Resistant Enterococcus faecalis and Enterococcus faecium Isolated from Clinical Specimens of Hospitalized Patients of North west of Iran

PubMed Central

Sharifi, Yaeghob; Hasani, Alka; Ghotaslou, Reza; Varshochi, Mojtaba; Hasani, Akbar; Aghazadeh, Mohammad; Milani, Morteza

2012-01-01

Recent data indicates an increasing rate of vancomycin resistance in clinical enterococcal isolates worldwide. The nosocomial enterococci are likely to harbor virulence elements that increase their ability to colonize hospitalized patients. The aim of this study was to characterize virulence determinants in vancomycin-resistant enterococci (VRE) obtained from various clinical sources. During the years 2008 to 2010, a total of 48 VRE isolates were obtained from three University teaching hospitals in Northwest, Iran. Initially, phenotypic speciation was done and minimum inhibitory concentrations (MICs) of vancomycin were determined by agar dilution method and E-test. Then, species identification and resistance genotypes along with detection of virulence genes (asa1, esp, gelE, ace and cpd) of the isolates were performed by multiplex PCR. Thirty eight isolates were identified as vancomycin-resistant Enterococcus faecium (VREfm) and ten as E. faecalis (VREfs). Irrespective of the species, vanA gene (89.58%) was dominant and three phenotypically vancomycin susceptible E. faecium isolates carried the vanB gene. Among virulence genes investigated, the esp was found in 27(71%) VREfm strains, but did not in any VREfs. Other virulence determinants were highly detected in VREfs strains. Our data indicate a high prevalence of E. faecium harboring vancomycin resistance with vanA genotype and the two VRE species displayed different virulence genes. PMID:22582098

Amino acid substitutions in the VanS sensor of the VanA-type vancomycin-resistant Enterococcus strains result in high-level vancomycin resistance and low-level teicoplanin resistance.

PubMed

Hashimoto, Y; Tanimoto, K; Ozawa, Y; Murata, T; Ike, Y

2000-04-15

The vancomycin-resistant enterococci GV1, GV2 and GV3, which were isolated from droppings from broiler farms in Japan have been characterized as VanA-type VRE, which express high-level vancomycin resistance (256 or 512 microg ml(-1), MIC) and low-level teicoplanin resistance (1 or 2 microg ml(-1), MIC). The vancomycin resistances were encoded on plasmids. The vancomycin resistance conjugative plasmid pMG2 was isolated from the GV2 strain. The VanA determinant of pMG2 showed the same genetic organization as that of the VanA genes encoded on the representative transposon Tn1546, which comprises vanRSHAXYZ. The nucleotide sequences of all the genes, except the gene related to the vanS gene on Tn1546, were completely identical to the genes encoded on Tn1546. Three amino acid substitutions in the N-terminal region of the deduced VanS were detected in the nucleotide sequence of vanS encoded on pMG2. There were also three amino acid substitutions in the vanS gene of the GV1 and GV3 strains in the same positions as in the vanS gene of pMG2. Vancomycin induced the increased teicoplanin resistance in these strains.

Pathogens Present in Acute Mangled Extremities From Afghanistan and Subsequent Pathogen Recovery

DTIC Science & Technology

2015-01-01

methicillin - resistant Staphylococcus aureus or vancomycin- resistant Enterococcus. Most wounds were colonized with low-virulence...there were no methicillin - resistant Staphylococcus aureus or vancomycin- resistant Enterococcus. Although Enterococcus was recovered at Role 3 and 4 in 9...available for furthermicrobiological analysis in this study.MDRwas defined asmethicillin- resistant Staphylococcus aureus , vancomycin- resistant

Identification of Risk Factors for Nephrotoxicity in Patients Receiving Extended-Duration, High-Trough Vancomycin Therapy

PubMed Central

Contreiras, Claire; Legal, Michael; Lau, Tim T Y; Thalakada, Rosanne; Shalansky, Stephen; Ensom, Mary H H

2014-01-01

Background: In the past, impurities in vancomycin formulations were thought to contribute to nephrotoxicity. In contrast, when current, purer formulations are dosed at conventional trough levels (i.e., 5–15 mg/L), the incidence of nephrotoxicity is relatively low. Recent guidelines have recommended targeting higher vancomycin trough levels in treatment of complicated methicillin-resistant Staphylococcus aureus infections. Dosing based on these higher trough levels may be associated with nephrotoxicity, so the potential risk factors for vancomycin-associated nephrotoxicity require clearer definition. Objectives: To determine the occurrence of nephrotoxicity in patients receiving more than 7 days of vancomycin therapy with high trough levels (15–20 mg/L) and to identify and evaluate specific risk factors related to development of vancomycin-associated nephrotoxicity (i.e., serum creatinine ≥ 44.2 μmol/L or increase ≥ 50% [i.e., ≥ 26.2 μmol/L] from baseline on 2 consecutive days). Methods: Health care records were reviewed for patients seen at 2 major teaching hospitals between January 2008 and March 2011. Patients who had attained high trough levels of vancomycin were screened for eligibility. Patients with unstable renal function, those undergoing hemodialysis, and those for whom dosage and/or sampling times were unclear were excluded. Univariate and multivariate analyses were performed to identify risk factors associated with nephrotoxicity. Univariate variables with p < 0.1 were included in the logistic regression model. Results: Of the 176 patients with high trough levels included in the analysis, 24 (14%) experienced nephrotoxicity. In univariate analysis, admission to a general medicine unit (the setting of care for 16 [67%] of the 24 patients with nephrotoxicity) and extended duration of vancomycin treatment were identified as risk factors for nephrotoxicity (p < 0.1). Other risk factors included gastrointestinal comorbidity (p = 0.056), malignancy (p = 0.044), and febrile neutropenia (p = 0.032). Multivariate analysis identified treatment on general medicine units and treatment courses longer than 7 days as independent predictors of vancomycin-associated nephrotoxicity. Conclusion: Patients being treated on general medicine units and those receiving vancomycin for more than 7 days had an increased likelihood of experiencing nephrotoxicity. The increased risk for patients on general medicine units is likely multifactorial. The relationship between treatment duration and risk of nephrotoxicity appeared to be linear. When using extended-duration, high-trough vancomycin therapy, clinicians should be vigilant in monitoring for nephrotoxicity. PMID:24799722

Selective digestive tract decontamination and vancomycin-resistant enterococcus isolation in the surgical intensive care unit.

PubMed

Dahms, R; Carlson, M; Lohr, B; Beilman, G

2000-09-01

Vancomycin-resistant Enterococcus (VRE) has emerged as a significant nosocomial pathogen in the surgical intensive care unit (SICU). We wished to test the hypothesis that the use of selective digestive tract decontamination (SDD) in the SICU affects the frequency of VRE isolation. A retrospective review of hospital records and the SICU database was performed using patients admitted to the SICU service for three or more days from January 1, 1996 to December 31, 1999 at our large tertiary-care teaching hospital. During this time use of SDD in selected patient populations decreased due to physician preference. Information gathered included length of SICU stay, presence of VRE infection or colonization, and use and duration of SDD protocol, vancomycin, and ceftazidime. There were 110 newly diagnosed VRE cases in the SICU during this time period. During the same time period 54 patients received SDD. Eight patients who received SDD had positive VRE cultures and seven had the initial positive culture after receiving SDD. Overall, 9.1% of eligible SICU patients received SDD, 18.5% of patients in the SICU for over 3 days had VRE, 7.3% of VRE patients received SDD, and 13.0% of the SICU patients who received SDD subsequently developed VRE. SDD use was not associated with VRE in univariate analysis. Logistic regression analysis showed higher odds ratios for SDD use in combination with vancomycin than for vancomycin use alone (OR=4.3 vs. 10.9). Odds ratios were over three times higher for SDD plus vancomycin plus ceftazidime use when compared to vancomycin plus ceftazidime use alone (OR=70.5 vs. 19.8). We conclude that administration of SDD alone did not correlate with increased VRE isolation, but that SDD use in conjunction with vancomycin and ceftazidime was associated with VRE isolation.

Cost-effectiveness analysis evaluating fidaxomicin versus oral vancomycin for the treatment of Clostridium difficile infection in the United States.

PubMed

Stranges, Paul M; Hutton, David W; Collins, Curtis D

2013-01-01

Fidaxomicin is a novel treatment for Clostridium difficile infections (CDIs). This new treatment, however, is associated with a higher acquisition cost compared with alternatives. The objective of this study was to evaluate the cost-effectiveness of fidaxomicin or oral vancomycin for the treatment of CDIs. We performed a cost-utility analysis comparing fidaxomicin with oral vancomycin for the treatment of CDIs in the United States by creating a decision analytic model from the third-party payer perspective. The incremental cost-effectiveness ratio with fidaxomicin compared with oral vancomycin was $67,576/quality-adjusted life-year. A probabilistic Monte Carlo sensitivity analysis showed that fidaxomicin had an 80.2% chance of being cost-effective at a willingness-to-pay threshold of $100,000/quality-adjusted life-year. Fidaxomicin remained cost-effective under all fluctuations of both fidaxomicin and oral vancomycin costs. The decision analytic model was sensitive to variations in clinical cure and recurrence rates. Secondary analyses revealed that fidaxomicin was cost-effective in patients receiving concominant antimicrobials, in patients with mild to moderate CDIs, and when compared with oral metronidazole in patients with mild to moderate disease. Fidaxomicin was dominated by oral vancomycin if CDI was caused by the NAP1/Bl/027 Clostridium difficile strain and was dominant in institutions that did not compound oral vancomycin. Results of our model showed that fidaxomicin may be a more cost-effective option for the treatment of CDIs when compared with oral vancomycin under most scenarios tested. Copyright © 2013 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Cost-effectiveness analysis of fidaxomicin versus vancomycin in Clostridium difficile infection

PubMed Central

Nathwani, Dilip; Cornely, Oliver A.; Van Engen, Anke K.; Odufowora-Sita, Olatunji; Retsa, Peny; Odeyemi, Isaac A. O.

2014-01-01

Objectives Fidaxomicin was non-inferior to vancomycin with respect to clinical cure rates in the treatment of Clostridium difficile infections (CDIs) in two Phase III trials, but was associated with significantly fewer recurrences than vancomycin. This economic analysis investigated the cost-effectiveness of fidaxomicin compared with vancomycin in patients with severe CDI and in patients with their first CDI recurrence. Methods A 1 year time horizon Markov model with seven health states was developed from the perspective of Scottish public healthcare providers. Model inputs for effectiveness, resource use, direct costs and utilities were obtained from published sources and a Scottish expert panel. The main model outcome was the incremental cost-effectiveness ratio (ICER), expressed as cost per quality-adjusted life year (QALY), for fidaxomicin versus vancomycin; ICERs were interpreted using willingness-to-pay thresholds of £20 000/QALY and £30 000/QALY. One-way and probabilistic sensitivity analyses were performed. Results Total costs were similar with fidaxomicin and vancomycin in patients with severe CDI (£14 515 and £14 344, respectively) and in patients with a first recurrence (£16 535 and £16 926, respectively). Improvements in clinical outcomes with fidaxomicin resulted in small QALY gains versus vancomycin (severe CDI, +0.010; patients with first recurrence, +0.019). Fidaxomicin was cost-effective in severe CDI (ICER £16 529/QALY) and dominant (i.e. more effective and less costly) in patients with a first recurrence. The probability that fidaxomicin was cost-effective at a willingness-to-pay threshold of £30 000/QALY was 60% for severe CDI and 68% in a first recurrence. Conclusions Fidaxomicin is cost-effective in patients with severe CDI and in patients with a first CDI recurrence versus vancomycin. PMID:25096079

A Systematic Literature Review of Economic Evaluations of Antibiotic Treatments for Clostridium difficile Infection.

PubMed

Burton, Hannah E; Mitchell, Stephen A; Watt, Maureen

2017-11-01

Clostridium difficile infection (CDI) is associated with high management costs, particularly in recurrent cases. Fidaxomicin treatment results in lower recurrence rates than vancomycin and metronidazole, but has higher acquisition costs in Europe and the USA. This systematic literature review summarises economic evaluations (EEs) of fidaxomicin, vancomycin and metronidazole for treatment of CDI. Electronic databases (MEDLINE ® , Embase, Cochrane Library) and conference proceedings (ISPOR, ECCMID, ICAAC and IDWeek) were searched for publications reporting EEs of fidaxomicin, vancomycin and/or metronidazole in the treatment of CDI. Reference bibliographies of identified manuscripts were also reviewed. Cost-effectiveness was evaluated according to the overall population of patients with CDI, as well as in subgroups with severe CDI or recurrent CDI, or those at higher risk of recurrence or mortality. Overall, 27 relevant EEs, conducted from the perspective of 12 different countries, were identified. Fidaxomicin was cost-effective versus vancomycin and/or metronidazole in 14 of 24 EEs (58.3%), vancomycin was cost-effective versus fidaxomicin and/or metronidazole in five of 27 EEs (18.5%) and metronidazole was cost-effective versus fidaxomicin and/or vancomycin in two of 13 EEs (15.4%). Fidaxomicin was cost-effective versus vancomycin in most of the EEs evaluating specific patient subgroups. Key cost-effectiveness drivers were cure rate, recurrence rate, time horizon, drug costs and length and cost of hospitalisation. In most EEs, fidaxomicin was demonstrated to be cost-effective versus metronidazole and vancomycin in patients with CDI. These results have relevance to clinical practice, given the high budgetary impact of managing CDI and increasing restrictions on healthcare budgets. This analysis was initiated and funded by Astellas Pharma Inc.

Clinical and economic benefits of fidaxomicin compared to vancomycin for Clostridium difficile infection.

PubMed

Gallagher, Jason C; Reilly, Joseph P; Navalkele, Bhagyashri; Downham, Gemma; Haynes, Kevin; Trivedi, Manish

2015-11-01

We studied the clinical and economic impact of a protocol encouraging the use of fidaxomicin as a first-line drug for treatment of Clostridium difficile infection (CDI) in patients hospitalized during a 2-year period. This study evaluated patients who received oral vancomycin or fidaxomicin for the treatment of CDI during a 2-year period. All included patients were eligible for administration of fidaxomicin via a protocol that encouraged its use for selected patients. The primary clinical endpoint was 90-day readmission with a diagnosis of CDI. Hospital charges and insurance reimbursements for readmissions were calculated along with the cost of CDI therapy to estimate the financial impact of the choice of therapy. Recurrences were seen in 10/49 (20.4%) fidaxomicin patients and 19/46 (41.3%) vancomycin patients (P = 0.027). In a multivariate analysis that included determinations of severity of CDI, serum creatinine increases, and concomitant antibiotic use, only fidaxomicin was significantly associated with decreased recurrence (adjusted odds ratio [aOR], 0.33; 95% confidence interval [CI], 0.12 to 0.93). The total lengths of stay of readmitted patients were 183 days for vancomycin and 87 days for fidaxomicin, with costs of $454,800 and $196,200, respectively. Readmissions for CDI were reimbursed on the basis of the severity of CDI, totaling $151,136 for vancomycin and $107,176 for fidaxomicin. Fidaxomicin drug costs totaled $62,112, and vancomycin drug costs were $6,646. We calculated that the hospital lost an average of $3,286 per fidaxomicin-treated patient and $6,333 per vancomycin-treated patient, thus saving $3,047 per patient with fidaxomicin. Fidaxomicin use for CDI treatment prevented readmission and decreased hospital costs compared to use of oral vancomycin. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Predicting Maintenance Doses of Vancomycin for Hospitalized Patients Undergoing Hemodialysis.

PubMed

El Nekidy, Wasim S; El-Masri, Maher M; Umstead, Greg S; Dehoorne-Smith, Michelle

2016-01-01

Methicillin-resistant Staphylococcus aureus is a leading cause of death in patients undergoing hemodialysis. However, controversy exists about the optimal dose of vancomycin that will yield the recommended pre-hemodialysis serum concentration of 15-20 mg/L. To develop a data-driven model to optimize the accuracy of maintenance dosing of vancomycin for patients undergoing hemodialysis. A prospective observational cohort study was performed with 164 observations obtained from a convenience sample of 63 patients undergoing hemodialysis. All vancomycin doses were given on the floor after completion of a hemodialysis session. Multivariate linear generalized estimating equation analysis was used to examine independent predictors of pre-hemodialysis serum vancomycin concentration. Pre-hemodialysis serum vancomycin concentration was independently associated with maintenance dose ( B = 0.658, p < 0.001), baseline pre-hemodialysis serum concentration of the drug ( B = 0.492, p < 0.001), and interdialytic interval ( B = -2.133, p < 0.001). According to the best of 4 models that were developed, the maintenance dose of vancomycin required to achieve a pre-hemodialysis serum concentration of 15-20 mg/L, if the baseline serum concentration of the drug was also 15-20 mg/L, was 5.9 mg/kg with interdialytic interval of 48 h and 7.1 mg/kg with interdialytic interval of 72 h. However, if the baseline pre-hemodialysis serum concentration was 10-14.99 mg/L, the required dose increased to 9.2 mg/kg with an interdialytic interval of 48 h and 10.0 mg/kg with an interdialytic interval of 72 h. The maintenance dose of vancomycin varied according to baseline pre-hemodialysis serum concentration of the drug and interdialytic interval. The current practice of targeting a pre-hemodialysis concentration of 15-20 mg/L may be difficult to achieve for the majority of patients undergoing hemodialysis.

ANTIBACTERIAL ACTIVITY OF BONE ALLOGRAFTS: COMPARISON OF A NEW VANCOMYCIN-TETHERED ALLOGRAFT WITH ALLOGRAFT LOADED WITH ADSORBED VANCOMYCIN

PubMed Central

Ketonis, Constantinos; Barr, Stephanie; Shapiro, Irving M.; Parvizi, Javad; Adams, Christopher S.; Hickok, Noreen J.

2010-01-01

Bacterial contamination of bone allograft is a significant complication of orthopaedic surgery. To address this issue, we have engineered a method for covalently modifying bone allograft tissue with the antibiotic vancomycin. The goal of this investigation was to compare the biocidal properties of this new allograft material with those of vancomycin physisorbed onto graft material. The duration of antibiotic release from the vancomycin-modified allograft matrix was determined and no elution was observed. In contrast, the adsorbed antibiotic showed a peak elution at 24 h that then decreased over several days. We next used an S. aureus disk diffusion assay to measure the activity of the eluted vancomycin. Again we found that no active antibiotic was eluted from the covalently–modified allograft. Similarly, when the vancomycin-modified allograft morsel was used in the assay, no measurable elution was observed; amounts of antibiotic released from the adsorbed samples inhibited S. aureus growth for 4-7 days. Probably the most telling property of the allograft was that after two weeks, the tethered-allograft was able to resist bacterial colonization. Unlike the elution system in which vancomycin was depleted over the course of days-weeks, the antibiotic on the allograft was stably bound even after 300 days, while its biocidal activity remained undiminished for 60 days. This finding was in stark contrast to the antibiotic impregnated allograft which was readily colonized by bacteria. Finally we chose to evaluate three indicators of cell function: expression of a key transcription factor, expression of selected transcripts, and assessment of cell morphology. Since the tethered antibiotic appeared to have little or no effect on any of these activities, it was concluded that the stable, tethered antibiotic prevented bacterial infection while not modifying bone cell function. PMID:21035576

Short- and long-term effects of oral vancomycin on the human intestinal microbiota.

PubMed

Isaac, Sandrine; Scher, Jose U; Djukovic, Ana; Jiménez, Nuria; Littman, Dan R; Abramson, Steven B; Pamer, Eric G; Ubeda, Carles

2017-01-01

Oral vancomycin remains the mainstay of therapy for severe infections produced by Clostridium difficile, the most prevalent cause of healthcare-associated infectious diarrhoea in developed countries. However, its short- and long-term effects on the human intestinal microbiota remain largely unknown. We utilized high-throughput sequencing to analyse the effects of vancomycin on the faecal human microbiota up to 22 weeks post-antibiotic cessation. The clinical relevance of the observed microbiota perturbations was studied in mice. During vancomycin therapy, most intestinal microbiota genera and operational taxonomic units (OTUs) were depleted in all analysed subjects, including all baseline OTUs from the phylum Bacteroidetes. This was accompanied by a vast expansion of genera associated with infections, including Klebsiella and Escherichia/Shigella. Following antibiotic cessation, marked differences in microbiota resilience were observed among subjects. While some individuals recovered a microbiota close to baseline composition, in others, up to 89% of abundant OTUs could no longer be detected. The clinical relevance of the observed microbiota changes was further demonstrated in mice, which developed analogous microbiota alterations. During vancomycin treatment, mice were highly susceptible to intestinal colonization by an antibiotic-resistant pathogen and, upon antibiotic cessation, a less-resilient microbiota allowed higher levels of pathogen colonization. Oral vancomycin induces drastic and consistent changes in the human intestinal microbiota. Upon vancomycin cessation, the microbiota recovery rate varied considerably among subjects, which could influence, as validated in mice, the level of susceptibility to pathogen intestinal colonization. Our results demonstrate the negative long-term effects of vancomycin, which should be considered as a fundamental aspect of the cost-benefit equation for antibiotic prescription. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

Cost-effectiveness analysis of initial treatment strategies for mild-to-moderate Clostridium difficile infection in hospitalized patients.

PubMed

Ford, Diana C; Schroeder, Mary C; Ince, Dilek; Ernst, Erika J

2018-06-14

The cost-effectiveness of initial treatment strategies for mild-to-moderate Clostridium difficile infection (CDI) in hospitalized patients was evaluated. Decision-analytic models were constructed to compare initial treatment with metronidazole, vancomycin, and fidaxomicin. The primary model included 1 recurrence, and the secondary model included up to 3 recurrences. Model variables were extracted from published literature with costs based on a healthcare system perspective. The primary outcome was the incremental cost-effective ratio (ICER) between initial treatment strategies. In the primary model, the overall percentage of patients cured was 94.23%, 95.19%, and 96.53% with metronidazole, vancomycin, and fidaxomicin, respectively. Expected costs per case were $1,553.01, $1,306.62, and $5,095.70, respectively. In both models, vancomycin was more effective and less costly than metronidazole, resulting in negative ICERs. The ICERs for fidaxomicin compared with those for metronidazole and vancomycin in the primary model were $1,540.23 and $2,828.69 per 1% gain in cure, respectively. Using these models, a hospital currently treating initial episodes of mild-to-moderate CDI with metronidazole could expect to save $246.39-$388.37 per case treated by using vancomycin for initial therapy. A decision-analytic model revealed vancomycin to be cost-effective, compared with metronidazole, for treatment of initial episodes of mild-to-moderate CDI in adult inpatients. From the hospital perspective, initial treatment with vancomycin resulted in a higher probability of cure and a lower probability of colectomy, recurrence, persistent recurrence, and cost per case treated, compared with metronidazole. Use of fidaxomicin was associated with an increased probability of cure compared with metronidazole and vancomycin, but at a substantially increased cost. Copyright © 2018 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Short- and long-term effects of oral vancomycin on the human intestinal microbiota

PubMed Central

Isaac, Sandrine; Scher, Jose U.; Djukovic, Ana; Jiménez, Nuria; Littman, Dan R.; Abramson, Steven B.; Pamer, Eric G.; Ubeda, Carles

2017-01-01

Background Oral vancomycin remains the mainstay of therapy for severe infections produced by Clostridium difficile, the most prevalent cause of healthcare-associated infectious diarrhoea in developed countries. However, its short- and long-term effects on the human intestinal microbiota remain largely unknown. Methods We utilized high-throughput sequencing to analyse the effects of vancomycin on the faecal human microbiota up to 22 weeks post-antibiotic cessation. The clinical relevance of the observed microbiota perturbations was studied in mice. Results During vancomycin therapy, most intestinal microbiota genera and operational taxonomic units (OTUs) were depleted in all analysed subjects, including all baseline OTUs from the phylum Bacteroidetes. This was accompanied by a vast expansion of genera associated with infections, including Klebsiella and Escherichia/Shigella. Following antibiotic cessation, marked differences in microbiota resilience were observed among subjects. While some individuals recovered a microbiota close to baseline composition, in others, up to 89% of abundant OTUs could no longer be detected. The clinical relevance of the observed microbiota changes was further demonstrated in mice, which developed analogous microbiota alterations. During vancomycin treatment, mice were highly susceptible to intestinal colonization by an antibiotic-resistant pathogen and, upon antibiotic cessation, a less-resilient microbiota allowed higher levels of pathogen colonization. Conclusions Oral vancomycin induces drastic and consistent changes in the human intestinal microbiota. Upon vancomycin cessation, the microbiota recovery rate varied considerably among subjects, which could influence, as validated in mice, the level of susceptibility to pathogen intestinal colonization. Our results demonstrate the negative long-term effects of vancomycin, which should be considered as a fundamental aspect of the cost–benefit equation for antibiotic prescription. PMID:27707993

Intravitreal Infliximab Injection to Treat Experimental Endophthalmitis.

PubMed

Ondas, Osman; Ates, Orhan; Keles, Sadullah; Yildirim, Kenan; Baykal, Orhan; Karamese, Selina Aksak; Karamese, Murat; Uslu, Hakan; Yildirim, Mustafa; Naldan, Muhammet Emin; Ates, Irem

2017-10-01

The purpose of this study was to compare the use of an intravitreal injection of infliximab and of dexamethasone combined with vancomycin to treat experimental endophthalmitis induced by Staphylococcus epidermidis. The study was conducted between March 25 and April 13, 2012. Twenty-five six-month-old healthy rabbits were used, each weighing 2.5-3 kg. The rabbits were randomized into five groups with five animals per group. Endophthalmitis was induced by 0.1 mL (103 colony-forming units) S. epidermidis in all groups. In group 1, injection was not implemented after the occurrence of endophthalmitis. In groups 2, 3, and 4, the following intravitreal injections were given 24 h after the occurrence of endophthalmitis: group 2, 0.1 mg/0.1 mL vancomycin; group 3, 1 mg/0.1 mL vancomycin and 1 mg/0.1 mL dexamethasone; and group 4, 1 mg/0.1 mL vancomycin and 2 mg/0.1 mL infliximab. Group 5 was the control/uninfected group. The rabbits were clinically assessed each day for seven days. On day 9, a histopathologic evaluation was performed after enucleation. After a clinical evaluation, no statistically significant difference was found between the vancomycin+infliximab and vancomycin+dexamethasone groups (p>0.05). The difference was significant when both groups were compared with the vancomycin group (p<0.001). After the histopathologic evaluation, no statistically significant difference was found among the three groups (p>0.05). An intravitreal injection of infliximab and of dexamethasone combined with vancomycin have similar clinical and histopathologic effects. To supplement the antibiotic treatment of endophthalmitis, infliximab in a safe dose range can be used as an alternative to dexamethasone to suppress inflammation and prevent ocular damage.

Emergence of dalbavancin non-susceptible, vancomycin-intermediate Staphylococcus aureus (VISA) after treatment of MRSA central line-associated bloodstream infection with a dalbavancin- and vancomycin-containing regimen.

PubMed

Werth, B J; Jain, R; Hahn, A; Cummings, L; Weaver, T; Waalkes, A; Sengupta, D; Salipante, S J; Rakita, R M; Butler-Wu, S M

2018-04-01

Dalbavancin is a long-acting lipoglycopeptide with activity against gram-positives, including methicillin-resistant Staphylococcus aureus (MRSA). The potential for lipoglycopeptides, with half-lives greater than 1 week, to select for resistance is unknown. Here we explore a case of MRSA central line-associated bloodstream infection in which dalbavancin and vancomycin non-susceptibility emerged in a urine isolate collected after the patient was treated with vancomycin and dalbavancin sequentially. Isolates from blood and urine underwent susceptibility testing, and whole genome sequencing (WGS). The blood isolate was subjected to successive passage in vitro in the presence of escalating dalbavancin concentrations and the emergent isolate was subjected to repeat susceptibility testing and WGS. The blood isolate was fully susceptible to vancomycin; however, MICs of the urine isolate to dalbavancin, vancomycin, telavancin, and daptomycin were at least fourfold higher than the blood-derived strain. Both strains were indistinguishable by spa and variable number tandem repeat (VNTR) typing, and WGS revealed only seven variants, indicating clonality. Four variants affected genes, including a 3bp in-frame deletion in yvqF, a gene which has been implicated in glycopeptide resistance. Vancomycin and dalbavancin non-susceptibility emerged in the blood isolate after successive passage in vitro in the presence of dalbavancin, and WGS identified a single non-synonymous variant in yvqF. This is the first case in which VISA has emerged in the context of a dalbavancin-containing regimen. The selection for cross-resistance to vancomycin in vitro by dalbavancin exposure alone is troubling. Clinicians should be aware of the possibility for emergence of dalbavancin non-susceptibility and glycopeptide cross-resistance arising following therapy. Copyright © 2017. Published by Elsevier Ltd.

Ultra high performance liquid chromatography-tandem mass spectrometry vs. commercial immunoassay for determination of vancomycin plasma concentration in children. Possible implications for everyday clinical practice.

PubMed

Barco, Sebastiano; Castagnola, Elio; Gennai, Iulian; Barbagallo, Laura; Loy, Anna; Tripodi, Gino; Cangemi, Giuliana

2016-10-01

Vancomycin therapeutic drug monitoring (TDM) is necessary for effective and safetherapy. The aim of the this paper was to develop a specific and robust ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for vancomycin quantification starting from low plasma volumes to be applied for the routine TDM in children. Samples from children receiving intravenous vancomycin were analysed using a TSQ Quantum Access MAX Triple Quadrupole system coupled with an Accela 1250 UHPLC system after a rapid protein precipitation. Gradient separation chromatography was carried out using a Hypersil GOLD aQ C18 column (50 × 2.1 mm, particle size 1.9 μm). Method performance was validated following international guidelines. UHPLC-MS/MS allowed a rapid and specific quantification of vancomycin over the range 0.1-128 μg/mL from 50 μL of plasma with high reproducibility and accuracy in the absence of matrix effect. The comparison with the commercial immunoassay performed on 138 samples demonstrated the presence of a proportional bias. The concentrations of vancomycin measured with immunoassay were found to be 4.5% (95% CI: 1.3-7.7) higher than those determined with UHPLC-MS/MS. Importantly, a clinical discordance was found in about 10% of samples analysed. This new UHPLC-MS/MS method is accurate and specific for the measurement of vancomycin starting from small (50 μL) plasma volumes. The use of UHPLC-MS/MS is recommended to prevent a misclassification of therapeutic or toxic vancomycin levels in paediatrics.

Are Vancomycin Trough Concentrations Adequate for Optimal Dosing?

PubMed Central

Youn, Gilmer; Jones, Brenda; Jelliffe, Roger W.; Drusano, George L.; Rodvold, Keith A.; Lodise, Thomas P.

2014-01-01

The current vancomycin therapeutic guidelines recommend the use of only trough concentrations to manage the dosing of adults with Staphylococcus aureus infections. Both vancomycin efficacy and toxicity are likely to be related to the area under the plasma concentration-time curve (AUC). We assembled richly sampled vancomycin pharmacokinetic data from three studies comprising 47 adults with various levels of renal function. With Pmetrics, the nonparametric population modeling package for R, we compared AUCs estimated from models derived from trough-only and peak-trough depleted versions of the full data set and characterized the relationship between the vancomycin trough concentration and AUC. The trough-only and peak-trough depleted data sets underestimated the true AUCs compared to the full model by a mean (95% confidence interval) of 23% (11 to 33%; P = 0.0001) and 14% (7 to 19%; P < 0.0001), respectively. In contrast, using the full model as a Bayesian prior with trough-only data allowed 97% (93 to 102%; P = 0.23) accurate AUC estimation. On the basis of 5,000 profiles simulated from the full model, among adults with normal renal function and a therapeutic AUC of ≥400 mg · h/liter for an organism for which the vancomycin MIC is 1 mg/liter, approximately 60% are expected to have a trough concentration below the suggested minimum target of 15 mg/liter for serious infections, which could result in needlessly increased doses and a risk of toxicity. Our data indicate that adjustment of vancomycin doses on the basis of trough concentrations without a Bayesian tool results in poor achievement of maximally safe and effective drug exposures in plasma and that many adults can have an adequate vancomycin AUC with a trough concentration of <15 mg/liter. PMID:24165176

Linezolid versus Vancomycin in Treatment of Complicated Skin and Soft Tissue Infections

PubMed Central

Weigelt, John; Itani, Kamal; Stevens, Dennis; Lau, William; Dryden, Matthew; Knirsch, Charles

2005-01-01

Skin and soft tissue infections (SSTIs) are a common cause of morbidity in both the community and the hospital. An SSTI is classified as complicated if the infection has spread to the deeper soft tissues, if surgical intervention is necessary, or if the patient has a comorbid condition hindering treatment response (e.g., diabetes mellitus or human immunodeficiency virus). The purpose of this study was to compare linezolid to vancomycin in the treatment of suspected or proven methicillin-resistant gram-positive complicated SSTIs (CSSTIs) requiring hospitalization. This was a randomized, open-label, comparator-controlled, multicenter, multinational study that included patients with suspected or proven methicillin-resistant Staphylococcus aureus (MRSA) infections that involved substantial areas of skin or deeper soft tissues, such as cellulitis, abscesses, infected ulcers, or burns (<10% of total body surface area). Patients were randomized (1:1) to receive linezolid (600 mg) every 12 h either intravenously (i.v.) or orally or vancomycin (1 g) every 12 h i.v. In the intent-to-treat population, 92.2% and 88.5% of patients treated with linezolid and vancomycin, respectively, were clinically cured at the test-of-cure (TOC) visit (P = 0.057). Linezolid outcomes (124/140 patients or 88.6%) were superior to vancomycin outcomes (97/145 patients or 66.9%) at the TOC visit for patients with MRSA infections (P < 0.001). Drug-related adverse events were reported in similar numbers in both the linezolid and the vancomycin arms of the trial. The results of this study demonstrate that linezolid therapy is well tolerated, equivalent to vancomycin in treating CSSTIs, and superior to vancomycin in the treatment of CSSTIs due to MRSA. PMID:15917519

Transplacental transfer of vancomycin and telavancin

PubMed Central

NANOVSKAYA, Tatiana; PATRIKEEVA, Svetlana; ZHAN, Ying; FOKINA, Valentina; HANKINS, Gary DV; AHMED, Mahmoud S.

2014-01-01

Objectives Determine the bidirectional transfer and distribution of vancomycin and telavancin across the dually perfused term human placental lobule. Study design The technique of dually perfused placental lobule was used in its recirculating mode to determine the Maternal-to-Fetal (n=20) and Fetal-to-Maternal (n=18) transfer of each antibiotic which were co-perfused with their radioactive isotopes. The concentrations of drugs were determined by liquid scintillation spectrometry. Results In the Maternal-to-Fetal direction, the transfer of vancomycin (9.6 ± 4%) and telavancin (6.5 ± 2%) were low; however, telavancin retention by the perfused lobule was greater than that of vancomycin (p < 0.01). The normalized transplacental transfer of telavancin across the placental lobule in the F→M direction was higher than in the M→F direction (p < 0.01), suggesting the involvement of placental efflux transporters. Conclusions The ex vivo perfusion experiments revealed low transfer of vancomycin and telavancin to the fetal circuit. PMID:22867688

Determination of antibiotic resistance of lactic acid bacteria isolated from traditional Turkish fermented dairy products.

PubMed

Erginkaya, Z; Turhan, E U; Tatlı, D

2018-01-01

In this study, the antibiotic resistance (AR) of lactic acid bacteria (LAB) isolated from traditional Turkish fermented dairy products was investigated. Yogurt, white cheese, tulum cheese, cokelek, camız cream and kefir as dairy products were collected from various supermarkets. Lactic acid bacteria such as Lactobacillus spp., Streptococcus spp., Bifidobacterium spp., and Enterecoccus spp. were isolated from these dairy products. Lactobacillus spp. were resistant to vancomycin (58%), erythromycin (10.8%), tetracycline (4.3%), gentamicin (28%), and ciprofloxacin (26%). Streptococcus spp. were resistant to vancomycin (40%), erythromycin (10%), chloramphenicol (10%), gentamicin (20%), and ciprofloxacin (30%). Bifidobacterium spp. were resistant to vancomycin (60%), E 15 (6.6%), gentamicin (20%), and ciprofloxacin (33%). Enterococcus spp. were resistant to vancomycin (100%), erythromycin (100%), rifampin (100%), and ciprofloxacin (100%). As a result, LAB islated from dairy products in this study showed mostly resistance to vancomycin.

Red man syndrome caused by vancomycin powder.

PubMed

Nagahama, Yasunori; VanBeek, Marta J; Greenlee, Jeremy D W

2018-04-01

Red man syndrome (RMS) is a well-known hypersensitivity reaction caused by intravenous administration of vancomycin, with symptoms ranging from flushing, erythematous rash, pruritus, mild to profound hypotension, and even cardiac arrest. RMS has not previously been described from local application of vancomycin powder in a surgical wound, a technique increasingly utilized for infection prophylaxis in many surgical disciplines including neurosurgery. We describe the first reported case of RMS as a result of local intra-wound application of vancomycin powder for infection prophylaxis. A 73-year-old male with a history of Parkinson's disease underwent 2-stage deep brain stimulation implantation surgeries. Vancomycin powder was applied locally in the surgical wounds for infection prophylaxis during both of the surgeries. The patient developed a well-demarcated, geometric erythematous pruritic rash following the second surgery that was clinically diagnosed as RMS and resolved without sequelae. Copyright © 2018 Elsevier Ltd. All rights reserved.

The role of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea.

PubMed

Tart, Serina B

2013-10-01

For the treatment of Clostridium difficile-associated diarrhea (CDAD), metronidazole and vancomycin remain the most commonly used agents. The major advantage of metronidazole is its low cost, while the advantage of oral vancomycin is a more favorable pharmacokinetic profile. The epidemiology and clinical severity of CDAD have changed due to the emergence of a hypervirulent strain (BI/NAP1/027). In 2010, the Infectious Diseases Society of America/Society for Health Care Epidemiology of America expert panel defined severe CDAD and recommended oral vancomycin to treat these patients. Metronidazole remains the preferred agent for treatment of mild to moderate CDAD.

Life-threatening haematuria caused by vancomycin-induced thrombocytopenia

PubMed Central

Lobo, Niyati; Ejiofor, Kandi; Thurairaja, Ramesh; Khan, Muhammad Shamim

2015-01-01

Thrombocytopenia is a rare side effect of vancomycin, an antibiotic that is often used to treat Gram-positive bacterial infections. A 67-year-old man developed bilateral pulmonary emboli and hospital-acquired pneumonia following left ureteric reimplantation. He was anticoagulated with rivaroxaban and started on intravenous vancomycin and gentamicin for treatment of pneumonia. After five doses of vancomycin, his platelet count dropped to a nadir of 0×109/L (baseline: 314×109/L) manifesting as visible heavy haematuria and haemodynamic instability due to excessive blood loss. Reversal of the thrombocytopenia was achieved with intravenous immunoglobulin, methylprednisolone and continuous platelet transfusions. PMID:25716041

Neutropenia is independently associated with sub-therapeutic serum concentration of vancomycin.

PubMed

Choi, Min Hyuk; Choe, Yeon Hwa; Lee, Sang-Guk; Jeong, Seok Hoon; Kim, Jeong-Ho

2017-02-01

We aimed to identify the impact of the presence of neutropenia on serum vancomycin concentration (SVC). A retrospective study was conducted from January 2005 to December 2015. The study population was comprised of adult patients who were performed serum concentration of vancomycin. Patients with renal failure or using non-conventional dosages of vancomycin were excluded. A total of 1307 adult patients were included in this study, of whom 163 (12.4%) were neutropenic. Patients with neutropenia presented significantly lower SVCs than non-neutropenic patients (P<0.0001). Multiple linear regressions showed significant association between neutropenia and trough SVC (beta coefficients, -2.351; P=0.004). Multiple logistic regression analysis also revealed a significant association between sub-therapeutic vancomycin concentrations (trough SVC values<10mg/l) and neutropenia (odds ratio, 1.75, P=0.029) CONCLUSIONS: The presence of neutropenia is significantly associated with low SVC, even after adjusting for other variables. Therefore, neutropenic patients had a higher risk of sub-therapeutic SVC compared with non-neutropenic patients. We recommended that vancomycin therapy should be monitored with TDM-guided optimization of dosage and intervals, especially in neutropenic patients. Copyright © 2016 Elsevier B.V. All rights reserved.

Deoxycytidine Deaminase-Deficient Escherichia coli Strains Display Acute Sensitivity to Cytidine, Adenosine, and Guanosine and Increased Sensitivity to a Range of Antibiotics, Including Vancomycin

PubMed Central

Kang, Tina Manzhu; Yuan, Jessica; Zhou, Alice; Beppler, Casey

2014-01-01

We show here that deoxycytidine deaminase (DCD)-deficient mutants of Escherichia coli are hypersensitive to killing by exogenous cytidine, adenosine, or guanosine, whereas wild-type cells are not. This hypersensitivity is reversed by exogenous thymidine. The mechanism likely involves the allosteric regulation of ribonucleotide reductase and severe limitations of the dTTP pools, resulting in thymineless death, the phenomenon of cell death due to thymidine starvation. We also report here that DCD-deficient mutants of E. coli are more sensitive to a series of different antibiotics, including vancomycin, and we show synergistic killing with the combination of vancomycin and cytidine. One possibility is that a very low, subinhibitory concentration of vancomycin enters Gram-negative cells and that this concentration is potentiated by chromosomal lesions resulting from the thymineless state. A second possibility is that the metabolic imbalance resulting from DCD deficiency affects the assembly of the outer membrane, which normally presents a barrier to drugs such as vancomycin. We consider these findings with regard to ideas of rendering Gram-negative bacteria sensitive to drugs such as vancomycin. PMID:24633874

[Synthesis of antibiotic loaded polylactic acid nanoparticles and their antibacterial activity against Escherichia coli O157:H7 and methicillin-resistant Staphylococcus aureus].

PubMed

Herrera, Mónica Tatiana; Artunduaga, Jhon Jhamilton; Ortiz, Claudia Cristina; Torres, Rodrigo Gonzalo

2017-01-24

Polymeric nanoparticles are promising nanotechnology tools to fight pathogenic bacteria resistant to conventional antibiotics. To synthesize polylactic acid nanoparticles loaded with ofloxacin and vancomycin, and to determine their antibacterial activity against Escherichia coli O157:H7 and methicillin-resistant Staphylococcus aureus (MRSA). We synthesized ofloxacin or vancomycin loaded polylactic acid nanoparticles by the emulsification-solvent evaporation method, and characterized them by dynamic light scattering, laser Doppler electrophoresis and scanning electron microscopy. We evaluated in vitro antibacterial activity of ofloxacin- and vancomycin-loaded polylactic acid nanoparticles against E. coli O157:H7 and MRSA using the broth microdilution method. Ofloxacin- and vancomycin-loaded polylactic acid nanoparticles registered a positive surface charge density of 21 mV and an average size lower than 379 nm. In vitro minimum inhibitory concentration (MIC50) of ofloxacin-polylactic acid nanoparticles was 0,001 μg/ml against E. coli O157:H7, i.e., 40 times lower than the free ofloxacin (MIC50: 0.04 μg/ml), indicating enhanced antibacterial activity while the in vitro MIC50 of vancomycin-polylactic acid nanoparticles was 0,005 μg/ml against MRSA, i.e., 100 times lower than that of free vancomycin (MIC50: 0.5 μg/ml). Polylactic acid nanoparticles loaded with ofloxacin and vancomycin showed a higher antibacterial activity. Polymeric nanoparticles are a possible alternative for drug design against pathogenic bacterial strains of public health interest.

Prevalence, outcome and risk factor associated with vancomycin-resistant Enterococcus faecalis and Enterococcus faecium at a Tertiary Care Hospital in Northern India.

PubMed

Tripathi, A; Shukla, S K; Singh, A; Prasad, K N

2016-01-01

To determine the prevalence, genotype, risk factors and mortality in patients having vancomycin-resistant Enterococcus faecalis (VR E. faecalis) and Enterococcus faecium (VR E. faecium) infection or colonisation. A total of 1488 clinical isolates of E. faecalis and E. faecium were tested for vancomycin resistance by phenotypic (disk diffusion, E-test and broth micro-dilution test) and genotypic polymerase chain reaction methods. Records of all 1488 patients who had E. faecalis or E. faecium infection or colonisation were reviewed for the identification of host, hospital and medication related risk factors associated with VR E. faecalis and VR E. faecium. Of 1488 isolates, 118 (7.9%) were vancomycin-resistant and their distributions were as follows: E. faecalis=72 (61%) and E. faecium=46 (39%). All 118 vancomycin-resistant isolates were vanA genotype (minimum inhibitory concentration [MIC] to vancomycin ≥64 μg/ml and MIC to teicoplanin≥32 μg/ml) and none of the isolates was vanB genotype. Multivariate logistic regression analysis identified ventilator support and hospital stay for ≥48 h as independent risk factors associated with VR E. faecalis and VR E. faecium infection or colonisation. Hospital stay≥48 h was the only independent risk factor for mortality in patients infected with vancomycin-resistant enterococci. Strategies to limit the nosocomial infection especially in patients on ventilator support can reduce VRE incidence and related mortality.

Effect of nosocomial vancomycin-resistant enterococcal bacteremia on mortality, length of stay, and costs.

PubMed

Song, Xiaoyan; Srinivasan, Arjun; Plaut, David; Perl, Trish M

2003-04-01

To determine the impact of vancomycin-resistant enterococcal bacteremia on patient outcomes and costs by assessing mortality, excess length of stay, and charges attributable to it. A population-based, matched, historical cohort study. A 1,025-bed, university-based teaching facility and referral hospital. Two hundred seventy-seven vancomycin-resistant enterococcal bacteremia case-patients and 277 matched control-patients identified between 1993 and 2000. The crude mortality rate was 50.2% and 19.9% for case-patients and control-patients, respectively, yielding a mortality rate of 30.3% attributable to vancomycin-resistant enterococcal bacteremia. The excess length of hospital stay attributable to vancomycin-resistant enterococcal bacteremia was 17 days, of which 12 days were spent in intensive care units. On average, dollars 77,558 in extra charges was attributable to each vancomycin-resistant enterococcal bacteremia. To adjust for severity of illness, 159 pairs of case-patients and control-patients, who had the same severity of illness (All Patient Refined-Diagnosis Related Group complexity level), were further analyzed. When patients were stratified by severity of illness, the crude mortality rate was 50.3% among case-patients compared with 27.7% among control-patients, accounting for an attributable mortality rate of 22.6%. Attributable excess length of stay and charges were 17 days and dollars 81,208, respectively. Vancomycin-resistant enterococcal bacteremia contributes significantly to excess mortality and economic loss, once severity of illness is considered. Efforts to prevent these infections will likely be cost-effective.

Evaluation of a protocol for vancomycin administration in critically patients with and without kidney dysfunction.

PubMed

Spadaro, Savino; Berselli, Angela; Fogagnolo, Alberto; Capuzzo, Maurizia; Ragazzi, Riccardo; Marangoni, Elisabetta; Bertacchini, Sara; Volta, Carlo Alberto

2015-06-27

Administration of vancomycin in critically ill patients needs close regulation. While subtherapeutical vancomycin serum concentration (VSC) is associated with increased mortality, accumulation is responsible for nephrotoxicity. Our study aimed to estimate the efficacy of a vancomycin-dosing protocol in reaching appropriate serum concentration in patients with and without kidney dysfunction. This was a retrospective study in critically ill patients treated with continuous infusion of vancomycin. Patients with creatinine clearance > 50 ml/min (Group A) were compared to those with creatinine clearance ≤ 50 ml/min (Group B). 348 patients were enrolled (210 in Group A, 138 in Group B). At first determination, patients with kidney dysfunction (Group B) had a statistically higher percentage of vancomycin in target range, while the percentage of patients with a VSC under the range was almost equal. These percentages differed at the subsequent measurements. The number of patients with low vancomycin concentration progressively decreased, except in those with augmented renal clearance; the percentage of patients with VSC over 30 mg/L was about 28 %, irrespective of the presence or absence of kidney dysfunction. Patients who reached a subtherapeutic level at the first VSC measurement had a significant correlation with in-hospital mortality. Our protocol seems to allow a rapid achievement of a target VSC particularly in patients with kidney dysfunction. In order to avoid subtherapeutical VSC, our algorithm should be implemented by the estimation of the presence of an augmented renal clearance.

Comparative Effectiveness of Vancomycin and Metronidazole for the Prevention of Recurrence and Death in Patients With Clostridium difficile Infection.

PubMed

Stevens, Vanessa W; Nelson, Richard E; Schwab-Daugherty, Elyse M; Khader, Karim; Jones, Makoto M; Brown, Kevin A; Greene, Tom; Croft, Lindsay D; Neuhauser, Melinda; Glassman, Peter; Goetz, Matthew Bidwell; Samore, Matthew H; Rubin, Michael A

2017-04-01

Metronidazole hydrochloride has historically been considered first-line therapy for patients with mild to moderate Clostridium difficile infection (CDI) but is inferior to vancomycin hydrochloride for clinical cure. The choice of therapy may likewise have substantial consequences on other downstream outcomes, such as recurrence and mortality, although these secondary outcomes have been less studied. To evaluate the risk of recurrence and all-cause 30-day mortality among patients receiving metronidazole or vancomycin for the treatment of mild to moderate and severe CDI. This retrospective, propensity-matched cohort study evaluated patients treated for CDI, defined as a positive laboratory test result for the presence of C difficile toxins or toxin genes in a stool sample, in the US Department of Veterans Affairs health care system from January 1, 2005, through December 31, 2012. Data analysis was performed from February 7, 2015, through November 22, 2016. Treatment with vancomycin or metronidazole. The outcomes of interest in this study were CDI recurrence and all-cause 30-day mortality. Recurrence was defined as a second positive laboratory test result within 8 weeks of the initial CDI diagnosis. All-cause 30-day mortality was defined as death from any cause within 30 days of the initial CDI diagnosis. A total of 47 471 patients (mean [SD] age, 68.8 [13.3] years; 1947 women [4.1%] and 45 524 men [95.9%]) developed CDI, were treated with vancomycin or metronidazole, and met criteria for entry into the study. Of 47 147 eligible first treatment episodes, 2068 (4.4%) were with vancomycin. Those 2068 patients were matched to 8069 patients in the metronidazole group for a total of 10 137 included patients. Subcohorts were constructed that comprised 5452 patients with mild to moderate disease and 3130 patients with severe disease. There were no differences in the risk of recurrence between patients treated with vancomycin vs those treated with metronidazole in any of the disease severity cohorts. Among patients in the any severity cohort, those who were treated with vancomycin were less likely to die (adjusted relative risk, 0.86; 95% CI, 0.74 to 0.98; adjusted risk difference, -0.02; 95% CI, -0.03 to -0.01). No significant difference was found in the risk of mortality between treatment groups among patients with mild to moderate CDI, but vancomycin significantly reduced the risk of all-cause 30-day mortality among patients with severe CDI (adjusted relative risk, 0.79; 95% CI, 0.65 to 0.97; adjusted risk difference, -0.04; 95% CI, -0.07 to -0.01). Recurrence rates were similar among patients treated with vancomycin and metronidazole. However, the risk of 30-day mortality was significantly reduced among patients who received vancomycin. Our findings may further justify the use of vancomycin as initial therapy for severe CDI.

Synchrotron radiation infrared microspectroscopy to assess the activity of vancomycin against endocarditis vegetation bacteria.

PubMed

Batard, Eric; Jamme, Frédéric; Montassier, Emmanuel; Bertrand, Dominique; Caillon, Jocelyne; Potel, Gilles; Dumas, Paul

2011-06-01

Infrared microspectroscopy was used to show that vancomycin alters infrared spectra of endocarditis vegetation bacteria, and that vancomycin effects on bacterial biochemical contents are unevenly distributed between peripheral and central areas of bacterial masses. Infrared microspectroscopy is useful to study the activity of antibacterial agents against bacteria in tissues. Copyright © 2011 Elsevier B.V. All rights reserved.

Cost-effectiveness of telavancin versus vancomycin for treatment of complicated skin and skin structure infections.

PubMed

Laohavaleeson, Somvadee; Barriere, Steven L; Nicolau, David P; Kuti, Joseph L

2008-12-01

To determine the cost-effectiveness of telavancin versus vancomycin for the treatment of complicated skin and skin structure infections (cSSSIs). Pharmacoeconomic analysis conducted from the hospital's perspective using data from the Assessment of Telavancin in Complicated Skin and Skin Structure Infections (ATLAS) phase III clinical trial. One hundred twenty-nine hospitals in the United States and internationally. A total of 1044 clinically evaluable patients who were hospitalized with a cSSSI during the ATLAS trial and who received at least one dose of telavancin or vancomycin in the hospital. Diagnosis-related group-specific hospital bed costs, antibiotic acquisition prices, and cost of vancomycin monitoring were applied to the resource utilization data collected during the ATLAS trial. Infection-related length of stay (LOS(ir)) and hospitalization costs (COST(ir)) were compared between the telavancin (514 patients) and vancomycin (530 patients) groups. Incremental cost-effectiveness ratios (ICERs) were calculated for the total population and a subset of patients infected with methicillin-resistant Staphylococcus aureus (MRSA) by using a 25,000-sample bootstrap analysis. During sensitivity analyses, the daily acquisition price for telavancin was increased from the equivalent to vancomycin ($13.44) to $50, $100, $150, or $200, and the rate of MRSA acquisition was varied between 30% and 75%. The median (interquartile range) LOS(ir) was 8 days (6-12 days) for both telavancin and vancomycin (p=0.742), and median (interquartile range) COST(ir) was $8118 ($6291-11,758) and $8185 ($6474-11,405), respectively (p=0.560). Similar findings were observed for the MRSA subset. Telavancin cost-effectiveness was greater for the MRSA population versus the total population. During bootstrap analyses of the MRSA population, the ICER for telavancin ranged from dominant (-$9560) to $27,889 as acquisition price was increased. Telavancin LOS(ir) and total COST(ir) were similar to those of vancomycin for the treatment of cSSSIs. Particularly in those infected with MRSA, telavancin may be more cost-effective than vancomycin over the range of acquisition prices tested.

The Relationship Between Vancomycin Trough Concentrations and AUC/MIC Ratios in Pediatric Patients: A Qualitative Systematic Review.

PubMed

Tkachuk, Stacey; Collins, Kyle; Ensom, Mary H H

2018-04-01

In adults, the area under the concentration-time curve (AUC) divided by the minimum inhibitory concentration (MIC) is associated with better clinical and bacteriological response to vancomycin in patients with methicillin-resistant Staphylococcus aureus who achieve target AUC/MIC ≥ 400. This target is often extrapolated to pediatric patients despite the lack of similar evidence. The impracticalities of calculating the AUC in practice means vancomycin trough concentrations are used to predict the AUC/MIC. This review aimed to determine the relationship between vancomycin trough concentrations and AUC/MIC in pediatric patients. We searched the MEDLINE and Embase databases, the Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials using the medical subject heading (MeSH) terms vancomycin and AUC and pediatric* or paediatric*. Articles were included if they were published in English and reported a relationship between vancomycin trough concentrations and AUC/MIC. Of 122 articles retrieved, 11 met the inclusion criteria. One trial reported a relationship between vancomycin trough concentrations, AUC/MIC, and clinical outcomes but was likely underpowered. Five studies found troughs 6-10 mg/l were sufficient to attain an AUC/MIC > 400 in most general hospitalized pediatric patients. One study in patients undergoing cardiothoracic surgery found a trough of 18.4 mg/l achieved an AUC/MIC > 400. Two oncology studies reported troughs ≥ 15 mg/l likely attained an AUC/MIC ≥ 400. In critical care patients: one study found a trough of 9 mg/l did not attain the AUC/MIC target; another found 7 mg/l corresponded to an AUC/MIC of 400. Potential vancomycin targets varied based on the population studied but, for general hospitalized pediatric patients, troughs of 6-10 mg/l are likely sufficient to achieve AUC/MIC ≥ 400. For MIC ≥ 2 mg/l, higher troughs are likely necessary to achieve an AUC/MIC ≥ 400. More research is needed to determine the relationships between vancomycin trough concentrations, AUC/MIC, and clinical outcomes.

Lactobacillus reuteri and Escherichia coli in the human gut microbiota may predict weight gain associated with vancomycin treatment

PubMed Central

Million, M; Thuny, F; Angelakis, E; Casalta, J-P; Giorgi, R; Habib, G; Raoult, D

2013-01-01

Background: Antibiotics, used for 60 years to promote weight gain in animals, have been linked to obesity in adults and in children when administered during early infancy. Lactobacillus reuteri has been linked to obesity and weight gain in children affected with Kwashiorkor using ready-to-use therapeutic food. In contrast, Escherichia coli has been linked with the absence of obesity. Both of these bacteria are resistant to vancomycin. Objectives and methods: We assessed vancomycin-associated weight and gut microbiota changes, and tested whether bacterial species previously linked with body mass index (BMI) predict weight gain at 1 year. All endocarditis patients treated with vancomycin or amoxicillin in our center were included from January 2008 to December 2010. Bacteroidetes, Firmicutes, Lactobacillus and Methanobrevibacter smithii were quantified using real-time PCR on samples obtained during the 4–6 weeks antibiotic regimen. L. reuteri, L. plantarum, L. rhamnosus, Bifidobacterium animalis and E. coli were quantified on stool samples obtained during the first week of antibiotics. Results: Of the193 patients included in the study, 102 were treated with vancomycin and 91 with amoxicillin. Vancomycin was associated with a 10% BMI increase (odds ratio (OR) 14.1; 95% confidence interval (CI; 1.03–194); P=0.047) and acquired obesity (4/41 versus 0/56, P=0.01). In patients treated with vancomycin, Firmicutes, Bacteroidetes and Lactobacillus increased, whereas M. smithii decreased (P<0.05). The absence of E. coli was an independent predictor of weight gain (OR=10.7; 95% CI (1.4–82.0); P=0.02). Strikingly, a patient with an 18% BMI increase showed a dramatic increase of L. reuteri but no increase of E. coli. Conclusion: The acquired obesity observed in patients treated with vancomycin may be related to a modulation of the gut microbiota rather than a direct antibiotic effect. L. reuteri, which is resistant to vancomycin and produces broad bacteriocins, may have an instrumental role in this effect. PMID:24018615

Industrially prefabricated cement spacers: do vancomycin- and gentamicin-impregnated spacers offer any advantage?

PubMed

Corona, Pablo S; Barro, Victor; Mendez, Marye; Cáceres, Enric; Flores, Xavier

2014-03-01

Industrially preformed antibiotic-loaded cement spacers are useful to facilitate the second stage of two-stage exchange arthroplasty for infected THAs and TKAs. However, whether gentamicin alone or a combination of antibiotics (such as vancomycin and gentamicin) is more effective is not known. We therefore sought to compare industrially prefabricated spacers containing either gentamicin or gentamicin and vancomycin with respect to (1) infection control, (2) complications, and (3) quality of life, pain, and patient satisfaction. We performed a review of 51 patients with chronic infections treated at one center using either gentamicin or vancomycin and gentamicin-prefabricated spacers. The former were used exclusively from January 2006 until May 2009, and the latter from June 2009 until July 2011, and there was no overlap. We collected data on demographics, immunologic status (McPherson classification), prosthetic joint infection location, type of prosthesis, microbiologic results, and time between stages. We evaluated the primary outcome of infection control or recurrence after at least 12 months followup. We also recorded complications. Each patient completed a quality-of-life survey, VAS, and a self-administered satisfaction scale. The overall infection control rate was 83% after a mean followup of 35 months (range, 12.4-64.7 months). There were no differences between gentamicin and vancomycin and gentamicin spacers in terms of infection eradication (80 % versus 85 %, respectively; p = 0.73), nor in terms of complications, quality of life, pain, or satisfaction scores. Prefabricated, antibiotic-loaded cement spacers has been proven effective for infection control in TKAs and THAs but with the numbers available, we did not find any differences between a gentamicin or vancomycin and gentamicin-prefabricated spacer, and therefore, we are unable to validate the superiority of the combination of vancomycin and gentamicin over gentamicin alone. Because of the higher costs involved with vancomycin and gentamicin spacers, and the potential risks of unselective use of vancomycin, further comparative studies are necessary to evaluate their role in the treatment of infected THAs or TKAs. Level III, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence.

Evaluation of BBL CHROMagar VanRE for detection of vancomycin-resistant Enterococci in rectal swab specimens.

PubMed

Stamper, Paul D; Shulder, Stephanie; Bekalo, Pearl; Manandhar, Deepika; Ross, Tracy L; Speser, Sharon; Kingery, Julie; Carroll, Karen C

2010-11-01

A study was performed on 517 surveillance rectal swabs to evaluate a selective and differential chromogenic medium, the BBL CHROMagar VanRE (CVRE), which enables recovery and identification of VanA- and VanB-containing Enterococcus faecium (ENFM) and Enterococcus faecalis (ENFS) isolates. Compared to BBL Enterococcosel agar, a bile-esculin-azide-vancomycin (BEAV) agar, the initial overall sensitivity, specificity, and positive and negative predictive values of CVRE for the detection of vancomycin-resistant ENFM and ENFS were 99.1% and 94.8% and 84.2% and 99.7%, respectively. Among our patient population, more vancomycin-resistant enterococci (VRE) were recovered with CVRE than BEAV.

Evaluation of BBL CHROMagar VanRE for Detection of Vancomycin-Resistant Enterococci in Rectal Swab Specimens▿

PubMed Central

Stamper, Paul D.; Shulder, Stephanie; Bekalo, Pearl; Manandhar, Deepika; Ross, Tracy L.; Speser, Sharon; Kingery, Julie; Carroll, Karen C.

2010-01-01

A study was performed on 517 surveillance rectal swabs to evaluate a selective and differential chromogenic medium, the BBL CHROMagar VanRE (CVRE), which enables recovery and identification of VanA- and VanB-containing Enterococcus faecium (ENFM) and Enterococcus faecalis (ENFS) isolates. Compared to BBL Enterococcosel agar, a bile-esculin-azide-vancomycin (BEAV) agar, the initial overall sensitivity, specificity, and positive and negative predictive values of CVRE for the detection of vancomycin-resistant ENFM and ENFS were 99.1% and 94.8% and 84.2% and 99.7%, respectively. Among our patient population, more vancomycin-resistant enterococci (VRE) were recovered with CVRE than BEAV. PMID:20739492

Bullous dermatosis associated with vancomycin extravasation.

PubMed

Bohm, Nicole M; Wong, Jeffrey G

2012-02-01

Cutaneous side effects related to vancomycin therapy have been reported including histamine-related reactions, linear IgA bullous dermatosis, Stevens-Johnson syndrome, maculopapular rash and drug rash with eosinophilia and systemic symptoms. In all instances, these reports were due to the systemic administration of vancomycin and subsequent immunological reactions to the medication. Drug extravasation into soft tissues can result in a variety of clinical outcomes usually related to physiochemical properties of the drug extravasated and its diluents or pharmacologic effects on the vasculature and tissue. The authors report a patient who experienced vancomycin extravasation that resulted in a localized bullous eruption resembling linear IgA bullous dermatosis, a phenomenon not previously described in the literature.

Peak Measurement for Vancomycin AUC Estimation in Obese Adults Improves Precision and Lowers Bias.

PubMed

Pai, Manjunath P; Hong, Joseph; Krop, Lynne

2017-04-01

Vancomycin area under the curve (AUC) estimates may be skewed in obese adults due to weight-dependent pharmacokinetic parameters. We demonstrate that peak and trough measurements reduce bias and improve the precision of vancomycin AUC estimates in obese adults ( n = 75) and validate this in an independent cohort ( n = 31). The precision and mean percent bias of Bayesian vancomycin AUC estimates are comparable between covariate-dependent ( R 2 = 0.774, 3.55%) and covariate-independent ( R 2 = 0.804, 3.28%) models when peaks and troughs are measured but not when measurements are restricted to troughs only ( R 2 = 0.557, 15.5%). Copyright © 2017 American Society for Microbiology.

Effectiveness of local vancomycin powder to decrease surgical site infections: a meta-analysis.

PubMed

Chiang, Hsiu-Yin; Herwaldt, Loreen A; Blevins, Amy E; Cho, Edward; Schweizer, Marin L

2014-03-01

Some surgeons use systemic vancomycin to prevent surgical site infections (SSIs), but patients who do not carry methicillin-resistant Staphylococcus aureus have an increased risk of SSIs when given vancomycin alone for intravenous prophylaxis. Applying vancomycin powder to the wound before closure could increase the local tissue vancomycin level without significant systemic levels. However, the effectiveness of local vancomycin powder application for preventing SSIs has not been established. Our objective was to systematically review and evaluate studies on the effectiveness of local vancomycin powder for decreasing SSIs. Meta-analysis. We included observational studies, quasi-experimental studies, and randomized controlled trials of patients undergoing surgical procedures that involved vancomycin powder application to surgical wounds, reported SSI rates, and had a comparison group that did not use local vancomycin powder. The primary outcome was postoperative SSIs. The secondary outcomes included deep incisional SSIs and S. aureus SSIs. We performed systematic literature searches in PubMed, the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, the Cochrane Central Register of Controlled Trials via Wiley, Scopus (including EMBASE abstracts), Web of Science, ClinicalTrials.gov, BMC Proceedings, ProQuest Dissertation, and Thesis in Health and Medicine, and conference abstracts from IDWeek, the Interscience Conference on Antimicrobial Agents and Chemotherapy, the Society for Healthcare Epidemiology of America, and the American Academy of Orthopedic Surgeons annual meetings, and also the Scoliosis Research Society Annual Meeting and Course. We ran the searches from inception on May 9, 2013 with no limits on date or language. After reviewing 373 titles or abstracts and 22 articles in detail, we included 10 independent studies and used a random-effects model when pooling risk estimates to assess the effectiveness of local vancomycin powder application for preventing SSIs, the outcome of interest. We used the I²-index, Q-statistic, and corresponding p value to assess the heterogeneity of the risk estimates, and funnel plots to assess publication bias. We included seven quasi-experimental studies, two cohort studies, and one randomized controlled trial, encompassing 5,888 surgical patients. The pooled effects showed that applying local vancomycin powder was significantly protective against SSIs (pooled odds ratio [pOR] 0.19; 95% confidence interval [CI] 0.09-0.38), deep incisional SSIs (pOR 0.23; 95% CI 0.09-0.57), and SSIs caused by S. aureus (pOR 0.22; 95% CI 0.08-0.58). However, significant heterogeneity was present for studies evaluating all SSIs or deep incisional SSIs. When we pooled the risk estimates from the eight studies that assessed patients undergoing spinal operations, vancomycin powder remained significantly protective against SSIs (pOR 0.16; 95% CI 0.09-0.30), deep incisional SSIs (pOR 0.18; 95% CI 0.09-0.36), and SSIs caused by S. aureus (pOR 0.11; 95% CI 0.03-0.36). The pooled ORs from studies of spinal operations were lower than those for all studies and the estimates from spinal operation studies were homogeneous. However, there was evidence of publication bias. Local administration of vancomycin powder appears to protect against SSIs, deep incisional SSIs, and S. aureus SSIs after spinal operations. Large, high-quality studies should be performed to evaluate this intervention before it is used routinely. Copyright © 2014 Elsevier Inc. All rights reserved.

Titanium-tethered vancomycin prevents resistance to rifampicin in Staphylococcus aureus in vitro.

PubMed

Rottman, Martin; Goldberg, Joel; Hacking, S Adam

2012-01-01

Rifampicin is currently recognized as the most potent drug against Gram positive implant related infections. The use of rifampicin is limited by the emergence of bacterial resistance, which is often managed by coadministration of a second antibiotic. The purpose of this study was to determine the effectiveness of soluble rifampicin in combination with vancomycin tethered to titanium metal as a means to control bacterial growth and resistance in vitro. Bacterial growth was inhibited when the vancomycin-tethered titanium discs were treated with Staphylococcus aureus inocula of ≤2×10⁶ CFU, however inocula greater than 2×10⁶ CFU/disc adhered and survived. The combination of surface-tethered vancomycin with soluble rifampicin enhanced the inhibitory effect of rifampicin for an inoculum of 10⁶ CFU/cm² by one dilution (combination MIC of 0.008 mg/L versus 0.015 mg/L for rifampicin alone). Moreover, surface tethered vancomycin prevented the emergence of a rifampicin resistant population in an inoculum of 2×10⁸ CFU.

Titanium-Tethered Vancomycin Prevents Resistance to Rifampicin in Staphylococcus aureus in vitro

PubMed Central

Hacking, S. Adam

2012-01-01

Rifampicin is currently recognized as the most potent drug against Gram positive implant related infections. The use of rifampicin is limited by the emergence of bacterial resistance, which is often managed by coadministration of a second antibiotic. The purpose of this study was to determine the effectiveness of soluble rifampicin in combination with vancomycin tethered to titanium metal as a means to control bacterial growth and resistance in vitro. Bacterial growth was inhibited when the vancomycin-tethered titanium discs were treated with Staphylococcus aureus inocula of ≤2×106 CFU, however inocula greater than 2×106 CFU/disc adhered and survived. The combination of surface-tethered vancomycin with soluble rifampicin enhanced the inhibitory effect of rifampicin for an inoculum of 106 CFU/cm2 by one dilution (combination MIC of 0.008 mg/L versus 0.015 mg/L for rifampicin alone). Moreover, surface tethered vancomycin prevented the emergence of a rifampicin resistant population in an inoculum of 2×108 CFU. PMID:23285213

Evaluation of the Tissue Culture Standard and Correlation with DNA probes and ELISA for the Detection of Chlamydia Trachomatis

DTIC Science & Technology

1988-08-01

include the aminoglycosides, the aminocyclitols (spectinomycin), nalidixic acid, trimethoprim, vancomycin, metronidazole , lincomycin, cephalosporins...and antifungal agents such as nystatin and amphotericin B. This is why gentamicin, streptomycin, vancomycin and antifungals may be used in...often used are gentamicin or streptomycin, vancomycin, and amphotericin B or nystatin . Using 2-SP with antimicrobials will keep over 99% of cell

Combined effect of bacteriocin produced by Lactobacillus plantarum ST8SH and vancomycin, propolis or EDTA for controlling biofilm development by Listeria monocytogenes.

PubMed

Todorov, Svetoslav D; de Paula, Otávio A L; Camargo, Anderson C; Lopes, Danilo A; Nero, Luís A

The Listeria monocytogenes strains selected in the present study exhibited similar behavior in biofilm formation, independently of the tested conditions (bacteriocin from L. plantarum ST8SH, vancomycin, propolis (a natural antimicrobial product) and EDTA (chelating agent)), individual or in associations. The individual application of vancomycin had better inhibitory activity than that of propolis and EDTA; however, the association of the previously mentioned antimicrobial agents with bacteriocins resulted in better performance. However, when we compared the effects of vancomycin, propolis and EDTA, we could clearly observe that the combined application of bacteriocin and vancomycin was more effective than the combination of bacteriocin and propolis, and bacteriocin and EDTA. Considering the current need to reduce the use of antimicrobials and chemical substances in food processing, propolis can represent an alternative to improve the inhibitory effect of bacteriocins against L. monocytogenes biofilm formation, based on the obtained results. In general, high concentrations of bacteriocin produced by L. plantarum ST8SH were more effective in biofilm inhibition, and similar results were observed for vancomycin and propolis; however, all tested EDTA concentrations had similar effect on biofilm formation. Copyright © 2017 Asociación Argentina de Microbiología. Publicado por Elsevier España, S.L.U. All rights reserved.

Vancomycin intermediate-resistant Staphylococcus aureus (VISA) isolated from a patient who never received vancomycin treatment.

PubMed

Zhu, Xuhui; Liu, Cailin; Gao, Sui; Lu, Yanfang; Chen, Zhongju; Sun, Ziyong

2015-04-01

With the abuse of antibiotics, the methicillin-resistant Staphylococcus aureus (MRSA) strain became prevalent. Furthermore, Staphylococcus aureus with a character of vancomycin intermediate-resistance (VISA) has been found globally since the first report in Japan. The main objectives of this study were to report a case of VISA isolated from a Chinese patient who had never undergone Vancomycin treatment, and to determine its molecular character. A total of 9 strains were recovered from a patient during the therapeutic process. Antimicrobial susceptibility testing was performed to determine their antibiotic susceptibility patterns. To detect the VISA strain's molecular epidemiological features, growth and morphological characters, we used multilocus sequence typing, autolysis assay and transmission electric microscope tests. Pulsed-field gel electrophoresis (PFGE) was performed to characterize the heterogeneities of all isolates. One isolate was found to exhibit vancomycin intermediated-resistant with MIC of 8 μg/ml. It was ST239-T030-agr-1, had thickened cell wall, and displayed a slower growth rate and reduced susceptibility to Triton X-100-induced autolysis than other strains. All 9 strains exhibited the same PFGE pattern. This is the first report of VISA found in central China from a patient who had never received vancomycin treatment. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Vancomycin-Rifampin Combination Therapy Has Enhanced Efficacy against an Experimental Staphylococcus aureus Prosthetic Joint Infection

PubMed Central

Niska, Jared A.; Shahbazian, Jonathan H.; Ramos, Romela Irene; Francis, Kevin P.; Bernthal, Nicholas M.

2013-01-01

Treatment of prosthetic joint infections often involves a two-stage exchange, with implant removal and antibiotic spacer placement followed by systemic antibiotic therapy and delayed reimplantation. However, if antibiotic therapy can be improved, one-stage exchange or implant retention may be more feasible, thereby decreasing morbidity and preserving function. In this study, a mouse model of prosthetic joint infection was used in which Staphylococcus aureus was inoculated into a knee joint containing a surgically placed metallic implant extending from the femur. This model was used to evaluate whether combination therapy of vancomycin plus rifampin has increased efficacy compared with vancomycin alone against these infections. On postoperative day 7, vancomycin with or without rifampin was administered for 6 weeks with implant retention. In vivo bioluminescence imaging, ex vivo CFU enumeration, X-ray imaging, and histologic analysis were carried out. We found that there was a marked therapeutic benefit when vancomycin was combined with rifampin compared with vancomycin alone. Taken together, our results suggest that the mouse model used could serve as a valuable in vivo preclinical model system to evaluate and compare efficacies of antibiotics and combinatory therapy for prosthetic joint infections before more extensive studies are carried out in human subjects. PMID:23917317

A novel injectable borate bioactive glass cement for local delivery of vancomycin to cure osteomyelitis and regenerate bone.

PubMed

Cui, Xu; Zhao, Cunju; Gu, Yifei; Li, Le; Wang, Hui; Huang, Wenhai; Zhou, Nai; Wang, Deping; Zhu, Yi; Xu, Jun; Luo, Shihua; Zhang, Changqing; Rahaman, Mohamed N

2014-03-01

Osteomyelitis (bone infection) is often difficult to cure. The commonly-used treatment of surgical debridement to remove the infected bone combined with prolonged systemic and local antibiotic treatment has limitations. In the present study, an injectable borate bioactive glass cement was developed as a carrier for the antibiotic vancomycin, characterized in vitro, and evaluated for its capacity to cure osteomyelitis in a rabbit tibial model. The cement (initial setting time = 5.8 ± 0.6 min; compressive strength = 25.6 ± 0.3 MPa) released vancomycin over ~25 days in phosphate-buffered saline, during which time the borate glass converted to hydroxyapatite (HA). When implanted in rabbit tibial defects infected with methicillin-resistant Staphylococcus aureus (MRSA)-induced osteomyelitis, the vancomycin-loaded cement converted to HA and supported new bone formation in the defects within 8 weeks. Osteomyelitis was cured in 87 % of the defects implanted with the vancomycin-loaded borate glass cement, compared to 71 % for the defects implanted with vancomycin-loaded calcium sulfate cement. The injectable borate bioactive glass cement developed in this study is a promising treatment for curing osteomyelitis and for regenerating bone in the defects following cure of the infection.

[Two cases of vancomycin-intermediate Staphylococcus aureus isolated from joint tissue or wound].

PubMed

Hong, Ki Ho; Park, Jeong Su; Kim, Eui-Chong

2008-12-01

Since its first isolation in 1997, vancomycin-intermediate Staphylococcus aureus (VISA) has been a clinical concern because it may lead to treatment failure. Up to the present, there were two reports of clinical VISA cases in Korea. We now report two additional cases of VISA with the minimum inhibitory concentration (MIC) of 4 microg/mL. The first patient was a 59 yr-old man who had undergone total hip replacement arthroplasty in 1999 due to avascular necrosis of femur heads. He had recurrent episodes of infected hip caused by methicillin-resistant Staphylococcus aureus (MRSA) and was treated with vancomycin. He underwent replacement operation of prosthesis. Cultures of joint fluid and joint tissue grew S. aureus. Vancomycin MIC as determined by a broth microdilution method was 4 microg/mL for the both isolates. The patient was treated with high enough doses of vancomycin to maintain serum trough concentrations at 20-25 microg/mL for 52 days and was discharged. The second patient was a 57 yr-old man with diabetes. He lost consciousness from drinking. After recovery of consciousness, he was diagnosed with aspiration pneumonia. MRSA and Acinetobacter baumannii were cultured from sputum and the patient was treated with vancomycin and meropenem. During hospitalization, bed sores developed in his ankle and back. A wound culture from the sore grew S. aureus with vancomycin MIC of 4 microg/mL. Since infection was localized, systemic antibiotics did not seem necessary, and the patient was transferred to another hospital for isolation and management.

Susceptibility Profile of Staphylococcus epidermidis and Staphylococcus haemolyticus Isolated from Blood Cultures to Vancomycin and Novel Antimicrobial Drugs over a Period of 12 Years.

PubMed

Pinheiro, Luiza; Brito, Carla Ivo; Pereira, Valéria Cataneli; Oliveira, Adilson; Bartolomeu, Ariane Rocha; Camargo, Carlos Henrique; Cunha, Maria Lourdes Ribeiro Souza

2016-06-01

The aim of this study was to evaluate the antimicrobial susceptibility profile of 85 Staphylococcus epidermidis and 84 Staphylococcus haemolyticus strains isolated from blood cultures to oxacillin, vancomycin, tigecycline, linezolid, daptomycin, and quinupristin/dalfopristin over a period of 12 years. S. epidermidis and S. haemolyticus isolated from blood cultures of inpatients, attended at a teaching hospital, were analyzed for the presence of the mecA gene and by SCCmec typing. The minimum inhibitory concentration (MIC) values of tigecycline, linezolid, daptomycin, quinupristin/dalfopristin, and vancomycin were determined. Isolates exhibiting vancomycin MICs of ≥2 μg/ml were typed by pulsed-field gel electrophoresis (PFGE). The rate of mecA positivity was 92.9% and 100% in S. epidermidis and S. haemolyticus, respectively. The most frequent SCCmec types were type III (53.2%) in S. epidermidis and type I (32.1%) in S. haemolyticus. All isolates were susceptible to linezolid and daptomycin, but 7.1% of S. haemolyticus and 2.3% of S. epidermidis isolates were resistant to tigecycline, and 1.2% each of S. haemolyticus and S. epidermidis were resistant and intermediately resistant to quinupristin/dalfopristin, respectively. S. epidermidis exhibited higher vancomycin MICs (40% with MIC of ≥2 μg/ml). Clonal typing of strains with vancomycin MIC of ≥2 μg/ml revealed the presence of different PFGE types of S. epidermidis and S. haemolyticus over a period of up to 4 years (2002-2004, 2005-2008, 2006-2009, 2010-2011). Despite the observation of a high prevalence of mecA, the clinical strains were fully susceptible to vancomycin and to the new drugs linezolid, daptomycin, tigecycline, and quinupristin/dalfopristin. The PFGE types with vancomycin MIC of ≥2 μg/ml exhibited a great diversity of SCCmec cassettes, demonstrating that S. epidermidis and S. haemolyticus may easily acquire these resistance-conferring genetic elements.

Sphygmomanometers and thermometers as potential fomites of Staphylococcus haemolyticus: biofilm formation in the presence of antibiotics.

PubMed

Sued, Bruna Pinto Ribeiro; Pereira, Paula Marcele Afonso; Faria, Yuri Vieira; Ramos, Juliana Nunes; Binatti, Vanessa Batista; Santos, Kátia Regina Netto Dos; Seabra, Sérgio Henrique; Hirata, Raphael; Vieira, Verônica Viana; Mattos-Guaraldi, Ana Luíza; Pereira, José Augusto Adler

2017-03-01

The association between Staphylococcus haemolyticus and severe nosocomial infections is increasing. However, the extent to which fomites contribute to the dissemination of this pathogen through patients and hospital wards remains unknown. In the present study, sphygmomanometers and thermometers were evaluated as potential fomites of oxacillin-resistant S. haemolyticus (ORSH). The influence of oxacillin and vancomycin on biofilm formation by ORSH strains isolated from fomites was also investigated. The presence of ORSH on swabs taken from fomite surfaces in a Brazilian hospital was assessed using standard microbiological procedures. Antibiotic susceptibility profiles were determined by the disk diffusion method, and clonal distribution was assessed in pulsed-field gel electrophoresis (PFGE) assays. Minimum inhibitory concentrations (MICs) of oxacillin and vancomycin were evaluated via the broth microdilution method. Polymerase chain reaction (PCR) assays were performed to detect the mecA and icaAD genes. ORSH strains grown in media containing 1/4 MIC of vancomycin or oxacillin were investigated for slime production and biofilm formation on glass, polystyrene and polyurethane catheter surfaces. ORSH strains comprising five distinct PFGE types were isolated from sphygmomanometers (n = 5) and a thermometer (n = 1) used in intensive care units and surgical wards. ORSH strains isolated from fomites showed susceptibility to only linezolid and vancomycin and were characterised as multi-drug resistant (MDR). Slime production, biofilm formation and the survival of sessile bacteria differed and were independent of the presence of the icaAD and mecA genes, PFGE type and subtype. Vancomycin and oxacillin did not inhibit biofilm formation by vancomycin-susceptible ORSH strains on abiotic surfaces, including on the catheter surface. Enhanced biofilm formation was observed in some situations. Moreover, a sub-lethal dose of vancomycin induced biofilm formation by an ORSH strain on polystyrene. Sphygmomanometers and thermometers are fomites for the transmission of ORSH. A sub-lethal dose of vancomycin may favor biofilm formation by ORSH on fomites and catheter surfaces.

Sphygmomanometers and thermometers as potential fomites of Staphylococcus haemolyticus: biofilm formation in the presence of antibiotics

PubMed Central

Sued, Bruna Pinto Ribeiro; Pereira, Paula Marcele Afonso; Faria, Yuri Vieira; Ramos, Juliana Nunes; Binatti, Vanessa Batista; dos Santos, Kátia Regina Netto; Seabra, Sérgio Henrique; Hirata, Raphael; Vieira, Verônica Viana; Mattos-Guaraldi, Ana Luíza; Pereira, José Augusto Adler

2017-01-01

BACKGROUND The association between Staphylococcus haemolyticus and severe nosocomial infections is increasing. However, the extent to which fomites contribute to the dissemination of this pathogen through patients and hospital wards remains unknown. OBJECTIVES In the present study, sphygmomanometers and thermometers were evaluated as potential fomites of oxacillin-resistant S. haemolyticus (ORSH). The influence of oxacillin and vancomycin on biofilm formation by ORSH strains isolated from fomites was also investigated. METHODS The presence of ORSH on swabs taken from fomite surfaces in a Brazilian hospital was assessed using standard microbiological procedures. Antibiotic susceptibility profiles were determined by the disk diffusion method, and clonal distribution was assessed in pulsed-field gel electrophoresis (PFGE) assays. Minimum inhibitory concentrations (MICs) of oxacillin and vancomycin were evaluated via the broth microdilution method. Polymerase chain reaction (PCR) assays were performed to detect the mecA and icaAD genes. ORSH strains grown in media containing 1/4 MIC of vancomycin or oxacillin were investigated for slime production and biofilm formation on glass, polystyrene and polyurethane catheter surfaces. FINDINGS ORSH strains comprising five distinct PFGE types were isolated from sphygmomanometers (n = 5) and a thermometer (n = 1) used in intensive care units and surgical wards. ORSH strains isolated from fomites showed susceptibility to only linezolid and vancomycin and were characterised as multi-drug resistant (MDR). Slime production, biofilm formation and the survival of sessile bacteria differed and were independent of the presence of the icaAD and mecA genes, PFGE type and subtype. Vancomycin and oxacillin did not inhibit biofilm formation by vancomycin-susceptible ORSH strains on abiotic surfaces, including on the catheter surface. Enhanced biofilm formation was observed in some situations. Moreover, a sub-lethal dose of vancomycin induced biofilm formation by an ORSH strain on polystyrene. MAIN CONCLUSIONS Sphygmomanometers and thermometers are fomites for the transmission of ORSH. A sub-lethal dose of vancomycin may favor biofilm formation by ORSH on fomites and catheter surfaces. PMID:28225903

Efficacy and safety of delafloxacin compared with vancomycin plus aztreonam for acute bacterial skin and skin structure infections: a Phase 3, double-blind, randomized study.

PubMed

Pullman, J; Gardovskis, J; Farley, B; Sun, E; Quintas, M; Lawrence, L; Ling, R; Cammarata, S

2017-12-01

Delafloxacin is an investigational anionic fluoroquinolone in development for oral or intravenous administration for the treatment of infections caused by Gram-positive (including MRSA), Gram-negative, atypical and anaerobic organisms. To establish the non-inferiority of delafloxacin compared with vancomycin plus aztreonam for the treatment of acute bacterial skin and skin structure infections and to compare the safety of the two antimicrobials. A Phase 3, multicentre, randomized, double-blind, active-controlled study with 660 patients compared delafloxacin 300 mg or vancomycin 15 mg/kg plus aztreonam 2 g each administered twice daily intravenously for 5-14 days. Non-inferiority was evaluated by objective response (≥20% erythema reduction) at 48-72 h after initiation of study drug, investigator subjective assessment of outcome and microbiological responses. Clinical Trials Registration: NCT01811732. EudraCT number: 2012-001767-71. In the ITT analysis set, the objective response was 78.2% in the delafloxacin arm and 80.9% in the vancomycin/aztreonam arm (mean treatment difference, -2.6%; 95% CI, -8.78% to 3.57%). Investigator-assessed cure was similar between the two groups at follow-up (52.0% versus 50.5%) and late follow-up (70.4% versus 66.6%). Bacterial eradication of MRSA was 100% and 98.5% in the delafloxacin group and the vancomycin/aztreonam group, respectively. Frequency of treatment-emergent adverse events in the delafloxacin and vancomycin/aztreonam groups was similar. Treatment-emergent adverse events leading to study drug discontinuation were higher in the vancomycin/aztreonam group compared with the delafloxacin group (4.3% versus 0.9%). Delafloxacin, an anionic fluoroquinolone, was statistically non-inferior to vancomycin/aztreonam at 48-72 h following the start of therapy and was well tolerated as monotherapy in the treatment of acute bacterial skin and skin structure infections. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

Efficacy and safety of delafloxacin compared with vancomycin plus aztreonam for acute bacterial skin and skin structure infections: a Phase 3, double-blind, randomized study

PubMed Central

Pullman, J; Gardovskis, J; Farley, B; Sun, E; Quintas, M; Lawrence, L; Ling, R; Cammarata, S

2017-01-01

Abstract Background Delafloxacin is an investigational anionic fluoroquinolone in development for oral or intravenous administration for the treatment of infections caused by Gram-positive (including MRSA), Gram-negative, atypical and anaerobic organisms. Objectives To establish the non-inferiority of delafloxacin compared with vancomycin plus aztreonam for the treatment of acute bacterial skin and skin structure infections and to compare the safety of the two antimicrobials. Patients and methods A Phase 3, multicentre, randomized, double-blind, active-controlled study with 660 patients compared delafloxacin 300 mg or vancomycin 15 mg/kg plus aztreonam 2 g each administered twice daily intravenously for 5–14 days. Non-inferiority was evaluated by objective response (≥20% erythema reduction) at 48–72 h after initiation of study drug, investigator subjective assessment of outcome and microbiological responses. Clinical Trials Registration: NCT01811732. EudraCT number: 2012-001767-71. Results In the ITT analysis set, the objective response was 78.2% in the delafloxacin arm and 80.9% in the vancomycin/aztreonam arm (mean treatment difference, −2.6%; 95% CI, −8.78% to 3.57%). Investigator-assessed cure was similar between the two groups at follow-up (52.0% versus 50.5%) and late follow-up (70.4% versus 66.6%). Bacterial eradication of MRSA was 100% and 98.5% in the delafloxacin group and the vancomycin/aztreonam group, respectively. Frequency of treatment-emergent adverse events in the delafloxacin and vancomycin/aztreonam groups was similar. Treatment-emergent adverse events leading to study drug discontinuation were higher in the vancomycin/aztreonam group compared with the delafloxacin group (4.3% versus 0.9%). Conclusions Delafloxacin, an anionic fluoroquinolone, was statistically non-inferior to vancomycin/aztreonam at 48–72 h following the start of therapy and was well tolerated as monotherapy in the treatment of acute bacterial skin and skin structure infections. PMID:29029278

Pharmacist-led implementation of a vancomycin guideline across medical and surgical units: impact on clinical behavior and therapeutic drug monitoring outcomes

PubMed Central

Phillips, Cameron J; Gordon, David L

2015-01-01

Background Vancomycin is the antibiotic of choice for the treatment of serious infections such as methicillin-resistant Staphylococcus aureus (MRSA). Inappropriate prescribing of vancomycin can lead to therapeutic failure, antibiotic resistance, and drug toxicity. Objective To examine the effectiveness of pharmacist-led implementation of a clinical practice guideline for vancomycin dosing and monitoring in a teaching hospital. Methods An observational pre–post study design was undertaken to evaluate the implementation of the vancomycin guideline. The implementation strategy principally involved education, clinical vignettes, and provision of pocket guidelines to accompany release of the guideline to the hospital Intranet. The target cohort for clinical behavioral change was junior medical officers, as they perform the majority of prescribing and monitoring of vancomycin in hospitals. Assessment measures were recorded for vancomycin prescribing, therapeutic drug monitoring, and patient outcomes. Results Ninety-nine patients, 53 pre- and 46 post-implementation, were included in the study. Prescribing of a loading dose increased from 9% to 28% (P=0.02), and guideline adherence to starting maintenance dosing increased from 53% to 63% (P=0.32). Dose adjustment by doctors when blood concentrations were outside target increased from 53% to 71% (P=0.12), and correct timing of initial concentration measurement increased from 43% to 57% (P=0.23). Appropriately timed trough concentrations improved from 73% to 81% (P=0.08). Pre-dose (trough) concentrations in target range rose from 33% to 44% (P=0.10), while potentially toxic concentrations decreased from 32% to 21% (P=0.05) post-implementation. Infection cure rates for patients increased from 85% to 96% (P=0.11) after the guideline was implemented. Conclusion The implementation strategy employed in this study demonstrated potential effectiveness, and should prompt additional larger studies to optimize strategies that will translate into improved clinical practice using vancomycin. PMID:29354529

Cost-effectiveness analysis of treatment strategies for initial Clostridium difficile infection.

PubMed

Varier, R U; Biltaji, E; Smith, K J; Roberts, M S; Jensen, M K; LaFleur, J; Nelson, R E

2014-12-01

Clostridium difficile infection (CDI) is costly. Current guidelines recommend metronidazole as first-line therapy and vancomycin as an alternative. Recurrence is common. Faecal microbiota transplantation (FMT) is an effective therapy for recurrent CDI (RCDI). This study explores the cost-effectiveness of FMT, vancomycin and metronidazole for initial CDI. We constructed a decision-analytic computer simulation using inputs from published literature to compare FMT with a 10-14-day course of oral metronidazole or vancomycin for initial CDI. Parameters included cure rates (baseline value (range)) for metronidazole (80% (65-85%)), vancomycin (90% (88-92%)) and FMT(91% (83-100%)). Direct costs of metronidazole, vancomycin and FMT, adjusted to 2011 dollars, were $57 ($43-72), $1347 ($1195-1499) and $1086 ($815-1358), respectively. Our effectiveness measure was quality-adjusted life years (QALYs). One-way and probabilistic sensitivity analyses were conducted from the third-party payer perspective. Analysis using baseline values showed that FMT($1669, 0.242 QALYs) dominated (i.e. was less costly and more effective) vancomycin ($1890, 0.241 QALYs). FMT was more costly and more effective than metronidazole ($1167, 0.238 QALYs), yielding an incremental cost-effectiveness ratio (ICER) of $124 964/QALY. One-way sensitivity analyses showed that metronidazole dominated both strategies if its probability of cure were >90%; FMT dominated if it cost <$584. In a probabilistic sensitivity analysis at a willingness-to-pay threshold of $100 000/QALY, metronidazole was favoured in 55% of model iterations; FMT was favoured in 38%. Metronidazole, as the first-line treatment for CDIs, is less costly. FMT and vancomycin are more effective. However, FMT is less likely to be economically favourable, and vancomycin is unlikely to be favourable as first-line therapy when compared with FMT. © 2014 The Authors Clinical Microbiology and Infection © 2014 European Society of Clinical Microbiology and Infectious Diseases.

Cost-effectiveness analysis of fidaxomicin versus vancomycin in Clostridium difficile infection.

PubMed

Nathwani, Dilip; Cornely, Oliver A; Van Engen, Anke K; Odufowora-Sita, Olatunji; Retsa, Peny; Odeyemi, Isaac A O

2014-11-01

Fidaxomicin was non-inferior to vancomycin with respect to clinical cure rates in the treatment of Clostridium difficile infections (CDIs) in two Phase III trials, but was associated with significantly fewer recurrences than vancomycin. This economic analysis investigated the cost-effectiveness of fidaxomicin compared with vancomycin in patients with severe CDI and in patients with their first CDI recurrence. A 1 year time horizon Markov model with seven health states was developed from the perspective of Scottish public healthcare providers. Model inputs for effectiveness, resource use, direct costs and utilities were obtained from published sources and a Scottish expert panel. The main model outcome was the incremental cost-effectiveness ratio (ICER), expressed as cost per quality-adjusted life year (QALY), for fidaxomicin versus vancomycin; ICERs were interpreted using willingness-to-pay thresholds of £20,000/QALY and £30,000/QALY. One-way and probabilistic sensitivity analyses were performed. Total costs were similar with fidaxomicin and vancomycin in patients with severe CDI (£14,515 and £14,344, respectively) and in patients with a first recurrence (£16,535 and £16,926, respectively). Improvements in clinical outcomes with fidaxomicin resulted in small QALY gains versus vancomycin (severe CDI, +0.010; patients with first recurrence, +0.019). Fidaxomicin was cost-effective in severe CDI (ICER £16,529/QALY) and dominant (i.e. more effective and less costly) in patients with a first recurrence. The probability that fidaxomicin was cost-effective at a willingness-to-pay threshold of £30,000/QALY was 60% for severe CDI and 68% in a first recurrence. Fidaxomicin is cost-effective in patients with severe CDI and in patients with a first CDI recurrence versus vancomycin. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection in patients aged ≥60 years (EXTEND): analysis of cost-effectiveness.

PubMed

Cornely, Oliver A; Watt, Maureen; McCrea, Charles; Goldenberg, Simon D; De Nigris, Enrico

2018-05-24

The randomized Phase IIIb/IV EXTEND trial showed that extended-pulsed fidaxomicin significantly improved sustained clinical cure and reduced recurrence versus vancomycin in patients ≥60 years old with Clostridium difficile infection (CDI). Cost-effectiveness of extended-pulsed fidaxomicin versus vancomycin as first-line therapy for CDI was evaluated in this patient population. Clinical results from EXTEND and inputs from published sources were used in a semi-Markov treatment-sequence model with nine health states and a 1 year time horizon to assess costs and QALYs. The model was based on a healthcare system perspective (NHS and Personal Social Services) in England. Sensitivity analyses were performed. Patients receiving first-line extended-pulsed fidaxomicin treatment had a 0.02 QALY gain compared with first-line vancomycin (0.6267 versus 0.6038 QALYs/patient). While total drug acquisition costs were higher for extended-pulsed fidaxomicin than for vancomycin when used first-line (£1356 versus £260/patient), these were offset by lower total hospitalization costs (which also included treatment monitoring and community care costs; £10 815 versus £11 459/patient) and lower costs of managing adverse events (£694 versus £1199/patient), reflecting the lower incidence of CDI recurrence and adverse events with extended-pulsed fidaxomicin. Extended-pulsed fidaxomicin cost £53 less per patient than vancomycin over 1 year. The probability that first-line extended-pulsed fidaxomicin was cost-effective at a willingness-to-pay threshold of £30 000/QALY was 76% in these patients. While fidaxomicin acquisition costs are higher than those of vancomycin, the observed reduced recurrence rate with extended-pulsed fidaxomicin makes it a more effective and less costly treatment strategy than vancomycin for first-line treatment of CDI in older patients.

Vancomycin for the treatment of Clostridium difficile Infection: for whom is this expensive bullet really magic?

PubMed

Pepin, Jacques

2008-05-15

The epidemiology, clinical severity, and case-fatality ratio of Clostridium difficile infection (CDI) changed dramatically with the emergence of a toxin hyperproducing strain (BI/NAP1/027) in North America and Europe in 2000. For the treatment of CDI, metronidazole and vancomycin remain the 2 most commonly used drugs. The 3 randomized controlled trials published thus far, as well as the upcoming tolevamer trial, use intermediate outcomes, rather than the outcomes that now preoccupy clinicians: the frequency of complications or recurrence. The major advantage of metronidazole is its low price. The major advantage of orally administered vancomycin is its more favorable pharmacokinetics. Facilitating vancomycin-resistant enterococci colonization and/or infection is a potential drawback of both drugs. Pending the development of a prospectively validated scoring system, members of the Infectious Diseases Society of America/Society for Healthcare Epidemiology of America expert committee will define severe CDI as present in any patient with a leukocyte count > or =15,000 cells/mm(3) or a creatinine level increased by > or =50% from baseline. For patients with mild-to-moderate CDI (defined by a leukocyte count <15000 cells/mm(3) and a creatinine level <1.5 times the baseline value), there is no evidence that treatment with vancomycin is superior to treatment with metronidazole (even for intermediate outcomes), and metronidazole therapy should be preferred. For patients with severe CDI who are not infected with BI/NAP1/027, there is reasonable evidence that the better pharmacokinetics of vancomycin translate into a lower probability of complications. For those patients who are infected with BI/NAP1/027, the superiority of vancomycin therapy remains to be proven. In practice, because it is not yet possible to rapidly type the strains, all patients with severe CDI should be treated with vancomycin. Future trials should use complicated CDI and recurrences as their primary outcomes.

“Slow VISA,” a Novel Phenotype of Vancomycin Resistance, Found In Vitro in Heterogeneous Vancomycin-Intermediate Staphylococcus aureus Strain Mu3

PubMed Central

Saito, Michie; Katayama, Yuki; Hishinuma, Tomomi; Iwamoto, Akira; Aiba, Yoshifumi; Kuwahara-Arai, Kyoko; Cui, Longzhu; Matsuo, Miki; Aritaka, Nanae

2014-01-01

Heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) clinical strain Mu3 spontaneously generates VISA strains at an extremely high frequency (≥1 × 10−6). The generated VISA strains usually grow more slowly than does the parent hVISA strain, but they form colonies on vancomycin-containing agar plates before 48 h of incubation. However, we noticed a curious group of VISA strains, designated “slow VISA” (sVISA), whose colonies appear only after 72 h of incubation. They have extremely prolonged doubling times but have vancomycin MICs of 8 to ∼24 mg/liter when determined after 72 to ∼144 h of incubation. We established strain Mu3-6R-P (6R-P), which has a vancomycin MIC of 16 mg/liter (at 72 h), as a representative sVISA strain. Its cell wall was thickened and autolytic activity was decreased compared to the respective qualities of the parent hVISA strain Mu3. Whole-genome sequencing of 6R-P revealed only one mutation, encoded by rpoB (R512P), which replaced the 512th arginine of the RNA polymerase β-subunit with proline. Its VISA phenotype was unstable, and the strain frequently reverted to hVISA with concomitant losses of pinpoint colony morphology and cell wall thickness and reduced autolytic activity. Sequencing of the rpoB genes of the phenotypic revertant strains revealed mutations affecting the 512th codon, where the proline of 6R-P was replaced with leucine, serine, or histidine. Slow VISA generated in the tissues of an infected patient serves as a temporary shelter for hVISA to survive vancomycin therapy. The sVISA strain spontaneously returns to hVISA when the threat of vancomycin is lifted. The rpoB(R512P) mutation may be regarded as a regulatory mutation that switches the reversible phenotype of sVISA on and off. PMID:24841271

"Slow VISA," a novel phenotype of vancomycin resistance, found in vitro in heterogeneous vancomycin-intermediate Staphylococcus aureus strain Mu3.

PubMed

Saito, Michie; Katayama, Yuki; Hishinuma, Tomomi; Iwamoto, Akira; Aiba, Yoshifumi; Kuwahara-Arai, Kyoko; Cui, Longzhu; Matsuo, Miki; Aritaka, Nanae; Hiramatsu, Keiichi

2014-09-01

Heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) clinical strain Mu3 spontaneously generates VISA strains at an extremely high frequency (≥1×10(-6)). The generated VISA strains usually grow more slowly than does the parent hVISA strain, but they form colonies on vancomycin-containing agar plates before 48 h of incubation. However, we noticed a curious group of VISA strains, designated "slow VISA" (sVISA), whose colonies appear only after 72 h of incubation. They have extremely prolonged doubling times but have vancomycin MICs of 8 to ∼24 mg/liter when determined after 72 to ∼144 h of incubation. We established strain Mu3-6R-P (6R-P), which has a vancomycin MIC of 16 mg/liter (at 72 h), as a representative sVISA strain. Its cell wall was thickened and autolytic activity was decreased compared to the respective qualities of the parent hVISA strain Mu3. Whole-genome sequencing of 6R-P revealed only one mutation, encoded by rpoB (R512P), which replaced the 512th arginine of the RNA polymerase β-subunit with proline. Its VISA phenotype was unstable, and the strain frequently reverted to hVISA with concomitant losses of pinpoint colony morphology and cell wall thickness and reduced autolytic activity. Sequencing of the rpoB genes of the phenotypic revertant strains revealed mutations affecting the 512th codon, where the proline of 6R-P was replaced with leucine, serine, or histidine. Slow VISA generated in the tissues of an infected patient serves as a temporary shelter for hVISA to survive vancomycin therapy. The sVISA strain spontaneously returns to hVISA when the threat of vancomycin is lifted. The rpoB(R512P) mutation may be regarded as a regulatory mutation that switches the reversible phenotype of sVISA on and off. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Trend in vancomycin susceptibility and correlation with molecular characteristics of methicillin-resistant Staphylococcus aureus causing invasive infections in Taiwan: results from the Tigecycline in vitro Surveillance in Taiwan (TIST) study, 2006-2010.

PubMed

Tsao, Shin-Ming; Wang, Wei-Yao; Ko, Wen-Chien; Huang, Cheng-Hua; Lu, Chin-Te; Chuang, Yin-Ching; Liu, Chia-Ying; Liao, Chun-Hsing; Chen, Yao-Shen; Liu, Yung-Ching; Chen, Wei-Yu; Jang, Tsrang-Neng; Lin, Hsiu-Chen; Chen, Chih-Ming; Shi, Zhi-Yuan; Pan, Sung-Ching; Yang, Jia-Ling; Kung, Hsiang-Chi; Liu, Chun-Eng; Cheng, Yu-Jen; Liu, Jien-Wei; Sun, Wu; Wang, Lih-Shinn; Yu, Kwok-Woon; Chiang, Ping-Cherng; Lee, Ming-Hsun; Lee, Chun-Ming; Hsu, Gwo-Jong; Chen, Yen-Hsu; Lu, Po-Liang; Thomas, Chang-Yao Tsao; Hsueh, Po-Ren

2014-10-01

This study was intended to investigate the trend in vancomycin susceptibility and correlation with molecular characteristics of methicillin-resistant Staphylococcus aureus (MRSA) causing invasive infections. A total of 670 MRSA isolates were collected from patients with invasive infections as part of bacterial collection in the Tigecycline in vitro Surveillance in Taiwan (TIST) from 2006 to 2010. MICs of the isolates to vancomycin were determined using the agar dilution method. Characteristics of staphylococcal cassette chromosome mec (SCCmec), mec-associated hypervariable region (dru), and accessory gene regulator (agr) of the isolates were identified by polymerase chain reaction methods. MRSA isolates with SCCmec types I, II, and III were molecularly defined as hospital-associated MRSA (HA-MRSA), and those with SCCmec types IV, V, and VT were assigned as community-associated MRSA (CA-MRSA). All but 1 MRSA isolates exhibited vancomycin MICs ≤1 mg/L. A declining trend in vancomycin MICs among MRSA isolates was noted, which was associated with the decline in proportion of HA-MRSA. The percentage of CA-MRSA increased from 25.6% in 2006 to 46.0% in 2010. An increase in the geometric mean of vancomycin MICs was found in MRSA with particular molecular types such as SCCmec types II and III, agr groups I and II, and dru10-14. A significant correlation among particular molecular types was found, including SCCmecII-agr group II-dru4, SCCmecIII-agr group I-dru11-14, SCCmecIV-agr group II-dru9, and SCCmecVT-agr group I-dru9 and dru11. There was no vancomycin creep among MRSA isolates, and the declining trend of vancomycin MIC against MRSA was attributed to the increasing prevalence of CA-MRSA over time. Copyright © 2014 Elsevier Inc. All rights reserved.

Antistaphylococcal activity of DX-619 alone and in combination with vancomycin, teicoplanin, and linezolid assessed by time-kill synergy testing.

PubMed

Credito, Kim; Lin, Genrong; Appelbaum, Peter C

2007-04-01

Time-kill synergy studies testing in vitro activity of DX-619 alone and with added vancomycin, teicoplanin, or linezolid against 101 Staphylococcus aureus strains showed synergy between DX-619 and teicoplanin at 12 to 24 h in 72 strains and between DX-619 and vancomycin in 28 strains. No synergy was found with linezolid, and no antagonism was observed with any combination.

Whole genome characterization of a naturally occurring vancomycin-dependent Enterococcus faecium from a patient with bacteremia.

PubMed

Mitchell, Stephanie L; Mattei, Lisa M; Alby, Kevin

2017-08-01

Vancomycin-dependent enterococci are a relatively uncommon phenotype recovered in the clinical laboratory. Recognition and recovery of these isolates are important, to provide accurate identification and susceptibility information to treating physicians. Herein, we describe the recovery of a vancomycin-dependent and revertant E. faecium isolates harboring vanB operon from a patient with bacteremia. Using whole genome sequencing, we found a unique single nucleotide polymorphism (S186N) in the D-Ala-D-Ala ligase (ddl) conferring vancomycin-dependency. Additionally, we found that a majority of in vitro revertants mutated outside ddl, with some strains harboring mutations in vanS, while others likely containing novel mechanisms of reversion. Copyright © 2017 Elsevier B.V. All rights reserved.

Vancomycin-Loaded Polymethylmethacrylate Spacers Fail to Eradicate Periprosthetic Joint Infection in a Clinically Representative Mouse Model.

PubMed

Carli, Alberto V; Bhimani, Samrath; Yang, Xu; de Mesy Bentley, Karen L; Ross, F Patrick; Bostrom, Mathias P G

2018-06-06

Periprosthetic joint infection (PJI) remains a devastating complication following total joint arthroplasty. Current animal models of PJI do not effectively recreate the clinical condition and thus provide limited help in understanding why treatments fail. We developed a mouse model of the first-stage surgery of a 2-stage revision for PJI involving a 3-dimensionally printed Ti-6Al-4V implant and a mouse-sized cement spacer that elutes vancomycin. Vancomycin was mixed with polymethylmethacrylate (PMMA) cement and inserted into custom-made mouse-sized spacer molds. Twenty C57BL/6 mice received a proximal tibial implant and an intra-articular injection of 3 × 10 colony-forming units of Staphylococcus aureus Xen36. At 2 weeks, 9 mice underwent irrigation and debridement of the leg with revision of the implant to an articulating vancomycin-loaded PMMA spacer. Postoperatively, mice underwent radiography and serum inflammatory-marker measurements. Following euthanasia of the mice at 6 weeks, bone and soft tissues were homogenized to quantify bacteria within periprosthetic tissues. Implants and articulating spacers were either sonicated to quantify adherent bacteria or examined under scanning electron microscopy (SEM) to characterize the biofilm. Vancomycin-loaded PMMA spacers eluted vancomycin for ≤144 hours and retained antimicrobial activity. Control mice had elevated levels of inflammatory markers, radiographic evidence of septic loosening of the implant, and osseous destruction. Mice treated with a vancomycin-loaded PMMA spacer had significantly lower levels of inflammatory markers (p < 0.01), preserved tibial bone, and no intra-articular purulence. Retrieved vancomycin-loaded spacers exhibited significantly lower bacterial counts compared with implants (p < 0.001). However, bacterial counts in periprosthetic tissue did not significantly differ between the groups. SEM identified S. aureus encased within biofilm on control implants, while vancomycin-loaded spacers contained no bacteria. This animal model is a clinically representative model of PJI treatment. The results suggest that the antimicrobial effects of PMMA spacers are tightly confined to the articular space and must be utilized in conjunction with thorough tissue debridement and systemic antibiotics. These data provide what we believe to be the first insight into the effect of antibiotic-loaded cement spacers in a clinically relevant animal model and justify the adjunctive use of intravenous antibiotics when performing a 2-stage revision for PJI.

A meta-analysis of metronidazole and vancomycin for the treatment of Clostridium difficile infection, stratified by disease severity.

PubMed

Di, Xiuzhen; Bai, Nan; Zhang, Xin; Liu, Bin; Ni, Wentao; Wang, Jin; Wang, Kai; Liang, Beibei; Liu, Youning; Wang, Rui

2015-01-01

The aim of this meta-analysis was to compare the efficacy of metronidazole and vancomycin for the treatment of Clostridium difficile infection, especially to investigate which agent was superior for treating either mild or severe C. difficile infection. A meta-analysis of randomized controlled trials and cohort studies identified in Pubmed, Embase, and the Cochrane Library was conducted. Four randomized controlled trials and two cohort studies involving 1218 patients were included in this meta-analysis. Metronidazole was inferior to vancomycin for treating C. difficile infection in terms of both initial clinical cure rates (risk ratio, RR=0.91, 95% confidence interval, CI=0.84-0.98, p=0.02) and sustained cure rates (RR=0.88, 95% CI=0.82-0.96, p=0.003). For mild C. difficile infection, the efficacy of metronidazole and vancomycin resulted in similar clinical cure rates (RR=0.94, 95% CI=0.84-1.04, p=0.21) and sustained cure rates (RR=0.93, 95% CI=0.83-1.05, p=0.26). For severe C. difficile infection the efficacy of vancomycin was superior to metronidazole in terms of clinical cure rates (RR=0.81, 95% CI=0.69-0.95, p=0.009), whereas sustained cure rates were similar (RR=0.86, 95% CI=0.72-1.02, p=0.08). Regarding microbiological cure metronidazole therapy was as effective as vancomycin therapy (RR=0.88, 95% CI=0.64-1.21, p=0.43). Recurrence rates with metronidazole and vancomycin for both mild C. difficile infection (RR=0.95, 95% CI=0.56-1.60, p=0.85) and severe C. difficile infection (RR=1.27, 95% CI=0.85-1.91, p=0.25) were not different. Likewise, no difference in all-cause mortality was found as well (RR=0.87, 95% CI=0.56-1.35, p=0.53). In conclusion, vancomycin provides improved initial clinical and sustained cure rates in patients with C. difficile infection compared with metronidazole, especially in patients with severe C. difficile infection. In view of these data, vancomycin may be considered first line therapy for severe C. difficile infection. Copyright © 2015 Elsevier Editora Ltda. All rights reserved.

Successful treatment of simulated Clostridium difficile infection in a human gut model by fidaxomicin first line and after vancomycin or metronidazole failure.

PubMed

Chilton, C H; Crowther, G S; Freeman, J; Todhunter, S L; Nicholson, S; Longshaw, C M; Wilcox, M H

2014-02-01

Fidaxomicin reduces the risk of recurrent Clostridium difficile infection (CDI) compared with vancomycin. We investigated fidaxomicin primary or secondary treatment efficacy using a gut model. Four triple-stage chemostat gut models were inoculated with faeces. After clindamycin induction of CDI, fidaxomicin (200 mg/L twice daily), vancomycin (125 mg/L four times daily) or metronidazole (9.3 mg/L three times daily) was administered for 7 days. Following failure/CDI recurrence, fidaxomicin (200 mg/L twice daily, 7 days) was instilled. C. difficile (CD) total viable counts (TVC), spore counts (SP), toxin titres (CYT), gut bacteria counts and antimicrobial concentrations were measured throughout. Fidaxomicin instillation reduced CD TVC/SP and CYT below the limit of detection (LOD) after 2 and 4 days, respectively, with no CDI recurrence. Metronidazole instillation failed to decrease CD TVC or CYT. Vancomycin instillation reduced CD TVC and CYT to LOD by day 4, but SP persisted. Recurrence occurred 13 days after vancomycin instillation; subsequent fidaxomicin instillation reduced CD TVC/SP/CYT below the LOD from day 2. CD was isolated sporadically, with no evidence of spore recrudescence or toxin production. Fidaxomicin had a minimal effect on the microflora, except for bifidobacteria. Fidaxomicin was detected for at least 21 days post-instillation, whereas other antimicrobials were undetectable beyond ∼4 days. Fidaxomicin successfully treated simulated primary and recurrent CDI. Fidaxomicin was superior to metronidazole in reducing CD TVC and SP, and superior to vancomycin in reducing SP without recurrence of vegetative cell growth. Fidaxomicin, but not vancomycin or metronidazole, persisted in the gut model for >20 days after instillation.

Glycopeptide Susceptibility Profiles of Staphylococcus haemolyticus Bloodstream Isolates

PubMed Central

Biavasco, Francesca; Vignaroli, Carla; Lazzarini, Raffaella; Varaldo, Pietro E.

2000-01-01

Twelve clinical strains of Staphylococcus haemolyticus (eight methicillin resistant and three methicillin susceptible), isolated from blood cultures between 1982 and 1997, were investigated for teicoplanin and vancomycin susceptibility profiles. On the basis of conventional MIC tests and breakpoints, four isolates were susceptible (MICs, 1 to 8 μg/ml) and eight were resistant (MICs, 32 to 64 μg/ml) to teicoplanin while all were susceptible to vancomycin (MICs, 1 to 2 μg/ml). All four strains for which the conventional teicoplanin MICs were within the range of susceptibility expressed heterogeneous resistance to teicoplanin and homogeneous vancomycin susceptibility. Of the eight strains for which the conventional teicoplanin MICs were within the range of resistance, six expressed heterogeneous and two expressed homogeneous teicoplanin resistance while seven showed heterogeneous vancomycin resistance profiles (with subpopulations growing on 8 μg of the drug per ml at frequencies of ≥10−6 for six strains and 10−7 for one) and one demonstrated homogeneous vancomycin susceptibility. Of six bloodstream isolates of other staphylococcal species (S. aureus, S. epidermidis, and S. simulans), for all of which the conventional teicoplanin MICs were ≥4 μg/ml and the vancomycin MICs were ≤2 μg/ml, none exhibited heterogeneous susceptibility profiles for teicoplanin while three showed homogeneous and three showed heterogeneous susceptibility profiles for vancomycin (with subpopulations growing on 8 μg of the drug per ml found for only one strain). The results of this study indicate that a heterogeneous response to glycopeptides is a common feature of S. haemolyticus isolates and suggest that susceptibility to glycopeptides as determined by conventional MIC tests may not be predictive of the outcome of glycopeptide therapy. PMID:11036034

Impact of Initial Vancomycin Trough Concentration on Clinical and Microbiological Outcomes of Methicillin-Resistant Staphylococcus aureus Bacteremia in Children.

PubMed

Yoo, Ree Nar; Kim, Seo Hee; Lee, Jina

2017-01-01

It is important to use vancomycin in a proper manner to ensure optimal drug exposure. Despite extensive use of vancomycin in children, studies on its optimal trough concentration (Ctrough) in the pediatric population remained rare. This retrospective study included children < 18 years old with culture-confirmed methicillin-resistant Staphylococcus aureus (MRSA) bacteremia who were hospitalized in our institute from January 2010 to April 2014. Clinical characteristics, initial vancomycin dose, Ctrough and clinical/microbiological outcomes were retrospectively collected from medical records. Forty-six MRSA bacteremia cases occurring to the patients with a mean age of 22.0 ± 46.9 months were included and all of them were healthcare-associated. Severe diseases requiring intensive care unit (ICU) stay, mechanical ventilation and/or resulting in death were observed in 57.8% (26/45); all-cause 30-day fatality was 11.1% (5/45). An initial Ctrough ≥ 15 μg/mL was achieved in only 4 (8.7%) cases with an average vancomycin dosage of 40.6 ± 7.9 mg/kg/day. Persistent bacteremia at 48 hours after initiation of vancomycin was observed more frequently in children with initial Ctrough < 10 μg/mL than in those with Ctrough ≥ 10 μg/mL (P = 0.032). However, there was no statistically significant difference between the two groups in terms of 30-day mortality and recurrent bacteremia (P = 0.899, and P = 0.754, respectively). Although initial Ctrough may be a useful parameter for minimizing early microbiological failure, it does not predict 30-day fatality or recurrence in pediatric MRSA bacteremia. Further prospective data on vancomycin dosing are needed to find the optimal drug exposure and clarify its impact on clinical outcomes in pediatric populations.

TD-1792 versus Vancomycin for Treatment of Complicated Skin and Skin Structure Infections

PubMed Central

Potgieter, Peter D.; Li, Yu-Ping; Barriere, Steven L.; Churukian, Allan; Kingsley, Jeff; Corey, G. Ralph

2012-01-01

TD-1792 is a first-in-class glycopeptide-cephalosporin heterodimer that exhibits bactericidal activity against Gram-positive pathogens. We conducted a randomized, double-blind, active-control, phase II trial in patients with complicated skin and skin structure infections caused by suspected or confirmed Gram-positive organisms. Patients 18 to 65 years old were randomized to receive 7 to 14 days of either TD-1792 (2 mg/kg of body weight intravenously [i.v.] every 24 h [q24h]) or vancomycin (1 g i.v. q12h, with dosage regimens adjusted per site-specific procedures). A total of 197 patients were randomized and received at least one dose of study medication. Rates of clinical success at the test-of-cure evaluation were similar in all analysis populations. Among 170 clinically evaluable patients, cure rates were 91.7% and 90.7% in the TD-1792 and vancomycin groups, respectively (95% confidence interval [CI] of −7.9 to 9.7 for the difference). In microbiologically evaluable patients with methicillin-resistant Staphylococcus aureus at baseline (n = 75), cure rates were 94.7% in the TD-1792 group and 91.9% in the vancomycin group. Microbiological eradication of Gram-positive pathogens (n = 126) was achieved in 93.7% and 92.1% of patients in the TD-1792 and vancomycin groups, respectively. Seven patients were discontinued from study medication due to an adverse event (AE): 2 and 5 in the TD-1792 and vancomycin groups, respectively. AEs were of similar types and severities between the two groups, other than pruritus, which was more common in patients who received vancomycin. No patients in the TD-1792 group experienced a serious AE. This study supports further clinical development of TD-1792 in patients with Gram-positive infection. PMID:22869571

Implementation of the systems approach to improve a pharmacist-managed vancomycin dosing service.

PubMed

Gagnon, David J; Roberts, Russel; Sylvia, Lynne

2014-12-01

Quality improvements achieved by applying the systems approach to assess the clinical effectiveness, operational efficiency, and financial feasibility of a pharmacist-managed vancomycin dosing service are described. Faced with increased patient volumes and resource demands, the pharmacy department at Tufts Medical Center conducted an evaluation of its adult inpatient vancomycin dosing service using the systems approach, which emphasizes multidisciplinary assessment of system inputs, processes, and outcomes and consensus-building methods to identify needed changes and recommended action steps. A multidisciplinary committee composed of representatives of the medical center's pharmacy, internal medicine, infectious diseases, nursing, phlebotomy, and clinical laboratory services was assembled; in a series of three moderated monthly sessions, committee members deliberated and ultimately reached consensus on a list of action items. Relative to a concurrent intradepartmental assessment of the vancomycin dosing service based solely on pharmacist feedback, the systems approach identified a greater number and wider array of needed improvements in key program areas. Quality improvements implemented as a direct result of the systems-based analysis included a policy change authorizing pharmacists to order serum vancomycin determinations without physician cosignature and inclusion of a vancomycin dosing algorithm in the institutional antibiotic dosing guide. Future changes based on deliverable action items will result in a structured process to help direct program resources toward the patients most in need of pharmacist-managed vancomycin dosing services. The systems approach allowed for a comprehensive multidisciplinary evaluation of the service, as indicated by the identification of process improvements not identified by the department of pharmacy alone. Copyright © 2014 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Heterologous expression of glycopeptide resistance vanHAX gene clusters from soil bacteria in Enterococcus faecalis.

PubMed

Hasman, Henrik; Aarestrup, Frank M; Dalsgaard, Anders; Guardabassi, Luca

2006-04-01

The aim of the study was to determine whether glycopeptide resistance gene clusters from soil bacteria could be heterologously expressed in Enterococcus faecalis and adapt to the new host following exposure to vancomycin. The vanHAX clusters from Paenibacillus thiaminolyticus PT-2B1, Paenibacillus apiarius PA-B2B and Amycolatopsis coloradensis DSM 44225 were separately cloned in an appropriately constructed shuttle vector containing the two-component regulatory system (vanRS) of Tn1546. The complete vanA(PT) operon (vanRSHAXY) from P. thiaminolyticus PT-2B1 was cloned in the same shuttle vector lacking enterococcal vanRS. All plasmid constructs were electroporated into E. faecalis JH2-2 and the MICs of vancomycin and teicoplanin were determined for each recombinant strain before and following exposure to sublethal concentrations of vancomycin. The vanHAX clusters from P. thiaminolyticus and P. apiarius conferred high-level vancomycin resistance (MIC > or = 125 mg/L) in E. faecalis JH2-2. In contrast, cloning of the vanHAX cluster from A. coloradensis did not result in a significant increase of vancomycin resistance (MIC = 0.7 mg/L). Resistance to vancomycin was not observed after cloning the complete vanA(PT) operon from P. thiaminolyticus (MIC = 2 mg/L), but this recombinant rapidly adapted to high concentrations of vancomycin (MIC = 500 mg/L) following exposure to sub-lethal concentrations of this antibiotic. The results showed that vanA(PT) in P. thiaminolyticus is a possible ancestor of vanA-mediated glycopeptide resistance in enterococci. Experimental evidence supported the hypothesis that enterococci did not acquire glycopeptide resistance directly from glycopeptide-producing organisms such as A. coloradensis.

Is Vancomycine Still a Choice for Chronic Osteomyelitis Empirical Therapy in Iran?

PubMed Central

Izadi, Morteza; Zamani, Mohammad Mahdi; Mousavi, Seyed Ahmad; Sadat, Seyed Mir Mostafa; Siami, Zeinab; Vais Ahmadi, Noushin; Jonaidi Jafari, Nematollah; Shirvani, Shahram; Majidi Fard, Mojgan; Imani Fooladi, Abbas Ali

2012-01-01

Background Pyogenic bacteria and especially Staphylococcus aurous (S. aurous) are the most common cause of chronic osteomyelitis. Not only treatment protocol of chronic osteomyelitis occasionally is amiss but also this malady responds to treatment difficultly. Objectives This study investigates antibiotic resistance pattern of S. aurous isolated from Iranian patients who suffer from chronic osteomyelitis by two methods: disk diffusion (Kirby bauyer) and E-test (Epsilometer test) to find Vancomycin susceptibility and MIC (Minimum inhibitory concentration). Patients and Methods One hundred and thirty one patients who suffer from chronic osteomyelitis which have been referred to both governmental and private hospitals at 2010 were tried out for culturing of osteomyelitis site (sites). Antibiotic susceptibility and MIC of isolated bacteria were investigated by Kirby bauyer and E-test respectively. Results Samples were collected from bone (73.4%), surrounding tissue (14.6%) and wound discharge (12%). S. aureus was isolated from 49.6% of the samples. According to disc diffusion, methicillin resistance S. aureus (MRSA) was 75% and Vancomycin resistance S. aurous (VRSA) was 0% and based on MIC, MRSA was 68.5% and VRSA was 0%. According to MIC experiments, maximum sensitivity was against to Vancomycin (90.2%) and ciprofloxacin (54.4%) respectively but based on disc diffusion, maximum sensitivity was against to Vancomycin (97.7%) and ciprofloxacin (43.2%), respectively (P = 0.001). E-test (9.8%) in comparison with Disc diffusion (2.3%) showed higher percent of intermediate susceptibility to Vancomycin (P = 0.017). Conclusions Comparison of antibiograms and MICs showed that Kirby bauyer technique especially for detection of VISA strains is not reliable comparison with E-test. Already VRSA strains have not detected in Iranian chronic osteomyelitis, Thus Vancomycin is the first choice for chronic osteomyelitis empirical therapy in Iran yet. PMID:23483042

Effects of using intravenous antibiotic only versus local intrawound vancomycin antibiotic powder application in addition to intravenous antibiotics on postoperative infection in spine surgery in 907 patients.

PubMed

Tubaki, Vijay Ramappa; Rajasekaran, S; Shetty, Ajoy Prasad

2013-12-01

A prospective randomized controlled trial. To assess the ability of local vancomycin powder in controlling postoperative infection in spine surgery. Despite improvements through the use of prophylactic systemic antibiotics, surgical site infections remain a significant problem in spine surgical procedures. Various retrospective and prospective studies have reported the efficacy of local application of vancomycin powder in reducing the infection in animal and human studies. However, there were no randomized control trials that reported on its efficacy. Prospective randomized controls of 907 patients with various spinal pathologies were treated surgically during a period of 18 months. The control group received standard systemic prophylaxis only, whereas the treatment group received vancomycin powder in the surgical wound in addition to systemic prophylaxis. Patient demographics, comorbidities, level of spinal pathology, estimated blood loss, nutritional status, and hemoglobin were recorded. Incidence of infection was the primary outcome evaluated. There were 8 infections (1.68%) in the control group (6 instrumented and 2 noninstrumented, 6 deep and 2 superficial) with bacteria cultured in 3 (1 Escherichia coli and 2 Staphylococcus aureus). In the treatment group, 7 infections (1.61%) were observed (6 instrumented and 1 noninstrumented surgical procedures, 6 deep and 1 superficial) with bacteria cultured in 3 (1 Staphylococcus aureus and 2 Klebsiella). No adverse effects were observed from the use of vancomycin powder. Statistically no significant difference was seen in infection rate between the treatment group and control group. The local application of vancomycin powder in surgical wounds did not significantly reduce the incidence of infection in patients with surgically treated spinal pathologies. The use of vancomycin powder may not be effective when incidence of infection is low.

Intravenous Vancomycin Associated With the Development of Nephrotoxicity in Patients With Class III Obesity.

PubMed

Choi, Yookyung Christy; Saw, Stephen; Soliman, Daniel; Bingham, Angela L; Pontiggia, Laura; Hunter, Krystal; Chuang, Linda; Siemianowski, Laura A; Ereshefsky, Benjamin; Hollands, James M

2017-11-01

A consensus statement recommends initial intravenous (IV) vancomycin dosing of 15-20 mg/kg every 8- 24 hours, with an optional 25- to 30-mg/kg loading dose. Although some studies have shown an association between weight and the development of vancomycin-associated nephrotoxicity, results have been inconsistent. To evaluate the correlation between incidence of nephrotoxicity associated with weight-based IV vancomycin dosing strategies in nonobese and obese patients. This retrospective cohort study evaluated hospitalized adult patients admitted who received IV vancomycin. Patients were stratified into nonobese (body mass index [BMI] <25 kg/m 2 ), obesity class I and II (BMI 30-39.9kg/m 2 ), and obesity class III (BMI≥40 kg/m 2 ) groups; patients who were overweight but not obese were excluded. Incidence of nephrotoxicity and serum vancomycin trough concentrations were evaluated. Of a total of 62 documented cases of nephrotoxicity (15.1%), 13 (8.7%), 23 (14.3%), and 26 (26.3%) cases were observed in nonobese, obesity class I and II, and obesity class III groups, respectively ( P=0.002). Longer durations of therapy ( P<0.0001), higher initial maintenance doses in both total milligrams/day ( P=0.0137) and milligrams/kilogram ( P=0.0307), and any trough level >20 mg/L ( P<0.0001) were identified as predictors of development of nephrotoxicity. Concomitant administration of piperacillin/tazobactam, diuretics, and IV contrast were associated with development of nephrotoxicity ( P<0.005, all). Patients with class III obesity were 3-times as likely to develop nephrotoxicity when compared with nonobese patients (odds ratio [OR]=2.99; CI=1.12-7.94) and obesity class I and II patients (OR=3.14; CI=1.27-7.75). Obesity and other factors are associated with a higher risk of vancomycin-associated nephrotoxicity.

Are Vancomycin Trough Concentrations of 15 to 20 mg/L Associated With Increased Attainment of an AUC/MIC ≥ 400 in Patients With Presumed MRSA Infection?

PubMed

Hale, Cory M; Seabury, Robert W; Steele, Jeffrey M; Darko, William; Miller, Christopher D

2017-06-01

To determine whether there is an association between higher vancomycin trough concentrations and attainment of a calculated area under the concentration-time curve (AUC)/minimum inhibitory concentration (MIC) ≥400. A retrospective analysis was conducted among vancomycin-treated adult patients with a positive methicillin-resistant Staphylococcus aureus (MRSA) culture. Attainment of a calculated AUC/MIC ≥400 was compared between patients with troughs in the reference range of 15 to 20 mg/L and those with troughs in the following ranges: <10, 10 to 14.9, and >20 mg/L. Nephrotoxicity was assessed as a secondary outcome based on corrected average vancomycin troughs over 10 days of treatment. Overall, 226 patients were reviewed and 100 included. Relative to troughs ≥10, patients with vancomycin troughs <10 mg/L were 73% less likely to attain an AUC/MIC ≥400 (odds ratio [OR] 0.27, 95% confidence interval [CI]: 0.01-0.75). No difference was found in the attainment of an AUC/MIC ≥400 in patients with troughs of 10 to 14.9 mg/L and >20 mg/L when compared to patients with troughs of 15 to 20 mg/L. The mean corrected average vancomycin trough was higher in patients developing nephrotoxicity compared to those who did not (19.5 vs 14.5 mg/L, P < .001). Achieving vancomycin serum trough concentrations of 15 to 20 mg/L did not result in an increased attainment of the AUC/MIC target relative to troughs of 10 to 14.9 mg/L but may increase nephrotoxicity risk.

A Phase 3, Randomized, Double-Blind, Multicenter Study to Evaluate the Safety and Efficacy of Intravenous Iclaprim Vs Vancomycin for the Treatment of Acute Bacterial Skin and Skin Structure Infections Suspected or Confirmed to be Due to Gram-Positive Pathogens: REVIVE-1.

PubMed

Huang, David B; O'Riordan, William; Overcash, J Scott; Heller, Barry; Amin, Faisal; File, Thomas M; Wilcox, Mark H; Torres, Antoni; Dryden, Matthew; Holland, Thomas L; McLeroth, Patrick; Shukla, Rajesh; Corey, G Ralph

2018-04-03

Our objective in this study was to demonstrate the safety and efficacy of iclaprim compared with vancomycin for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSIs). REVIVE-1 was a phase 3, 600-patient, double-blinded, randomized (1:1), active-controlled trial among patients with ABSSSI that compared the safety and efficacy of iclaprim 80 mg fixed dose with vancomycin 15 mg/kg, both administered intravenously every 12 hours for 5-14 days. The primary endpoint of this study was a ≥20% reduction in lesion size (early clinical response [ECR]) compared with baseline among patients randomized to iclaprim or vancomycin at the early time point (ETP), 48 to 72 hours after the start of administration of study drug in the intent-to-treat population. ECR among patients who received iclaprim and vancomycin at the ETP was 80.9% (241 of 298) of patients receiving iclaprim compared with 81.0% (243 of 300) of those receiving vancomycin (treatment difference, -0.13%; 95% confidence interval, -6.42%-6.17%). Iclaprim was well tolerated in the study, with most adverse events categorized as mild. Iclaprim achieved noninferiority (10% margin) at ETP compared with vancomycin and was well tolerated in this phase 3 clinical trial for the treatment of ABSSSI. Based on these results, iclaprim appears to be an efficacious and safe treatment for ABSSSI suspected or confirmed to be due to gram-positive pathogens. NCT02600611.

Activity of Tedizolid in Methicillin-Resistant Staphylococcus epidermidis Experimental Foreign Body-Associated Osteomyelitis.

PubMed

Park, Kyung-Hwa; Greenwood-Quaintance, Kerryl E; Schuetz, Audrey N; Mandrekar, Jayawant N; Patel, Robin

2017-02-01

We developed a rat model of methicillin-resistant Staphylococcus epidermidis (MRSE) foreign body-associated osteomyelitis and used it to compare tedizolid alone and in combination with rifampin against rifampin alone, vancomycin plus rifampin, and vancomycin alone. A clinical strain of MRSE was inoculated into the proximal tibia, and a stainless steel wire with a precolonized MRSE biofilm was implanted. Following a 1-week infection period, 92 rats received either no treatment (n = 17) or 14 days of intraperitoneal tedizolid (n = 15), tedizolid plus rifampin (n = 15), rifampin (n = 15), vancomycin plus rifampin (n = 15), or vancomycin (n = 15). Quantitative bone and wire cultures were performed after treatment completion and also 1 week after infection in a separate group of five rats. The median quantity of staphylococci in bone after the 1-week infection period was 4.89 log 10 CFU/g bone (interquartile range, 3.83 to 5.33 log 10 CFU/g bone); staphylococci were recovered from all associated wires. A median quantity of staphylococci of 3.70 log 10 CFU/g bone was detected in bones of untreated control rats after 3 weeks. Quantities of staphylococci in bones of all treatment groups except the group receiving vancomycin alone (2.78 log 10 CFU/g) were significantly lower than those for untreated controls, with no staphylococci being detected in the groups receiving rifampin monotherapy, tedizolid-plus-rifampin combination therapy, and vancomycin-plus-rifampin combination therapy. Quantities of staphylococci on wires from all treatment groups that included rifampin were significantly lower than those for untreated controls. No resistance to rifampin, tedizolid, or vancomycin was detected. Tedizolid combined with rifampin was active in a rat model of MRSE foreign body-associated osteomyelitis. Copyright © 2017 American Society for Microbiology.

A Mutation in the PP2C Phosphatase Gene in a Staphylococcus aureus USA300 Clinical Isolate with Reduced Susceptibility to Vancomycin and Daptomycin

PubMed Central

Passalacqua, Karla D.; Satola, Sarah W.; Crispell, Emily K.

2012-01-01

Methicillin-resistant Staphylococcus aureus (MRSA) strains with reduced susceptibility to vancomycin (MIC of 4 to 8 μg/ml) are referred to as vancomycin-intermediate S. aureus (VISA). In this study, we characterized two isogenic USA300 S. aureus isolates collected sequentially from a single patient with endocarditis where the S. aureus isolate changed from being susceptible to vancomycin (VSSA) (1 μg/ml) to VISA (8 μg/ml). In addition, the VISA isolate lost beta-lactamase activity and showed increased resistance to daptomycin and linezolid. The two strains did not differ in growth rate, but the VISA isolate had a thickened cell wall and was less autolytic. Transcriptome sequencing (RNA-seq) analysis comparing the two isolates grown to late exponential phase showed significant differences in transcription of cell surface protein genes (spa, SBI [second immunoglobulin-binding protein of S. aureus], and fibrinogen-binding proteins), regulatory genes (agrBCA, RNAIII, sarT, and saeRS), and others. Using whole-genome shotgun resequencing, we identified 6 insertion/deletion mutations between the VSSA and VISA isolates. A protein phosphatase 2C (PP2C) family phosphatase had a 6-bp (nonframeshift) insertion mutation in a highly conserved metal binding domain. Complementation of the clinical VISA isolate with a wild-type copy of the PP2C gene reduced the vancomycin and daptomycin MICs and increased autolytic activity, suggesting that this gene contributed to the reduced vancomycin susceptibility phenotype acquired in vivo. Creation of de novo mutants from the VSSA strain resulted in different mutations, demonstrating that reduced susceptibility to vancomycin in USA300 strains can occur via multiple routes, highlighting the complex nature of the VISA phenotype. PMID:22850507

Evaluating the Relationship between Vancomycin Trough Concentration and 24-Hour Area under the Concentration-Time Curve in Neonates.

PubMed

Tseng, Sheng-Hsuan; Lim, Chuan Poh; Chen, Qi; Tang, Cheng Cai; Kong, Sing Teang; Ho, Paul Chi-Lui

2018-04-01

Bacterial sepsis is a major cause of morbidity and mortality in neonates, especially those involving methicillin-resistant Staphylococcus aureus (MRSA). Guidelines by the Infectious Diseases Society of America recommend the vancomycin 24-h area under the concentration-time curve to MIC ratio (AUC 24 /MIC) of >400 as the best predictor of successful treatment against MRSA infections when the MIC is ≤1 mg/liter. The relationship between steady-state vancomycin trough concentrations and AUC 24 values (mg·h/liter) has not been studied in an Asian neonatal population. We conducted a retrospective chart review in Singapore hospitals and collected patient characteristics and therapeutic drug monitoring data from neonates on vancomycin therapy over a 5-year period. A one-compartment population pharmacokinetic model was built from the collected data, internally validated, and then used to assess the relationship between steady-state trough concentrations and AUC 24 A Monte Carlo simulation sensitivity analysis was also conducted. A total of 76 neonates with 429 vancomycin concentrations were included for analysis. Median (interquartile range) was 30 weeks (28 to 36 weeks) for postmenstrual age (PMA) and 1,043 g (811 to 1,919 g) for weight at the initiation of treatment. Vancomycin clearance was predicted by weight, PMA, and serum creatinine. For MRSA isolates with a vancomycin MIC of ≤1, our major finding was that the minimum steady-state trough concentration range predictive of achieving an AUC 24 /MIC of >400 was 8 to 8.9 mg/liter. Steady-state troughs within 15 to 20 mg/liter are unlikely to be necessary to achieve an AUC 24 /MIC of >400, whereas troughs within 10 to 14.9 mg/liter may be more appropriate. Copyright © 2018 American Society for Microbiology.

Berberine blocks the relapse of Clostridium difficile infection in C57BL/6 mice after standard vancomycin treatment.

PubMed

Lv, Zhi; Peng, Guoli; Liu, Weihua; Xu, Hufeng; Su, JianRong

2015-07-01

Vancomycin is a preferred antibiotic for treating Clostridium difficile infection (CDI) and has been associated with a rate of recurrence of CDI of as high as 20% in treated patients. Recent studies have suggested that berberine, an alternative medical therapy for gastroenteritis and diarrhea, exhibits several beneficial effects, including induction of anti-inflammatory responses and restoration of the intestinal barrier function. This study investigated the therapeutic effects of berberine on preventing CDI relapse and restoring the gut microbiota in a mouse model. Berberine was administered through gavage to C57BL/6 mice with established CDI-induced intestinal injury and colitis. The disease activity index (DAI), mean relative weight, histopathology scores, and levels of toxins A and B in fecal samples were measured. An Illumina sequencing-based analysis of 16S rRNA genes was used to determine the overall structural change in the microbiota in the mouse ileocecum. Berberine administration significantly promoted the restoration of the intestinal microbiota by inhibiting the expansion of members of the family Enterobacteriaceae and counteracting the side effects of vancomycin treatment. Therapy consisting of vancomycin and berberine combined prevented weight loss, improved the DAI and the histopathology scores, and effectively decreased the mortality rate. Berberine prevented CDIs from relapsing and significantly improved survival in the mouse model of CDI. Our data indicate that a combination of berberine and vancomycin is more effective than vancomycin alone for treating CDI. One of the possible mechanisms by which berberine prevents a CDI relapse is through modulation of the gut microbiota. Although this conclusion was generated in the case of the mouse model, use of the combination of vancomycin and berberine and represent a novel therapeutic approach targeting CDI. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Genomic and expression analysis of the vanG-like gene cluster of Clostridium difficile.

PubMed

Peltier, Johann; Courtin, Pascal; El Meouche, Imane; Catel-Ferreira, Manuella; Chapot-Chartier, Marie-Pierre; Lemée, Ludovic; Pons, Jean-Louis

2013-07-01

Primary antibiotic treatment of Clostridium difficile intestinal diseases requires metronidazole or vancomycin therapy. A cluster of genes homologous to enterococcal glycopeptides resistance vanG genes was found in the genome of C. difficile 630, although this strain remains sensitive to vancomycin. This vanG-like gene cluster was found to consist of five ORFs: the regulatory region consisting of vanR and vanS and the effector region consisting of vanG, vanXY and vanT. We found that 57 out of 83 C. difficile strains, representative of the main lineages of the species, harbour this vanG-like cluster. The cluster is expressed as an operon and, when present, is found at the same genomic location in all strains. The vanG, vanXY and vanT homologues in C. difficile 630 are co-transcribed and expressed to a low level throughout the growth phases in the absence of vancomycin. Conversely, the expression of these genes is strongly induced in the presence of subinhibitory concentrations of vancomycin, indicating that the vanG-like operon is functional at the transcriptional level in C. difficile. Hydrophilic interaction liquid chromatography (HILIC-HPLC) and MS analysis of cytoplasmic peptidoglycan precursors of C. difficile 630 grown without vancomycin revealed the exclusive presence of a UDP-MurNAc-pentapeptide with an alanine at the C terminus. UDP-MurNAc-pentapeptide [d-Ala] was also the only peptidoglycan precursor detected in C. difficile grown in the presence of vancomycin, corroborating the lack of vancomycin resistance. Peptidoglycan structures of a vanG-like mutant strain and of a strain lacking the vanG-like cluster did not differ from the C. difficile 630 strain, indicating that the vanG-like cluster also has no impact on cell-wall composition.

Efficacy and Safety of Oritavancin Relative to Vancomycin for Patients with Acute Bacterial Skin and Skin Structure Infections (ABSSSI) in the Outpatient Setting: Results From the SOLO Clinical Trials.

PubMed

Lodise, Thomas P; Redell, Mark; Armstrong, Shannon O; Sulham, Katherine A; Corey, G Ralph

2017-01-01

The objective of this analysis was to evaluate the efficacy and safety of oritavancin compared with vancomycin for patients with acute bacterial skin and skin structure infections (ABSSSIs) who received treatment in the outpatient setting in the Phase 3 SOLO clinical trials. SOLO I and SOLO II were 2 identically designed comparative, multicenter, double-blind, randomized studies to evaluate the efficacy and safety of a single 1200-mg dose of intravenous (IV) oritavancin versus 7-10 days of twice-daily IV vancomycin for the treatment of ABSSSI. Protocols were amended to allow enrolled patients to complete their entire course of antimicrobial therapy in an outpatient setting. The primary efficacy outcome was a composite endpoint (cessation of spread or reduction in size of the baseline lesion, absence of fever, and no rescue antibiotic at early clinical evaluation [ECE]) (48 to 72 hours). Key secondary endpoints included investigator-assessed clinical cure 7 to 14 days after end of treatment (posttherapy evaluation [PTE]) and 20% or greater reduction in lesion area at ECE. Safety was assessed until day 60. Seven hundred ninety-two patients (oritavancin, 392; vancomycin, 400) received entire course of treatment in the outpatient setting. Efficacy response rates at ECE and PTE were similar (primary composite endpoint at ECE: 80.4% vs 77.5% for oritavancin and vancomycin, respectively) as was incidence of adverse events. Five patients (1.3%) who received oritavancin and 9 (2.3%) vancomycin patients were subsequently admitted to a hospital. Oritavancin provides a single-dose alternative to multidose vancomycin for treatment of ABSSSI in the outpatient setting. © The Author 2017. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

Antistaphylococcal Activity of DX-619 Alone and in Combination with Vancomycin, Teicoplanin, and Linezolid Assessed by Time-Kill Synergy Testing▿ †

PubMed Central

Credito, Kim; Lin, Genrong; Appelbaum, Peter C.

2007-01-01

Time-kill synergy studies testing in vitro activity of DX-619 alone and with added vancomycin, teicoplanin, or linezolid against 101 Staphylococcus aureus strains showed synergy between DX-619 and teicoplanin at 12 to 24 h in 72 strains and between DX-619 and vancomycin in 28 strains. No synergy was found with linezolid, and no antagonism was observed with any combination. PMID:17261625

AUC-Guided Vancomycin Dosing in Adolescent Patients With Suspected Sepsis.

PubMed

Lanke, Shankar; Yu, Tian; Rower, Joseph E; Balch, Alfred H; Korgenski, E Kent; Sherwin, Catherine M

2017-01-01

Vancomycin is a first-line treatment for β-lactam-resistant Gram-positive bacterial infections. Understanding the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of vancomycin in an adolescent population is of clinical importance in this often overlooked pediatric population. This retrospective study investigated vancomycin PK-PD in an adolescent cohort (12 to 18 years of age) of 463 patients (57% male, 81% white) admitted to the Intermountain Healthcare System between January 2006 and December 2013. Population PK modeling was performed in NONMEM 7.3. Vancomycin PK was well described with a 1-compartment model that identified both body weight (WT) and creatinine clearance (CRCL) as covariates significantly impacting vancomycin disposition. The model was then utilized to determine dosing strategies that achieved the targeted area under the 24-hour time curve vs minimum inhibitory concentration (AUC 0-24 /MIC) ratio of ≥400. Additionally, these data were correlated with minimum steady-state concentrations (C ss,min ) to find an acceptable target trough concentration range in adolescents. This analysis demonstrated that C ss,min ranging from 10 to 12.5 mg/L were highly predictive of achieving an AUC 0-24 /MIC ≥400 when the MIC was ≤1 mg/L. These results suggest that the target trough concentration for adolescents may be lower than that for adults. © 2016, The American College of Clinical Pharmacology.

A vancomycin drug use evaluation and economic analysis in a cancer treatment centre.

PubMed

Dranitsaris, G; Pilla, N J; McGreer, A

1994-04-01

Princess Margaret Hospital is a 140-bed university affiliated cancer treatment centre. Vancomycin was the only formulary agent available for the treatment of methicillin-resistant gram-positive organisms. The high cost and potential toxicity of this drug warranted a closer examination of its use. The purpose of this study was to evaluate vancomycin use and to determine the economic impact when it was used contrary to newly developed hospital guidelines. A sample of 100 vancomycin orders was randomly selected from all prescriptions filled in 1992. The indication, dose, and duration of therapy for each order were compared against the hospital guidelines. The cost savings associated with altering the sample of prescriptions to meet hospital guidelines were then determined. Nine percent of the prescriptions were for nonapproved indications. The actual dose used did not meet criteria in 32% of cases and the length of therapy was beyond the approved duration in 45% of the orders. If the cases had been altered to meet the guidelines then a total savings of $13,581 would have been realized. The projected savings for the entire year (1992) would have been $100,907. The critical problem areas in vancomycin prescribing were the duration of therapy and dose. The results have provided the impetus to initiate a hospital wide prospective Drug Utilization Evaluation (DUE) study to optimize vancomycin prescribing. The program costs would be easily covered by the expected savings.

The Sustainable Release of Vancomycin and Its Degradation Products From Nanostructured Collagen/Hydroxyapatite Composite Layers.

PubMed

Suchý, Tomáš; Šupová, Monika; Klapková, Eva; Horný, Lukáš; Rýglová, Šárka; Žaloudková, Margit; Braun, Martin; Sucharda, Zbyněk; Ballay, Rastislav; Veselý, Jan; Chlup, Hynek; Denk, František

2016-03-01

Infections of the musculoskeletal system present a serious problem with regard to the field of orthopedic and trauma medicine. The aim of the experiment described in this study was to develop a resorbable nanostructured composite layer with the controlled elution of antibiotics. The layer is composed of collagen, hydroxyapatite nanoparticles, and vancomycin hydrochloride (10 wt%). The stability of the collagen was enhanced by means of cross-linking. Four cross-linking agents were studied, namely an ethanol solution, a phosphate buffer solution of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride/N-hydroxysuccinimide, genipin, and nordihydroguaiaretic acid. High performance liquid chromatography was used so as to characterize the in vitro release rates of the vancomycin and its crystalline degradation antibiotically inactive products over a 21-day period. The maximum concentration of the released active form of vancomycin (approximately 265 mg/L) exceeded the minimum inhibitory concentration up to an order of 17 times without triggering the burst releasing effect. At the end of the experiment, the minimum inhibitory concentration was exceeded by up to 6 times (approximately 100 mg/L). It was determined that the modification of collagen with hydroxyapatite nanoparticles does not negatively influence the sustainable release of vancomycin. The balance of vancomycin and its degradation products was observed after 14 days of incubation. Copyright © 2016. Published by Elsevier Inc.

Vancomycin Injection

MedlinePlus

... is in a class of medications called glycopeptide antibiotics. It works by killing bacteria that cause infections.Antibiotics such as vancomycin injection will not work for colds, flu, or other viral infections. Taking ...

High MICs for Vancomycin and Daptomycin and Complicated Catheter-Related Bloodstream Infections with Methicillin-Sensitive Staphylococcus aureus

PubMed Central

Viedma, Esther; Chaves, Fernando; Lalueza, Antonio; Fortún, Jesús; Loza, Elena; Pujol, Miquel; Ardanuy, Carmen; Morales, Isabel; de Cueto, Marina; Resino-Foz, Elena; Morales-Cartagena, Alejandra; Rico, Alicia; Romero, María P.; Orellana, María Ángeles; López-Medrano, Francisco; Fernández-Ruiz, Mario; Aguado, José María

2016-01-01

We investigated the prognostic role of high MICs for antistaphylococcal agents in patients with methicillin-sensitive Staphylococcus aureus catheter-related bloodstream infection (MSSA CRBSI). We prospectively reviewed 83 episodes from 5 centers in Spain during April 2011–June 2014 that had optimized clinical management and analyzed the relationship between E-test MICs for vancomycin, daptomycin, oxacillin, and linezolid and development of complicated bacteremia by using multivariate analysis. Complicated MSSA CRBSI occurred in 26 (31.3%) patients; MICs for vancomycin and daptomycin were higher in these patients (optimal cutoff values for predictive accuracy = 1.5 μg/mL and 0.5 μg/mL). High MICs for vancomycin (hazard ratio 2.4, 95% CI 1.2–5.5) and daptomycin (hazard ratio 2.4, 95% CI 1.1–5.9) were independent risk factors for development of complicated MSSA CRBSI. Our data suggest that patients with MSSA CRBSI caused by strains that have high MICs for vancomycin or daptomycin are at increased risk for complications. PMID:27192097

Prediction of Vancomycin Dose for Recommended Trough Concentrations in Pediatric Patients With Cystic Fibrosis.

PubMed

Amin, Raid W; Guttmann, Rodney P; Harris, Quianna R; Thomas, Janesha W

2018-05-01

Vancomycin is a key antibiotic used in the treatment of multiple conditions including infections associated with cystic fibrosis and methicillin-resistant Staphylococcus aureus. The present study sought to develop a model based on empirical evidence of optimal vancomycin dose as judged by clinical observations that could accelerate the achievement of desired trough level in children with cystic fibrosis. Transformations of dose and trough were used to arrive at regression models with excellent fit for dose based on weight or age for a target trough. Results of this study indicate that the 2 proposed regression models are robust to changes in age or weight, suggesting that the daily dose on a per-kilogram basis is determined primarily by the desired trough level. The results show that to obtain a vancomycin trough level of 20 μg/mL, a dose of 80 mg/kg/day is needed. This analysis should improve the efficiency of vancomycin usage by reducing the number of titration steps, resulting in improved patient outcome and experience. © 2018, The American College of Clinical Pharmacology.

In Vitro Activities of Co-Amoxiclav at Concentrations Achieved in Human Serum against the Resistant Subpopulation of Heteroresistant Staphylococcus aureus: a Controlled Study with Vancomycin

PubMed Central

Prieto, J.; Aguilar, L.; Giménez, M. J.; Toro, D.; Gómez-Lus, M. L.; Dal-Ré, R.; Balcabao, I. P.

1998-01-01

The effects of concentrations that simulated those in human serum after a single intravenous dose of amoxicillin (2 g), amoxicillin-clavulanic acid (2,000 and 200 mg, respectively), or vancomycin (500 mg), on the viability and β-lactamase activity of two isogenic (β-lactamase and non-β-lactamase producer) heteroresistant Staphylococcus aureus strains were studied in an in vitro pharmacodynamic model. A reduction of ≥97% of the initial inoculum was obtained with vancomycin and amoxicillin-clavulanic acid against both strains, with respect to the total bacterial population and the oxacillin-resistant subpopulation. The same pattern was observed with amoxicillin and the β-lactamase-negative strain. β-Lactamase activity in the β-lactamase-positive strain changed over time parallel to viability, decreasing with amoxicillin-clavulanic acid or vancomycin and increasing in the amoxicillin and control groups. Clavulanic acid concentrations achievable in serum that changed over time allowed amoxicillin to act against the β-lactamase-producing methicillin-resistant S. aureus to a similar extent as vancomycin. PMID:9660985

Vancomycin resistant enterococci in farm animals – occurrence and importance

PubMed Central

Nilsson, Oskar

2012-01-01

The view on enterococci has over the years shifted from harmless commensals to opportunistic but important pathogens mainly causing nosocomial infections. One important part of this development is the emergence of vancomycin resistance enterococci (VRE). The term VRE includes several combinations of bacterial species and resistance genes of which the most clinically important is Enterococcus faecium with vanA type vancomycin resistance. This variant is also the most common VRE among farm animals. The reason for VRE being present among farm animals is selection by extensive use of the vancomycin analog avoparcin for growth promotion. Once the use of avoparcin was discontinued, the prevalence of VRE among farm animals decreased. However, VRE are still present among farm animals and by spread via food products they could potentially have a negative impact on public health. This review is based on the PhD thesis Vancomycin Resistant Enterococci in Swedish Broilers – Emergence, Epidemiology and Elimination and makes a short summary of VRE in humans and food producing animals. The specific situation regarding VRE in Swedish broiler production is also mentioned. PMID:22957131

In vitro activity of salicylamide derivatives against vancomycin-resistant enterococci.

PubMed

Pospisilova, Sarka; Michnova, Hana; Kauerova, Tereza; Pauk, Karel; Kollar, Peter; Vinsova, Jarmila; Imramovsky, Ales; Cizek, Alois; Jampilek, Josef

2018-07-01

A series of 13 salicylamide derivatives was assessed for antibacterial activity against three isolates of vancomycin-resistant Enterococcus faecalis (VRE) and Enterococcus faecalis ATCC 29212 as a quality standard. The minimum inhibitory concentration was determined by the broth microdilution method with subsequent subcultivation of aliquots to assess minimum bactericidal concentration. The growth kinetics was established by the time-kill assay. Ampicillin, ciprofloxacin, tetracycline and vancomycin were used as the reference antibacterial drugs. Three of the investigated compounds showed strong bacteriostatic activity against VRE (0.199-25 µM) comparable to or more potent than ampicillin and ciprofloxacin. In addition, these compounds were tested for synergistic effect with vancomycin, ciprofloxacin and tetracycline, while 5-chloro-2-hydroxy-N-[4-(trifluoromethyl)phenyl]benzamide showed the highest potency as well as synergistic activity with vancomycin against VRE 368. Screening of the cytotoxicity of the most effective compounds was performed using human monocytic leukemia THP-1 cells, and based on LD 50 values, it can be stated that the compounds have insignificant toxicity against human cells. Copyright © 2018 Elsevier Ltd. All rights reserved.

[New antimicrobials against Gram-positive organisms].

PubMed

Montejo, M

2008-01-01

Glycopeptides have been the antimicrobials most commonly used for infections by Gram-positive organisms and methicillin resistant S. aureus (MRSA). In recent years, however, glycopeptide resistance and tolerance have become a serious problem. Thus, enterococci highly resistant to vancomycin, vancomycin-intermediate/ resistant S. aureus (VISA), and vancomycin tolerance in S. aureus are found, and increased therapeutic failure and mortality are clinically reported with vancomycin MIC for S. aureus > or = 1.5-2 microg/mL. When faced with these organisms, we therefore need potent bactericidal antimicrobials that may be empirically administered, effective against susceptible and resistant pathogens, easily dosed, with few adverse effects and no significant interaction with other drugs, and that can be administered in an outpatient setting. In bacteremia by methicillin-susceptible S. aureus, use of vancomycin is associated to a greater failure and mortality rate as compared to semisynthetic penicillins. New treatment options for MRSA infections include daptomycin, linezolid, tygecycline, and quinupristin/dalfopristin. New anti-MRSA drugs are also under development, including glycopeptides (dalbavancin, telavancin, and oritavancin), ceftobiprole, and iclaprim. This paper reviews the new antimicrobials against Gram-positive organisms.

Identification of Low-Level Vancomycin Resistance in Staphylococcus aureus in the Era of Informatics.

PubMed

Ford, Bradley A

2016-04-01

Vancomycin-intermediateStaphylococcus aureus(VISA) and heteroresistant VISA (hVISA) are pathogens for which accurate antimicrobial susceptibility testing (AST) would rule out standard treatment with vancomycin. Unfortunately, AST for vancomycin is relatively slow and standard methods are unable to reliably detect VISA and hVISA. An article in this issue (C. A. Mather, B. J. Werth, S. Sivagnanam, D. J. SenGupta, and S. M. Butler-Wu, J Clin Microbiol 54:883-890, 2016, doi:http://dx.doi.org/10.1128/JCM.02428-15) describes a rapid whole-cell matrix-assisted laser desorption ionization-time of flight proxy susceptibility method that highlights current innovations and challenges with rapid AST, VISA/hVISA identification, and clinical bioinformatics. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Co-immobilization of active antibiotics and cell adhesion peptides on calcium based biomaterials.

PubMed

Palchesko, Rachelle N; Buckholtz, Gavin A; Romeo, Jared D; Gawalt, Ellen S

2014-07-01

Two bioactive molecules with unrelated functions, vancomycin and a cell adhesion peptide, were immobilized on the surface of a potential bone scaffold material, calcium aluminum oxide. In order to accomplish immobilization and retain bioactivity three sequential surface functionalization strategies were compared: 1.) vancomycin was chemically immobilized before a cell adhesion peptide (KRSR), 2.) vancomycin was chemically immobilized after KRSR and 3.) vancomycin was adsorbed after binding the cell adhesion peptide. Both molecules remained on the surface and active using all three reaction sequences and after autoclave sterilization based on osteoblast attachment, bacterial turbidity and bacterial zone inhibition test results. However, the second strategy was superior at enhancing osteoblast attachment and significantly decreasing bacterial growth when compared to the other sequences. Copyright © 2014 Elsevier B.V. All rights reserved.

Vancomycin-resistant Staphylococcus aureus (VRSA) in hepatic cirrhosis patient: a case report

NASA Astrophysics Data System (ADS)

Ramazoni, M.; Siregar, M. L.; Jamil, K. F.

2018-03-01

The irrational use of vancomycin in methicillin-resistant Staphylococcus aureus (MRSA) infections result in the emergence of vancomycin-resistant Staphylococcus aureus (VRSA) pathogen, which can pose a threat to the world healthcare. A 32-year-old male with hepatic cirrhosis patient admitted with recurrent gastrointestinal bleeding with a wound in his left leg since 6 months ago; the result microbiological culture showed a VRSA with minimum inhibitory concentration (MIC) vancomycin ≥32μg/mL The patient was treated with trimethoprim/sulfamethoxazole combination according to cultural sensitivity. The second microbiological culture showed thesame result. VRSA is a rare and difficult condition to handle. The success of therapy for this VRSA case warn us how important to cut the S. aureus distribution chain with a high level of resistance.

[Vancomycin-resistant enterococcus--chronicle of a foretold problem].

PubMed

Bonten, Marc J M; Willems, Rob J

2012-01-01

There have recently been 12 outbreaks of infection caused by vancomycin-resistant enterococci (VRE) in Dutch hospitals. Although the first VRE outbreaks were reported almost 12 years ago, such outbreaks remained uncommon and the question is why they are occurring now. Based on molecular epidemiological studies we have learned that a subpopulation of Enterococcus faecium, resistant to amoxicillin but susceptible to vancomycin, has become highly endemic in Dutch hospitals in the past 12 years. Initial analyses suggest that several transposons containing vancomycin-resistance genes have been introduced into this population, followed by nosocomial spread. We recommend that hospitals without detected VRE outbreaks screen high-risk patients for the presence of VRE. If transmission has already occurred in many hospitals, it will be extremely difficult (and costly) to eradicate VRE.

Comparison of performance of the novel chromogenic spectra VRE agar to that of bile esculin azide and Campylobacter agars for detection of vancomycin-resistant enterococci in fecal samples.

PubMed

Jenkins, S G; Raskoshina, L; Schuetz, A N

2011-11-01

A total of 142 stool specimens were evaluated for vancomycin-resistant enterococcus (VRE). Twenty-four-hour sensitivities and specificities, respectively, were 98% and 95% for Spectra VRE chromogenic agar (Remel, Lenexa, KS), 86% and 92% for bile esculin azide with vancomycin (BEAV; Remel), and 96.5% and 92% for Campylobacter agar (CAMPY; Remel). Spectra VRE and CAMPY are significantly more sensitive at 24 h than BEAV.

Vancomycin analogues containing monosaccharides exhibit improved antibiotic activity: a combined one-pot enzymatic glycosylation and chemical diversification strategy.

PubMed

Thayer, Desiree A; Wong, Chi-Huey

2006-09-18

Many natural products contain carbohydrate moieties that contribute to their biological activity. Manipulation of the carbohydrate domain of natural products through multiple glycosylations to identify new derivatives with novel biological activities has been a difficult and impractical process. We report a practical one-pot enzymatic approach with regeneration of cosubstrates to synthesize analogues of vancomycin that contain an N-alkyl glucosamine, which exhibited marked improvement in antibiotic activity against a vancomycin-resistant strain of Enterococcus.

First outbreak of linezolid-resistant vancomycin-resistant Enterococcus faecium in an Irish hospital, February to September 2014.

PubMed

O'Driscoll, C; Murphy, V; Doyle, O; Wrenn, C; Flynn, A; O'Flaherty, N; Fenelon, L E; Schaffer, K; FitzGerald, S F

2015-12-01

An outbreak of linezolid-resistant vancomycin-resistant Enterococcus faecium (LRVREfm) occurred in the hepatology ward of a tertiary referral hospital in Ireland between February and September 2014. LRVREfm was isolated from 15 patients; pulsed-field gel electrophoresis confirmed spread of a single clone. This is the first report of an outbreak of linezolid-resistant vancomycin-resistant enterococcus in Ireland. Copyright © 2015 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

The Monoclonal Antitoxin Antibodies (Actoxumab-Bezlotoxumab) Treatment Facilitates Normalization of the Gut Microbiota of Mice with Clostridium difficile Infection.

PubMed

Džunková, Mária; D'Auria, Giuseppe; Xu, Hua; Huang, Jun; Duan, Yinghua; Moya, Andrés; Kelly, Ciarán P; Chen, Xinhua

2016-01-01

Antibiotics have significant and long-lasting impacts on the intestinal microbiota and consequently reduce colonization resistance against Clostridium difficile infection (CDI). Standard therapy using antibiotics is associated with a high rate of disease recurrence, highlighting the need for novel treatment strategies that target toxins, the major virulence factors, rather than the organism itself. Human monoclonal antibodies MK-3415A (actoxumab-bezlotoxumab) to C. difficile toxin A and toxin B, as an emerging non-antibiotic approach, significantly reduced the recurrence of CDI in animal models and human clinical trials. Although the main mechanism of protection is through direct neutralization of the toxins, the impact of MK-3415A on gut microbiota and its restoration has not been examined. Using a CDI murine model, we compared the bacterial diversity of the gut microbiome of mice under different treatments including MK-3415A, vancomycin, or vancomycin combined with MK-3415A, sampled longitudinally. Here, we showed that C. difficile infection resulted in the prevalence of Enterobacter species. Sixty percent of mice in the vehicle group died after 2 days and their microbiome was almost exclusively formed by Enterobacter . MK-3415A treatment resulted in lower Enterobacter levels and restoration of Blautia, Akkermansia , and Lactobacillus which were the core components of the original microbiota. Vancomycin treatment led to significantly lower survival rate than the combo treatment of MK-3415A and vancomycin. Vancomycin treatment decreased bacterial diversity with predominant Enterobacter and Akkermansia , while Staphylococcus expanded after vancomycin treatment was terminated. In contrast, mice treated by vancomycin combined with MK-3415A also experienced decreased bacterial diversity during vancomycin treatment. However, these animals were able to recover their initial Blautia and Lactobacillus proportions, even though episodes of Staphylococcus overgrowth were detected by the end of the experiments. In conclusion, MK-3415A (actoxumab-bezlotoxumab) treatment facilitates normalization of the gut microbiota in CDI mice. It remains to be examined whether or not the prevention of recurrent CDI by the antitoxin antibodies observed in clinical trials occurs through modulation of microbiota.

Is the mazEF toxin-antitoxin system responsible for vancomycin resistance in clinical isolates of Enterococcus faecalis?

PubMed

Sadeghifard, Nourkhoda; Soheili, Sara; Sekawi, Zamberi; Ghafourian, Sobhan

2014-01-01

The current study was conducted to investigate the relationship between vancomycin-resistant Enterococcus faecalis (VRE) and the presence of mazEF toxin-antitoxin (TA) system, which may be useful as target for novel antimicrobial therapy concepts. The susceptibility of E. faecalis was determined by MIC, and the presence of the mazEF TA system was evaluated by PCR. Among 200 E. faecalis isolates 39.5% showed resistance to vancomycin (VRE), while 60.5% were susceptible strains (VSE). The mazEF TA system was positive in all VRE isolates (100%), but less prevalent (38/121, 31.4%) among the 121 VSE strains. In conclusion, our study demonstrated a positive relationship between the presence of vancomycin resistance and mazEF TA system. This observation may introduce therapeutic options against a novel antimicrobial target in enterococci.

In vitro activity of daptomycin and comparator agents against Staphylococcus aureus isolates from intravenous drug users with right endocarditis.

PubMed

Sanchez-Porto, Antonio; Casanova-Roman, Manuel; Casas-Ciria, Javier; Santaella, Maria Jose; Sanchez-Morenilla, Immaculada; Eiros-Bouza, Jose Maria

2010-06-01

There is an increasing need for alternative agents in endocarditis, especially with the increasing incidence of vancomycin-intermediate Staphylococcus aureus (VISA). We evaluated the in vitro activity of daptomycin and several comparator agents against 33 non-duplicate clinical Staphylococcus aureus isolates from intravenous drug users with right endocarditis. Wider microdilution panels were used for all the comparator agents and daptomycin. Daptomycin was also tested using E-test strips. E-test strips were used to confirm the vancomycin MICs. Methicillin-resistant Staphylococcus aureus (MRSA isolates with vancomycin MICs ≥ 2 g/mL were screened using the E-test GRD. In all, 30 isolates were methicillin-susceptible (MSSA) and 3 MRSA. The three MRSA isolates exhibited a false vancomycin MIC >2 g/mL determined by Wider microdilution panels. They were screened using the E-test GRD and they were GRD negative. Their final MIC was 2 g/mL. Three MSSA and three MRSA isolates had a vancomycin MIC of 2 g/mL. Four MSSA isolates had a vancomycin MIC of 1.5 g/mL, daptomycin MIC90 0.25 g/mL, linezolid MIC90 2 g/mL. As regards daptomycin, wider microdilution panels and E-test strips yielded the same results. Our findings suggest that daptomycin and linezolid are a viable alternative for treating right endocarditis and bacteraemia caused by MSSA, MRSA and hVISA.

Gene Expression Analysis Reveals New Possible Mechanisms of Vancomycin-Induced Nephrotoxicity and Identifies Gene Markers Candidates

PubMed Central

Dieterich, Christine; Puey, Angela; Lyn, Sylvia; Swezey, Robert; Furimsky, Anna; Fairchild, David; Mirsalis, Jon C.; Ng, Hanna H.

2009-01-01

Vancomycin, one of few effective treatments against methicillin-resistant Staphylococcus aureus, is nephrotoxic. The goals of this study were to (1) gain insights into molecular mechanisms of nephrotoxicity at the genomic level, (2) evaluate gene markers of vancomycin-induced kidney injury, and (3) compare gene expression responses after iv and ip administration. Groups of six female BALB/c mice were treated with seven daily iv or ip doses of vancomycin (50, 200, and 400 mg/kg) or saline, and sacrificed on day 8. Clinical chemistry and histopathology demonstrated kidney injury at 400 mg/kg only. Hierarchical clustering analysis revealed that kidney gene expression profiles of all mice treated at 400 mg/kg clustered with those of mice administered 200 mg/kg iv. Transcriptional profiling might thus be more sensitive than current clinical markers for detecting kidney damage, though the profiles can differ with the route of administration. Analysis of transcripts whose expression was changed by at least twofold compared with vehicle saline after high iv and ip doses of vancomycin suggested the possibility of oxidative stress and mitochondrial damage in vancomycin-induced toxicity. In addition, our data showed changes in expression of several transcripts from the complement and inflammatory pathways. Such expression changes were confirmed by relative real-time reverse transcription–polymerase chain reaction. Finally, our results further substantiate the use of gene markers of kidney toxicity such as KIM-1/Havcr1, as indicators of renal injury. PMID:18930951

Gene expression analysis reveals new possible mechanisms of vancomycin-induced nephrotoxicity and identifies gene markers candidates.

PubMed

Dieterich, Christine; Puey, Angela; Lin, Sylvia; Lyn, Sylvia; Swezey, Robert; Furimsky, Anna; Fairchild, David; Mirsalis, Jon C; Ng, Hanna H

2009-01-01

Vancomycin, one of few effective treatments against methicillin-resistant Staphylococcus aureus, is nephrotoxic. The goals of this study were to (1) gain insights into molecular mechanisms of nephrotoxicity at the genomic level, (2) evaluate gene markers of vancomycin-induced kidney injury, and (3) compare gene expression responses after iv and ip administration. Groups of six female BALB/c mice were treated with seven daily iv or ip doses of vancomycin (50, 200, and 400 mg/kg) or saline, and sacrificed on day 8. Clinical chemistry and histopathology demonstrated kidney injury at 400 mg/kg only. Hierarchical clustering analysis revealed that kidney gene expression profiles of all mice treated at 400 mg/kg clustered with those of mice administered 200 mg/kg iv. Transcriptional profiling might thus be more sensitive than current clinical markers for detecting kidney damage, though the profiles can differ with the route of administration. Analysis of transcripts whose expression was changed by at least twofold compared with vehicle saline after high iv and ip doses of vancomycin suggested the possibility of oxidative stress and mitochondrial damage in vancomycin-induced toxicity. In addition, our data showed changes in expression of several transcripts from the complement and inflammatory pathways. Such expression changes were confirmed by relative real-time reverse transcription-polymerase chain reaction. Finally, our results further substantiate the use of gene markers of kidney toxicity such as KIM-1/Havcr1, as indicators of renal injury.

PEGylated liposomal vancomycin: a glimmer of hope for improving treatment outcomes in MRSA pneumonia.

PubMed

Pumerantz, Andrew S

2012-12-01

Methicillin-resistant Staphylococcus aureus (MRSA) plays a significant role in the pandemic of multidrug resistant bacterial infections and is a major cause of hospital-acquired pneumonia. MRSA pneumonia carries a high morbidity and mortality rate especially in elderly diabetics with chronic kidney disease. S. aureus is highly virulent and successful respiratory pathogen. Vancomycin and linezolid are the only two antimicrobial agents FDA-approved to treat MRSA pneumonia. Standard vancomycin dosing is associated with high clinical failure rates and higher dosages are associated with increased nephrotoxicity. Pharmacokinetic and pharmacodynamic limitations are major contributors to poor outcomes with vancomycin. New agents are needed to improve treatment outcomes with MRSA pneumonia. Recently released antimicrobials with in vitro activity are not FDA-approved for treating MRSA pneumonia. Other novel agents are being investigated though none are in late-stage development. Pharmaceutical industry perception of low returns on investment, a Sisyphean regulatory environment, and obstacles to patentability have contributed to declining interest in both the development of novel antibiotics and the improvement of existing generic formulations. Despite decades of investigation into liposomal encapsulation as a drug delivery system that would increase efficacy and decrease toxicity, only liposomal amphotericin B and doxorubicin are commercially available. In this article, the pharmacokinetics and biodistribution of a novel PEGylated liposomal vancomycin formulation along with passive targeting and the enhanced permeability and retention effect of liposomal drug delivery; the pathogenesis of MRSA pneumonia; and recent patents of novel anti-MRSA agents, including inhalational liposomal vancomycin, are reviewed.

High vancomycin MICs within the susceptible range in Staphylococcus aureus bacteraemia isolates are associated with increased cell wall thickness and reduced intracellular killing by human phagocytes.

PubMed

Falcón, Rocío; Martínez, Alba; Albert, Eliseo; Madrid, Silvia; Oltra, Rosa; Giménez, Estela; Soriano, Mario; Vinuesa, Víctor; Gozalbo, Daniel; Gil, María Luisa; Navarro, David

2016-05-01

Vancomycin minimum inhibitory concentrations (MICs) at the upper end of the susceptible range for Staphylococcus aureus have been associated with poor clinical outcomes of bloodstream infections. We tested the hypothesis that high vancomycin MICs in S. aureus bacteraemia isolates are associated with increased cell wall thickness and suboptimal bacterial internalisation or lysis by human phagocytes. In total, 95 isolates were evaluated. Original vancomycin MICs were determined by Etest. The susceptibility of S. aureus isolates to killing by phagocytes was assessed in a human whole blood assay. Internalisation of bacterial cells by phagocytes was investigated by flow cytometry. Cell wall thickness was evaluated by transmission electron microscopy. Genotypic analysis of S. aureus isolates was performed using a DNA microarray system. Vancomycin MICs were significantly higher (P=0.006) in isolates that were killed suboptimally (killing index <60%) compared with those killed efficiently (killing index >70%) and tended to correlate inversely (P=0.08) with the killing indices. Isolates in both killing groups were internalised by human neutrophils and monocytes with comparable efficiency. The cell wall was significantly thicker (P=0.03) in isolates in the low killing group. No genotypic differences were found between the isolates in both killing groups. In summary, high vancomycin MICs in S. aureus bacteraemia isolates were associated with increased cell wall thickness and reduced intracellular killing by phagocytes. Copyright © 2016 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection in patients 60 years and older (EXTEND): a randomised, controlled, open-label, phase 3b/4 trial.

PubMed

Guery, Benoit; Menichetti, Francesco; Anttila, Veli-Jukka; Adomakoh, Nicholas; Aguado, Jose Maria; Bisnauthsing, Karen; Georgopali, Areti; Goldenberg, Simon D; Karas, Andreas; Kazeem, Gbenga; Longshaw, Chris; Palacios-Fabrega, Jose Alejandro; Cornely, Oliver A; Vehreschild, Maria J G T

2018-03-01

Clostridium difficile infection causes severe complications and frequently recurs. An extended-pulsed fidaxomicin regimen might facilitate sustained clinical cure by prolonging C difficile suppression and supporting gut microbiota recovery. We aimed to compare clinical outcomes of extended-pulsed fidaxomicin with standard vancomycin. In this randomised, controlled, open-label, superiority study, we recruited hospitalised adults aged 60 years and older with confirmed C difficile infection at 86 European hospitals. Patients were randomly assigned (1:1) using an interactive web response system to receive extended-pulsed fidaxomicin (200 mg oral tablets, twice daily on days 1-5, then once daily on alternate days on days 7-25) or vancomycin (125 mg oral capsules, four times daily on days 1-10), stratified by baseline C difficile infection severity, cancer presence, age (≥75 years vs <75 years), and number of previous C difficile infection occurrences. The primary endpoint was sustained clinical cure 30 days after end of treatment (day 55 for extended-pulsed fidaxomicin and day 40 for vancomycin), assessed in all randomised patients who met the inclusion criteria and received at least one dose of study medication (modified full analysis set). Adverse events were assessed in all patients who received at least one dose of study drug. The study is registered with ClinicalTrials.gov, number NCT02254967. Between Nov 6, 2014, and May 5, 2016, 364 patients were enrolled and randomly assigned to receive extended-pulsed fidaxomicin or vancomycin. 362 patients received at least one dose of study medication (181 in each group). 124 (70%) of 177 patients in the modified full analysis set receiving extended-pulsed fidaxomicin achieved sustained clinical cure 30 days after end of treatment, compared with 106 (59%) of 179 patients receiving vancomycin (difference 11% [95% CI 1·0-20·7], p=0·030; odds ratio 1·62 [95% CI 1·04-2·54]). Incidence of treatment-emergent adverse events did not differ between extended-pulsed fidaxomicin (121 [67%] of 181) and vancomycin (128 [71%] of 181) treatment arms. One death in the vancomycin arm was considered by the investigator to be related to study drug. Extended-pulsed fidaxomicin was superior to standard-dose vancomycin for sustained cure of C difficile infection, and, to our knowledge, extended-pulsed fidaxomicin recurrence rates in this study are the lowest observed in a randomised clinical trial of antibiotic treatment for C difficile infection. Astellas Pharma, Inc. Copyright © 2018 Elsevier Ltd. All rights reserved.

Clinical features and treatment outcomes of vancomycin-intermediate Staphylococcus aureus (VISA) and heteroresistant vancomycin-intermediate Staphylococcus aureus (hVISA) in a tertiary care institution in Singapore.

PubMed

Fong, R K C; Low, J; Koh, T H; Kurup, A

2009-08-01

This retrospective case-control study was undertaken to review the clinical features associated with heteroresistant vancomycin-intermediate Staphylococcus aureus (hVISA) and vancomycin-intermediate S. aureus (VISA) infections and the local impact they have on clinical outcome. Compared with vancomycin-susceptible S. aureus (n = 30), hVISA and VISA infections (n = 10) are found to be associated with a longer period of prior glycopeptide use (P = 0.01), bone/joint (P < 0.01) and prosthetic infections (P = 0.04), as well as treatment failure, as evidenced by longer bacteremic (P < 0.01) and culture positivity (P < 0.01) periods. This was observed to have resulted in longer hospital length of stay (P < 0.01) and total antibiotic therapy duration (P = 0.01). There was, however, no significant difference in the overall patient mortality or the hospitalization cost (P = 0.12) in both groups. Clinicians should be cognizant of the association between hVISA/VISA with high bacterial load deep-seated infections. We recommend targeted and even universal screening for hVISA/VISA in methicillin-resistant S. aureus (MRSA) infections.

Role of Vancomycin as a Component of Oral Nonabsorbable Antibiotics for Microbial Suppression in Leukemic Patients

PubMed Central

Bender, John F.; Schimpff, Stephen C.; Young, Viola Mae; Fortner, Clarence L.; Brouillet, Mary D.; Love, Lillian J.; Wiernik, Peter H.

1979-01-01

A total of 38 adult patients with acute leukemia who were undergoing remission induction chemotherapy in regular patient rooms were randomly allocated to one of two oral nonabsorbable antibiotic regimens for infection prophylaxis (gentamicin, vancomycin, and nystatin [GVN] or gentamicin and nystatin [GN]) to evaluate whether vancomycin was a necessary component. The patient population in both groups were comparable. Tolerance to GVN was less than GN but compliance was approximately equal (>85% in both groups). Patients receiving vancomycin demonstrated greater overall alimentary tract microbial suppression; however, acquisition of potential pathogens was approximately equal in both groups. The incidence of bacteremia, as well as the overall incidence of infection as related to the number of days at various granulocyte levels, was also approximately equal in both groups. Group D Streptococcus species were poorly suppressed by GN compared with GVN, although no patient developed an infection with these organisms. Colonization by newly acquired gram-negative bacilli was significantly less in the GN group (GN, 3 colonizations; GVN, 13 colonizations; P < 0.01). It is concluded that vancomycin may be safely eliminated from the GVN regimen provided microbiological data is monitored to detect resistant organisms. PMID:464573

Direct replacement of antibodies with molecularly imprinted polymer (MIP) nanoparticles in ELISA – development of a novel assay for vancomycin

PubMed Central

Chianella, Iva; Guerreiro, Antonio; Moczko, Ewa; Caygill, J. Sarah; Piletska, Elena V.; Perez De Vargas Sansalvador, Isabel M.; Whitcombe, Michael J.; Piletsky, Sergey A.

2016-01-01

A simple and straightforward technique for coating microplate wells with molecularly imprinted polymer nanoparticles (nanoMIPs) to develop ELISA type assays is presented here for the first time. NanoMIPs were synthesized by a solid phase approach with immobilized vancomycin (template) and characterized using Biacore 3000, dynamic light scattering and electron microscopy. Immobilization, blocking and washing conditions were optimized in microplate format. The detection of vancomycin was achieved in competitive binding experiments with a HRP-vancomycin conjugate. The assay was capable of measuring vancomycin in buffer and in blood plasma within the range 0.001-70 nM with a detection limit of 0.0025 nM (2.5 pM). The sensitivity of the assay was three orders of magnitude better than a previously described ELISA based on antibodies. In these experiments nanoMIPs have shown high affinity and minimal interference from blood plasma components. Immobilized nanoMIPs were stored for 1 month at room temperature without any detrimental effects to their binding properties. The high affinity of nanoMIPs and the lack of a requirement for cold chain logistics make them an attractive alternative to traditional antibodies used in ELISA. PMID:23947402

A facile and efficient single-step approach for the fabrication of vancomycin functionalized polymer-based monolith as chiral stationary phase for nano-liquid chromatography.

PubMed

Xu, Dongsheng; Shao, Huikai; Luo, Rongying; Wang, Qiqin; Sánchez-López, Elena; Fanali, Salvatore; Marina, Maria Luisa; Jiang, Zhengjin

2018-07-06

A facile single-step preparation strategy for fabricating vancomycin functionalized organic polymer-based monolith within 100μm fused-silica capillary was developed. The synthetic chiral functional monomer, i.e 2-isocyanatoethyl methacrylate (ICNEML) derivative of vancomycin, was co-polymerized with the cross-linker ethylene dimethacrylate (EDMA) in the presence of methanol and dimethyl sulfoxide as the selected porogens. The co-polymerization conditions were systematically optimized in order to obtain satisfactory column performance. Adequate permeability, stability and column morphology were observed for the optimized poly(ICNEML-vancomycin-co-EDMA) monolith. A series of chiral drugs were evaluated on the monolith in either polar organic-phase or reversed-phase modes. After the optimization of separation conditions, baseline or partial enantioseparation were obtained for series of drugs including thalidomide, colchicine, carteolol, salbutamol, clenbuterol and several other β-blockers. The proposed single-step approach not only resulted in a vancomycin functionalized organic polymer-based monolith with acceptable performance, but also significantly simplified the preparation procedure by reducing time and labor. Copyright © 2018 Elsevier B.V. All rights reserved.

Comparison of Performance of the Novel Chromogenic Spectra VRE Agar to That of Bile Esculin Azide and Campylobacter Agars for Detection of Vancomycin-Resistant Enterococci in Fecal Samples ▿

PubMed Central

Jenkins, S. G.; Raskoshina, L.; Schuetz, A. N.

2011-01-01

A total of 142 stool specimens were evaluated for vancomycin-resistant enterococcus (VRE). Twenty-four-hour sensitivities and specificities, respectively, were 98% and 95% for Spectra VRE chromogenic agar (Remel, Lenexa, KS), 86% and 92% for bile esculin azide with vancomycin (BEAV; Remel), and 96.5% and 92% for Campylobacter agar (CAMPY; Remel). Spectra VRE and CAMPY are significantly more sensitive at 24 h than BEAV. PMID:21880967

Influence of Age on Frequency of Vancomycin Dosing

PubMed Central

Legal, Michael; Wan, Marisa

2010-01-01

Background: Vancomycin is commonly prescribed at the authors’ institution because of a high prevalence of invasive infections caused by methicillin-resistant Staphylococcus aureus (MRSA) in a generally younger population. The most commonly prescribed empiric dosing interval is every 12 h (q12h). However, observations have suggested that younger adult patients require more frequent dosing, such as every 8 h (q8h). Initial underdosing of vancomycin may increase the risk of antibiotic failure. Objective: To determine whether patients under 40 years of age are more likely than older patients to require q8h dosing of vancomycin and whether recommendations can be made to alter current prescribing practices. Methods: This retrospective unmatched case–control study involved patients who had received vancomycin for suspected or confirmed severe MRSA infections. The cases were patients who had been confirmed as requiring q8h dosing, and the controls were patients who had been confirmed as requiring q12h dosing (on the basis of target predose serum levels). The influence of age (the predictor variable) on outcome (the vancomycin regimen) was evaluated by logistic regression. Results: The odds ratio for patients under 40 years of age requiring q8h dosing was 3.1 (95% confidence interval 1.5–6.3) (p = 0.002). Sixty percent of patients under 40 ultimately required a q8h regimen to achieve target predose serum levels. Patients who required q8h dosing took longer to achieve their first therapeutic serum level than those with q12h dosing (median 6 versus 4 days; p < 0.001). Conclusions: In this patient population, age less than 40 years was a strong predictor for requiring more frequent dosing of vancomycin. The authors suggest that doses of 15 mg/kg IV q8h be used empirically for younger patients with severe infections and normal renal function. PMID:22478948

Complete Reconstitution of the Vancomycin-Intermediate Staphylococcus aureus Phenotype of Strain Mu50 in Vancomycin-Susceptible S. aureus

PubMed Central

Sekine, Miwa; Hishinuma, Tomomi; Aiba, Yoshifumi; Hiramatsu, Keiichi

2016-01-01

Complete reconstitution of the vancomycin-intermediate Staphylococcus aureus (VISA) phenotype of strain Mu50 was achieved by sequentially introducing mutations into six genes of vancomycin-susceptible S. aureus (VSSA) strain N315ΔIP. The six mutated genes were detected in VISA strain Mu50 but not in N315ΔIP. Introduction of the mutation Ser329Leu into vraS, encoding the sensor histidine kinase of the vraSR two-component regulatory (TCR) system, and another mutation, Glu146Lys, into msrR, belonging to the LytR-CpsA-Psr (LCP) family, increased the level of vancomycin resistance to that detected in heterogeneous vancomycin-intermediate S. aureus (hVISA) strain Mu3. Introduction of two more mutations, Asn197Ser into graR of the graSR TCR system and His481Tyr into rpoB, encoding the β subunit of RNA polymerase, converted the hVISA strain into a VISA strain with the same level of vancomycin resistance as Mu50. Surprisingly, however, the constructed quadruple mutant strain ΔIP4 did not have a thickened cell wall, a cardinal feature of the VISA phenotype. Subsequent study showed that cell wall thickening was an inducible phenotype in the mutant strain, whereas it was a constitutive one in Mu50. Finally, introduction of the Ala297Val mutation into fdh2, which encodes a putative formate dehydrogenase, or a 67-amino-acid sequence deletion into sle1 [sle1(Δ67aa)], encoding the hydrolase of N-acetylmuramyl-l-alanine amidase in the peptidoglycan, converted inducible cell wall thickening into constitutive cell wall thickening. sle1(Δ67aa) was found to cause a drastic decrease in autolysis activity. Thus, all six mutated genes required for acquisition of the VISA phenotype were directly or indirectly involved in the regulation of cell physiology. The VISA phenotype seemed to be achieved through multiple genetic events accompanying drastic changes in cell physiology. PMID:27067329

Vancomycin-Resistant Gram-Positive Cocci Isolated from the Saliva of Wild Songbirds

PubMed Central

Ishihara, Shingo; Bitner, Jessica J.; Farley, Greg H.

2014-01-01

We analyzed highly vancomycin-resistant Gram-positive bacteria isolated from the saliva of migratory songbirds captured, sampled, and released from a birdbanding station in western Kansas. Individual bacterial isolates were identified by partial 16S rRNA sequencing. Most of the bacteria in this study were shown to be Staphylococcus succinus with the majority being isolated from the American Robin. Some of these bacteria were shown to carry vanA, vanB, and vanC vancomycin-resistance genes and have the ability to form biofilms. One of the van gene-carrying isolates is also coagulase positive, which is normally considered a virulence factor. Other organisms isolated included Staphylococcus saprophyticus as well as Enterococcus gallinarum. Given the wide range of the American Robin and ease of horizontal gene transfer between Gram-positive cocci, we postulate that these organisms could serve as a reservoir of vancomycin-resistance genes capable of transferring to human pathogens. PMID:23224296

Vancomycin-resistant gram-positive cocci isolated from the saliva of wild songbirds.

PubMed

Ishihara, Shingo; Bitner, Jessica J; Farley, Greg H; Gillock, Eric T

2013-04-01

We analyzed highly vancomycin-resistant Gram-positive bacteria isolated from the saliva of migratory songbirds captured, sampled, and released from a bird-banding station in western Kansas. Individual bacterial isolates were identified by partial 16S rRNA sequencing. Most of the bacteria in this study were shown to be Staphylococcus succinus with the majority being isolated from the American Robin. Some of these bacteria were shown to carry vanA, vanB, and vanC vancomycin-resistance genes and have the ability to form biofilms. One of the van gene-carrying isolates is also coagulase positive, which is normally considered a virulence factor. Other organisms isolated included Staphylococcus saprophyticus as well as Enterococcus gallinarum. Given the wide range of the American Robin and ease of horizontal gene transfer between Gram-positive cocci, we postulate that these organisms could serve as a reservoir of vancomycin-resistance genes capable of transferring to human pathogens.

Synthesis and In Vitro Activity of Polyhalogenated 2-phenylbenzimidazoles as a New Class of anti-MRSA and Anti-VRE Agents.

PubMed

Göker, Hakan; Karaaslan, Cigdem; Püsküllü, Mustafa Orhan; Yildiz, Sulhiye; Duydu, Yalcin; Üstündağ, Aylin; Yalcin, Can Özgür

2016-01-01

A series of novel polyhalogenated 2-phenylbenzimidazoles have been synthesized and evaluated for in vitro antistaphylococcal activity against drug-resistant bacterial strains (methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus faecium. Certain compounds inhibit bacterial growth perfectly. 11 was active than vancomycin (0.78 μg/mL) with the lowest MIC values with 0.19 μg/mL against methicillin-resistant Staphylococcus aureus, 8 and 35 exhibited best inhibitory activity against vancomycin-resistant Enterococcus faecium (1.56 μg/mL). The mechanism of action for this class of compounds appears to be different than clinically used antibiotics. These polyhalogenated benzimidazoles have potential for further investigation as a new class of potent anti-methicillin-resistant Staphylococcus aureus and anti-vancomycin-resistant Enterococcus faecium agents. © 2015 John Wiley & Sons A/S.

Is the mazEF toxin-antitoxin system responsible for vancomycin resistance in clinical isolates of Enterococcus faecalis?

PubMed Central

Sadeghifard, Nourkhoda; Soheili, Sara; Sekawi, Zamberi; Ghafourian, Sobhan

2014-01-01

The current study was conducted to investigate the relationship between vancomycin-resistant Enterococcus faecalis (VRE) and the presence of mazEF toxin-antitoxin (TA) system, which may be useful as target for novel antimicrobial therapy concepts. The susceptibility of E. faecalis was determined by MIC, and the presence of the mazEF TA system was evaluated by PCR. Among 200 E. faecalis isolates 39.5% showed resistance to vancomycin (VRE), while 60.5% were susceptible strains (VSE). The mazEF TA system was positive in all VRE isolates (100%), but less prevalent (38/121, 31.4%) among the 121 VSE strains. In conclusion, our study demonstrated a positive relationship between the presence of vancomycin resistance and mazEF TA system. This observation may introduce therapeutic options against a novel antimicrobial target in enterococci. PMID:24653969

Current treatment of gram-positive infections: focus on efficacy, safety, and cost minimalization analysis of teicoplanin.

PubMed

Crane, V S; Garabedian-Ruffalo, S M

1992-12-01

The current health care environment has had a significant impact on hospital Pharmacy and Therapeutics Committee formulary decisions. In evaluating a new therapy for formulary inclusion, a cost savings along with equivalent or an improvement in patient care and safety is optimal. Teicoplanin is an investigational glycopeptide antimicrobial agent with a spectrum of activity similar to vancomycin. Unlike vancomycin, however, teicoplanin has a long elimination half-life permitting administration once daily, and is well tolerated when given intramuscularly. In addition, teicoplanin is associated with a favorable safety profile. Red man syndrome does not appear to be a significant clinical problem. Results of our cost minimalization analysis using the average acquisition costs of vancomycin revealed that teicoplanin (400 mg), at an average acquisition cost of less than $28.46 when administered intravenously and $30.93 when administered intramuscularly, offers a clinically efficacious, safe, and less expensive alternative to vancomycin therapy.

Delivery of Antibiotics from Cementless Titanium-Alloy Cubes May Be a Novel Way to Control Postoperative Infections

PubMed Central

Bezuidenhout, Martin B.; van Staden, Anton D.; Oosthuizen, Gert A.; Dimitrov, Dimitar M.; Dicks, Leon M. T.

2015-01-01

Bacterial colonisation and biofilm formation onto orthopaedic devices are difficult to eradicate. In most cases infection is treated by surgical removal of the implant and cleaning of the infected area, followed by extensive treatment with broad-spectrum antibiotics. Such treatment causes great discomfort, is expensive, and is not always successful. In this study we report on the release of vancomycin through polyethersulfone membranes from channels in cementless titanium-alloy cubes. The cubes were constructed with LaserCUSING from Ti6Al4V ELI powder. Vancomycin was released by non-Fickian anomalous (constraint) diffusion. Approximately 50% of the vancomycin was released within the first 17 h. However, sustained delivery of vancomycin for 100 h was possible by reinjecting the channels. Refillable implants may be a novel way to control postoperative infections. PMID:25861649

Digital antimicrobial susceptibility testing using the MilliDrop technology.

PubMed

Jiang, L; Boitard, L; Broyer, P; Chareire, A-C; Bourne-Branchu, P; Mahé, P; Tournoud, M; Franceschi, C; Zambardi, G; Baudry, J; Bibette, J

2016-03-01

We present the MilliDrop Analyzer (MDA), a droplet-based millifluidic system for digital antimicrobial susceptibility testing (D-AST), which enables us to determine minimum inhibitory concentrations (MICs) precisely and accurately. The MilliDrop technology was validated by using resazurin for fluorescence readout, for comparison with standard methodology, and for conducting reproducibility studies. In this first assessment, the susceptibility of a reference Gram-negative strain Escherichia coli ATCC 25922 to gentamicin, chloramphenicol, and nalidixic acid were tested by the MDA, VITEK®2, and broth microdilution as a reference standard. We measured the susceptibility of clinically relevant Gram-positive strains of Staphylococcus aureus to vancomycin, including vancomycin-intermediate S. aureus (VISA), heterogeneous vancomycin-intermediate S. aureus (hVISA), and vancomycin-susceptible S. aureus (VSSA) strains. The MDA provided results which were much more accurate than those of VITEK®2 and standard broth microdilution. The enhanced accuracy enabled us to reliably discriminate between VSSA and hVISA strains.

Fidaxomicin versus Vancomycin as a First-Line Treatment for Clostridium difficile-Associated Diarrhea in Specific Patient Populations: A Pharmacoeconomic Evaluation.

PubMed

Reveles, Kelly R; Backo, Jennifer L; Corvino, Frank A; Zivkovic, Marko; Broderick, Kelly C

2017-12-01

The reduction in recurrent Clostridium difficile-associated diarrhea (CDAD) with fidaxomicin therapy may reduce hospital readmissions and lead to lower overall CDAD costs. However, studies assessing the cost-effectiveness of fidaxomicin as first-line therapy from the U.S. hospital perspective are lacking. This study evaluated the costs associated with utilizing fidaxomicin or vancomycin as a first-line therapy for CDAD in specific patient populations from a U.S. hospital perspective. A decision-analytic model was developed to estimate total costs (hospitalization and drug costs) associated with using fidaxomicin or vancomycin as first-line therapy for a first episode and up to two recurrences of CDAD in five patient populations: general population, elderly, patients receiving concomitant antibiotics, and patients with renal impairment or cancer. The total cost of CDAD treatment using fidaxomicin first line in the general population was $14,442 per patient versus $14,179 per patient with vancomycin first line. In subgroup analyses, fidaxomicin use resulted in total hospital cost savings of $616 per patient in patients with cancer and $312 in patients with concomitant antibiotic use; vancomycin use was associated with total hospital cost savings of $243 per patient in the elderly and $371 in patients with renal impairment. Fidaxomicin as first-line CDAD therapy is associated with similar total costs as compounded vancomycin oral solution in the general population. In elderly and renally impaired patients, slight increases in hospital cost were observed with fidaxomicin therapy, and in patients with cancer or concomitant antibiotic use, hospital cost savings were observed. © 2017 Pharmacotherapy Publications, Inc.

Ceftaroline fosamil use in hospitalized patients with acute bacterial skin and skin structure infections: Budget impact analysis from a hospital perspective.

PubMed

Huang, Xingyue; Beresford, Eric; Lodise, Thomas; Friedland, H David

2013-06-15

The budgetary impact of adding ceftaroline fosamil to a hospital formulary for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) was evaluated. A three-year hospital budget impact model was constructed with three initial treatment options for ABSSSIs: ceftaroline fosamil, vancomycin plus aztreonam, and other vancomycin-containing regimens. The target population was hospitalized adult patients with an ABSSSI. Clinical cure rates with initial treatment were assumed to be similar to those from ceftaroline fosamil clinical trials. Patients who did not respond to initial treatment were assumed to be treated successfully with second-line antimicrobial therapy. Length of stay and cost per hospital day (by success or failure with initial treatment) were estimated based on a large database from more than 100 U.S. hospitals. Other model inputs included the annual number of ABSSSI admissions, projected annual case growth rate, proportion of ABSSSI target population receiving vancomycin-containing regimen, expected proportion of ABSSSI target population to be treated with ceftaroline fosamil, drug acquisition cost, cost of antibiotic administration, and cost of vancomycin monitoring. Sensitivity analysis using 95% confidence limits of clinical cure rates was also performed. The estimated total cost of care for treating a patient with an ABSSSI was $395 lower with ceftaroline fosamil ($15,087 versus $15,482) compared with vancomycin plus aztreonam and $72 lower ($15,087 versus $15,159) compared with other vancomycin-containing regimens. Model estimates indicated that adding ceftaroline fosamil to the hospital formulary would not have a negative effect on a hospital's budget for ABSSSI treatment.

An unusual case of acute kidney injury due to vancomycin lessons learnt from reliance on eGFR.

PubMed

Barraclough, Katherine; Harris, Marianne; Montessori, Val; Levin, Adeera

2007-08-01

We present a case of renal impairment in an emaciated HIV-infected male that initially went unrecognized because of reliance on serum creatinine and estimated glomerular filtration rate (eGFR). Inaccurate vancomycin dosing led to toxic drug levels (66 mg/l), associated with acute and severe worsening of kidney function. This occurred in the context of escalating doses of vancomycin given in the presence of changing kidney function, albeit kidney function that always remained well within the normal range (serum creatinine 29 - 42 mumol/l). In the absence of other plausible explanations, a presumptive diagnosis of vancomycin nephrotoxicity was made. Given the rarity of this diagnosis in the current era, we discuss the pathophysiology of vancomycin nephrotoxicity. We also explore the potential reasons for inaccuracy of GFR prediction equations in the HIV population, and discuss the potential pitfalls associated with application of eGFR or even serum creatinine without appropriate understanding of their limitations. We believe our case highlights a number of important teaching points: Vancomycin nephrotoxitiy is rare but can occur in the setting of kidney dysfunction. Current assessment of kidney function using creatinine and eGFR requires awareness of the clinical caveats in which these measures may be misleading. Acute changes in kidney function, irrespective of the test used, should be contextualized to the individual situation. Persons with HIV and low muscle mass constitute a specific subgroup in whom assessment of kidney function may be problematic using creatinine. We support ongoing efforts to develop or refine equations for specific unique and easily identifiable populations.

Diversity of Tn1546 in vanA-positive Enterococcus faecium clinical isolates with VanA, VanB, and VanD phenotypes and susceptibility to vancomycin.

PubMed

Cha, J O; Yoo, J I; Kim, H K; Kim, H S; Yoo, J S; Lee, Y S; Jung, Y H

2013-10-01

To investigate diversity in the vanA cluster in Enterococcus faecium isolates from nontertiary hospitals. We identified 43 vanA-positive Ent. faecium isolates, including two vancomycin-susceptible isolates, from hospitals between 2003 and 2006. Of these isolates, >85% were resistant to ampicillin, erythromycin and ciprofloxacin. The vanA cluster was classified into six types using overlapping PCR, but the prototype transposon Tn1546 was not found. Most vanA-positive vancomycin-resistant Enterococcus (VRE) carried IS1216V and belonged to Type III (58·1%) or Type II (20·9%). vanY, vanZ and IS1216V were observed in the left and right ends of Type III with long-range PCR. IS1216V was also observed within vanS and vanX in the two vancomycin-susceptible isolates and in two vancomycin-resistant isolates. No VRE isolates with VanB and VanD phenotypes contained point mutations in vanS, unlike in previous reports. Sequence types (STs) of all isolates belonged to clonal complex 17, and ST78 was predominant. Insertion sequences, especially IS1216V, cause structural variation in the vanA cluster. We report the first observation of vanY and vanZ at the left end of Tn1546 in clinical isolates. This is the first report of the frequency of vancomycin resistance and diversity of Tn1546 in vanA-positive Ent. faecium isolates from nontertiary hospitals. © 2013 The Society for Applied Microbiology.

Characterization of Tn1546 in vancomycin-resistant Enterococcus faecium isolated from canine urinary tract infections: evidence of gene exchange between human and animal enterococci.

PubMed

Simjee, S; White, D G; McDermott, P F; Wagner, D D; Zervos, M J; Donabedian, S M; English, L L; Hayes, J R; Walker, R D

2002-12-01

Thirty-five enterococcal isolates were recovered from dogs diagnosed with urinary tract infections at the Michigan State University Veterinary Teaching Hospital over a 2-year period (1996 to 1998). Isolated species included Enterococcus faecium (n = 13), Enterococcus faecalis (n = 7), Enterococcus gallinarum (n = 11), and Enterococcus casseliflavus (n = 4). Antimicrobial susceptibility testing revealed several different resistance phenotypes, with the majority of the enterococcal isolates exhibiting resistance to three or more antibiotics. One E. faecium isolate, CVM1869, displayed high-level resistance to vancomycin (MIC > 32 micro g/ml) and gentamicin (MIC > 2,048 micro g/ml). Molecular analysis of this isolate revealed the presence of Tn1546 (vanA), responsible for high-level vancomycin resistance, and Tn5281 carrying aac6'-aph2", conferring high-level aminoglycoside resistance. Pulsed-field gel electrophoresis analysis revealed that CVM1869 was a canine E. faecium clone that had acquired Tn1546, perhaps from a human vancomycin-resistant E. faecium. Transposons Tn5281 and Tn1546 were located on two different conjugative plasmids. Sequence analysis revealed that in Tn1546, ORF1 had an 889-bp deletion and an IS1216V insertion at the 5' end and an IS1251 insertion between vanS and vanH. To date, this particular form of Tn1546 has only been described in human clinical vancomycin-resistant enterococcus isolates unique to the United States. Additionally, this is the first report of a vancomycin-resistant E. faecium isolated from a companion animal in the United States.

Auditory function after application of ototopical vancomycin and mupirocin solutions in a murine model.

PubMed

Rutherford, Kimberley D; Kavanagh, Katherine; Parham, Kourosh

2011-03-01

To determine whether mupirocin (440 µg/mL) and vancomycin otic drops (25 mg/mL) show evidence of ototoxicity in CBA/J mice immediately following a 7-day course of daily intratympanic (IT) injections and 1 month following treatment. Nonrandomized controlled trial. Academic hospital laboratory. Twenty CBA/J mice. Mean auditory brainstem response (ABR) thresholds increased in all drug- and saline-treated ears immediately after 7 days of IT injections but returned to baseline for most stimulus frequencies by 30 days later. This finding appeared to be correlated with the presence and subsequent resolution of tympanic membrane (TM) perforations and granulation tissue at the injection sites. Mupirocin-treated ears showed no significant difference in ABR thresholds compared to saline-treated ears. No significant differences were noted between vancomycin- and saline-treated ears, but there was a significant interaction between testing day and stimulus frequency (P < .001). Further analysis revealed that ABR thresholds at 32 kHz remained significantly elevated in vancomycin-treated mice despite the resolution of TM perforations and granulation tissue 30 days after completion of IT injections (95% confidence interval, -13.5 to -5.5, P < .01). Although IT application of mupirocin solution (440 µg/mL) caused no significant change in the ABR thresholds in a murine model, vancomycin solution (25 mg/mL) resulted in high-frequency threshold elevations in both the ear directly injected and the contralateral ear. Mupirocin solution may be beneficial in managing otitis externa and media caused by resistant pathogens. Further studies of ototopical vancomycin are needed to define parameters governing its safe use.

3D printed bioceramics for dual antibiotic delivery to treat implant-associated bone infection.

PubMed

Inzana, J A; Trombetta, R P; Schwarz, E M; Kates, S L; Awad, H A

2015-11-04

Surgical implant-associated bone infections (osteomyelitis) have severe clinical and socioeconomic consequences. Treatment of chronic bone infections often involves antibiotics given systemically and locally to the affected site in poly (methyl methacrylate) (PMMA) bone cement. Given the high antibiotic concentrations required to affect bacteria in biofilm, local delivery is important to achieve high doses at the infection site. PMMA is not suitable to locally-deliver some biofilm-specific antibiotics, including rifampin, due to interference with PMMA polymerisation. To examine the efficacy of localised, combinational antibiotic delivery compared to PMMA standards, we fabricated rifampin- and vancomycin-laden calcium phosphate scaffolds (CPS) by three-dimensional (3D) printing to treat an implant-associated Staphylococcus aureus bone infection in a murine model. All vancomycin- and rifampin-laden CPS treatments significantly reduced the bacterial burden compared with vancomycin-laden PMMA. The bones were bacteria culture negative in 50 % of the mice that received sustained release vancomycin- and rifampin-laden CPS. In contrast, 100 % of the bones treated with vancomycin monotherapy using PMMA or CPS were culture positive. Yet, the monotherapy CPS significantly reduced the bacterial metabolic load following revision compared to PMMA. Biofilm persisted on the fixation hardware, but the infection-induced bone destruction was significantly reduced by local rifampin delivery. These data demonstrate that, despite the challenging implant-retaining infection model, co-delivery of rifampin and vancomycin from 3D printed CPS, which is not possible with PMMA, significantly improved the outcomes of implant-associated osteomyelitis. However, biofilm persistence on the fixation hardware reaffirms the importance of implant exchange or other biofilm eradication strategies to complement local antibiotics.

Rapid Identification of Vancomycin Resistant Enterococcus Faecalis Clinical Isolates using a Sugar Fermentation Method

PubMed Central

Raeisi, Javad; Saifi, Mahnaz; Pourshafie, Mohammad Reza; Habibi, Mehri; Mohajerani, Hamid Reza; Akbari, Neda

2017-01-01

Introduction Vancomycin Resistant Enterococci (VRE) can be found all over the world. Thus, rapid detection of the isolates could be of high importance in the treatment or prevention of the associated disease. Aim To measure the turanose fermentation in Enterococcus faecalis clinical isolates for rapid differentiation of VRE and Vancomycin-Susceptible E. faecalis (VSE) isolates. Materials and Methods Forty E. faecalis samples were isolated from 200 clinical samples in Tehran Medical Center, Iran, from October 2012 to December 2012. These isolates were detected according to the standard microbial and biochemical tests. Detection of VRE isolates was originally performed by disk diffusion using 1 μg vancomycin disk, followed by Polymerase Chain Reaction (PCR) amplification of the vanA gene. Finally, the turanose consumption in 1%, 0.7% and 0.5% dilutions was detected by a phenotypic method. Results Among the 40 E. faecalis isolates, 20 vancomycin-susceptible and 20 vancomycin-resistant E. faecalis were isolated according to the disk diffusion and PCR of the vanA gene. There was a considerable difference between VRE and VSE isolates in 0.7% dilution of turanose. However, there was no significant difference between VRE and VSE in 1% and 0.5% dilutions of turanose. Conclusion Since detection of VRE isolates is of high importance, especially in nosocomial infections, phenotypic methods may be highly useful for this purpose. In conclusion, our data indicate that VRE isolated from clinical samples could be distinguished from VSE isolates by turanose fermentation at dilution 0.7%. PMID:28511382

Multicenter, Randomized Study of the Efficacy and Safety of Intravenous Iclaprim in Complicated Skin and Skin Structure Infections▿

PubMed Central

Krievins, D.; Brandt, R.; Hawser, S.; Hadvary, P.; Islam, K.

2009-01-01

Iclaprim is a novel antibacterial agent that is currently in development for the treatment of complicated skin and skin structure infections (cSSSI). Iclaprim specifically and selectively inhibits bacterial dihydrofolate reductase, a critical enzyme in the bacterial folate pathway, and exhibits an extended spectrum of activity against various resistant pathogens, including methicillin (meticillin)-resistant Staphylococcus aureus (MRSA). The objective of this randomized, double-blind phase II study was to compare the efficacy and safety of iclaprim to those of vancomycin in patients with cSSSI. Patients were randomized to receive 0.8 mg iclaprim/kg of body weight, 1.6 mg/kg iclaprim, or 1 g vancomycin twice a day for 10 days. Clinical cure rates for the 0.8- and 1.6-mg/kg-iclaprim treatment groups were comparable to that for the vancomycin treatment group (26/28 patients [92.9%], 28/31 patients [90.3%], and 26/28 patients [92.9%], respectively). Iclaprim also showed high microbiological eradication rates. Iclaprim exhibited an eradication rate of 80% and 72% versus 59% observed with vancomycin for S. aureus, the pathogen most frequently isolated at baseline. Five MRSA cases were observed, four in the 0.8-mg/kg-iclaprim arm and one in the vancomycin arm, and all were both clinically and microbiologically cured. Iclaprim exhibited a safety profile similar to that of vancomycin, an established drug for the treatment of cSSSI. Results from this study indicate that iclaprim is a promising new therapy for the treatment of cSSSI, in particular those caused by S. aureus, including MRSA. PMID:19414572

Treatment of methicillin-resistant Staphylococcus aureus: vancomycin and beyond.

PubMed

Holmes, Natasha E; Tong, Steven Y C; Davis, Joshua S; van Hal, Sebastiaan J

2015-02-01

There has been a welcome increase in the number of agents available for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). Vancomycin remains an acceptable treatment option, with moves toward individualized dosing to a pharmacokinetic/pharmacodynamic (PK/PD) target. Numerous practicalities, however, would need to be resolved before implementation. Lipoglycopeptides as a class show excellent in vitro potency. Their long half-lives and complex PKs may preclude these agents being used in critically ill patients. Anti-MRSA cephalosporins provide great promise in the treatment of MRSA. These agents, despite broad-spectrum activity, should be reserved for patients with MRSA infections as it is likely that usage will be associated with increased rates of resistance. Daptomycin is currently the only antibiotic to have shown noninferiority to vancomycin in the treatment of MRSA bacteremia. The results of an open-labeled trial to address the superiority of daptomycin compared with vancomycin in reduced vancomycin susceptibility infections are eagerly anticipated. No drug to date has shown superiority to vancomycin in the treatment of MRSA infections with the possible exception of linezolid in hospital-acquired pneumonia (HAP), making linezolid an important option in the treatment of MRSA-proven HAP. Whether these strengths and features are agent or class specific are unclear but will likely be answered with the marketing of tedizolid. There are insufficient data to recommend either quinupristin/dalfopristin or tigecycline, as first line in the treatment of severe MRSA infections. These agents however remain options in patients with no other alternatives. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

[Measurements of vancomycin concentrations in the blood - a method of personalization the antibiotic therapy in patients with chronic kidney disease].

PubMed

Pondel, Joanna; Krajewski, Piotr; Królikowska, Natalia; Tobiasz, Aleksandra; Augustyniak-Bartosik, Hanna; Hurkacz, Magdalena

2017-04-21

Therapeutic Drug Monitoring is a recognized method of personalizing treatment, having particular application in patients with chronic kidney disease who have frequent infections, requiring administration of vancomycin. International guidelines indicate the need to adjust the dose of the drug to the state of renal function. The recommended therapeutic ranges of minimum and maximum levels should be achieved in order to increase the effectiveness and safety of treatment. The aim of this study was to evaluate the usefulness of measuring the concentration of vancomycin in patients with chronic kidney disease due to bacterial infection. The study included 96 adult patients with chronic kidney disease of varying severity treated with vancomycin Patients were divided into 3 groups: treated by haemodialysis (hd), after renal transplantations (ktx), do not require renal replacement therapy (nef). In subjects were examined the minimum and maximum concentrations of vancomycin in steady-state and were compared with recommended therapeutic ranges. Statistically significant decrease of inflammatory markers was observed only in patients treated with dialysis. In the other groups not significant changes in values of inflammatory parameters were confirmed. Trough concentrations of vancomycin marked in patients were consistent with the recommendation of EUCAST, but exceeded the value recommended by the manufacturers of the drug. Considering absolute values of the minimum concentrations, only about 50% of patients achieved the therapeutic range (58% for recommendation EUCAST and 36% for the manufacturer's instructions). Peak concentration values indicated in dialyzed patients were below the prescribed range of 20-50 mg/l and averaged 17.7 mg / l. In the other subgroups they were correct. The rating of the absolute values of the peak concentrations of vancomycin also showed that only 46% (64% in the ktx, 30% - hd and 53% - nef) was within the recommended range, while 50% were classified as concentrations of sub-therapeutic (36% in the ktx, 42% of the nef group and 65% in hd). Vancomycin concentrations measured in patients with chronic kidney disease, both minimum and maximum, were not fully comply with the recommended therapeutic ranges, despite the use of doses determined based on a calculation of glomerular filtration rate. This points to the need for particularly careful monitoring of therapy and analysis of antibiotic concentrations to improve the effectiveness and reduce the incidence of undesirable consequences of treatment.

Comparative study of selective chromogenic (chromID VRE) and bile esculin agars for isolation and identification of vanB-containing vancomycin-resistant enterococci from feces and rectal swabs.

PubMed

Grabsch, E A; Ghaly-Derias, S; Gao, W; Howden, B P

2008-12-01

The new chromogenic agar chromID VRE (cIDVRE; bioMérieux) was compared with bile esculin agar (BD) containing 6 mg/liter vancomycin for the detection of colonization with vanB-containing vancomycin-resistant enterococci (VRE). At 48 h of incubation, the results obtained with both media were comparable. However, cIDVRE detected significantly more VRE at 24 h (39.3% versus 21.3%, P = 0.003), and its use may facilitate the timely implementation of infection control procedures.

The Rise and Fall of Metronidazole for Clostridium difficile Infection.

PubMed

Chahine, Elias B

2018-06-01

Clostridium difficile is posing urgent health threats. Older studies have shown that metronidazole and vancomycin are equally effective in the treatment of Clostridium difficile infection (CDI). Given its inexpensive cost and low propensity to select antimicrobial resistant organisms, metronidazole became rapidly the drug of choice despite its pharmacokinetic limitations in the treatment of CDI. However, newer studies demonstrated that metronidazole is inferior to vancomycin, prompting clinicians to change their long-standing position on using metronidazole for mild to moderate infections and on reserving vancomycin for severe infections. Moving forward, metronidazole will fall out of favor in the treatment of CDI.

Current and novel antibiotics against resistant Gram-positive bacteria.

PubMed

Perez, Federico; Salata, Robert A; Bonomo, Robert A

2008-01-01

The challenge posed by resistance among Gram-positive bacteria, epitomized by methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE) and vancomycin-intermediate and -resistant S. aureus (VISA and VRSA) is being met by a new generation of antimicrobials. This review focuses on the new β-lactams with activity against MRSA (ceftobiprole and ceftaroline) and on the new glycopeptides (oritavancin, dalbavancin, and telavancin). It will also consider the role of vancomycin in an era of existing alternatives such as linezolid, daptomycin and tigecycline. Finally, compounds in early development are described, such as iclaprim, friulimicin, and retapamulin, among others.

[Vancomycin-resistant Staphylococcus aureus].

PubMed

Rodríguez, Carlos Andrés; Vesga, Omar

2005-12-01

The evolution and molecular mechanisms of vancomycin resistance in Staphylococcus aureus were reviewed. Case reports and research studies on biochemestry, electron microscopy and molecular biology of Staphylococcus aureus were selected from Medline database and summarized in the following review. After almost 40 years of successful treatment of S. aureus with vancomycin, several cases of clinical failures have been reported (since 1997). S. aureus strains have appeared with intermediate susceptibility (MIC 8-16 microg/ml), as well as strains with heterogeneous resistance (global MIC < or =4 microg/ml), but with subpopulations of intermediate susceptibility. In these cases, resistance is mediated by cell wall thickening with reduced cross linking. This traps the antibiotic before it reaches its major target, the murein monomers in the cell membrane. In 2002, a total vancomycin resistant strain (MIC > or =32 microg/ml) was reported with vanA genes from Enterococcus spp. These genes induce the change of D-Ala-D-Ala terminus for D-Ala-D-lactate in the cell wall precursors, leading to loss of affinity for glycopeptides. Vancomycin resistance in S. aureus has appeared; it is mediated by cell wall modifications that trap the antibiotic before it reaches its action site. In strains with total resistance, Enterococcus spp. genes have been acquired that lead to modification of the glycopeptide target.

Renal Function Descriptors in Neonates: Which Creatinine-Based Formula Best Describes Vancomycin Clearance?

PubMed

Bhongsatiern, Jiraganya; Stockmann, Chris; Yu, Tian; Constance, Jonathan E; Moorthy, Ganesh; Spigarelli, Michael G; Desai, Pankaj B; Sherwin, Catherine M T

2016-05-01

Growth and maturational changes have been identified as significant covariates in describing variability in clearance of renally excreted drugs such as vancomycin. Because of immaturity of clearance mechanisms, quantification of renal function in neonates is of importance. Several serum creatinine (SCr)-based renal function descriptors have been developed in adults and children, but none are selectively derived for neonates. This review summarizes development of the neonatal kidney and discusses assessment of the renal function regarding estimation of glomerular filtration rate using renal function descriptors. Furthermore, identification of the renal function descriptors that best describe the variability of vancomycin clearance was performed in a sample study of a septic neonatal cohort. Population pharmacokinetic models were developed applying a combination of age-weight, renal function descriptors, or SCr alone. In addition to age and weight, SCr or renal function descriptors significantly reduced variability of vancomycin clearance. The population pharmacokinetic models with Léger and modified Schwartz formulas were selected as the optimal final models, although the other renal function descriptors and SCr provided reasonably good fit to the data, suggesting further evaluation of the final models using external data sets and cross validation. The present study supports incorporation of renal function descriptors in the estimation of vancomycin clearance in neonates. © 2015, The American College of Clinical Pharmacology.

Fidaxomicin versus vancomycin for Clostridium difficile infection: meta-analysis of pivotal randomized controlled trials.

PubMed

Crook, Derrick W; Walker, A Sarah; Kean, Yin; Weiss, Karl; Cornely, Oliver A; Miller, Mark A; Esposito, Roberto; Louie, Thomas J; Stoesser, Nicole E; Young, Bernadette C; Angus, Brian J; Gorbach, Sherwood L; Peto, Timothy E A

2012-08-01

Two recently completed phase 3 trials (003 and 004) showed fidaxomicin to be noninferior to vancomycin for curing Clostridium difficile infection (CDI) and superior for reducing CDI recurrences. In both studies, adults with active CDI were randomized to receive blinded fidaxomicin 200 mg twice daily or vancomycin 125 mg 4 times a day for 10 days. Post hoc exploratory intent-to-treat (ITT) time-to-event analyses were undertaken on the combined study 003 and 004 data, using fixed-effects meta-analysis and Cox regression models. ITT analysis of the combined 003/004 data for 1164 patients showed that fidaxomicin reduced persistent diarrhea, recurrence, or death by 40% (95% confidence interval [CI], 26%-51%; P < .0001) compared with vancomycin through day 40. A 37% (95% CI, 2%-60%; P = .037) reduction in persistent diarrhea or death was evident through day 12 (heterogeneity P = .50 vs 13-40 days), driven by 7 (1.2%) fidaxomicin versus 17 (2.9%) vancomycin deaths at <12 days. Low albumin level, low eosinophil count, and CDI treatment preenrollment were risk factors for persistent diarrhea or death at 12 days, and CDI in the previous 3 months was a risk factor for recurrence (all P < .01). Fidaxomicin has the potential to substantially improve outcomes from CDI.

Direct replacement of antibodies with molecularly imprinted polymer nanoparticles in ELISA--development of a novel assay for vancomycin.

PubMed

Chianella, Iva; Guerreiro, Antonio; Moczko, Ewa; Caygill, J Sarah; Piletska, Elena V; De Vargas Sansalvador, Isabel M Perez; Whitcombe, Michael J; Piletsky, Sergey A

2013-09-03

A simple and straightforward technique for coating microplate wells with molecularly imprinted polymer nanoparticles (nanoMIPs) to develop assays similar to the enzyme-linked immunosorbent assay (ELISA) is presented here for the first time. NanoMIPs were synthesized by a solid-phase approach with an immobilized vancomycin (template) and characterized using Biacore 3000, dynamic light scattering, and electron microscopy. Immobilization, blocking, and washing conditions were optimized in microplate format. The detection of vancomycin was achieved in competitive binding experiments with a horseradish peroxidase-vancomycin conjugate. The assay was capable of measuring vancomycin in buffer and in blood plasma within the range of 0.001-70 nM with a detection limit of 0.0025 nM (2.5 pM). The sensitivity of the assay was 3 orders of magnitude better than a previously described ELISA based on antibodies. In these experiments, nanoMIPs have shown high affinity and minimal interference from blood plasma components. Immobilized nanoMIPs were stored for 1 month at room temperature without any detrimental effects to their binding properties. The high affinity of nanoMIPs and the lack of a requirement for cold chain logistics make them an attractive alternative to traditional antibodies used in ELISA.

OCCURRENCE OF INTRINSIC VANCOMYCIN RESISTANT ENTEROCOCCI IN ANIMAL FECES

EPA Science Inventory

A survey was conducted to determine the occurrence of vancomycin resistant enterococci (VRE) in animal and human fecal samples. Fecal samples from 14 animal species and humans were analyzed by quantitative culture for enterococci and VRE. Over 800 VRE isolates were characterize...

Impact of Oral Fidaxomicin Administration on the Intestinal Microbiota and Susceptibility to Clostridium difficile Colonization in Mice.

PubMed

Ajami, N J; Cope, J L; Wong, M C; Petrosino, J F; Chesnel, L

2018-05-01

Clostridium difficile infection (CDI), a common cause of hospital-acquired infections, typically occurs after disruption of the normal gut microbiome by broad-spectrum antibiotics. Fidaxomicin is a narrow-spectrum antibiotic that demonstrates a reduced impact on the normal gut microbiota and is approved for the treatment of CDI. To further explore the benefits of this property, we used a murine model to examine the effects of fidaxomicin versus vancomycin on gut microbiota and susceptibility to C. difficile colonization while tracking microbiota recovery over time. Mice were exposed to fidaxomicin or vancomycin by oral gavage for 3 days and subsequently challenged with C. difficile spores at predetermined time points up to 21 days postexposure to antibiotics. Fecal samples were subsequently collected for analysis. Twenty-four hours postchallenge, mice were euthanized and the colon contents harvested. The microbiota was characterized using 16S rRNA gene sequencing. All fidaxomicin-exposed mice (except for one at day 8) were resistant to C. difficile colonization. However, 9 of 15 vancomycin-exposed mice were susceptible to C. difficile colonization until day 12. All vancomycin-exposed mice recovered colonization resistance by day 16. Bacterial diversity was similar prior to antibiotic exposure in both arms and decreased substantially after exposure. A shift in taxonomic structure and composition occurred after both exposures; however, the shift was greater in vancomycin-exposed than in fidaxomicin-exposed mice. In summary, compared with vancomycin, fidaxomicin exposure had less impact on microbiota composition, promoted faster microbial recovery, and had less impact on the loss of C. difficile colonization resistance. Copyright © 2018 American Society for Microbiology.

Economic Impact of Oritavancin for the Treatment of Acute Bacterial Skin and Skin Structure Infections in the Emergency Department or Observation Setting: Cost Savings Associated with Avoidable Hospitalizations.

PubMed

Lodise, Thomas P; Fan, Weihong; Sulham, Katherine A

2016-01-01

Data indicate that acute bacterial skin and skin structure infection (ABSSSI) patients without major comorbidities can be managed effectively in the outpatient setting. Because most patients with ABSSSIs present to the emergency department, it is essential that clinicians identify candidates for outpatient treatment given the substantially higher costs associated with inpatient care. We examined the potential cost avoidance associated with shifting care from inpatient treatment with vancomycin to outpatient treatment with oritavancin for ABSSSI patients without major complications or comorbidities. A decision analytic, cost-minimization model was developed to compare costs of inpatient vancomycin versus outpatient oritavancin treatment of ABSSSI patients with few or no comorbidities (Charlson Comorbidity Index score ≤1) and no life-threatening conditions presenting to emergency department. Hospital discharge data from the Premier Research Database was used to determine the costs associated with inpatient vancomycin treatment. Mean costs for inpatient treatment with vancomycin ranged from $5973 to $9885, depending on Charlson Comorbidity Index score and presence of systemic symptoms. Switching an individual patient from inpatient vancomycin treatment to outpatient oritavancin treatment was estimated to save $1752.46 to $6475.87 per patient, depending on Charlson Comorbidity Index score, presence of systemic symptoms, and use of observation status. Assuming some patients may be admitted to the hospital after treatment with oritavancin, it is estimated that up to 38.12% of patients could be admitted while maintaining budget neutrality. This cost-minimization model indicates that use of oritavancin in the emergency department or observation setting is associated with substantial cost savings compared with inpatient treatment with vancomycin. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

A cost-effectiveness and budget impact analysis of first-line fidaxomicin for patients with Clostridium difficile infection (CDI) in Germany.

PubMed

Watt, Maureen; McCrea, Charles; Johal, Sukhvinder; Posnett, John; Nazir, Jameel

2016-10-01

Clostridium difficile infection (CDI) represents a significant economic healthcare burden, especially the cost of recurrent disease. Fidaxomicin produced significantly lower recurrence rates and higher sustained cure rates in clinical trials. We evaluated the cost-effectiveness and budget impact of fidaxomicin compared with vancomycin in Germany in the first-line treatment of patient subgroups with CDI at increased risk of recurrence. A semi-Markov model was used to compare the cost-effectiveness and budget impact of fidaxomicin vs. vancomycin from a payer perspective in Germany. The model cycle length was 10 days. The time horizon was 1 year. Model inputs were probability of clinical cure, 30-day probability of recurrence, and 30-day attributable mortality based on evidence from two randomized controlled trials comparing fidaxomicin and vancomycin in patients with CDI. Cost-effectiveness outcomes were cost per quality-adjusted life year gained, cost per bed-day saved, and cost per recurrence avoided. Despite higher drug acquisition costs, fidaxomicin was dominant in the cancer subgroup (less costly and more effective) and cost-effective in the other subgroups, with incremental cost-effectiveness ratios vs. vancomycin ranging from €26,900 to €44,500. Hospitalization costs of the first-line treatment of CDI with fidaxomicin vs. vancomycin were lower in every patient subgroup, resulting in budget impacts ranging from -€1325 (in patients ≥65 years) to -€2438 (in cancer patients). Reductions in the cost of treating recurrence with fidaxomicin ranged from -€574.32 per patient in those receiving concomitant antibiotics to -€1500.68 per patient in renally impaired patients. In patient subgroups with CDI at increased recurrence risk, fidaxomicin was cost-effective vs. vancomycin, and less costly and more effective in patients with cancer.

Economic assessment of fidaxomicin for the treatment of Clostridium difficile infection (CDI) in special populations (patients with cancer, concomitant antibiotic treatment or renal impairment) in Spain.

PubMed

Rubio-Terrés, C; Cobo Reinoso, J; Grau Cerrato, S; Mensa Pueyo, J; Salavert Lletí, M; Toledo, A; Anguita, P; Rubio-Rodríguez, D; Watt, M; Gani, R

2015-11-01

The objective of this paper was to assess the cost-utility of fidaxomicin versus vancomycin in the treatment of Clostridium difficile infection (CDI) in three specific CDI patient subgroups: those with cancer, treated with concomitant antibiotic therapy or with renal impairment. A Markov model with six health states was developed to assess the cost-utility of fidaxomicin versus vancomycin in the patient subgroups over a period of 1 year from initial infection. Cost and outcome data used to parameterise the model were taken from Spanish sources and published literature. The costs were from the Spanish hospital perspective, in Euros (€) and for 2013. For CDI patients with cancer, fidaxomicin was dominant versus vancomycin [gain of 0.016 quality-adjusted life-years (QALYs) and savings of €2,397 per patient]. At a cost-effectiveness threshold of €30,000 per QALY gained, the probability that fidaxomicin was cost-effective was 96 %. For CDI patients treated with concomitant antibiotic therapy, fidaxomicin was the dominant treatment versus vancomycin (gain of 0.014 QALYs and savings of €1,452 per patient), with a probability that fidaxomicin was cost-effective of 94 %. For CDI patients with renal impairment, fidaxomicin was also dominant versus vancomycin (gain of 0.013 QALYs and savings of €1,432 per patient), with a probability that fidaxomicin was cost-effective of 96 %. Over a 1-year time horizon, when fidaxomicin is compared to vancomycin in CDI patients with cancer, treated with concomitant antibiotic therapy or with renal impairment, the use of fidaxomicin would be expected to result in increased QALYs for patients and reduced overall costs.

The AAHKS Clinical Research Award: Intraosseous Regional Prophylaxis Provides Higher Tissue Concentrations in High BMI Patients in Total Knee Arthroplasty: A Randomized Trial.

PubMed

Chin, Seung Joon; Moore, Grant A; Zhang, Mei; Clarke, Henry D; Spangehl, Mark J; Young, Simon W

2018-07-01

Obesity is an established risk factor for periprosthetic joint infections after total knee arthroplasty (TKA). In obese patients, a larger dose of prophylactic vancomycin based on actual body weight is required to reach therapeutic concentrations. It is unclear how tissue concentrations are affected when intraosseous regional administration (IORA) is used in this population. This study compared tissue concentrations of low-dose vancomycin via IORA vs actual body weight-adjusted systemic intravenous (IV) dose in primary TKA. Twenty-two patients with a body mass index (BMI) >35 undergoing TKA were randomized into 2 groups. The IV group received 15 mg/kg (maximum of 2 g) of systemic IV vancomycin and the IORA group received 500 mg vancomycin into the tibia. Subcutaneous fat and bone samples were taken at regular intervals. Tissue antibiotic concentrations were measured using liquid chromatography coupled with tandem mass spectrometry. A blood sample was taken 1 to 2 hours after tourniquet deflation to measure systemic concentration. The mean BMI was 41.1 in the IORA group and 40.1 in the IV systemic group. The overall mean tissue concentration in subcutaneous fat was 39.3 μg/g in the IORA group and 4.4 μg/g in the IV systemic group (P < .01). Mean tissue concentrations in bones were 34.4 μg/g in the IORA group and 6.1 μg/g in the IV systemic group (P < .01). Low-dose IORA was effective in the high-BMI population group, providing tissue concentrations of vancomycin 5-9 times higher than systemic administration. IORA optimizes timing of vancomycin administration and provides high tissue antibiotic concentrations during TKA in this high-risk patient group. Copyright © 2018 Elsevier Inc. All rights reserved.

Modeling the economic impact of linezolid versus vancomycin in confirmed nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus.

PubMed

Patel, Dipen A; Shorr, Andrew F; Chastre, Jean; Niederman, Michael; Simor, Andrew; Stephens, Jennifer M; Charbonneau, Claudie; Gao, Xin; Nathwani, Dilip

2014-07-22

We compared the economic impacts of linezolid and vancomycin for the treatment of hospitalized patients with methicillin-resistant Staphylococcus aureus (MRSA)-confirmed nosocomial pneumonia. We used a 4-week decision tree model incorporating published data and expert opinion on clinical parameters, resource use and costs (in 2012 US dollars), such as efficacy, mortality, serious adverse events, treatment duration and length of hospital stay. The results presented are from a US payer perspective. The base case first-line treatment duration for patients with MRSA-confirmed nosocomial pneumonia was 10 days. Clinical treatment success (used for the cost-effectiveness ratio) and failure due to lack of efficacy, serious adverse events or mortality were possible clinical outcomes that could impact costs. Cost of treatment and incremental cost-effectiveness per successfully treated patient were calculated for linezolid versus vancomycin. Univariate (one-way) and probabilistic sensitivity analyses were conducted. The model allowed us to calculate the total base case inpatient costs as $46,168 (linezolid) and $46,992 (vancomycin). The incremental cost-effectiveness ratio favored linezolid (versus vancomycin), with lower costs ($824 less) and greater efficacy (+2.7% absolute difference in the proportion of patients successfully treated for MRSA nosocomial pneumonia). Approximately 80% of the total treatment costs were attributed to hospital stay (primarily in the intensive care unit). The results of our probabilistic sensitivity analysis indicated that linezolid is the cost-effective alternative under varying willingness to pay thresholds. These model results show that linezolid has a favorable incremental cost-effectiveness ratio compared to vancomycin for MRSA-confirmed nosocomial pneumonia, largely attributable to the higher clinical trial response rate of patients treated with linezolid. The higher drug acquisition cost of linezolid was offset by lower treatment failure-related costs and fewer days of hospitalization.

Combination of Vancomycin and β-Lactam Therapy for Methicillin-Resistant Staphylococcus aureus Bacteremia: A Pilot Multicenter Randomized Controlled Trial.

PubMed

Davis, Joshua S; Sud, Archana; O'Sullivan, Matthew V N; Robinson, James O; Ferguson, Patricia E; Foo, Hong; van Hal, Sebastiaan J; Ralph, Anna P; Howden, Benjamin P; Binks, Paula M; Kirby, Adrienne; Tong, Steven Y C; Tong, Steven; Davis, Joshua; Binks, Paula; Majumdar, Suman; Ralph, Anna; Baird, Rob; Gordon, Claire; Jeremiah, Cameron; Leung, Grace; Brischetto, Anna; Crowe, Amy; Dakh, Farshid; Whykes, Kelly; Kirkwood, Maria; Sud, Archana; Menon, Mahesh; Somerville, Lucy; Subedi, Shrada; Owen, Shirley; O'Sullivan, Matthew; Liu, Eunice; Zhou, Fei; Robinson, Owen; Coombs, Geoffrey; Ferguson, Patrician; Ralph, Anna; Liu, Eunice; Pollet, Simon; Van Hal, Sebastian; Foo, Hong; Van Hal, Sebastian; Davis, Rebecca

2016-01-15

In vitro laboratory and animal studies demonstrate a synergistic role for the combination of vancomycin and antistaphylococcal β-lactams for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Prospective clinical data are lacking. In this open-label, multicenter, clinical trial, adults with MRSA bacteremia received vancomycin 1.5 g intravenously twice daily and were randomly assigned (1:1) to receive intravenous flucloxacillin 2 g every 6 hours for 7 days (combination group) or no additional therapy (standard therapy group). Participants were stratified by hospital and randomized in permuted blocks of variable size. Randomization codes were kept in sealed, sequentially numbered, opaque envelopes. The primary outcome was the duration of MRSA bacteremia in days. We randomly assigned 60 patients to receive vancomycin (n = 29), or vancomycin plus flucloxacillin (n = 31). The mean duration of bacteremia was 3.00 days in the standard therapy group and 1.94 days in the combination group. According to a negative binomial model, the mean time to resolution of bacteremia in the combination group was 65% (95% confidence interval, 41%-102%; P = .06) that in the standard therapy group. There was no difference in the secondary end points of 28- and 90-day mortality, metastatic infection, nephrotoxicity, or hepatotoxicity. Combining an antistaphylococcal β-lactam with vancomycin may shorten the duration of MRSA bacteremia. Further trials with a larger sample size and objective clinically relevant end points are warranted. Australian New Zealand Clinical Trials Registry: ACTRN12610000940077 (www.anzctr.org.au). © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

3D printed bioceramics for dual antibiotic delivery to treat implant-associated bone infection

PubMed Central

Inzana, Jason A.; Trombetta, Ryan P.; Schwarz, Edward M.; Kates, Stephen L.; Awad, Hani A.

2015-01-01

Surgical implant-associated bone infections (osteomyelitis) have severe clinical and socioeconomic consequences. Treatment of chronic bone infections often involves antibiotics given systemically and locally to the affected site via poly(methyl methacrylate) (PMMA) bone cement. Given the high antibiotic concentrations required to affect bacteria in biofilm, local delivery is important to achieve high doses at the infection site. PMMA is not suitable to locally deliver some biofilm-specific antibiotics, including rifampin, due to interference with PMMA polymerization. To examine the efficacy of localized, combinational antibiotic delivery compared to PMMA standards, we fabricated rifampin- and vancomycin-laden calcium phosphate scaffolds (CPS) by three-dimensional (3D) printing to treat an implant-associated Staphylococcus aureus bone infection in a murine model. All vancomycin- and rifampin-laden CPS treatments significantly reduced the bacterial burden compared with vancomycin-laden PMMA. The bones were bacteria culture negative in 50% of the mice that received sustained release vancomycin- and rifampin-laden CPS. In contrast, 100% of the bones treated with vancomycin monotherapy via PMMA or CPS were culture positive. Yet, the monotherapy CPS significantly reduced the bacterial metabolic load following revision compared to PMMA. Biofilm persisted on the fixation hardware, but the infection-induced bone destruction was significantly reduced by local rifampin delivery. These data demonstrate that, despite the challenging implant-retaining infection model, co-delivery of rifampin and vancomycin from 3D printed CPS, which is not possible with PMMA, significantly improved the outcomes of implant-associated osteomyelitis. However, biofilm persistence on the fixation hardware reaffirms the importance of implant exchange or other biofilm eradication strategies to complement local antibiotics. PMID:26535494

Rapid Detection of Vancomycin-Intermediate Staphylococcus aureus by Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry

PubMed Central

Mather, Cheryl A.; Werth, Brian J.; Sivagnanam, Shobini; SenGupta, Dhruba J.

2016-01-01

Vancomycin is the standard of care for the treatment of invasive methicillin-resistant Staphylococcus aureus (MRSA) infections. Infections with vancomycin-nonsusceptible MRSA, including vancomycin-intermediate S. aureus (VISA) and heterogeneous VISA (hVISA), are clinically challenging and are associated with poor patient outcomes. The identification of VISA in the clinical laboratory depends on standard susceptibility testing, which takes at least 24 h to complete after isolate subculture, whereas hVISA is not routinely detected in clinical labs. We therefore sought to determine whether VISA and hVISA can be differentiated from vancomycin-susceptible S. aureus (VSSA) using the spectra produced by matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS). Strains of MRSA were characterized for vancomycin susceptibility phenotype by broth microdilution and modified population analysis. We tested 21 VISA, 21 hVISA, and 38 VSSA isolates by MALDI-TOF MS. Susceptibility phenotypes were separated by using a support vector machine (SVM) machine learning algorithm. The resulting model was validated by leave-one-out cross validation. Models were developed and validated by using spectral profiles generated under various subculture conditions, as well as with and without hVISA strains. Using SVM, we correctly identified 100% of the VISA and 97% of the VSSA isolates with an overall classification accuracy of 98%. Addition of hVISA to the model resulted in 76% hVISA identification, 100% VISA identification, and 89% VSSA identification, for an overall classification accuracy of 89%. We conclude that VISA/hVISA and VSSA isolates are separable by MALDI-TOF MS with SVM analysis. PMID:26763961

Vancomycin-Resistant Enterococci and Bacterial Community Structure following a Sewage Spill into an Aquatic Environment.

PubMed

Young, Suzanne; Nayak, Bina; Sun, Shan; Badgley, Brian D; Rohr, Jason R; Harwood, Valerie J

2016-09-15

Sewage spills can release antibiotic-resistant bacteria into surface waters, contributing to environmental reservoirs and potentially impacting human health. Vancomycin-resistant enterococci (VRE) are nosocomial pathogens that have been detected in environmental habitats, including soil, water, and beach sands, as well as wildlife feces. However, VRE harboring vanA genes that confer high-level resistance have infrequently been found outside clinical settings in the United States. This study found culturable Enterococcus faecium harboring the vanA gene in water and sediment for up to 3 days after a sewage spill, and the quantitative PCR (qPCR) signal for vanA persisted for an additional week. Culturable levels of enterococci in water exceeded recreational water guidelines for 2 weeks following the spill, declining about five orders of magnitude in sediments and two orders of magnitude in the water column over 6 weeks. Analysis of bacterial taxa via 16S rRNA gene sequencing showed changes in community structure through time following the sewage spill in sediment and water. The spread of opportunistic pathogens harboring high-level vancomycin resistance genes beyond hospitals and into the broader community and associated habitats is a potential threat to public health, requiring further studies that examine the persistence, occurrence, and survival of VRE in different environmental matrices. Vancomycin-resistant enterococci (VRE) are harmful bacteria that are resistant to the powerful antibiotic vancomycin, which is used as a last resort against many infections. This study followed the release of VRE in a major sewage spill and their persistence over time. Such events can act as a means of spreading vancomycin-resistant bacteria in the environment, which can eventually impact human health. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Simple and rapid quantification of vancomycin in serum, urine and peritoneal/pleural effusion via UHPLC-MS/MS applicable to personalized antibiotic dosing research.

PubMed

Javorska, Lenka; Krcmova, Lenka Kujovska; Solich, Petr; Kaska, Milan

2017-08-05

Management of the therapy of life-threatening bacterial infection is extremely based on an optimal antibiotic treatment. Achieving the correct vancomycin dosage in blood and target tissues can be complicated in special situations, e.g., where large fluid sequestration and/or acute renal failure occur. A UHPLC-MS/MS method operating in electrospray (ESI) positive ion mode was applied for the determination of vancomycin in serum, urine and peritoneal/pleural effusion. Sample pretreatment was composed of dilution and simple protein precipitation where only a small volume (50μL) of serum, urine or peritoneal/pleural effusion was required. The separation of vancomycin was performed on a Meteoric Core C18 BIO column (100×4.6mm, 2.7μm) by gradient elution with 0.1% formic acid in water and acetonitrile. The total time of analysis was 4.5min. The method was found to be linear in the range of 2-60μM (or 0.5-10μM) for serum, 0.27-10μM (or 2-60μM) for peritoneal/pleural effusion and 25-300μM for urine, which was adequate for the determination of vancomycin in patient samples. The intra- and inter-day precision was below 8% RSD, and accuracy was from 89 to 104%. The UHPLC/MS-MS method offers a fast and reliable approach to determine vancomycin concentrations in three different human body fluid samples (serum, urine and peritoneal/pleural effusion) with a simple sample pretreatment that was the same for all selected specimens. This method should be applicable to large sample series in clinical (pharmacokinetic/pharmacodynamic) studies. Copyright © 2017 Elsevier B.V. All rights reserved.

Vancomycin-Resistant Enterococci and Bacterial Community Structure following a Sewage Spill into an Aquatic Environment

PubMed Central

Young, Suzanne; Nayak, Bina; Sun, Shan; Badgley, Brian D.; Rohr, Jason R.

2016-01-01

ABSTRACT Sewage spills can release antibiotic-resistant bacteria into surface waters, contributing to environmental reservoirs and potentially impacting human health. Vancomycin-resistant enterococci (VRE) are nosocomial pathogens that have been detected in environmental habitats, including soil, water, and beach sands, as well as wildlife feces. However, VRE harboring vanA genes that confer high-level resistance have infrequently been found outside clinical settings in the United States. This study found culturable Enterococcus faecium harboring the vanA gene in water and sediment for up to 3 days after a sewage spill, and the quantitative PCR (qPCR) signal for vanA persisted for an additional week. Culturable levels of enterococci in water exceeded recreational water guidelines for 2 weeks following the spill, declining about five orders of magnitude in sediments and two orders of magnitude in the water column over 6 weeks. Analysis of bacterial taxa via 16S rRNA gene sequencing showed changes in community structure through time following the sewage spill in sediment and water. The spread of opportunistic pathogens harboring high-level vancomycin resistance genes beyond hospitals and into the broader community and associated habitats is a potential threat to public health, requiring further studies that examine the persistence, occurrence, and survival of VRE in different environmental matrices. IMPORTANCE Vancomycin-resistant enterococci (VRE) are harmful bacteria that are resistant to the powerful antibiotic vancomycin, which is used as a last resort against many infections. This study followed the release of VRE in a major sewage spill and their persistence over time. Such events can act as a means of spreading vancomycin-resistant bacteria in the environment, which can eventually impact human health. PMID:27422829

Vancomycin added to the wash solution of the cell-saver. Effect on bacterial contamination.

PubMed

Perez-Ferrer, A; Gredilla-Díaz, E; de Vicente-Sánchez, J; Navarro-Suay, R; Gilsanz-Rodríguez, F

2017-04-01

The aim of this study is to test whether the addition of a low-dose of antibiotic (vancomycin) to the wash solution (saline) of the cell-saver reduces the incidence of bacterial contamination of the autologous red blood cell (RBCs) concentrate recovered. Experimental, randomized, double-blind, parallel group study performed on 20 consecutive patients scheduled for posterior spinal fusion surgery. Intraoperative bleeding was processed through a cell-saver: HaemoLite ® 2+, in which the RBCs were washed according to randomization group, with saline (control group) or saline+10μg/ml -1 vancomycin (vanco group). Data regarding age, weight, processed and recovered volume, blood count, blood culture, and vancomycin concentration in RBCs concentrates obtained and incidence of fever after reinfusion were collected. Processed volume was 843±403ml and recovered volume 121±29ml, with haemoglobin concentration 10.4±5.0g/dl -1 and haematocrit 29.1±15.9% (mean±SD). Recovered RBC concentrate cultures were positive for coagulase-negative Staphylococcus in 5 cases (50%) of the control group while all cultures were negative in the vanco group (P=.016). The difference between the theoretical concentration of vancomycin administered and the concentration determined in the recovered RBC concentrate was 1.31μg/ml -1 (95% CI 1.19 to 1.43; P=.074). The addition of vancomycin at a concentration of 10ug/ml -1 to the wash solution of the cell-saver achieved similar concentrations in the autologous blood concentrate recovered allowing for bacterial removal, with negative blood cultures in all cases. Copyright © 2016 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.

Synergy of ambroxol with vancomycin in elimination of catheter-related Staphylococcus epidermidis biofilm in vitro and in vivo.

PubMed

Zhang, Yunhui; Fu, Yakun; Yu, Jialin; Ai, Qing; Li, Junshuai; Peng, Ningning; Song, Sijie; He, Yu; Wang, Zhengli

2015-11-01

Central venous catheters are widely used in neonatal intensive care units (NICUs) nowadays. The commonest cause of catheter-related bloodstream infections (CRBSIs) is coagulase-negative staphylococci (CoNS). Ambroxol, an active metabolite of bromhexine, exhibits antimicrobial activity against strains producing biofilm and enhances the bactericidal effect of some antibiotic by breaking the structure of biofilm. In this study, we aimed to determine the effect of ambroxol with vancomycin on the biofilm of Staphylococcus epidermidis (S. epidermidis) in vitro and in vivo. In the in vitro study, the biofilm of S. epidermidis was assessed by XTT reduction assay and analysed by confocal laser scanning microscopy (CLSM). In the in vivo study, a rabbit model of CRBSIs was created by intravenous intubation with a tube covered with S. epidermidis biofilm. The rabbits received one of the following four treatments by means of antibiotic lock therapy: normal heparin, ambroxol, vancomycin, or vancomycin plus ambroxol each for 3 days. The microstructure of the biofilm was assessed by scanning electron microscopy (SEM). The number of bacterial colonies in the organs (liver, heart, and kidney) and on the intravenous tubes was measured on agar plates. Pathological changes in the organs (liver, heart, and kidney) were observed with Hematoxylin-Eosin staining. The ambroxol exhibits significant efficacy to potentiate the bactericidal effect of vancomycin on S. epidermidis biofilm both in vitro and in vivo. The antibiotic lock therapy using a combination of ambroxol and vancomycin reveals a high ability to eradicate S. epidermidis biofilms in vivo. These results provide the basis of a useful anti-infection strategy for the treatment of CRBSIs. Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Rapid Detection of Vancomycin-Intermediate Staphylococcus aureus by Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry.

PubMed

Mather, Cheryl A; Werth, Brian J; Sivagnanam, Shobini; SenGupta, Dhruba J; Butler-Wu, Susan M

2016-04-01

Vancomycin is the standard of care for the treatment of invasive methicillin-resistantStaphylococcus aureus(MRSA) infections. Infections with vancomycin-nonsusceptible MRSA, including vancomycin-intermediateS. aureus(VISA) and heterogeneous VISA (hVISA), are clinically challenging and are associated with poor patient outcomes. The identification of VISA in the clinical laboratory depends on standard susceptibility testing, which takes at least 24 h to complete after isolate subculture, whereas hVISA is not routinely detected in clinical labs. We therefore sought to determine whether VISA and hVISA can be differentiated from vancomycin-susceptibleS. aureus(VSSA) using the spectra produced by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). Strains of MRSA were characterized for vancomycin susceptibility phenotype by broth microdilution and modified population analysis. We tested 21 VISA, 21 hVISA, and 38 VSSA isolates by MALDI-TOF MS. Susceptibility phenotypes were separated by using a support vector machine (SVM) machine learning algorithm. The resulting model was validated by leave-one-out cross validation. Models were developed and validated by using spectral profiles generated under various subculture conditions, as well as with and without hVISA strains. Using SVM, we correctly identified 100% of the VISA and 97% of the VSSA isolates with an overall classification accuracy of 98%. Addition of hVISA to the model resulted in 76% hVISA identification, 100% VISA identification, and 89% VSSA identification, for an overall classification accuracy of 89%. We conclude that VISA/hVISA and VSSA isolates are separable by MALDI-TOF MS with SVM analysis. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Pharmacologic treatment options for nosocomial pneumonia involving methicillin-resistant Staphylococcus aureus.

PubMed

Maclayton, Darego O; Hall, Ronald G

2007-02-01

To discuss current and potential treatment options for nosocomial pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA). A MEDLINE search (1966-January 2007) was conducted to identify English-language literature on pharmacotherapy of nosocomial pneumonia and the bibliographies of pertinent articles. Programs and abstracts from infectious disease meetings were also searched. Search terms included MRSA, nosocomial pneumonia, pulmonary infections, vancomycin, quinupristin/dalfopristin, linezolid, daptomycin, tigecycline, dalbavancin, oritavancin, and ceftobiprole. DATA SELECTION AND DATA EXTRACTION: All articles were critically evaluated and all pertinent information was included in this review. Vancomycin has been the drug of choice for MRSA infections for many years. Recent data suggest that linezolid may be superior to vancomycin in the treatment of MRSA nosocomial pneumonia. However, there are limitations to the available data. Therefore, prospective, randomized studies are needed before linezolid is recommended as the preferred first-line therapy. Other approved agents for nosocomial MRSA infections, such as quinupristin/dalfopristin and daptomycin, should not be used in the treatment of MRSA pneumonia, as they were inferior in clinical trials. Tigecycline has excellent activity against MRSA in vitro, but should not be routinely used for the treatment of MRSA pneumonia, as clinical data are lacking. In a Phase III clinical trial, an anti-MRSA cephalosporin, ceftobiprole, is being evaluated for effectiveness against nosocomial pneumonia. Investigational glycopeptides may eventually have a role in the treatment of nosocomial pneumonia, but data are currently lacking. Vancomycin is still the drug of choice for treatment of MRSA pneumonia, and linezolid should be used as an alternative agent. Linezolid should carry strong consideration for patients with vancomycin-induced nephrotoxicity or a documented lack of response to vancomycin. Tigecycline and investigational agents with activity against MRSA may be future options for nosocomial pneumonia due to MRSA.

DETECTION OF INTRINSIC VANCOMYCIN RESISTANT ENTEROCOCCI IN ANIMAL AND HUMAN FECES

EPA Science Inventory

A survey was conducted to determine the occurrence of vancomycin resistant enterococci (VRE) in animal and human fecal samples. Fecal samples from 14 animal species and humans were analyzed by quantitative culture for enterococci and VRE. Over 800 VRE isolates were characterize...

Relationship between group JK corynebacteria and the biotypes of Corynebacterium genitalium and Corynebacterium pseudogenitalium.

PubMed

Evangelista, A T; Coppola, K M; Furness, G

1984-08-01

Twenty-six strains of group JK corynebacteria had the same colonial morphology and biological reactions as the biotypes of the biovars of Corynebacterium genitalium and C. pseudogenitalium. Therefore, group JK corynebacteria can be assigned to the biovars of C. genitalium or C. pseudogenitalium. Although the strains differed in sensitivity to 16 antibiotics tested by Sensi-Discs or by the Micro-Media technique, they are uniformly sensitive to 4-5 micrograms/mL of vancomycin. Medium containing 10 micrograms vancomycin/mL was bactericidal and the killing time was dependent on the concentration. The rate of mutation to resistance to 10 micrograms vancomycin was greater than 1 in 10(10) corynebacteria. Therefore, vancomycin sensitivity is a stable characteristic of these corynebacteria which also indicates that group JK corynebacteria are strains of either C. genitalium or C. pseudogenitalium. Since group JK corynebacteria are considered pathogens, this finding supports the belief that C. genitalium is a pathogen and suggests that some biotypes of the commensal C. pseudogenitalium may infect compromised hosts.

Novel Inhibitors of Staphyloxanthin Virulence Factor in Comparison with Linezolid and Vancomycin versus Methicillin-Resistant, Linezolid-Resistant, and Vancomycin-Intermediate Staphylococcus aureus Infections in Vivo.

PubMed

Ni, Shuaishuai; Wei, Hanwen; Li, Baoli; Chen, Feifei; Liu, Yifu; Chen, Wenhua; Xu, Yixiang; Qiu, Xiaoxia; Li, Xiaokang; Lu, Yanli; Liu, Wenwen; Hu, Linhao; Lin, Dazheng; Wang, Manjiong; Zheng, Xinyu; Mao, Fei; Zhu, Jin; Lan, Lefu; Li, Jian

2017-10-12

Our previous work ( Wang et al. J. Med. Chem. 2016 , 59 , 4831 - 4848 ) revealed that effective benzocycloalkane-derived staphyloxanthin inhibitors against methicillin-resistant Staphylococcus aureus (S. aureus) infections were accompanied by poor water solubility and high hERG inhibition and dosages (preadministration). In this study, 92 chroman and coumaran derivatives as novel inhibitors have been addressed for overcoming deficiencies above. Derivatives 69 and 105 displayed excellent pigment inhibitory activities and low hERG inhibition, along with improvement of solubility by salt type selection. The broad and significantly potent antibacterial spectra of 69 and 105 were displayed first with normal administration in the livers and hearts in mice against pigmented S. aureus Newman, Mu50 (vancomycin-intermediate S. aureus), and NRS271 (linezolid-resistant S. aureus), compared with linezolid and vancomycin. In summary, both 69 and 105 have the potential to be developed as good antibacterial candidates targeting virulence factors.

Role of Combination Antimicrobial Therapy for Vancomycin-Resistant Enterococcus faecium Infections: Review of the Current Evidence.

PubMed

Yim, Juwon; Smith, Jordan R; Rybak, Michael J

2017-05-01

Enterococcus species are the second most common cause of nosocomial infections in the United States and are particularly concerning in critically ill patients with preexisting comorbid conditions. Rising resistance to antimicrobials that were historically used as front-line agents for treatment of enterococcal infections, such as ampicillin, vancomycin, and aminoglycosides, further complicates the treatment of these infections. Of particular concern are Enterococcus faecium strains that are associated with the highest rate of vancomycin resistance. The introduction of antimicrobial agents with specific activity against vancomycin-resistant Enterococcus (VRE) faecium including daptomycin, linezolid, quinupristin-dalfopristin, and tigecycline did not completely resolve this clinical dilemma. In this review, the mechanisms of action and resistance to currently available anti-VRE antimicrobial agents including newer agents such as oritavancin and dalbavancin will be presented. In addition, novel combination therapies including β-lactams and fosfomycin, and the promising results from in vitro, animal studies, and clinical experience in the treatment of VRE faecium will be discussed. © 2017 Pharmacotherapy Publications, Inc.

Treatment of recurrent Clostridium difficile infection: a systematic review

PubMed Central

O'Horo, J. C.; Jindai, K.; Kunzer, B.; Safdar, N.

2014-01-01

Background Clostridium difficile infection (CDI) recurs in nearly one-third of patients who develop an initial infection. Recurrent CDI (RCDI) is associated with considerable morbidity, mortality, and cost. Treatment for RCDI has not been not well examined. Methods A systematic review. Results Sixty-four articles were identified evaluating eight different treatment approaches: metronidazole, vancomycin, fidaxomicin, nitazoxanide, rifampin, immunoglobulins, probiotics, and fecal bacteriotherapy. The meta-analysis found vancomycin to have a similar efficacy to metronidazole, although studies used varying doses and durations of therapy. Fidaxomicin was slightly more efficacious than vancomycin, though the number of studies was small. Good evidence for probiotics was limited. Fecal bacteriotherapy was found to be highly efficacious in a single randomized trial. Conclusion Metronidazole and vancomycin have good evidence for use in RCDI but heterogeneity in treatment duration and dose precludes robust conclusions. Fidaxomicin may have a role in treatment, but evidence is limited to subgroup analyses. Fecal bacteriotherapy was the most efficacious. Saccharomyces boulardii may have a role as adjunctive treatment. PMID:23839210

A dirty cause of vancomycin-mediated Henoch-Schonlein purpura: oxygen tubing is not a foley.

PubMed

Shah, Nikhil H; Kline, Kristopher P; Shukla, Manas K

2017-06-20

A 59-year-old male presented with methicillin-resistant Staphylococcus aureus bacteraemia from a prostatic abscess and was treated with vancomycin. Two weeks into his treatment course, he developed severe joint pains, abdominal pain with bloody, mucinous stools and a diffuse palpable purpuric rash on his extremities. Biopsy of the rash showed IgA immune-complex deposition consistent with Henoch-Schönlein purpura. After treatment with glucocorticoids, his symptoms resolved completely. Vancomycin is an extremely commonly used antibiotic with certain well-known adverse effects. Henoch-Schönlein purpura, a vasculitis involving abdominal pain, arthralgias and palpable purpura, is a much less common side effect, as seen in this patient. Given that vancomycin is widely used internationally, clinicians should be aware of the risks entailed by its use. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

In vitro and in vivo drug release and antibacterial properties of the novel vancomycin-loaded bone-like hydroxyapatite/poly amino acid scaffold

PubMed Central

Cao, Zhidong; Jiang, Dianming; Yan, Ling; Wu, Jun

2017-01-01

Antibiotic-loaded carriers were developed to fill cavities and locally deliver antibiotics following implantation. However, the most commonly used antibiotic carrier, polymethyl methacrylate (PMMA), has many disadvantages including that it does not promote bone regeneration or conduction. Vancomycin-loaded bone-like hydroxyapatite/poly amino acid (V-BHA/PAA) was successfully fabricated by a homogeneous method, certified as biosafe and known to promote osteogenesis. To evaluate its drug-release features, the quantity of the vancomycin in the elution was obtained every 2 days after in vitro simulated body fluid immersion. The drug concentration in the elution was determined to obtain the drug-release curve. The in vitro drug release was a three-phase process with two release peaks. Its antibacterial activity was evaluated in vitro using an antibacterial zone assay, antibacterial inhibition, and scanning electron microscopy (SEM) observation. Scaffolds of V-BHA/PAA were implanted into a rabbit model of chronic osteomyelitis. The antibacterial activity of the material was evaluated in vivo by gross observations, X-ray, and histological and ultrastructural observations. During the first 48 h, the vancomycin release was more rapid, followed by a period of sustained slow release. Use of V-BHA/PAA could achieve relatively long-term vancomycin delivery of 38 days in vitro and 42 days in vivo. V-BHA/PAA showed a significant and consistent bactericidal effect toward both Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) in vitro and in vivo. Moreover, the bactericidal effect was stronger than that of vancomycin-loaded polymethyl meth acrylate (V-PMMA). The duration of the antibacterial effect of V-BHA/PAA toward both S. aureus and MRSA exceeded 28 days in vitro, while that of V-PMMA lasted only 14 days. The curative rate for V-BHA/PAA in the chronic osteomyelitis model was 75% for regular S. aureus and 66.67% for MRSA infection, which significantly exceeded that of V-PMMA (50% and 41.67%, respectively). Vancomycin released from the V-BHA/PAA scaffold was significantly superior to that delivered by V-PMMA. PMID:28331309

Performance of the EUCAST Disk Diffusion Method, the CLSI Agar Screen Method, and the Vitek 2 Automated Antimicrobial Susceptibility Testing System for Detection of Clinical Isolates of Enterococci with Low- and Medium-Level VanB-Type Vancomycin Resistance: a Multicenter Study

PubMed Central

Giske, Christian G.; Haldorsen, Bjørg; Matuschek, Erika; Schønning, Kristian; Leegaard, Truls M.; Kahlmeter, Gunnar

2014-01-01

Different antimicrobial susceptibility testing methods to detect low-level vancomycin resistance in enterococci were evaluated in a Scandinavian multicenter study (n = 28). A phenotypically and genotypically well-characterized diverse collection of Enterococcus faecalis (n = 12) and Enterococcus faecium (n = 18) strains with and without nonsusceptibility to vancomycin was examined blindly in Danish (n = 5), Norwegian (n = 13), and Swedish (n = 10) laboratories using the EUCAST disk diffusion method (n = 28) and the CLSI agar screen (n = 18) or the Vitek 2 system (bioMérieux) (n = 5). The EUCAST disk diffusion method (very major error [VME] rate, 7.0%; sensitivity, 0.93; major error [ME] rate, 2.4%; specificity, 0.98) and CLSI agar screen (VME rate, 6.6%; sensitivity, 0.93; ME rate, 5.6%; specificity, 0.94) performed significantly better (P = 0.02) than the Vitek 2 system (VME rate, 13%; sensitivity, 0.87; ME rate, 0%; specificity, 1). The performance of the EUCAST disk diffusion method was challenged by differences in vancomycin inhibition zone sizes as well as the experience of the personnel in interpreting fuzzy zone edges as an indication of vancomycin resistance. Laboratories using Oxoid agar (P < 0.0001) or Merck Mueller-Hinton (MH) agar (P = 0.027) for the disk diffusion assay performed significantly better than did laboratories using BBL MH II medium. Laboratories using Difco brain heart infusion (BHI) agar for the CLSI agar screen performed significantly better (P = 0.017) than did those using Oxoid BHI agar. In conclusion, both the EUCAST disk diffusion and CLSI agar screening methods performed acceptably (sensitivity, 0.93; specificity, 0.94 to 0.98) in the detection of VanB-type vancomycin-resistant enterococci with low-level resistance. Importantly, use of the CLSI agar screen requires careful monitoring of the vancomycin concentration in the plates. Moreover, disk diffusion methodology requires that personnel be trained in interpreting zone edges. PMID:24599985

Fidaxomicin: the newest addition to the armamentarium against Clostridium difficile infections.

PubMed

Lancaster, Jason W; Matthews, S James

2012-01-01

Fidaxomicin, a macrolide antibiotic, was the first medication for the management of Clostridium difficile infections (CDI) to be approved by the US Food and Drug Administration in more than 20 years. This article reviews published literature on fidaxomicin for management of CDI, including its chemistry, spectrum of activity, pharmacokinetic properties, pharmacodynamics, therapeutic efficacy, adverse events, dosing, administration, and pharmacoeconomic considerations. Pertinent English-language literature was reviewed through searches of MEDLINE, EMBASE, and BIOSIS from 1975 through September 2011. Reference lists of identified publications and published abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy meetings were also reviewed. Search terms included, but were not limited to, fidaxomicin, difimicin, lipiarmycin, tiacumicin B, OPT-80, Clostridium spp, and diarrhea. A total of 79 publications were identified and 10 were excluded; 6 review articles and 4 abstracts that were later published as articles. Fidaxomicin's in vitro profile is favorable compared with oral metronidazole and vancomycin, with minimum inhibitory concentrations against C difficile that are 2 dilutions lower. From the 2 published Phase III trials, fidaxomicin was deemed to be noninferior in the treatment of mild to moderate CDI compared with oral vancomycin. Recurrence rates for all strains of CDI were lower with fidaxomicin than vancomycin. Adverse events associated with fidaxomicin were similar to placebo, with nausea and vomiting being the most common. Although no pharmacoeconomic studies have compared fidaxomicin with metronidazole or vancomycin, the current price exceeds $2500 (US) per treatment course. Reports suggest that fidaxomicin is noninferior to oral vancomycin in the treatment of mild or moderate CDI, although no published comparisons with metronidazole exist to date. Additionally, fidaxomicin improved outcomes compared with oral vancomycin in terms of rates of relapse and recurrent CDI, and in patients who might require concomitant antibiotics. Prospective, randomized studies comparing fidaxomicin with metronidazole in the treatment of mild or moderate CDI, as well as against vancomycin for severe CDI, should be undertaken to clarify the exact role of fidaxomicin in clinical practice. Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.

Bacillus coagulans GBI-30, 6086 limits the recurrence of Clostridium difficile-Induced colitis following vancomycin withdrawal in mice.

PubMed

Fitzpatrick, Leo R; Small, Jeffrey S; Greene, Wallace H; Karpa, Kelly D; Farmer, Sean; Keller, David

2012-10-22

Recently, we found that the probiotic strain Bacillus coagulans GBI-30, 6086 (GanedenBC30) improved indices of Clostridium difficile (C. difficile)-induced colitis in mice (Fitzpatrick et al., Gut Pathogens, 2011). Our goal was to determine if BC30 could also prevent the recurrence of C. difficile-induced colitis in mice, following initial treatment with vancomycin. During study days 0 through 5, mice were treated with antibiotics. On day 6, the C. difficile strain VPI 10463 was given by oro-gastric gavage at ≈ 5x104 CFU to induce colitis. Mice were treated on study days 6 to 10 with vancomycin (50 mg/kg) (vanco) or vehicle (saline) by gavage. On days 10 to16, mice were dosed by gavage with saline vehicle or BC30 (2 x 109 CFU per day). Mice were monitored for mortality, weight loss and diarrhea. On study days 14, 16 and 17, stools and colons were collected for analyzing other parameters of colitis. The mean stool consistency score in Vehicle/C.difficile/Vanco mice increased from 0.4 (day 10) to a range of 1.1 to 1.4 (days 14 to 17), indicating the recurrence of colitis. On days 13 through 17, the stool consistency scores for the vancomycin/BC30 mice were significantly lower (p< 0.05) than for the vancomycin/vehicle cohort of animals. On day 17, 88.9% of mice treated with BC30 had normal stools, while this value was 0% with vehicle treatment (p value = 0.0004). Colonic myeloperoxidase (Units/2 cm colon) was significantly (p < 0.05) reduced from 4.3 ± 0.7 (Vehicle/C.difficile/Vanco) to 2.6 ± 0.2 (BC30/C. Difficle/Vanco). The colonic histology score and Keratinocyte derived-chemokine level in the colon were also lower in BC30 treated mice. In BC30-treated mice, there was evidence of better stool consistency, as well as improved biochemical and histological indices of colitis, following initial treatment of animals with vancomycin. BC30 limited the recurrence of CD-induced colitis following vancomycin withdrawal in mice.

Bacillus coagulans GBI-30, 6086 limits the recurrence of Clostridium difficile-Induced colitis following vancomycin withdrawal in mice

PubMed Central

2012-01-01

Background Recently, we found that the probiotic strain Bacillus coagulans GBI-30, 6086 (GanedenBC30) improved indices of Clostridium difficile (C. difficile)-induced colitis in mice (Fitzpatrick et al., Gut Pathogens, 2011). Our goal was to determine if BC30 could also prevent the recurrence of C. difficile-induced colitis in mice, following initial treatment with vancomycin. During study days 0 through 5, mice were treated with antibiotics. On day 6, the C. difficile strain VPI 10463 was given by oro-gastric gavage at ≈ 5x104 CFU to induce colitis. Mice were treated on study days 6 to 10 with vancomycin (50 mg/kg) (vanco) or vehicle (saline) by gavage. On days 10 to16, mice were dosed by gavage with saline vehicle or BC30 (2 x 109 CFU per day). Mice were monitored for mortality, weight loss and diarrhea. On study days 14, 16 and 17, stools and colons were collected for analyzing other parameters of colitis. Results The mean stool consistency score in Vehicle/C.difficile/Vanco mice increased from 0.4 (day 10) to a range of 1.1 to 1.4 (days 14 to 17), indicating the recurrence of colitis. On days 13 through 17, the stool consistency scores for the vancomycin/BC30 mice were significantly lower (p< 0.05) than for the vancomycin/vehicle cohort of animals. On day 17, 88.9% of mice treated with BC30 had normal stools, while this value was 0% with vehicle treatment (p value = 0.0004). Colonic myeloperoxidase (Units/2 cm colon) was significantly (p < 0.05) reduced from 4.3 ± 0.7 (Vehicle/C.difficile/Vanco) to 2.6 ± 0.2 (BC30/C. Difficle/Vanco). The colonic histology score and Keratinocyte derived-chemokine level in the colon were also lower in BC30 treated mice. Summary In BC30-treated mice, there was evidence of better stool consistency, as well as improved biochemical and histological indices of colitis, following initial treatment of animals with vancomycin. Conclusion BC30 limited the recurrence of CD-induced colitis following vancomycin withdrawal in mice. PMID:23088680

Development and Validation of a Novel Vancomycin Dosing Nomogram for Achieving High-Target Trough Levels at 2 Canadian Teaching Hospitals

PubMed Central

Thalakada, Rosanne; Legal, Michael; Lau, Tim T Y; Luey, Tiffany; Batterink, Josh; Ensom, Mary H H

2012-01-01

Background: Recent guidelines recommend a vancomycin trough (predose) level between 15 and 20 mg/L in the treatment of invasive gram-positive infections, but most initial dosing nomograms are designed to achieve lower targets (5–15 mg/L). Clinicians need guidance about appropriate initial dosing to achieve the higher target. Objective: To develop and validate a high-target vancomycin dosing nomogram to achieve trough levels of 15–20 mg/L. Methods: A retrospective study was conducted at 2 teaching hospitals, St Paul’s Hospital and Vancouver General Hospital in Vancouver, British Columbia. Patients who were treated with vancomycin between January 2008 and June 2010 and who had achieved a trough level of 14.5–20.5 mg/L were identified. Demographic and clinical data were collected. Multiple linear regression was used to develop a vancomycin dosing nomogram for each hospital site. An integrated nomogram was constructed by merging the data from the 2 hospitals. A unique set of patients at each institution was used for validating their respective nomograms and a pooled group of patients for validating the integrated nomogram. Predictive success was evaluated, and a nomogram was deemed significantly different from another nomogram if p < 0.05 via “χ2 testing. Results: Data from 78 patients at one hospital and 91 patients at the other were used in developing the respective institutional nomograms. For each hospital’s data set, both age and initial serum creatinine were significantly associated with the predicted dosing interval (p < 0.001). Validation in a total of 105 test patients showed that the integrated nomogram had a predictive success rate of 56%. Conclusions: A novel vancomycin dosing nomogram was developed and validated at 2 Canadian teaching hospitals. This integrated nomogram is a tool that clinicians can use in selecting appropriate initial vancomycin regimens on the basis of age and serum creatinine, to achieve high-target levels of 15–20 mg/L. The nomogram should not replace clinical judgment for patients with unstable and/or reduced renal function. PMID:22783028

Does contemporary vancomycin dosing achieve therapeutic targets in a heterogeneous clinical cohort of critically ill patients? Data from the multinational DALI study

PubMed Central

2014-01-01

Introduction The objective of this study was to describe the pharmacokinetics of vancomycin in ICU patients and to examine whether contemporary antibiotic dosing results in concentrations that have been associated with favourable response. Methods The Defining Antibiotic Levels in Intensive Care (DALI) study was a prospective, multicentre pharmacokinetic point-prevalence study. Antibiotic dosing was as per the treating clinician either by intermittent bolus or continuous infusion. Target trough concentration was defined as ≥15 mg/L and target pharmacodynamic index was defined as an area under the concentration-time curve over a 24-hour period divided by the minimum inhibitory concentration of the suspected bacteria (AUC0–24/MIC ratio) >400 (assuming MIC ≤1 mg/L). Results Data of 42 patients from 26 ICUs were eligible for analysis. A total of 24 patients received vancomycin by continuous infusion (57%). Daily dosage of vancomycin was 27 mg/kg (interquartile range (IQR) 18 to 32), and not different between patients receiving intermittent or continuous infusion. Trough concentrations were highly variable (median 27, IQR 8 to 23 mg/L). Target trough concentrations were achieved in 57% of patients, but more frequently in patients receiving continuous infusion (71% versus 39%; P = 0.038). Also the target AUC0–24/MIC ratio was reached more frequently in patients receiving continuous infusion (88% versus 50%; P = 0.008). Multivariable logistic regression analysis with adjustment by the propensity score could not confirm continuous infusion as an independent predictor of an AUC0–24/MIC >400 (odds ratio (OR) 1.65, 95% confidence interval (CI) 0.2 to 12.0) or a Cmin ≥15 mg/L (OR 1.8, 95% CI 0.4 to 8.5). Conclusions This study demonstrated large interindividual variability in vancomycin pharmacokinetic and pharmacodynamic target attainment in ICU patients. These data suggests that a re-evaluation of current vancomycin dosing recommendations in critically ill patients is needed to more rapidly and consistently achieve sufficient vancomycin exposure. PMID:24887569

Mutation of RNA polymerase beta subunit (rpoB) promotes hVISA-to-VISA phenotypic conversion of strain Mu3.

PubMed

Matsuo, Miki; Hishinuma, Tomomi; Katayama, Yuki; Cui, Longzhu; Kapi, Maria; Hiramatsu, Keiichi

2011-09-01

The clinical vancomycin-intermediate Staphylococcus aureus (VISA) strain Mu50 carries two mutations in the vraSR and graRS two-component regulatory systems (TCRSs), namely, vraS(I5N) and graR(N197S) (hereinafter designated graR). The clinical heterogeneously vancomycin-intermediate S. aureus (hVISA) strain Mu3 shares with Mu50 the mutation in vraS that encodes the VraS two-component histidine kinase. Previously, we showed that introduction of the plasmid pgraR, carrying the mutated two-component response regulator graR, converted the hVISA strain Mu3 into VISA (vancomycin MIC = 4 mg/liter). Subsequently, however, we found that the introduction of a single copy of graR into the Mu3 chromosome by a gene replacement method did not confer on Mu3 the VISA phenotype. The gene-replaced strain Mu3graR thus obtained remained hVISA (MIC ≤ 2 mg/liter), although a small increase in vancomycin MIC was observed compared to that of the parent strain Mu3. Reevaluation of the Mu3 and Mu50 genomes revealed the presence of another mutation responsible for the expression of the VISA phenotype in Mu50. Here, we demonstrate that in addition to the two regulator mutations, a third mutation found in the Mu50 rpoB gene, encoding the RNA polymerase β subunit, was required for Mu3 to achieve the level of vancomycin resistance of Mu50. The selection of strain Mu3graR with rifampin gave rise to rpoB mutants with various levels of increased vancomycin resistance. Furthermore, 3 (33%) of 10 independently isolated VISA strains established from the heterogeneous subpopulations of Mu3graR were found to possess rpoB mutations with or without an accompanying rifampin-resistance phenotype. The data indicate that a sizable proportion of the resistant hVISA cell subpopulations is composed of spontaneous rpoB mutants with various degrees of increased vancomycin resistance.

Alternatives to vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections.

PubMed

Micek, Scott T

2007-09-15

Vancomycin remains the reference standard for the treatment of systemic infection caused by methicillin-resistant Staphylococcus aureus (MRSA). However, as a result of limited tissue distribution, as well as the emergence of isolates with reduced susceptibility and in vitro resistance to vancomycin, the need for alternative therapies that target MRSA has become apparent. New treatment options for invasive MRSA infections include linezolid, daptomycin, tigecycline, and quinupristin/dalfopristin. Additionally, a number of new anti-MRSA compounds are in development, including novel glycopeptides (dalbavancin, telavancin, and oritavancin), ceftobiprole, and iclaprim. The present article will review clinical issues surrounding the newly marketed and investigational agents with activity against MRSA.

21 CFR 862.3950 - Vancomycin test system.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Vancomycin test system. 862.3950 Section 862.3950 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...

21 CFR 862.3950 - Vancomycin test system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Vancomycin test system. 862.3950 Section 862.3950 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...

21 CFR 862.3950 - Vancomycin test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Vancomycin test system. 862.3950 Section 862.3950 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...

21 CFR 862.3950 - Vancomycin test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Vancomycin test system. 862.3950 Section 862.3950 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...

Effect of dual delivery of antibiotics (vancomycin and cefazolin) and BMP-7 from chitosan microparticles on Staphylococcus epidermidis and pre-osteoblasts in vitro

PubMed Central

Mantripragada, Venkata P.; Jayasuriya, Ambalangodage C.

2016-01-01

The main aims of this manuscript are to: i) determine the effect of commonly used antibiotics to treat osteoarticular infections on osteoblast viability, ii) study the dual release of the growth factor (BMP-7) and antibiotics (vancomycin and cefazolin) from chitosan microparticles iii) demonstrate the bioactivity of the antibiotics released in vitro on Staphylococcus epidermidis. The novelty of this work is dual delivery of growth factor and antibiotic from the chitosan microparticles in a controlled manner without affecting their bioactivity. Cefazolin and vancomycin have different therapeutic concentrations for their action in vivo and therefore, two different concentrations of the drugs were used. Osteoblast cytotoxicity test concluded that cefazolin concentrations of 50 and 100 μg/ml were found to have positive influence on osteoblast proliferation. A significant increase in osteoblast proliferation was observed in the presence of cefazolin and BMP-7 in comparison with BMP-7 alone group; indicating cefazolin might play a role in osteoblast proliferation. On the other hand, vancomycin concentration of 1000 μg/ml was found to significantly reduce (p < 0.01) osteoblast proliferation in comparison with controls. The microbial study indicated that cefazolin at a minimum concentration of 21.5 μg/ml could inhibit ~85% growth of S. epidermidis, whereas vancomycin at a concentration of 30 μg/ml was found to inhibit ~80% bacterial growth. PMID:27287137

Teicoplanin. A pharmacoeconomic evaluation of its use in the treatment of gram-positive infections.

PubMed

Spencer, C M; Bryson, H M

1995-04-01

Teicoplanin, a glycopeptide antibiotic, is active against Gram-positive organisms, including methicillin-resistant staphylococci. It has demonstrated similar efficacy to vancomycin in the treatment of Gram-positive infections in febrile patients with neutropenia; fewer comparative data are available in patients with other infection types. Compared with vancomycin, teicoplanin is associated with less nephrotoxicity, appears to cause fewer anaphylactoid reactions, requires less monitoring and is more convenient to administer (once daily by intravenous bolus or intramuscular injection vs 2 to 4 times daily by intravenous infusion). Two European cost-minimisation studies have demonstrated that while the acquisition cost per dose of teicoplanin was approximately twice that of vancomycin, the cost of 2 weeks' therapy with either agent was similar (difference of 1 to 2%). However, in order to fully explore potential differences between these agents, a full economic analysis which considers all treatment-related costs is needed. Home therapy of Gram-positive infections, a setting in which teicoplanin may be preferred over vancomycin because of its tolerability profile and ease of administration, is particularly worthy of future economic study. Thus, there are a number of areas needing further study before the optimum formulary positioning of teicoplanin can be definitely stated. Nevertheless, present evidence suggests that teicoplanin is likely to have pharmacoeconomic advantages over vancomycin in at least some situations.

Accumulation of phosphatidic acid increases vancomycin resistance in Escherichia coli.

PubMed

Sutterlin, Holly A; Zhang, Sisi; Silhavy, Thomas J

2014-09-01

In Gram-negative bacteria, lipopolysaccharide (LPS) contributes to the robust permeability barrier of the outer membrane, preventing entry of toxic molecules such as antibiotics. Mutations in lptD, the beta-barrel component of the LPS transport and assembly machinery, compromise LPS assembly and result in increased antibiotic sensitivity. Here, we report rare vancomycin-resistant suppressors that improve barrier function of a subset of lptD mutations. We find that all seven suppressors analyzed mapped to the essential gene cdsA, which is responsible for the conversion of phosphatidic acid to CDP-diacylglycerol in phospholipid biosynthesis. These cdsA mutations cause a partial loss of function and, as expected, accumulate phosphatidic acid. We show that this suppression is not confined to mutations that cause defects in outer membrane biogenesis but rather that these cdsA mutations confer a general increase in vancomycin resistance, even in a wild-type cell. We use genetics and quadrupole time of flight (Q-TOF) liquid chromatography-mass spectrometry (LC-MS) to show that accumulation of phosphatidic acid by means other than cdsA mutations also increases resistance to vancomycin. We suggest that increased levels of phosphatidic acid change the physical properties of the outer membrane to impede entry of vancomycin into the periplasm, hindering access to its target, an intermediate required for the synthesis of the peptidoglycan cell wall. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Fidaxomicin Versus Vancomycin for Clostridium difficile Infection: Meta-analysis of Pivotal Randomized Controlled Trials

PubMed Central

Crook, Derrick W.; Walker, A. Sarah; Kean, Yin; Weiss, Karl; Cornely, Oliver A.; Miller, Mark A.; Esposito, Roberto; Louie, Thomas J.; Stoesser, Nicole E.; Young, Bernadette C.; Angus, Brian J.; Gorbach, Sherwood L.; Peto, Timothy E. A.

2012-01-01

Two recently completed phase 3 trials (003 and 004) showed fidaxomicin to be noninferior to vancomycin for curing Clostridium difficile infection (CDI) and superior for reducing CDI recurrences. In both studies, adults with active CDI were randomized to receive blinded fidaxomicin 200 mg twice daily or vancomycin 125 mg 4 times a day for 10 days. Post hoc exploratory intent-to-treat (ITT) time-to-event analyses were undertaken on the combined study 003 and 004 data, using fixed-effects meta-analysis and Cox regression models. ITT analysis of the combined 003/004 data for 1164 patients showed that fidaxomicin reduced persistent diarrhea, recurrence, or death by 40% (95% confidence interval [CI], 26%–51%; P < .0001) compared with vancomycin through day 40. A 37% (95% CI, 2%–60%; P = .037) reduction in persistent diarrhea or death was evident through day 12 (heterogeneity P = .50 vs 13–40 days), driven by 7 (1.2%) fidaxomicin versus 17 (2.9%) vancomycin deaths at <12 days. Low albumin level, low eosinophil count, and CDI treatment preenrollment were risk factors for persistent diarrhea or death at 12 days, and CDI in the previous 3 months was a risk factor for recurrence (all P < .01). Fidaxomicin has the potential to substantially improve outcomes from CDI. PMID:22752871

Erysipelothrix rhusiopathiae endocarditis and presumed osteomyelitis

PubMed Central

Romney, Marc; Cheung, Stephen; Montessori, Valentina

2001-01-01

Erysipelothrix rhusiopathiae is known to cause infections in humans following exposure to decaying organic matter or animals colonized with the organism, such as swine and fish. Invasive infections with this organism are unusual and are manifested primarily as infective endocarditis. The present report is believed to be the first to report a case of E rhusiopathiae endocarditis and presumptive osteomyelitis. E rhusiopathiae appears to have intrinsic resistance to vancomycin. Because vancomycin is often used empirically for the treatment of endocarditis, rapid differentiation of E rhusiopathiae from other Gram-positive organisms is critical. In patients with endocarditis caused by a Gram-positive bacillus and epidemiological risk factors for E rhusiopathiae exposure, empirical treatment with vancomycin should be reconsidered. PMID:18159347

Erysipelothrix rhusiopathiae endocarditis and presumed osteomyelitis.

PubMed

Romney, M; Cheung, S; Montessori, V

2001-07-01

Erysipelothrix rhusiopathiae is known to cause infections in humans following exposure to decaying organic matter or animals colonized with the organism, such as swine and fish. Invasive infections with this organism are unusual and are manifested primarily as infective endocarditis. The present report is believed to be the first to report a case of E rhusiopathiae endocarditis and presumptive osteomyelitis. E rhusiopathiae appears to have intrinsic resistance to vancomycin. Because vancomycin is often used empirically for the treatment of endocarditis, rapid differentiation of E rhusiopathiae from other Gram-positive organisms is critical. In patients with endocarditis caused by a Gram-positive bacillus and epidemiological risk factors for E rhusiopathiae exposure, empirical treatment with vancomycin should be reconsidered.

Comparative in vitro activities of dalbavancin and seven comparator agents against 41 Staphylococcus species cultured from osteomyelitis infections and 18 VISA and hVISA strains.

PubMed

Citron, Diane M; Tyrrell, Kerin L; Goldstein, Ellie J C

2014-08-01

Due to a high rate of relapse, osteomyelitis remains difficult to treat, requiring prolonged parenteral therapy. MICs for 41 consecutive Staphylococcus species recovered from patients with osteomyelitis were determined for dalbavancin, daptomycin, doxycycline, levofloxacin, linezolid, vancomycin, trimethoprim-sulfamethoxazole, rifampin, and vancomycin. Strains of vancomycin-intermediate Staphylococcus aureus (VISA) and heteroresistant VISA were included for additional comparison. Except for rifampin, dalbavancin was the most active agent tested. Dalbavancin is given once a week, making treatment of infections such as osteomyelitis potentially more convenient and thus could help reduce the rate of hospitalizations and outpatient costs. Copyright © 2014 Elsevier Inc. All rights reserved.

Good Outcomes with the Intraventricular Vancomycin Therapy in a Patient with Ruptured Brain Abscesses

PubMed Central

Doan, Ninh; Nguyen, Ha; Luyuan, Li; Shabani, Saman; Gelsomino, Michael; Johnson, Vijay

2018-01-01

Brain abscesses are associated with high morbidity and mortality rates. In particular, patients with intraventricular rupture of brain abscess (IVROBA) exhibit mortality rates up to 85%. Treatment options are lacking for IVROBA, once patients become refractory to intravenous antibiotics and surgical drainage. Limited data exist regarding the risks and benefits of intraventricular therapy in such a scenario. We report a patient with IVROBA, who deteriorated while on systemic antibiotics; once intraventricular vancomycin was employed, the patient demonstrated remarkable improvement without perceivable side effects. This case suggests that intraventricular vancomycin may be a safe, effective, and viable option for the treatment of IVROBA, especially for patients becoming refractory to systemic antibiotics. PMID:29682042

Enrichment of hexachlorobenzene and 1,3,5-trichlorobenzene transforming bacteria from sediments in Germany and Vietnam.

PubMed

Duan, Tran Hoa; Adrian, Lorenz

2013-07-01

Bacterial cultures were enriched from sediments in Germany and Vietnam reductively dechlorinating hexachlorobenzene and the highly persistent 1,3,5-trichlorobenzene to monochlorobenzene. The main products of the reductive dechlorination of hexachlorobenzene were monochlorobenzene and dichlorobenzenes (1,2-; 1,3- and 1,4-dichlorobenzene) while no trichlorobenzenes accumulated. For the reductive dechlorination of 1,3,5-trichlorobenzene with the mixed culture from Vietnam sediment, 1,3- dichlorobenzene and monochlorobenzene were produced as intermediate and final end-product, respectively. The pattern of dechlorination did not change when the cultures were repeatedly exposed to oxygen over seven transfers demonstrating oxygen tolerance of the dechlorinating bacteria. However, reductive dechlorination of 1,3,5-trichlorobenzene was inhibited by vancomycin at a concentration of 5 mg L(-1). Vancomycin delayed reductive dechlorination of hexachlorobenzene in mixed cultures by about 6 months. When repeatedly applied, vancomycin completely abolished the ability of the mixed culture to transform hexachlorobenzene. Sensitivity to vancomycin and insensitivity to brief exposure of oxygen indicates that the dechlorinating bacteria in the mixed cultures did not belong to the genus Dehalococcoides.

Application of matrix-assisted laser desorption ionization time-of-flight mass spectrometry in the screening of vanA-positive Enterococcus faecium.

PubMed

Wang, Li-jun; Lu, Xin-xin; Wu, Wei; Sui, Wen-jun; Zhang, Gui

2014-01-01

In order to evaluate a rapid matrix-assisted laser desorption ionization-time of flight mass spectrometry (MAIDI-TOF MS) assay in screening vancomycin-resistant Enterococcus faecium, a total of 150 E. faecium clinical strains were studied, including 60 vancomycin-resistant E. faecium (VREF) isolates and 90 vancomycin-susceptible (VSEF) strains. Vancomycin resistance genes were detected by sequencing. E. faecium were identified by MALDI-TOF MS. A genetic algorithm model with ClinProTools software was generated using spectra of 30 VREF isolates and 30 VSEF isolates. Using this model, 90 test isolates were discriminated between VREF and VSEF. The results showed that all sixty VREF isolates carried the vanA gene. The performance of VREF detection by the genetic algorithm model of MALDI-TOF MS compared to the sequencing method was sensitivity = 80%, specificity = 90%, false positive rate =10%, false negative rate =10%, positive predictive value = 80%, negative predictive value= 90%. MALDI-TOF MS can be used as a screening test for discrimination between vanA-positive E. faecium and vanA-negative E. faecium.

In vitro activity of flomoxef and cefazolin in combination with vancomycin.

PubMed

Simon, C; Simon, M

1991-01-01

207 clinical isolates from strains of patients from the University Children's Hospital of Kiel were investigated for their in vitro activity with the agar dilution method against flomoxef and cefazolin (alone and partially in combination with vancomycin). Staphylococci were also tested with other cephalosporins (cefoxitin, cefamandole, cefotaxime, cefotetan and latamoxef). Flomoxef and cefazolin always acted more vigorously on staphylococci than the other cephalosporins. Resistance of Staphylococcus aureus strains against flomoxef and cefazolin did not occur but was found in 15 and 5 of 98 Staphylococcus epidermidis strains, respectively. Enterococcus faecalis strains were always resistant against both drugs; Streptococcus faecium strains were only moderately sensitive. Combined testing of flomoxef or cefazolin with vancomycin showed synergism in almost all staphylococcal strains. Synergism was stronger when S. epidermidis strains were only weakly sensitive to or resistant against flomoxef and cefazolin in comparison to highly sensitive strains. Flomoxef (or cefazolin) acted synergistically in combination with vancomycin on E. faecalis and S. faecium with the exception of two strains of E. faecalis which showed an additive effect of both drugs.

Enhanced Membrane Pore Formation through High-Affinity Targeted Antimicrobial Peptides

PubMed Central

Arnusch, Christopher J.; Pieters, Roland J.; Breukink, Eefjan

2012-01-01

Many cationic antimicrobial peptides (AMPs) target the unique lipid composition of the prokaryotic cell membrane. However, the micromolar activities common for these peptides are considered weak in comparison to nisin, which follows a targeted, pore-forming mode of action. Here we show that AMPs can be modified with a high-affinity targeting module, which enables membrane permeabilization at low concentration. Magainin 2 and a truncated peptide analog were conjugated to vancomycin using click chemistry, and could be directed towards specific membrane embedded receptors both in model membrane systems and whole cells. Compared with untargeted vesicles, a gain in permeabilization efficacy of two orders of magnitude was reached with large unilamellar vesicles that included lipid II, the target of vancomycin. The truncated vancomycin-peptide conjugate showed an increased activity against vancomycin resistant Enterococci, whereas the full-length conjugate was more active against a targeted eukaryotic cell model: lipid II containing erythrocytes. This study highlights that AMPs can be made more selective and more potent against biological membranes that contain structures that can be targeted. PMID:22768121

Effect of dual delivery of antibiotics (vancomycin and cefazolin) and BMP-7 from chitosan microparticles on Staphylococcus epidermidis and pre-osteoblasts in vitro.

PubMed

Mantripragada, Venkata P; Jayasuriya, Ambalangodage C

2016-10-01

The main aims of this manuscript are to: i) determine the effect of commonly used antibiotics to treat osteoarticular infections on osteoblast viability, ii) study the dual release of the growth factor (BMP-7) and antibiotics (vancomycin and cefazolin) from chitosan microparticles iii) demonstrate the bioactivity of the antibiotics released in vitro on Staphylococcus epidermidis. The novelty of this work is dual delivery of growth factor and antibiotic from the chitosan microparticles in a controlled manner without affecting their bioactivity. Cefazolin and vancomycin have different therapeutic concentrations for their action in vivo and therefore, two different concentrations of the drugs were used. Osteoblast cytotoxicity test concluded that cefazolin concentrations of 50 and 100μg/ml were found to have positive influence on osteoblast proliferation. A significant increase in osteoblast proliferation was observed in the presence of cefazolin and BMP-7 in comparison with BMP-7 alone group; indicating cefazolin might play a role in osteoblast proliferation. On the other hand, vancomycin concentration of 1000μg/ml was found to significantly reduce (p<0.01) osteoblast proliferation in comparison with controls. The microbial study indicated that cefazolin at a minimum concentration of 21.5μg/ml could inhibit ~85% growth of S. epidermidis, whereas vancomycin at a concentration of 30μg/ml was found to inhibit ~80% bacterial growth. Copyright © 2016 Elsevier B.V. All rights reserved.

The Impact of AUC-Based Monitoring on Pharmacist-Directed Vancomycin Dose Adjustments in Complicated Methicillin-Resistant Staphylococcus aureus Infection.

PubMed

Stoessel, Andrew M; Hale, Cory M; Seabury, Robert W; Miller, Christopher D; Steele, Jeffrey M

2018-01-01

This study aimed to assess the impact of area under the curve (AUC)-based vancomycin monitoring on pharmacist-initiated dose adjustments after transitioning from a trough-only to an AUC-based monitoring method at our institution. A retrospective cohort study of patients treated with vancomycin for complicated methicillin-resistant Staphylococcus aureus (MRSA) infection between November 2013 and December 2016 was conducted. The frequency of pharmacist-initiated dose adjustments was assessed for patients monitored via trough-only and AUC-based approaches for trough ranges: 10 to 14.9 mg/L and 15 to 20 mg/L. Fifty patients were included: 36 in the trough-based monitoring and 14 in the AUC-based-monitoring group. The vancomycin dose was increased in 71.4% of patients when troughs were 10 to 14.9 mg/L when a trough-only approach was used and in only 25% of patients when using AUC estimation ( P = .048). In the AUC group, the dose was increased only when AUC/minimum inhibitory concentration (MIC) <400; unchanged regimens had an estimated AUC/MIC ≥400. The AUC-based monitoring did not significantly increase the frequency of dose reductions when trough concentrations were 15 to 20 mg/L (AUC: 33.3% vs trough: 4.6%; P = .107). The AUC-based monitoring resulted in fewer patients with dose adjustments when trough levels were 10 to 14.9 mg/L. The AUC-based monitoring has the potential to reduce unnecessary vancomycin exposure and warrants further investigation.

In vitro activities of ramoplanin, teicoplanin, vancomycin, linezolid, bacitracin, and four other antimicrobials against intestinal anaerobic bacteria.

PubMed

Citron, D M; Merriam, C V; Tyrrell, K L; Warren, Y A; Fernandez, H; Goldstein, E J C

2003-07-01

By using an agar dilution method, the in vitro activities of ramoplanin, teicoplanin, vancomycin, linezolid, and five other agents were determined against 300 gram-positive and 54 gram-negative strains of intestinal anaerobes. Ramoplanin was active at or=256 microg/ml. Ramoplanin displays excellent activity against C. difficile and other gram-positive enteric anaerobes, including vancomycin-resistant strains; however, it has poor activity against most gram-negative anaerobes and thus potentially has a lesser effect on the ecological balance of normal fecal flora.

TOC-39, a novel parenteral broad-spectrum cephalosporin with excellent activity against methicillin-resistant Staphylococcus aureus.

PubMed Central

Hanaki, H; Akagi, H; Masaru, Y; Otani, T; Hyodo, A; Hiramatsu, K

1995-01-01

TOC-39, a new parenteral cephalosporin, is a hydroxyimino-type cephem antibiotic with vinylthio-pyridyl moiety at the 3 position. TOC-39 was evaluated for antibacterial activity against various clinically isolated strains. TOC-39 had excellent activity, stronger than that of methicillin, oxacillin, the cephalosporins tested, imipenem, gentamicin, minocycline, tobramycin, ofloxacin, and ciprofloxacin against methicillin-resistant Staphylococcus aureus (MRSA) and had an MIC comparable to that of vancomycin (the MICs of TOC-39 and vancomycin for 90% of the strains tested were 3.13 and 1.56 micrograms/ml, respectively). Against Enterococcus faecalis strains, which are resistant to cephalosporins, TOC-39 was twice as active as ampicillin. Against methicillin-susceptible S. aureus, coagulase-negative Staphylococcus spp., and Streptococcus pneumoniae, TOC-39 was twice as active as or more active than cefotiam, ceftazidime, flomoxef, and cefpirome. Against Streptococcus pyogenes, TOC-39 was superior to cefotiam, ceftazidime, and flomoxef and was similar to cefpirome. In addition, the activity of TOC-39 was equal to or greater than that of cefotiam, ceftazidime, flomoxef, and cefpirome against Haemophilus influenzae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Morganella morganii. In terms of bactericidal effect against MRSA, TOC-39 was superior to vancomycin. No mutant resistant to TOC-39 or vancomycin was obtained from susceptible MRSA strains. In murine systemic infection models, TOC-39 showed potent activity against S. aureus and E. coli. Against highly MRSA, the activity of TOC-39 was comparable to that of vancomycin. PMID:7625799

Antibiotic Resistance Patterns of Enterococci and Occurrence of Vancomycin-Resistant Enterococci in Raw Minced Beef and Pork in Germany

PubMed Central

Klein, Günter; Pack, Alexander; Reuter, Gerhard

1998-01-01

The food chain, especially raw minced meat, is thought to be responsible for an increase in the incidence of vancomycin-resistant enterococci (VRE) in human nosocomial infections. Therefore, 555 samples from 115 batches of minced beef and pork from a European Union-licensed meat-processing plant were screened for the occurrence of VRE. The processed meat came from 45 different slaughterhouses in Germany. Enterococci were isolated directly from Enterococcosel selective agar plates and also from Enterococcosel selective agar plates supplemented with 32 mg of vancomycin per liter. In addition, peptone broth was used in a preenrichment procedure, and samples were subsequently plated onto Enterococcosel agar containing vancomycin. To determine resistance, 209 isolates from 275 samples were tested with the glycopeptides vancomycin, teicoplanin, and avoparcin and 19 other antimicrobial substances by using a broth microdilution test. When the direct method was used, VRE were found in 3 of 555 samples (0.5%) at a concentration of 1.0 log CFU/g of minced meat. When the preenrichment procedure was used, 8% of the samples were VRE positive. Our findings indicate that there is a low incidence of VRE in minced meat in Germany. In addition, the resistance patterns of the VRE isolates obtained were different from the resistance patterns of clinical isolates. A connection between the occurrence of VRE in minced meat and nosocomial infections could not be demonstrated on the basis of our findings. PMID:9572958

Association between Vancomycin Day 1 Exposure Profile and Outcomes among Patients with Methicillin-Resistant Staphylococcus aureus Infective Endocarditis

PubMed Central

Casapao, Anthony M.; Lodise, Thomas P.; Davis, Susan L.; Claeys, Kimberly C.; Kullar, Ravina; Levine, Donald P.

2015-01-01

Given the critical importance of early appropriate therapy, a retrospective cohort (2002 to 2013) was performed at the Detroit Medical Center to evaluate the association between the day 1 vancomycin exposure profile and outcomes among patients with MRSA infective endocarditis (IE). The day 1 vancomycin area under the concentration-time curve (AUC0–24) and the minimum concentration at 24 h (Cmin 24) was estimated for each patient using the Bayesian procedure in ADAPT 5, an approach shown to accurately predict the vancomycin exposure with low bias and high precision with limited pharmacokinetic sampling. Initial MRSA isolates were collected and vancomycin MIC was determined by broth microdilution (BMD) and Etest. The primary outcome was failure, defined as persistent bacteremia (≥7 days) or 30-day attributable mortality. Classification and regression tree analysis (CART) was used to determine the vancomycin exposure variables associated with an increased probability of failure. In total, 139 patients met study criteria; 76.3% had right-sided IE, 16.5% had left-sided IE, and 7.2% had both left and right-sided IE. A total of 89/139 (64%) experienced failure by composite definition. In the CART analysis, failure was more pronounced in patients with an AUC0–24/MIC as determined by BMD of ≤600 relative to those with AUC0–24/MIC as determined by BMD of >600 (69.8% versus 54.7%, respectively, P = 0.073). In the logistic regression analysis, an AUC/MIC as determined by BMD of ≤600 (adjusted odds ratio, 2.3; 95% confidence interval, 1.01 to 5.37; P = 0.047) was independently associated with failure. Given the retrospective nature of the present study, further prospective studies are required but these data suggest that patients with an AUC0–24/MIC as determined by BMD of ≤600 present an increased risk of failure. PMID:25753631

Prospective randomized double-blinded trial comparing 2 anti-MRSA agents with supplemental coverage of cefazolin before lower extremity revascularization.

PubMed

Stone, Patrick A; AbuRahma, Ali F; Campbell, James R; Hass, Stephen M; Mousa, Albeir Y; Nanjundappa, Aravinda; Srivastiva, Mohit; Modak, Asmita; Emmett, Mary

2015-09-01

To compare with antibiotics with methicillin-resistant microbial coverage in a prospective fashion. Current antibiotic prophylaxis for vascular procedures includes a first generation cephalosporin. No changes in recommendations have occurred despite changes in reports of incidence of MRSA related surgical site infections. Does supplemental anti-MRSA prophylactic coverage provide a significant reduction in Gram-positive or MRSA infections? Single center prospective double blinded randomized study of patients undergoing lower extremity vascular procedures from 2011 to 2014. One hundred seventy-eight (178) patients were evaluated at 90 days for surgical site infection. Infections were categorized as early infections less than 30 days of the index procedure and late after 90 days. Early vascular surgical site infection occurred in 7(8.24%) of patients in the Vancomycin arm, and 11 (11.83%) in the Daptomycin arm (P = 0.43). Gram-positive related infections and MRSA infections occurred in 1(1.18%)/0(0%) of Vancomycin patients and 9 (9.68%)/1 (1.08%) of Daptomycin patients, respectively (P < 0.02 and P = 1.00). Readmissions related to surgical site infections occurred in 4(4.71%) in the Vancomycin group and 11 (11.8%) in the Daptomycin group (P = 0.11). Patients undergoing operative exploration occurred in 5 (5.88%) in the Vancomycin group and 10 (10.75%) of the Daptomycin group (P = 0.17). Late infections were reported in 3 patients, 2 of which were in the combined Daptomycin group. Median hospital charges related to readmissions due to a surgical site infection was $50,823 in the combination Vancomycin arm and $110,920 in the combination Daptomycin group; however, no statistical significance was appreciated (P = 0.11). Vancomycin supplemental prophylaxis seems to reduce the incidence of Gram-positive infection compared with adding supplemental Daptomycin prophylaxis. The Incidence of MRSA-related surgical site infections is low with the addition of either anti-MRSA agents compared with historical incidence of MRSA-related infection.

A randomized pharmacokinetic and pharmacodynamic evaluation of every 8-hour and 12-hour dosing strategies of vancomycin and cefepime in neurocritically-ill patients.

PubMed

Kassel, Lynn E; Van Matre, Edward T; Foster, Charles J; Fish, Douglas N; Mueller, Scott W; Sherman, Deb S; Wempe, Michael F; MacLaren, Robert; Neumann, Robert T; Kiser, Tyree H

2018-06-15

Neurocritically-ill patients have clinically significant alterations in pharmacokinetic parameters of renally-eliminated medications, which may result in subtherapeutic plasma and cerebrospinal fluid antibiotic concentrations. Prospective, randomized, open-label study of adult neurocritically-ill patients treated with vancomycin and cefepime. Vancomycin 15 mg/kg and cefepime 2 g were dosed at every 8 or 12-hour intervals. The primary outcomes were the achievement of pharmacodynamic targets related to time of unbound drug above minimum inhibitory concentrations (MIC) for 60% or more of the dosing interval (fT>MIC ≥60%) for β-lactams and ratio of 24-hour area under the curve (AUC):MIC of 400 or greater for vancomycin. Twenty patients were included in the study. Patients were divided equally between the every 12-hour (n=10) and every 8-hour (n=10) dosing groups. Patients (mean age of 51.8 ± 11 years) were primarily male (60%) and Caucasian (95%), and the majority had an admission diagnosis of intracranial hemorrhage (80%). Compared to the every 12-hour group, the every 8-hour vancomycin group achieved target trough concentrations (>15 μg/ml) significantly more frequently at initial measurement (0% vs 80%, p<0.01) and at 7 to 10 days (0% vs 90%, p=0.045) and achieved pharmacodynamic targets more frequently at increasing MICs. Similarly, compared to every 12-hour dosing, the every 8-hour cefepime dosing strategy significantly increased pharmacodynamic target attainment (fT>MIC ≥60%) at an MIC of 8 μg/ml (20% vs 70%, p=0.02). This study demonstrated that more frequent dosing of vancomycin and cefepime is required to achieve optimal pharmacodynamic targets in adult neurocritically-ill patients. The need for increased total daily doses is potentially secondary to the development of augmented renal clearance. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Treatment of osteomyelitis defects by a vancomycin-loaded gelatin/β-tricalcium phosphate composite scaffold

PubMed Central

Zhou, J.; Zhou, X. G.; Wang, J. W.; Zhou, H.; Dong, J.

2018-01-01

Objective In the present study, we aimed to assess whether gelatin/β-tricalcium phosphate (β-TCP) composite porous scaffolds could be used as a local controlled release system for vancomycin. We also investigated the efficiency of the scaffolds in eliminating infections and repairing osteomyelitis defects in rabbits. Methods The gelatin scaffolds containing differing amounts of of β-TCP (0%, 10%, 30% and 50%) were prepared for controlled release of vancomycin and were labelled G-TCP0, G-TCP1, G-TCP3 and G-TCP5, respectively. The Kirby-Bauer method was used to examine the release profile. Chronic osteomyelitis models of rabbits were established. After thorough debridement, the osteomyelitis defects were implanted with the scaffolds. Radiographs and histological examinations were carried out to investigate the efficiency of eliminating infections and repairing bone defects. Results The prepared gelatin/β-TCP scaffolds exhibited a homogeneously interconnected 3D porous structure. The G-TCP0 scaffold exhibited the longest duration of vancomycin release with a release duration of eight weeks. With the increase of β-TCP contents, the release duration of the β-TCP-containing composite scaffolds was decreased. The complete release of vancomycin from the G-TCP5 scaffold was achieved within three weeks. In the treatment of osteomyelitis defects in rabbits, the G-TCP3 scaffold showed the most efficacious performance in eliminating infections and repairing bone defects. Conclusions The composite scaffolds could achieve local therapeutic drug levels over an extended duration. The G-TCP3 scaffold possessed the optimal porosity, interconnection and controlled release performance. Therefore, this scaffold could potentially be used in the treatment of chronic osteomyelitis defects. Cite this article: J. Zhou, X. G. Zhou, J. W. Wang, H. Zhou, J. Dong. Treatment of osteomyelitis defects by a vancomycin-loaded gelatin/β-tricalcium phosphate composite scaffold. Bone Joint Res 2018;7:46–57. DOI: 10.1302/2046-3758.71.BJR-2017-0129.R2. PMID:29330343

Vancomycin Reduces Cell Wall Stiffness and Slows Swim Speed of the Lyme Disease Bacterium.

PubMed

Harman, Michael W; Hamby, Alex E; Boltyanskiy, Ross; Belperron, Alexia A; Bockenstedt, Linda K; Kress, Holger; Dufresne, Eric R; Wolgemuth, Charles W

2017-02-28

Borrelia burgdorferi, the spirochete that causes Lyme disease, is a tick-transmitted pathogen that requires motility to invade and colonize mammalian and tick hosts. These bacteria use a unique undulating flat-wave shape to penetrate and propel themselves through host tissues. Previous mathematical modeling has suggested that the morphology and motility of these spirochetes depends crucially on the flagellar/cell wall stiffness ratio. Here, we test this prediction using the antibiotic vancomycin to weaken the cell wall. We found that low to moderate doses of vancomycin (≤2.0 μg/mL for 24 h) produced small alterations in cell shape and that as the dose was increased, cell speed decreased. Vancomycin concentrations >1.0 μg/mL also inhibited cell growth and led to bleb formation on a fraction of the cells. To quantitatively assess how vancomycin affects cell stiffness, we used optical traps to bend unflagellated mutants of B. burgdorferi. We found that in the presence of vancomycin, cell wall stiffness gradually decreased over time, with a 40% reduction in the bending stiffness after 36 h. Under the same conditions, the swimming speed of wild-type B. burgdorferi slowed by ∼15%, with only marginal changes to cell morphology. Interestingly, our biophysical model for the swimming dynamics of B. burgdorferi suggested that cell speed should increase with decreasing cell stiffness. We show that this discrepancy can be resolved if the periplasmic volume decreases as the cell wall becomes softer. These results provide a testable hypothesis for how alterations of cell wall stiffness affect periplasmic volume regulation. Furthermore, since motility is crucial to the virulence of B. burgdorferi, the results suggest that sublethal doses of antibiotics could negatively impact spirochete survival by impeding their swim speed, thereby enabling their capture and elimination by phagocytes. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Adjunctive vancomycin powder in pediatric spine surgery is safe.

PubMed

Gans, Itai; Dormans, John P; Spiegel, David A; Flynn, John M; Sankar, Wudbhav N; Campbell, Robert M; Baldwin, Keith D

2013-09-01

Therapeutic level II cohort study. To evaluate the safety of adjunctive local application of vancomycin powder (VP) for infection prophylaxis in posterior instrumented thoracic and lumbar spine wounds in pediatric patients weighing more than 25 kg. Spine surgeons have largely turned to vancomycin prophylaxis in an attempt to decrease the incidence of late surgical site infection and acute surgical site infection from methicillin-resistant Staphylococcus aureus. In adult patients, the adjunctive local application of VP with an intravenous cephalosporin has been shown to decrease postsurgical wound infection rates significantly; however, the safety of VP as an adjunct in pediatric spine surgery has not been reported. We reviewed data collected under a systematic protocol specifically designed to monitor the safety profile of VP. We measured changes in creatinine and systemic vancomycin levels after intrawound application of 500 mg of unreconstituted VP during spine deformity correction surgery in patients weighing more than 25 kg (patients also received routine intravenous cephalosporin prophylaxis). Laboratory values were measured preoperatively and on postoperative days 1 and 4. Any adverse reactions and infections through available follow-up (2-8 mo) were recorded. Eighty-seven consecutive pediatric patients with spinal deformity weighing more than 25 kg who received intraoperative VP during a 9-month period were identified. Sixty-three percent of the patients in this series had adolescent idiopathic scoliosis, 15% congenital scoliosis, 15% neuromuscular scoliosis, and 5% spondylolisthesis. The average change in creatinine levels between the preoperative and postoperative day 1 draw was -0.03 and between the preoperative and postoperative day 4 draw was -0.075. The postoperative systemic vancomycin levels remained undetectable. None of the patients experienced nephrotoxicity or red man syndrome. Three of the 87 patients developed a surgical site infection. In this cohort there were no clinically significant changes in creatinine level or systemic vancomycin level caused by use of intraoperative VP. 2.

Is Intraoperative Local Vancomycin Powder the Answer to Surgical Site Infections in Spine Surgery?

PubMed

Hey, Hwee Weng Dennis; Thiam, Desmond Wei; Koh, Zhi Seng Darren; Thambiah, Joseph Shantakumar; Kumar, Naresh; Lau, Leok-Lim; Liu, Ka-Po Gabriel; Wong, Hee-Kit

2017-02-15

This is a retrospective cohort comparative study of all patients who underwent instrumented spine surgery at a single institution. To compare the rate of surgical site infection (SSI) between the treatment (vancomycin) and the control group (no vancomycin) in patients undergoing instrumented spine surgery. SSI after spine surgery is a dreaded complication associated with increased morbidity and mortality. Prophylactic intraoperative local vancomycin powder to the wound has been recently adopted as a strategy to reduce SSI but results have been variable. In the present study, there were 117 (30%) patients in the treatment group and 272 (70%) patients in the comparison cohort. All patients received identical standard operative and postoperative care procedures based on protocolized department guidelines. The present study compared the rate of SSI with and without the use of prophylactic intraoperative local vancomycin powder in patients undergoing various instrumented spine surgery, adjusted for confounders. The overall rate of SSI was 4.7% with a decrease in infection rate found in the treatment group (0.9% vs. 6.3%). This was statistically significant (P = 0.049) with an odds ratio of 0.13 (95% confidence interval 0.02-0.99). The treatment group had a significantly shorter onset of infection (5 vs. 16.7 days; P < 0.001) and shorter duration of infection (8.5 vs. 26.8 days; P < 0.001). The most common causative organism was Pseudomonas aeruginosa (35.2%). Patient diagnosis, surgical approach, and intraoperative blood loss were significant risk factors for SSI after multivariable analysis. Prophylactic Intraoperative local vancomycin powder reduces the risk and morbidity of SSI in patients undergoing instrumented spine surgery. P. aeruginosa infection is common in the treatment arm. Future prospective randomized controlled trials in larger populations involving other spine surgeries with a long-term follow-up duration are recommended. 3.

Contribution of Selected Gene Mutations to Resistance in Clinical Isolates of Vancomycin-Intermediate Staphylococcus aureus

PubMed Central

Hafer, Cory; Lin, Ying; Kornblum, John; Lowy, Franklin D.

2012-01-01

Infections with vancomycin-intermediate Staphylococcus aureus (VISA) have been associated with vancomycin treatment failures and poor clinical outcomes. Routine identification of clinical isolates with increased vancomycin MICs remains challenging, and no molecular marker exists to aid in diagnosis of VISA strains. We tested vancomycin susceptibilities by using microscan, Etest, and population analyses in a collection of putative VISA, methicillin-resistant S. aureus, and methicillin-sensitive S. aureus (VSSA) infectious isolates from community- or hospital-associated S. aureus infections (n = 77) and identified 22 VISA and 9 heterogeneous VISA (hVISA) isolates. Sequencing of VISA candidate loci vraS, vraR, yvqF, graR, graS, walR, walK, and rpoB revealed a high diversity of nonsynonymous single-nucleotide polymorphisms (SNPs). For vraS, vraR, yvqF, walK, and rpoB, SNPs were more frequently present in VISA and hVISA than in VSSA isolates, whereas mutations in graR, graS, and walR were exclusively detected in VISA isolates. For each of the individual loci, SNPs were only detected in about half of the VISA isolates. All but one VISA isolate had at least one SNP in any of the genes sequenced, and isolates with an MIC of 6 or 8 μg/ml harbored at least 2 SNPs. Overall, increasing vancomycin MICs were paralleled by a higher proportion of isolates with SNPs. Depending on the clonal background, SNPs appeared to preferentially accumulate in vraS and vraR for sequence type 8 (ST8) and in walK and walR for ST5 isolates. Taken together, by comparing VISA, hVISA, and VSSA controls, we observed preferential clustering of SNPs in VISA candidate genes, with an unexpectedly high diversity across these loci. Our results support a polygenetic etiology of VISA. PMID:22948864

Vancomycin resistant Enterococcus spp. from crows and their environment in metropolitan Washington State, USA: Is there a correlation between VRE positive crows and the environment?

PubMed

Roberts, Marilyn C; No, David B; Marzluff, John M; Delap, Jack H; Turner, Robert

2016-10-15

Vancomycin-resistant enterococci [VRE] have been isolated from municipal, hospital and agricultural wastewater, recreational beaches, wild animals, birds and food animals around the world. In this study, American crows (Corvus brachyrhynchos) from sewage treatment plants (WWTP), dairy farms, and a large roost in a restored wetland with corresponding environmental samples were cultured for VRE. A total of 245 samples [156 crows, 89 environmental] were collected and screened for acquired vanA, vanB and/or intrinsic vanC1 genes. Samples were enriched overnight in BHI supplemented with 20μg/mL aztreonam, 4μg/mL vancomycin and plated on m-Enterococcus agar media supplemented with 6μg/mL vancomycin. Selected colonies were grown on BHI media supplemented with 18μg/mL vancomycin. Of these, 24.5% of the crow and 55% the environmental/cow samples were VRE positive as defined by Enterococcus spp. able to grow on media supplemented with 18μg/mL vancomycin. A total of 122 VRE isolates, 43 crow and 79 environmental isolates were screened, identified to species level using 16S sequencing and further characterized. Four vanA E. faecium and multiple vanC1 E. gallinarum were identified from crows isolated from three sites. E. faecium vanA and E. gallinarum vanC1 along with other Enterococcus spp. carrying vanA, vanB, vanC1 were isolated from three environments. All enterococci were multidrug resistant. Crows were more likely to carry vanA E. faecium than either the cow feces or wetland waters/soils. Comparing E. gallinarum vanC1 from crows and their environment would be useful in determining whether crows share VRE strains with their environment. Copyright © 2016 Elsevier B.V. All rights reserved.

Single-Dose Oritavancin Treatment of Acute Bacterial Skin and Skin Structure Infections: SOLO Trial Efficacy by Eron Severity and Management Setting.

PubMed

Deck, Daniel H; Jordan, Jennifer M; Holland, Thomas L; Fan, Weihong; Wikler, Matthew A; Sulham, Katherine A; Ralph Corey, G

2016-09-01

Introduction of new antibiotics enabling single-dose administration, such as oritavancin may significantly impact site of care decisions for patients with acute bacterial skin and skin structure infections (ABSSSI). This analysis compared the efficacy of single-dose oritavancin with multiple-dose vancomycin in patients categorized according to disease severity via modified Eron classification and management setting. SOLO I and II were phase 3 studies evaluating single-dose oritavancin versus 7-10 days of vancomycin for treatment of ABSSSI. Patient characteristics were collected at baseline and retrospectively analyzed. Study protocols were amended, allowing outpatient management at the discretion of investigators. In this post hoc analysis, patients were categorized according to a modified Eron severity classification and management setting (outpatient vs. inpatient) and the efficacy compared. Overall, 1910 patients in the SOLO trials were categorized into Class I (520, 26.5%), II (790, 40.3%), and III (600, 30.6%). Of the 767 patients (40%) in the SOLO trials who were managed entirely in the outpatient setting 40.3% were categorized as Class II and 30.6% were Class III. Clinical efficacy was similar between oritavancin and vancomycin treatment groups, regardless of severity classification and across inpatient and outpatient settings. Class III patients had lower response rates (oritavancin 73.3%, vancomycin 76.6%) at early clinical evaluation when compared to patients in Class I (82.6%) or II (86.1%); however, clinical cure rates at the post-therapy evaluation were similar for Class III patients (oritavancin 79.8%, vancomycin 79.9%) when compared to Class I and II patients (79.1-85.7%). Single-dose oritavancin therapy results in efficacy comparable to multiple-dose vancomycin in patients categorized according to modified Eron disease severity classification regardless of whether management occurred in the inpatient or outpatient setting. The Medicines Company, Parsippany, NJ, USA. ClinicalTrials.gov identifiers, NCT01252719 (SOLO I) and NCT01252732 (SOLO II).

Vancomycin modifies the expression of the agr system in multidrug-resistant Staphylococcus aureus clinical isolates

PubMed Central

Cázares-Domínguez, Vicenta; Ochoa, Sara A.; Cruz-Córdova, Ariadnna; Rodea, Gerardo E.; Escalona, Gerardo; Olivares, Alma L.; Olivares-Trejo, José de Jesús; Velázquez-Guadarrama, Norma; Xicohtencatl-Cortes, Juan

2015-01-01

Staphylococcus aureus is an opportunistic pathogen that colonizes human hosts and causes a wide variety of diseases. Two interacting regulatory systems called agr (accessory gene regulator) and sar (staphylococcal accessory regulator) are involved in the regulation of virulence factors. The aim of this study was to evaluate the effect of vancomycin on hld and spa gene expression during the exponential and post-exponential growth phases in multidrug-resistant (MDR) S. aureus. Methods: Antibiotic susceptibility was evaluated by the standard microdilution method. The phylogenetic profile was obtained by pulsed-field gel electrophoresis (PFGE). Polymorphisms of agr and SCCmec (staphylococcal cassette chromosome mec) were analyzed by multiplex polymerase chain reaction (PCR). The expression levels of hld and spa were analyzed by reverse transcription-PCR. An enzyme-linked immunosorbent assay (ELISA) was performed to detect protein A, and biofilm formation was analyzed via crystal violet staining. Results: In total, 60.60% (20/33) of S. aureus clinical isolates were MDR. Half (10/20) of the MDR S. aureus isolates were distributed in subcluster 10, with >90% similarity among them. In the isolates of this subcluster, a high prevalence (100%) for the agrII and the cassette SCCmec II polymorphisms was found. Our data showed significant increases in hld expression during the post-exponential phase in the presence and absence of vancomycin. Significant increases in spa expression, protein A production and biofilm formation were observed during the post-exponential phase when the MDR S. aureus isolates were challenged with vancomycin. Conclusion: The polymorphism agrII, which is associated with nosocomial isolates, was the most prevalent polymorphism in MDR S. aureus. Additionally, under our study conditions, vancomycin modified hld and spa expression in these clinical isolates. Therefore, vancomycin may regulate alternative systems that jointly participate in the regulation of these virulence factors. PMID:25999924

Molecular modeling of Gram-positive bacteria peptidoglycan layer, selected glycopeptide antibiotics and vancomycin derivatives modified with sugar moieties.

PubMed

Ślusarz, Rafał; Szulc, Monika; Madaj, Janusz

2014-05-07

Proper understanding of the mechanisms of binding to Gram-positive bacteria cell wall layers-especially to the peptidoglycan (PG) layer, seems to be crucial for proper development of new drug candidates which are effective against these bacteria. In this work we have constructed two different models of the Gram-positive bacteria PG layer: the layered and the scaffold models. PG conformational changes during geometry optimization, models relaxation, and molecular dynamics were described and discussed. We have found that the border surface of both PG layer models differs from the surface located away from the edge of models and the chains formed by disaccharide units prefer helix-like conformation. This curling of PG chains significantly affects the shape of antibiotic-accessible surface and the process is thus crucial for new drug development. Glycopeptide antibiotics effective against Gram-positive bacteria, such as vancomycin and its semisynthetic derivatives-oritavancin and telavancin, bind to d-alanyl-d-alanine stem termini on the peptidoglycan precursors of the cell wall. This binding inhibits cross-linking between the peptides and subsequently prevents cell wall synthesis. In this study some of the aspects of conformational freedom of vancomycin and restrictions from the modifications of vancomycin structure introduced into oritavancin and telavancin and five other vancomycin derivatives (with addition of 2-acetamido-2-deoxy-β-d-galactopyranosylamine, 2-acetamido-2-deoxy-β-d-glucopyranosylamine, 1-amine-1-deoxy-d-glucitol, 2-amino-2-deoxy-d-galactitol, or 2-amino-2-deoxy-d-glucitol to the C-terminal amino acid group in the vancomycin) are presented and discussed. The resulting molecular dynamics trajectories, root mean square deviation changes of aglycon and saccharide moieties as well as a comparative study of possible interactions with cyclic and chain forms of modified groups have been carried out, measured, and analyzed. Energetically advantageous conformations show close similarity to the structures known from the experimental data, but the diversity of others suggest very high conformational freedom of all modeled antibiotics and vancomycin derivatives. Alditol derivatives move closer to the peptidoglycan chain more easily but they also form intramolecular interactions more frequently than their homologous cyclic forms. One of the proposed derivatives seems to be a promising agent which is efficient in treatment of infections caused by Gram-positive bacteria. Copyright © 2014 Elsevier Ltd. All rights reserved.

Nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus treated with linezolid or vancomycin: A secondary economic analysis of resource use from a Spanish perspective.

PubMed

Rello, J; Nieto, M; Solé-Violán, J; Wan, Y; Gao, X; Solem, C T; De Salas-Cansado, M; Mesa, F; Charbonneau, C; Chastre, J

2016-11-01

Adopting a unique Spanish perspective, this study aims to assess healthcare resource utilization (HCRU) and the costs of treating nosocomial pneumonia (NP) produced by methicillin-resistant Staphylococcus aureus (MRSA) in hospitalized adults using linezolid or vancomycin. An evaluation is also made of the renal failure rate and related economic outcomes between study groups. An economic post hoc evaluation of a randomized, double-blind, multicenter phase 4 study was carried out. Nosocomial pneumonia due to MRSA in hospitalized adults. The modified intent to treat (mITT) population comprised 224 linezolid- and 224 vancomycin-treated patients. Costs and HCRU were evaluated between patients administered either linezolid or vancomycin, and between patients who developed renal failure and those who did not. Analysis of HCRU outcomes and costs. Total costs were similar between the linezolid- (€17,782±€9,615) and vancomycin-treated patients (€17,423±€9,460) (P=.69). The renal failure rate was significantly lower in the linezolid-treated patients (4% vs. 15%; P<.001). The total costs tended to be higher in patients who developed renal failure (€19,626±€10,840 vs. €17,388±€9,369; P=.14). Among the patients who developed renal failure, HCRU (days on mechanical ventilation: 13.2±10.7 vs. 7.6±3.6 days; P=.21; ICU stay: 14.4±10.5 vs. 9.9±6.6 days; P=.30; hospital stay: 19.5±9.5 vs. 16.1±11.0 days; P=.26) and cost (€17,219±€8,792 vs. €20,263±€11,350; P=.51) tended to be lower in the linezolid- vs. vancomycin-treated patients. There were no statistically significant differences in costs per patient-day between cohorts after correcting for mortality (€1000 vs. €1,010; P=.98). From a Spanish perspective, there were no statistically significant differences in total costs between the linezolid and vancomycin pneumonia cohorts. The drug cost corresponding to linezolid was partially offset by fewer renal failure adverse events. Copyright © 2016 Elsevier España, S.L.U. y SEMICYUC. All rights reserved.

Evaluating the Effect of a Web-Based E-Learning Tool for Health Professional Education on Clinical Vancomycin Use: Comparative Study.

PubMed

Bond, Stuart Evan; Crowther, Shelley P; Adhikari, Suman; Chubaty, Adriana J; Yu, Ping; Borchard, Jay P; Boutlis, Craig Steven; Yeo, Wilfred Winston; Miyakis, Spiros

2018-02-26

Internet-based learning for health professional education is increasing. It offers advantages over traditional learning approaches, as it enables learning to be completed at a time convenient to the user and improves access where facilities are geographically disparate. We developed and implemented the Vancomycin Interactive (VI) e-learning tool to improve knowledge on the clinical use of the antibiotic vancomycin, which is commonly used for treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA). The aims of this study were to evaluate the effect of the VI e-learning tool on (1) survey knowledge scores and (2) clinical use of vancomycin among health professionals. We conducted a comparative pre-post intervention study across the 14 hospitals of two health districts in New South Wales, Australia. A knowledge survey was completed by nurses, doctors, and pharmacists before and after release of a Web-based e-learning tool. Survey scores were compared with those obtained following traditional education in the form of an email intervention. Survey questions related to dosing, administration, and monitoring of vancomycin. Outcome measures were survey knowledge scores among the three health professional groups, vancomycin plasma trough levels, and vancomycin approvals recorded on a computerized clinical decision support system. Survey response rates were low at 26.87% (577/2147) preintervention and 8.24% (177/2147) postintervention. The VI was associated with an increase in knowledge scores (maximum score=5) among nurses (median 2, IQR 1-2 to median 2, IQR 1-3; P<.001), but not among other professional groups. The comparator email intervention was associated with an increase in knowledge scores among doctors (median 3, IQR 2-4 to median 4, IQR 2-4; P=.04). Participants who referred to Web-based resources while completing the e-learning tool achieved higher overall scores than those who did not (P<.001). The e-learning tool was not shown to be significantly more effective than the comparator email in the clinical use of vancomycin, as measured by plasma levels within the therapeutic range. The e-learning tool was associated with improved knowledge scores among nurses, whereas the comparator email was associated with improved scores among doctors. This implies that different strategies may be required for optimizing the effectiveness of education among different health professional groups. Low survey response rates limited conclusions regarding the tool's effectiveness. Improvements to design and evaluation methodology may increase the likelihood of a demonstrable effect from e-learning tools in the future. ©Stuart Evan Bond, Shelley P Crowther, Suman Adhikari, Adriana J Chubaty, Ping Yu, Jay P Borchard, Craig Steven Boutlis, Wilfred Winston Yeo, Spiros Miyakis. Originally published in JMIR Medical Education (http://mededu.jmir.org), 26.02.2018.

Assessment by Time-Kill Methodology of the Synergistic Effects of Oritavancin in Combination with Other Antimicrobial Agents against Staphylococcus aureus▿

PubMed Central

Belley, Adam; Neesham-Grenon, Eve; Arhin, Francis F.; McKay, Geoffrey A.; Parr, Thomas R.; Moeck, Gregory

2008-01-01

Oritavancin is a semisynthetic lipoglycopeptide in clinical development for serious gram-positive infections. This study describes the synergistic activity of oritavancin in combination with gentamicin, linezolid, moxifloxacin, or rifampin in time-kill studies against methicillin-susceptible, vancomycin-intermediate, and vancomycin-resistant Staphylococcus aureus. PMID:18644953

Suppression by Saccharomyces boulardii of toxigenic Clostridium difficile overgrowth after vancomycin treatment in hamsters.

PubMed Central

Elmer, G W; McFarland, L V

1987-01-01

Saccharomyces boulardii prevented the development of high counts of Clostridium difficile, high titers of toxin B, and positive latex agglutination tests after cessation of vancomycin treatment for hamsters. The protocol used was designed to stimulate relapse of human C. difficile-associated colitis. S. boulardii was protective in this model. PMID:3566236

Molecular characterization of vancomycin-resistant Enterococcus faecium isolates from Bermuda

PubMed Central

Akpaka, Patrick Eberechi; Kissoon, Shivnarine; Wilson, Clyde; Jayaratne, Padman; Smith, Ashley; Golding, George R.

2017-01-01

Molecular characteristics of vancomycin resistant enterococci isolates from Bermuda Island is currently unknown. This study was conducted to investigate phenotypic and genotypic characteristics of VRE isolates from Bermuda Island using the chromogenic agar, E-tests, polymerase chain reaction (PCR), pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). Eighteen E. faecium isolates were completely analyzed and were all resistant to vancomycin, susceptible to linezolid and quinupristin/dalfopristin, positive for vanA and esp genes. The MLST analysis confirmed most isolates were of the sequence types linked to clonal complex 17 (CC17) that is widely associated with outbreaks in hospitals. Infection control measures, antibiotic stewardship, and surveillance activities will continue to be a priority in hospital on the Island. PMID:28267763

Molecular characterization of vancomycin-resistant Enterococcus faecium isolates from Bermuda.

PubMed

Akpaka, Patrick Eberechi; Kissoon, Shivnarine; Wilson, Clyde; Jayaratne, Padman; Smith, Ashley; Golding, George R

2017-01-01

Molecular characteristics of vancomycin resistant enterococci isolates from Bermuda Island is currently unknown. This study was conducted to investigate phenotypic and genotypic characteristics of VRE isolates from Bermuda Island using the chromogenic agar, E-tests, polymerase chain reaction (PCR), pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). Eighteen E. faecium isolates were completely analyzed and were all resistant to vancomycin, susceptible to linezolid and quinupristin/dalfopristin, positive for vanA and esp genes. The MLST analysis confirmed most isolates were of the sequence types linked to clonal complex 17 (CC17) that is widely associated with outbreaks in hospitals. Infection control measures, antibiotic stewardship, and surveillance activities will continue to be a priority in hospital on the Island.

ANTI-ADHESIVE AND ANTI-BIOFILM ACTIVITIES IN VITRO OF LINEZOLID, VANCOMYCIN, TIGECYCLINE AND DAPTOMYCIN AGAINST STAPHYLOCOCCUS HAEMOLYTICUS.

PubMed

Juda, Marek; Helon, Pawel; Malm, Anna

2016-11-01

Biofilm may be formed on wide variety of surfaces, including indwelling medical devices, leading to several infectious diseases, e.g., bacteremia and sepsis. The most,important pathogens related with infections associated with medical devices are coagulase-negative staphylococci, including Staphylococcus haeinolyticus - bacterial species which express quite often the multidrug resistance. The four clinical multiresistant and methicillin-resistant S. haenzolyticus were included in the present study. The evaluation of drug susceptibility was performed by using disc-diffusion method and broth microdilution method according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines. The biofilm formation on the Nelaton catheter and the effect of linezolid, vancomycin, tigecycline and daptomycin on the biofilm formation and disruption of mature structure was based on the method with TTC (2,3,5-triphenyltetrazolium chloride). The adhesion process of S. haenzolyticus to the Nelaton catheter was inhibited by antibiotics, as follows: line-zolid at concentration 0.25-0.5 x MIC, vancomycin - concentration 0.5 x MIC, tigecycline - concentration 0.25-4 x MIC and daptomycin - concentration 0.06-1 x MIC, depending on the isolate. Linezolid inhibited the biofilm formation at concentration between 0.5-1 x MIC, vancomycin - 1-2 x MIC, tigecycline - 0.5-4 x MIC and daptomycin - 0.06-2 x MIC. The concentration of linezolid eradicating the mature biofilm was found to be 1-2 x MIC, vancomycin - 2-8 x MIC, tigecycline - 2-4 x MIC and daptomycin - 0.06-2 x MIC. The most active antibiotic against S. haentolyticus biofilm formation and disruption of mature structure seems to be daptomycin.

No infections in 1300 anterior cruciate ligament reconstructions with vancomycin pre-soaking of hamstring grafts.

PubMed

Phegan, Michael; Grayson, Jane E; Vertullo, Christopher J

2016-09-01

To investigate the pre-soaking of hamstring grafts in topical vancomycin, in addition to IV prophylaxis, during anterior cruciate ligament (ACL) reconstruction to reduce the incidence of post-operative infection, and to describe an evidence-based diagnostic and treatment algorithm to facilitate early diagnosis and appropriate management of possible knee sepsis post-operatively after ACL reconstruction. This study is a controlled observational series comprising of 1585 individuals who underwent ACL reconstruction over a 13-year period. All surgeries were performed by a single surgeon at the same hospital. Group 1 consisted of 285 patients who received pre-operative IV antibiotics without topical graft pre-soaking. Group 2 consisted of 1300 individuals who received IV antibiotics and graft pre-soaking in a vancomycin solution of 5 mg/mL. In group 1, a total of four patients suffered a post-operative joint infection (1.4 %). Three out of the four were culture positive for Staphylococcus species. The fourth was culture negative but was managed as an acute infection. Group 2 suffered no post-operative infections (0 %). Statistical analysis of the vancomycin pre-soak with IV antibiotics group, compared with IV antibiotics-alone group, revealed a significantly reduced post-operative infection rate using a Fisher's exact test (P = 0.0011) and Chi-square test with Yates' correction (P = 0.0003). Pre-soaking of hamstrings grafts with topical vancomycin reduced the rate of post-operative infection when compared to IV antibiotics alone. This technique should be utilised by surgeons to reduce the overall incidence of knee sepsis post-ACL reconstruction. III.

Prevalence of Diverse Clones of Vancomycin-Resistant Enterococcus faecium ST78 in a Chinese Hospital.

PubMed

Yang, Jiyong; Jiang, Yufeng; Guo, Ling; Ye, LIyan; Ma, Yanning; Luo, Yanping

2016-06-01

Vancomycin-resistant Enterococcus (VRE) has been identified in China. However, little is known about the spread of VRE isolates. The genetic relatedness of vancomycin-resistant Enterococcus faecium (VREfm) isolates was analyzed by pulsed-field gel electrophoresis (PFGE), their antimicrobial susceptibilities were analyzed by E-test and the VITEK 2 AST-GP67 test Kit, and their sequence types (STs) were investigated by multilocus sequence typing (MLST). S1-PFGE was used for plasmid profiling, and PCR and subsequent sequencing were performed to identify the virulence genes. A total of 96 nonduplicated VREfm isolates were obtained and categorized into 38 PFGE types (type 1-38). The predominant MLST type was ST78, while ST17, ST341, and ST342 were also sporadically identified. All types of clinical VREfm strains harbored the vanA gene; however, they carried plasmids of different sizes. While 92.1%, 71.1%, and 60.5% of VREfm strains carried hyl, scm, and ecbA genes, respectively, all of them were positive for esp, acm, sgrA, pilA, and pilB genes. Clonal VREfm spread was observed, and nonplasmid-mediated horizontal transfer of vancomycin-resistant gene might have conveyed resistance to some vancomycin-susceptible E. faecium strains. E. faecium ST78 carrying vanA gene was the most prevalent clone in this study. The high prevalence of virulence genes, including esp, hyl, acm, scm, ecbA, sgrA, pilA, and pilB, confirmed their important roles in the emergence of VREfm ST78 in nosocomial infections.

Wounds, Functional Disability, and Indwelling Devices Are Associated With Cocolonization by Methicillin-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci in Southeast Michigan

PubMed Central

Wang, Linda; Zöllner, Sebastian; Foxman, Betsy; Mobley, Harry L. T.; Mody, Lona

2011-01-01

Background. Methicillin-resistant Staphylococcus aureus (MRSA) remains sensitive to vancomycin; when vancomycin-resistant S. aureus (VRSA) emerges, treatment becomes more complex. VRSA emergence is attributed to conjugative transfer of the vancomycin-resistance gene cluster from vancomycin-resistant enterococci (VRE) to MRSA. Because cocolonization with MRSA and VRE precedes VRSA development, this study investigates the epidemiology of cocolonization in skilled nursing facility (SNF) residents at high risk for MRSA or VRE colonization. Methods. A prospective observational study conducted at 15 SNFs in southeast Michigan. Overall, 178 residents (90 with indwelling urinary catheters and/or feeding tubes and 88 device-free) were cultured monthly for MRSA and VRE, and clinical data were recorded. Results. The incidence of MRSA/VRE cocolonization among residents with indwelling devices was 6.5 per 100 resident-months; 5.2 (95% confidence interval [CI]: 1.49–18.1) times that among those without devices. MRSA/VRE cocolonization in the device group occurred most frequently in wounds (4.1 per 100 resident-months). In a logistic regression analysis limited to residents with devices, functional disability (rate ratio [RR], 1.3; 95% CI: 1.1–1.4) and wound presence (RR, 3.4; 95% CI: 1.4–8.6) were independent risk factors of cocolonization. Conclusions. In a population of SNF residents, individuals with indwelling devices who also had functional disability or wounds were at greatest risk of MRSA/VRE cocolonization. These individuals should be routinely monitored for the presence of VRSA colonization. PMID:22080118

[Vancomycin-resistant enterococci - the nature of resistance and risk of transmission from animals to humans].

PubMed

Hermanovská, Lýdia; Bardoň, Jan; Čermák, Pavel

2016-06-01

Enterococci are part of the normal intestinal flora of humans and animals. Under certain circumstances, they are capable of extraintestinal conversion to opportunistic pathogens. They cause endogenous as well as exogenous community and nosocomial infections. The gastrointestinal tract of mammals provides them with favorable conditions for acquisition and spread of resistance genes, for example to vancomycin (van), from other symbiotic bacteria. Thus, vancomycin-resistant enterococci (VRE) become potential reservoirs and vectors of the van genes. Their occurrence in the population of the Czech Republic was first reported by Kolář et al. in 1997. Some variants of the vanA gene cluster carried on Tn1546 which encode resistance to vancomycin are identical in humans and in animals. It means that animals, especially cattle, poultry and pigs, could be an important reservoir of VRE for humans. Kolář and Bardoň detected VRE in animals in the Czech Republic for the first time in 2000. In Europe, the glycopeptide antibiotic avoparcin, used as a growth stimulator, is responsible for selection of VRE strains in animals. Strains of Enterococcus faecium from animals may offer genes of antimicrobial resistance to other enterococci or they can be directly dangerous to human. This is demonstrated by finding isolates of E. faecalis from human patients and from pigs having very similar profiles of resistance and virulence genes. The goal of the paper was to point out the similarity between isolates of human and animal strains of enterococci resistant to vancomycin, and the possibility of their bilateral transfer between humans and animals.

In Vitro Activities of Ramoplanin, Teicoplanin, Vancomycin, Linezolid, Bacitracin, and Four Other Antimicrobials against Intestinal Anaerobic Bacteria

PubMed Central

Citron, D. M.; Merriam, C. V.; Tyrrell, K. L.; Warren, Y. A.; Fernandez, H.; Goldstein, E. J. C.

2003-01-01

By using an agar dilution method, the in vitro activities of ramoplanin, teicoplanin, vancomycin, linezolid, and five other agents were determined against 300 gram-positive and 54 gram-negative strains of intestinal anaerobes. Ramoplanin was active at ≤2 μg/ml against 287 of 300 (95.7%) gram-positive organisms, including 18 strains of Clostridium difficile for which MICs of ramoplanin were 0.25 to 0.5 μg/ml; for 3 of these, linezolid MICs were 8 to 16 μg/ml. Nineteen Clostridium innocuum strains for which the vancomycin MIC at which 90% of strains were inhibited was 16 μg/ml were susceptible to ramoplanin at 0.06 to 0.25 μg/ml and to teicoplanin at 0.125 to 1.0 μg/ml. All strains of Eubacterium, Actinomyces, Propionibacterium, and Peptostreptococcus spp. were inhibited by ≤0.25 μg of ramoplanin per ml and ≤1 μg of vancomycin per ml. Ramoplanin was also active at ≤4 μg/ml against 15 of 22 of the Prevotella and Porphyromonas strains tested, but ramoplanin MICs for all 31 strains of the Bacteroides fragilis group, the Fusobacterium mortiferum-Fusobacterium varium group, and Veillonella spp. were ≥256 μg/ml. Ramoplanin displays excellent activity against C. difficile and other gram-positive enteric anaerobes, including vancomycin-resistant strains; however, it has poor activity against most gram-negative anaerobes and thus potentially has a lesser effect on the ecological balance of normal fecal flora. PMID:12821492

Vancomycin-modified implant surface inhibits biofilm formation and supports bone-healing in an infected osteotomy model in sheep: a proof-of-concept study.

PubMed

Stewart, Suzanne; Barr, Stephanie; Engiles, Julie; Hickok, Noreen J; Shapiro, Irving M; Richardson, Dean W; Parvizi, Javad; Schaer, Thomas P

2012-08-01

Implant-associated infections contribute to patient morbidity and health care costs. We hypothesized that surface modification of titanium fracture hardware with vancomycin would support bone-healing and prevent bacterial colonization of the implant in a large-animal model. A unilateral transverse mid-diaphyseal tibial osteotomy was performed and repaired with a titanium locking compression plate in nine sheep. Four control animals were treated with an unmodified plate and five experimental animals were treated with a vancomycin-modified plate. The osteotomy was inoculated with 2.5 × 106 colony-forming units of Staphylococcus aureus. The animals were killed at three months postoperatively, and implants were retrieved aseptically. Microbiologic and histologic analyses, scanning electron and confocal microscopy, and microcomputed tomography were performed. All animals completed the study. Compared with the treatment cohort, control animals exhibited protracted lameness in the operatively treated leg. Gross findings during necropsy were consistent with an infected osteotomy accompanied by a florid and lytic callus. Microcomputed tomography and histologic analysis of the tibiae further supported the presence of septic osteomyelitis in the control cohort. Thick biofilms were also evident, and bacterial cultures were positive for Staphylococcus aureus in three of four control animals. In contrast, animals treated with vancomycin-treated plates exhibited a healed osteotomy site with homogenous remodeling, there was no evidence of biofilm formation on the retrieved plate, and bacterial cultures from only one of five animals were positive for Staphylococcus aureus. Vancomycin-derivatized plate surfaces inhibited implant colonization with Staphylococcus aureus and supported bone-healing in an infected large-animal model.

[Individualized treatment strategies for Clostridium difficile infections].

PubMed

Solbach, P; Dersch, P; Bachmann, O

2017-07-01

Upon hospitalization, up to 15.5% of patients are already colonized with a toxigenic Clostridium difficile strain (TCD). The rate of asymptomatic colonization is 0-3% in healthy adults and up to 20-40% in hospitalized patients. The incidence and mortality of C. difficile infection (CDI) has significantly increased during recent years. Mortality lies between 3 and 14%. CDI is generally caused by intestinal dysbiosis, which can be triggered by various factors, including antibiotics or immune suppressants. If CDI occurs, ongoing antibiotic therapy should be discontinued. The choice of treatment is guided by the clinical situation: Mild courses of CDI should be treated with metronidazole. Oral vancomycin is suitable as a first-line therapy of mild CDI occurring during pregnancy and lactation, as well as in cases of intolerance or allergy to metronidazole. Severe courses should be treated with vancomycin. Recurrence should be treated with vancomycin or fidaxomicin. Multiple recurrences should be treated with vancomycin or fidaxomicin; if necessary, a vancomycin taper regimen may also be used. An alternative is fecal microbiota transplant (FMT), with healing rates of more than 80%. Bezlotoxumab is the first available monoclonal antibody which neutralizes the C. difficile toxin B, and in combination with an antibiotic significantly reduces the rate of a new C. difficile infection compared to placebo. A better definition of clinical and microbiota-associated risk factors and the ongoing implementation of molecular diagnostics are likely to lead to optimized identification of patients at risk, and an increasing individualization of prophylactic and therapeutic approaches.

Cost-effectiveness analysis on the use of fidaxomicin and vancomycin to treat Clostridium difficile infection in France.

PubMed

Watt, Maureen; Dinh, Aurélien; Le Monnier, Alban; Tilleul, Patrick

2017-07-01

Fidaxomicin is a macrocyclic antibiotic with proven efficacy against Clostridium difficile infection (CDI) in adults. It was licensed in France in 2012, but, due to higher acquisition costs compared with existing treatments, healthcare providers require information on its cost/benefit profile. To compare healthcare costs and health outcomes of fidaxomicin and vancomycin, as reference treatment for CDI. A Markov model was used to simulate the treatment pathway, over 1 year, of adult patients with CDI receiving fidaxomicin or vancomycin. Several patient sub-groups (severe CDI; recurrent CDI; concomitant antibiotics; cancer; renal failure; elderly) were evaluated. Cost-effectiveness was analyzed based on cure and recurrence rates derived from published randomized clinical trials comparing fidaxomicin and vancomycin, and costs calculated from the payer perspective using French hospitalization data and drug cost databases. Model outputs included costs in euros (reference year 2014) and health outcomes (recurrence; sustained cure rates). Alternative scenario and sensitivity analyses were performed using data from other clinical trials in CDI, including one conducted in real-life clinical practice in France. Drug acquisition costs were €1,692 higher in fidaxomicin-treated patients, but this was offset by the lower hospitalization costs with fidaxomicin, which were reduced by €1,722. The reduction in the cost of hospitalization was driven by the significantly lower number of recurrences in fidaxomicin-treated patients, offsetting the acquisition cost of fidaxomicin in all sub-groups except recurrent CDI and concomitant antibiotics. This study demonstrated that, despite higher acquisition costs, the lower recurrence rate with fidaxomicin resulted in cost savings or low incremental costs compared with vancomycin.

Evolution of Multidrug Resistance during Staphylococcus aureus Infection Involves Mutation of the Essential Two Component Regulator WalKR

PubMed Central

Howden, Benjamin P.; McEvoy, Christopher R. E.; Allen, David L.; Chua, Kyra; Gao, Wei; Harrison, Paul F.; Bell, Jan; Coombs, Geoffrey; Bennett-Wood, Vicki; Porter, Jessica L.; Robins-Browne, Roy; Davies, John K.; Seemann, Torsten; Stinear, Timothy P.

2011-01-01

Antimicrobial resistance in Staphylococcus aureus is a major public health threat, compounded by emergence of strains with resistance to vancomycin and daptomycin, both last line antimicrobials. Here we have performed high throughput DNA sequencing and comparative genomics for five clinical pairs of vancomycin-susceptible (VSSA) and vancomycin-intermediate ST239 S. aureus (VISA); each pair isolated before and after vancomycin treatment failure. These comparisons revealed a frequent pattern of mutation among the VISA strains within the essential walKR two-component regulatory locus involved in control of cell wall metabolism. We then conducted bi-directional allelic exchange experiments in our clinical VSSA and VISA strains and showed that single nucleotide substitutions within either walK or walR lead to co-resistance to vancomycin and daptomycin, and caused the typical cell wall thickening observed in resistant clinical isolates. Ion Torrent genome sequencing confirmed no additional regulatory mutations had been introduced into either the walR or walK VISA mutants during the allelic exchange process. However, two potential compensatory mutations were detected within putative transport genes for the walK mutant. The minimal genetic changes in either walK or walR also attenuated virulence, reduced biofilm formation, and led to consistent transcriptional changes that suggest an important role for this regulator in control of central metabolism. This study highlights the dramatic impacts of single mutations that arise during persistent S. aureus infections and demonstrates the role played by walKR to increase drug resistance, control metabolism and alter the virulence potential of this pathogen. PMID:22102812

High-throughput determination of vancomycin in human plasma by a cost-effective system of two-dimensional liquid chromatography.

PubMed

Sheng, Yanghao; Zhou, Boting

2017-05-26

Therapeutic drug monitoring (TDM) is one of the most important services of clinical laboratories. Two main techniques are commonly used: the immunoassay and chromatography method. We have developed a cost-effective system of two-dimensional liquid chromatography with ultraviolet detection (2D-LC-UV) for high-throughput determination of vancomycin in human plasma that combines the automation and low start-up costs of the immunoassay with the high selectivity and sensitivity of the liquid chromatography coupled with mass spectrometric detection without incurring their disadvantages, achieving high cost-effectiveness. This 2D-LC system offers a large volume injection to provide sufficient sensitivity and uses simulated gradient peak compression technology to control peak broadening and to improve peak shape. A middle column was added to reduce the analysis cycle time and make it suitable for high-throughput routine clinical assays. The analysis cycle time was 4min and the peak width was 0.8min. Compared with other chromatographic methods that have been developed, the analysis cycle time and peak width for vancomycin was reduced significantly. The lower limit of quantification was 0.20μg/mL for vancomycin, which is the same as certain LC-MS/MS methods that have been recently developed and validated. The method is rapid, automated, and low-cost and has high selectivity and sensitivity for the quantification of vancomycin in human plasma, thus making it well-suited for use in hospital clinical laboratories. Copyright © 2017 Elsevier B.V. All rights reserved.

Weissella confusa: a rare cause of vancomycin-resistant Gram-positive bacteraemia.

PubMed

Kumar, Anil; Augustine, Deepthi; Sudhindran, S; Kurian, Anu M; Dinesh, Kavitha R; Karim, Shamsul; Philip, Rosamma

2011-10-01

We describe a case of bacteraemia caused by Weissella confusa in a 48-year-old male who was operated on for adenocarcinoma of the gastro-oesophageal junction and maintained on total parenteral nutrition. Blood cultures were positive for a vancomycin-resistant streptococcus-like organism which was identified as W. confusa by 16S rRNA gene sequencing.

Heterogeneous resistance to vancomycin in Staphylococcus epidermidis, Staphylococcus haemolyticus and Staphylococcus warneri clinical strains: characterisation of glycopeptide susceptibility profiles and cell wall thickening.

PubMed

Nunes, Ana Paula Ferreira; Teixeira, Lúcia Martins; Iorio, Natália Lopes Pontes; Bastos, Carla Callegário Reis; de Sousa Fonseca, Leila; Souto-Padrón, Thaís; dos Santos, Kátia Regina Netto

2006-04-01

The population analysis profile (PAP) method as well as analysis of autolytic activity and cellular ultrastructure by transmission electron microscopy (TEM) were used to characterise Staphylococcus epidermidis, Staphylococcus haemolyticus and Staphylococcus warneri clinical strains with reduced susceptibility to glycopeptides. All strains showed heterogeneous profiles to vancomycin and teicoplanin by the PAP method. Subpopulations that grew in the presence of high concentrations of each drug were selected from the PAP as derivative strains. Their glycopeptide minimal inhibitory concentrations (MICs) were determined and subsequently all parental and derivative strains were grown in one-half of the MIC of vancomycin or teicoplanin. An increase in cell wall thickness of all derivative strains was seen by TEM, with statistically significant values (P<0.01) compared with their respective parental strains. In general, variable rates of autolysis among the strains were observed. Cell wall thickness is an important factor involved in glycopeptide resistance and, in association with PAP results, confirmed the Brazilian coagulase-negative staphylococci clinical isolates as being heteroresistant to glycopeptides. Detection of these heteroresistant organisms is important in order to achieve more judicious use of vancomycin and teicoplanin in hospitals.

A new risk factor for neonatal vancomycin-resistant Enterococcus colonisation: bacterial probiotics.

PubMed

Topcuoglu, Sevilay; Gursoy, Tugba; Ovalı, Fahri; Serce, Ozge; Karatekin, Guner

2015-08-01

Vancomycin-resistant Enterococcus (VRE) colonisation can be controlled with strict adherence to infection control measures. We describe a VRE outbreak coincident with bacterial probiotic trial. Relationship between probiotic and VRE colonisation, and other possible risk factors were investigated. Two hundred and ten infants with gestational age less than 32 weeks had been randomised for a trial with probiotic preparation containing Lactobacillus casei, Lactobacillus rhamnosus, Lactobacillus plantarum, Bifidobacterium lactis, fructooligosaccharide, galactooligosaccharide, colostrums and lactoferrin (NBL probiotic ATP®; Nobel, Istanbul, Turkey) between February 2012 and August 2013 when a VRE outbreak also took place. The existence of a relationship between this probiotic preparation and VRE colonisation was investigated. The begining and end of the outbreak were coincident with the beginning and end of the probiotic trial. Demographic and clinical features of neonates did not differ between VRE colonised (n = 94) and non-colonised infants (n = 116) except for vancomycin (p = 0.012) and probiotic (p < 0.001) use. Probiotic and vancomycin exposure were significant risk factors for VRE colonisation. The acquisition and transfer of resistance genes of bacteria may be mediated by probiotics. Therefore, the safety of probiotics is a concern and should be investigated further.

Enterocin A Mutants Identified by Saturation Mutagenesis Enhance Potency Towards Vancomycin-Resistant Enterococci

PubMed Central

McClintock, Maria K.; Kaznessis, Yiannis N.; Hackel, Benjamin J.

2016-01-01

Vancomycin-resistant Enterococci infections are a significant clinical problem. One proposed solution is to use probiotics, such as lactic acid bacteria, to produce antimicrobial peptides at the site of infection. Enterocin A, a class 2a bacteriocin, exhibits inhibitory activity against E. faecium and E. faecalis, which account for 86% of vancomycin-resistant Enterococci infections. In this study, we aimed to engineer enterocin A mutants with enhanced potency within a lactic acid bacterial production system. Peptide mutants resulting from saturation mutagenesis at sites A24 and T27 were efficiently screened in a 96-well plate assay for inhibition of pathogen growth. Several mutants exhibit increased potency relative to wild-type enterocin A in both liquid- and solid-medium growth assays. In particular, A24P and T27G exhibit enhanced inhibition of multiple strains of E. faecium and E. faecalis, including clinically isolated vancomycin-resistant strains. A24P and T27G enhance killing of E. faecium 8 by 13±3- and 18±4-fold, respectively. The engineered enterocin A/lactic acid bacteria systems offer significant potential to combat antibiotic-resistant infections. PMID:26191783

Enterocin A mutants identified by saturation mutagenesis enhance potency towards vancomycin-resistant Enterococci.

PubMed

McClintock, Maria K; Kaznessis, Yiannis N; Hackel, Benjamin J

2016-02-01

Vancomycin-resistant Enterococci infections are a significant clinical problem. One proposed solution is to use probiotics, such as lactic acid bacteria, to produce antimicrobial peptides at the site of infection. Enterocin A, a class 2a bacteriocin, exhibits inhibitory activity against E. faecium and E. faecalis, which account for 86% of vancomycin-resistant Enterococci infections. In this study, we aimed to engineer enterocin A mutants with enhanced potency within a lactic acid bacterial production system. Peptide mutants resulting from saturation mutagenesis at sites A24 and T27 were efficiently screened in a 96-well plate assay for inhibition of pathogen growth. Several mutants exhibit increased potency relative to wild-type enterocin A in both liquid- and solid-medium growth assays. In particular, A24P and T27G exhibit enhanced inhibition of multiple strains of E. faecium and E. faecalis, including clinically isolated vancomycin-resistant strains. A24P and T27G enhance killing of E. faecium 8 by 13 ± 3- and 18 ± 4-fold, respectively. The engineered enterocin A/lactic acid bacteria systems offer significant potential to combat antibiotic-resistant infections. © 2015 Wiley Periodicals, Inc.

Pre-emptive intrathecal vancomycin therapy reduces external ventricular drain infection: a single centre retrospective case-control study.

PubMed

Fu, Richard Z; Anwar, Durria R; Laban, James T; Maratos, Eleni C; Minhas, Pawanjit S; Martin, Andrew J

2017-02-01

External ventricular drain (EVD)-related infection is a significant source of morbidity in neurosurgical patients. Recently, there has been a drive to adopt new catheters with bactericidal properties to reduce infection rates. We propose that the use of standard catheters combined with pre-emptive intrathecal vancomycin (ITV) 10 mg daily provides an effective alternative. Retrospective study of all patients with EVDs between 2010 and 2012, comparing infection rates in those who did and did not receive pre-emptive ITV. All EVDs were of the standard silicon catheter type. CSF infection was defined, as per Centre for Disease Control (CDC) guidelines, as clinical suspicion ± positive CSF gram stain/culture or leucocytosis. Infection rates were compared using Pearson's chi-squared test. 262 EVDs were included in the study, of which 111 were managed with pre-emptive ITV. The infection rate was 2.7% in the vancomycin group and 11.9% in the control group (p<.01). There were no cases of vancomycin-resistant infection in either group. The use of pre-emptive ITV is associated with a significantly lower EVD infection rate. This compares favourably with those reported in the literature for bactericidal catheters.

Infrequent occurrence of vancomycin-resistant enterococci in poultry from Malaysian wet markets.

PubMed

Ong, C H S; Asaad, M; Lim, K C; Ngeow, Y F

2002-12-01

Fifty samples of chicken, duck and geese faeces were obtained from 13 wet markets in Kuala Lumpur to study the prevalence of vancomycin-resistant enterococci (VRE) among local market poultry. Biotyping of colonies grown on azide agar incubated at 45 degrees C yielded E. pseudoavium, E. faecalis, E. faecium and E. gallinarum from chicken faeces and E. malodoratus, E. faecalis, E. faecium, E. gallinarum, E. hirae/dispar, and E. durans from goose and duck faeces. On agar containing 6 mg/ l of vancomycin, one strain of E. flavescens was identified, giving a VRE detection rate of 2.0%. This isolate had a vancomycin M.I.C. of 8 mg/l as determined by the Etest, and the van C-3 gene that was identified by PCR followed by sequence analysis. The prevalence of VRE among poultry sold in local markets appears to be low, and may reflect the infrequent use of antimicrobials in our poultry farms. Nevertheless, the possibility of human acquisition of microbes via the food chain cautions against the use of antimicrobials in animal husbandry that may encourage the emergence and spread of multi-drug resistant organisms like the VRE among animal microbial flora.

[Heterogeneity of Brain Heart Infusion agar media (BHI): effects on the determination of the vancomycin and the teicoplanin minimal inhibitory concentrations (MIC) of Staphylococcus aureus strains].

PubMed

Martin, C

2004-10-01

The influence of BHI media commercially available on the results of glycopeptides MIC measured by E-test method was studied on 36 S. aureus isolates (21 MRSA and 15 MSSA). The MIC obtained with the vancomycin and the teicoplanin determined by the E-test method, on the ready prepared BHI plates (AES) and the plate prepared at the laboratory among the four dehydrated bases (AES, Biorad, Oxoid, and Becton Dickinson), were compared. The mean of the MIC showed variations from 3.14 (Biorad) to 5.25 mg/L (Oxoid) and from 3.33 (Biorad) to 9.75 mg/L (ready prepared AES) respectively for the vancomycin and for the teicoplanin. A variance analysis (Test de Friedman) showed a significant difference between the five media (p <0.001) with the two antibiotics. The comparison of media 2 by 2 allowed that all combinations excepted one (Biorad vs Becton with the vancomycin) were statistically different (p <0.001). The variation of the MIC observed in relation to the origin of the product of BHI media requires the inclusion of glycopeptide-intermediate S. aureus reference strains to control the prepared culture media.

Antibiotic treatment for Clostridium difficile-associated diarrhoea in adults.

PubMed

Nelson, Richard L; Suda, Katie J; Evans, Charlesnika T

2017-03-03

Clostridium difficile (C. difficile) is recognized as a frequent cause of antibiotic-associated diarrhoea and colitis. This review is an update of a previously published Cochrane review. The aim of this review is to investigate the efficacy and safety of antibiotic therapy for C. difficile-associated diarrhoea (CDAD), or C. difficile infection (CDI), being synonymous terms. We searched MEDLINE, EMBASE, CENTRAL and the Cochrane IBD Group Specialized Trials Register from inception to 26 January 2017. We also searched clinicaltrials.gov and clinicaltrialsregister.eu for ongoing trials. Only randomised controlled trials assessing antibiotic treatment for CDI were included in the review. Three authors independently assessed abstracts and full text articles for inclusion and extracted data. The risk of bias was independently rated by two authors. For dichotomous outcomes, we calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI). We pooled data using a fixed-effect model, except where significant heterogeneity was detected, at which time a random-effects model was used. The following outcomes were sought: sustained symptomatic cure (defined as initial symptomatic response and no recurrence of CDI), sustained bacteriologic cure, adverse reactions to the intervention, death and cost. Twenty-two studies (3215 participants) were included. The majority of studies enrolled patients with mild to moderate CDI who could tolerate oral antibiotics. Sixteen of the included studies excluded patients with severe CDI and few patients with severe CDI were included in the other six studies. Twelve different antibiotics were investigated: vancomycin, metronidazole, fusidic acid, nitazoxanide, teicoplanin, rifampin, rifaximin, bacitracin, cadazolid, LFF517, surotomycin and fidaxomicin. Most of the studies were active comparator studies comparing vancomycin with other antibiotics. One small study compared vancomycin to placebo. There were no other studies that compared antibiotic treatment to a placebo or a 'no treatment' control group. The risk of bias was rated as high for 17 of 22 included studies. Vancomycin was found to be more effective than metronidazole for achieving symptomatic cure. Seventy-two per cent (318/444) of metronidazole patients achieved symptomatic cure compared to 79% (339/428) of vancomycin patients (RR 0.90, 95% CI 0.84 to 0.97; moderate quality evidence). Fidaxomicin was found to be more effective than vancomycin for achieving symptomatic cure. Seventy-one per cent (407/572) of fidaxomicin patients achieved symptomatic cure compared to 61% (361/592) of vancomycin patients (RR 1.17, 95% CI 1.04 to 1.31; moderate quality evidence). Teicoplanin may be more effective than vancomycin for achieving a symptomatic cure. Eightly-seven per cent (48/55) of teicoplanin patients achieved symptomatic cure compared to 73% (40/55) of vancomycin patients (RR 1.21, 95% CI 1.00 to 1.46; very low quality evidence). For other comparisons including the one placebo-controlled study the quality of evidence was low or very low due to imprecision and in many cases high risk of bias because of attrition and lack of blinding. One hundred and forty deaths were reported in the studies, all of which were attributed by study authors to the co-morbidities of the participants that lead to acquiring CDI. Although many other adverse events were reported during therapy, these were attributed to the participants' co-morbidities. The only adverse events directly attributed to study medication were rare nausea and transient elevation of liver enzymes. Recent cost data (July 2016) for a 10 day course of treatment shows that metronidazole 500 mg is the least expensive antibiotic with a cost of USD 13 (Health Warehouse). Vancomycin 125 mg costs USD 1779 (Walgreens for 56 tablets) compared to fidaxomicin 200 mg at USD 3453.83 or more (Optimer Pharmaceuticals) and teicoplanin at approximately USD 83.67 (GBP 71.40, British National Formulary). No firm conclusions can be drawn regarding the efficacy of antibiotic treatment in severe CDI as most studies excluded patients with severe disease. The lack of any 'no treatment' control studies does not allow for any conclusions regarding the need for antibiotic treatment in patients with mild CDI beyond withdrawal of the initiating antibiotic. Nonetheless, moderate quality evidence suggests that vancomycin is superior to metronidazole and fidaxomicin is superior to vancomycin. The differences in effectiveness between these antibiotics were not too large and the advantage of metronidazole is its far lower cost compared to the other two antibiotics. The quality of evidence for teicoplanin is very low. Adequately powered studies are needed to determine if teicoplanin performs as well as the other antibiotics. A trial comparing the two cheapest antibiotics, metronidazole and teicoplanin, would be of interest.

Thieno[2,3-d]pyrimidinedione derivatives as antibacterial agents

PubMed Central

Dewal, Mahender B.; Wani, Amit S.; Vidaillac, Celine; Oupicky, David; Rybak, Michael J.

2012-01-01

Several thieno[2,3-d]pyrimidinediones have been synthesized and examined for antibacterial activity against a range of Gram-positive and Gram-negative pathogens. Two compounds displayed potent activity (2–16 mg/L) against multi-drug resistant Gram-positive organisms, including methicillin, vancomycin-intermediate, and vancomycin-resistant Staphylococcus aureus (MRSA, VISA, VRSA) and vancomycin-resistant enterococci (VRE). Only one of these agents possessed moderate activity (16–32 mg/L) against Gram-negative strains. An examination of the cytotoxicity of these agents revealed that they displayed low toxicity (40–50 mg/L) against mammalian cell and very low hemolytic activity (2–7%). Taken together, these studies suggest that thieno[2,3-d]pyrimidinediones are interesting scaffolds for the development of novel Gram-positive antibacterial agents. PMID:22405289

Intermediate-type vancomycin resistance (VISA) in genetically-distinct Staphylococcus aureus isolates is linked to specific, reversible metabolic alterations.

PubMed

Alexander, Elizabeth L; Gardete, Susana; Bar, Haim Y; Wells, Martin T; Tomasz, Alexander; Rhee, Kyu Y

2014-01-01

Intermediate (VISA-type) vancomycin resistance in Staphylococcus aureus has been associated with a range of physiologic and genetic alterations. Previous work described the emergence of VISA-type resistance in two clonally-distinct series of isolates. In both series (the first belonging to MRSA clone ST8-USA300, and the second to ST5-USA100), resistance was conferred by a single mutation in yvqF (a negative regulator of the vraSR two-component system associated with vancomycin resistance). In the USA300 series, resistance was reversed by a secondary mutation in vraSR. In this study, we combined systems-level metabolomic profiling with statistical modeling techniques to discover specific, reversible metabolic alterations associated with the VISA phenotype.

A review of telavancin activity in in vitro biofilms and animal models of biofilm-associated infections.

PubMed

Chan, Cynthia; Hardin, Thomas C; Smart, Jennifer I

2015-01-01

Tissue- and device-associated biofilm infections are important medical problems. These infections are difficult to treat due to a high-level of tolerance to antibiotics. Telavancin has been studied in several in vitro biofilm models and has demonstrated efficacy against staphylococcal and enterococcal-associated biofilm infections, including those formed by methicillin-resistant Staphylococcus aureus. Telavancin was effective against the difficult-to-treat vancomycin- and glycopeptide-intermediate strains of S. aureus in these models. Furthermore, the efficacy of telavancin has been evaluated in several biofilm-related in vivo models, including osteomyelitis, endocarditis and device-associated infections in rabbits. Overall, telavancin exhibited similar or greater efficacy than vancomycin and other comparators in these animal models and maintained activity against vancomycin-intermediate and daptomycin nonsusceptible strains of S. aureus.

Interference of the antimicrobial peptide lactoferricin B with the action of various antibiotics against Escherichia coli and Staphylococcus aureus.

PubMed

Vorland, L H; Osbakk, S A; Perstølen, T; Ulvatne, H; Rekdal, O; Svendsen, J S; Gutteberg, T J

1999-01-01

The antimicrobial peptide, lactoferricin, can be generated upon gastric pepsin cleavage of lactoferrin. We have examined the interaction of lactoferricin of bovine origin, Lf-cin B, with the antibiotics penicillin G, vancomycin, gentamicin, colistin, D-cycloserine and erythromycin against E. coli ATCC 25922 and Staphylococcus aureus ATCC 25923. We demonstrated synergism between Lf-cin B and erythromycin against E. coli, and partial synergism between Lf-cin B and penicillin G, vancomycin and gentamicin against E. coli. Only penicillin G acted in partial synergism with Lf-cin B against S. aureus. Lf-cin B antagonized vancomycin and gentamicin against S. aureus in low concentration. We conclude that Lf-cin B may facilitate the uptake of antibiotics across the cell envelope.

Regional Intraosseous Administration of Prophylactic Antibiotics is More Effective Than Systemic Administration in a Mouse Model of TKA.

PubMed

Young, Simon W; Roberts, Tim; Johnson, Sarah; Dalton, James P; Coleman, Brendan; Wiles, Siouxsie

2015-11-01

In human TKA studies, intraosseous regional administration (IORA) of prophylactic antibiotics achieves local tissue antibiotic concentrations 10 times greater than systemic administration. However, it is unclear if such high concentrations provide more effective prophylaxis. We asked: (1) What prophylaxis dosage and route (intravenous [IV] versus IORA of prophylactic antibiotics) produce less in vivo bacterial burden compared with no-antibiotic controls? (2) Compared with controls, what prophylaxis dosage and route yield fewer colony-forming units (CFUs) in euthanized animals in a model of TKA? (3) Is prophylactic IORA of antibiotics more effective than same-dose IV antibiotic administration in reducing CFUs? Mice (six to nine per group) were block randomized to one of six prophylaxis regimens: control, systemic cefazolin (C100IV), IORA of cefazolin (C100IORA), systemic vancomycin (V110IV), low-dose systemic vancomycin (V25IV), and low-dose IORA of vancomycin (V25IORA). Surgery involved placement of an intraarticular knee prosthesis, followed by an inoculum of bioluminescent Staphylococcus aureus strain Xen36. Biophotonic imaging assessed in vivo bacterial loads, and after 4 days bacterial load was quantified using culture-based techniques. Comparisons were made for each prophylactic regimen to controls and between same-dose IV and IORA of prophylactic antibiotic regimens. Mice treated with systemic high-dose vancomycin, IORA of vancomycin, or IORA of cefazolin had lower in vivo Staphylococcus aureus burdens (median area under curve, Control: 5.0 × 10(6); V110IV: 1.5 × 10(6), difference of medians 3.5 × 10(6), p = 0.003; V25IV: 1.94 × 10(6), difference 3.07 × 10(6), p = 0.49; V25IORA: 1.51 × 10(6), difference 3.5 × 10(6), p = 0.0011; C100IORA: 1.55 × 10(6), difference 3.46 × 10(6), p = 0.0016; C100IV: 2.35 × 10(6), difference 2.66 × 10(6), p = 0.23.) Similar findings were seen with culture-based techniques on recovered implants. IORA of prophylactic antibiotics was more effective than same-dose IV administration in reducing bacterial load on recovered implants (median CFUs < 7.0 × 10(0) vs 2.83 × 10(2), p = 0.0183). IORA of prophylactic cefazolin and vancomycin was more effective than the same dose of antibiotic given systemically. The effectiveness of vancomycin in particular was enhanced by IORA of prophylactic antibiotics despite using a lower dose. Our study supports previous studies of IORA of prophylactic antibiotics in humans and suggests this novel form of administration has the potential to enhance the effectiveness of prophylaxis in TKA. Because of concerns regarding antibiotic stewardship, IORA of prophylactic vancomycin may be more appropriately restricted to patients having TKA who are at greater risk of infection, and clinical trials are in progress.

Population Genomics of Reduced Vancomycin Susceptibility in Staphylococcus aureus

PubMed Central

Rishishwar, Lavanya; Kraft, Colleen S.

2016-01-01

ABSTRACT The increased prevalence of vancomycin-intermediate Staphylococcus aureus (VISA) is an emerging health care threat. Genome-based comparative methods hold great promise to uncover the genetic basis of the VISA phenotype, which remains obscure. S. aureus isolates were collected from a single individual that presented with recurrent staphylococcal bacteremia at three time points, and the isolates showed successively reduced levels of vancomycin susceptibility. A population genomic approach was taken to compare patient S. aureus isolates with decreasing vancomycin susceptibility across the three time points. To do this, patient isolates were sequenced to high coverage (~500×), and sequence reads were used to model site-specific allelic variation within and between isolate populations. Population genetic methods were then applied to evaluate the overall levels of variation across the three time points and to identify individual variants that show anomalous levels of allelic change between populations. A successive reduction in the overall levels of population genomic variation was observed across the three time points, consistent with a population bottleneck resulting from antibiotic treatment. Despite this overall reduction in variation, a number of individual mutations were swept to high frequency in the VISA population. These mutations were implicated as potentially involved in the VISA phenotype and interrogated with respect to their functional roles. This approach allowed us to identify a number of mutations previously implicated in VISA along with allelic changes within a novel class of genes, encoding LPXTG motif-containing cell-wall-anchoring proteins, which shed light on a novel mechanistic aspect of vancomycin resistance. IMPORTANCE The emergence and spread of antibiotic resistance among bacterial pathogens are two of the gravest threats to public health facing the world today. We report the development and application of a novel population genomic technique aimed at uncovering the evolutionary dynamics and genetic determinants of antibiotic resistance in Staphylococcus aureus. This method was applied to S. aureus cultures isolated from a single patient who showed decreased susceptibility to the vancomycin antibiotic over time. Our approach relies on the increased resolution afforded by next-generation genome-sequencing technology, and it allowed us to discover a number of S. aureus mutations, in both known and novel gene targets, which appear to have evolved under adaptive pressure to evade vancomycin mechanisms of action. The approach we lay out in this work can be applied to resistance to any number of antibiotics across numerous species of bacterial pathogens. PMID:27446992

High-Level Fosfomycin Resistance in Vancomycin-Resistant Enterococcus faecium

PubMed Central

Guo, Yan; Tomich, Adam D.; McElheny, Christi L.; Cooper, Vaughn S.; Tait-Kamradt, Amelia; Wang, Minggui; Hu, Fupin; Rice, Louis B.; Sluis-Cremer, Nicolas

2017-01-01

Of 890 vancomycin-resistant Enterococcus faecium isolates obtained by rectal screening from patients in Pittsburgh, Pennsylvania, USA, 4 had MICs >1,024 μg/mL for fosfomycin. These isolates had a Cys119Asp substitution in the active site of UDP-N-acetylglucosamine enolpyruvyl transferase. This substitution increased the fosfomycin MIC >4-fold and rendered this drug inactive in biochemical assays. PMID:29048285

Discontinuation of reflex testing of stool samples for vancomycin-resistant enterococci resulted in increased prevalence.

PubMed

Bodily, Mandy; McMullen, Kathleen M; Russo, Anthony J; Kittur, Nupur D; Hoppe-Bauer, Joan; Warren, David K

2013-08-01

Discontinuation of reflex testing of stool submitted for Clostridium difficile testing for vancomycin-resistant enterococci (VRE) led to an increase in the number of patients with healthcare-associated VRE bacteremia and bacteriuria (0.21 vs 0.36 cases per 1,000 patient-days; P<.01). Cost-benefit analysis showed reflex screening and isolation of VRE reduced hospital costs.

Linezolid: a pharmacoeconomic review of its use in serious Gram-positive infections.

PubMed

Plosker, Greg L; Figgitt, David P

2005-01-01

Linezolid (Zyvox), the first available oxazolidinone antibacterial agent, has good activity against Gram-positive pathogens, including multidrug-resistant organisms such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium. Randomised multicentre trials in patients with various types of serious Gram-positive infections showed that clinical cure rates with linezolid were similar to those with vancomycin or teicoplanin. In some subgroup analyses, which must be interpreted with a degree of caution, clinical advantages were noted for linezolid (e.g. versus vancomycin in confirmed MRSA nosocomial pneumonia and MRSA-complicated skin and soft tissue infections). Although generally well tolerated, gastrointestinal adverse effects are relatively common with linezolid and it has been associated with thrombocytopenia and myelosuppression. The oral bioavailability of linezolid is approximately 100%, thus allowing sequential intravenous-to-oral administration without changing the drug or dosage regimen. Healthcare resource use data from various countries indicate that this practical advantage translates into at least a trend towards reduced length of hospital stay compared with vancomycin, which may offset its several-fold higher acquisition cost. Modelled analyses from the US, despite some limitations, indicate that, compared with vancomycin, linezolid is associated with lower total hospitalisation costs for the treatment of patients with cellulitis and has a favourable incremental cost-effectiveness ratio of approximately US30,000 dollars per QALY gained (2001 value) for patients with ventilator-associated pneumonia. Broadly similar results have also been reported in modelled analyses from other countries. In conclusion, for patients with serious Gram-positive infections, including those caused by suspected or proven multidrug-resistant pathogens such as MRSA, linezolid is an effective and generally well tolerated therapeutic option. Linezolid is currently the only antibacterial agent with good activity against MRSA that can be administered orally (as well as intravenously). It may be particularly useful as an alternative to vancomycin in patients who have impaired renal function, poor or no intravenous access, require outpatient therapy, or who have been unable to tolerate glycopeptides. Healthcare resource use studies and pharmacoeconomic analyses generally support the use of linezolid in some subgroups of patients, although results should be interpreted with due consideration of the study limitations.

Molecular Characterization of Virulence Genes in Vancomycin-Resistant and Vancomycin-Sensitive Enterococci

PubMed Central

Biswas, Priyanka Paul; Dey, Sangeeta; Sen, Aninda; Adhikari, Luna

2016-01-01

Background: The aim of this study was to find out the correlation between presence of virulence (gelatinase [gel E], enterococcal surface protein [esp], cytolysin A [cyl A], hyaluronidase [hyl], and aggregation substance [asa1]) and vancomycin-resistant genes (van A and van B) in enterococci, with their phenotypic expression. Materials and Methods: A total of 500 isolates (250 each clinical and fecal) were processed. Enterococci were isolated from various clinical samples and from fecal specimens of colonized patients. Various virulence determinants namely asa1, esp, hyl, gel E, and cyl were detected by phenotypic methods. Minimum inhibitory concentration (MIC) of vancomycin was determined by agar dilution method. Multiplex polymerase chain reaction (PCR) was used to detect the presence of virulence and van genes. Results: Out of all the samples processed, 12.0% (60/500) isolates carried van A or van B genes as confirmed by MIC test and PCR methods. Genes responsible for virulence were detected by multiplex PCR and at least one of the five was detected in all the clinical vancomycin-resistant enterococci (VRE) and vancomycin-sensitive enterococci (VSE). gel E, esp, and hyl genes were found to be significantly higher in clinical VRE. Of the fecal isolates, presence of gel E, esp, and asa1 was significantly higher in VRE as compared to VSE. The presence of hyl gene in the clinical VRE was found to be statistically significant (P = 0.043) as against the fecal VRE. Correlation between the presence of virulence genes and their expression as detected by phenotypic tests showed that while biofilm production was seen in 61.1% (22/36) of clinical VRE, the corresponding genes, i.e., asa1 and esp were detected in 30.5% (11/36) and 27.8% (10/36) of strains only. Conclusion: Enterococcus faecium isolates were found to carry esp gene, a phenomenon that has been described previously only for Enterococcus faecalis, but we were unable to correlate the presence of esp with their capacity to form biofilms. PMID:27013840

Vancomycin tolerance in enterococci.

PubMed

Saribas, Suat; Bagdatli, Yasar

2004-11-01

Tolerance can be defined as the ability of bacteria to grow in the presence of high concentrations of bactericide antimicrobics, so that the killing action of the drug is avoided but the minimal inhibitory concentration (MIC) remains the same. We investigated vancomycin tolerance in the Enterococcus faecium and Enterococcus faecalis strains isolated from different clinical specimens. Vancomycin was obtained from Sigma Chemical Co. We studied 100 enterococci strains. Fifty-six and 44 of Enterococcus strains were idendified as E. feacalis and E. faecium, respectively. To determine MICs and minimal bactericidal concentration (MBC), we inoculated strains from an overnight agar culture to Muller-Hinton broth and incubated them for 4-6 h at 37 degrees C with shaking to obtain a logarithmic phase culture. The inoculum was controlled by performing a colony count for each test. We determined MBC values and MBC/MIC ratios to study tolerance to vancomycin. Vancomycin tolerance was defined as a high MBC value and an MBC/MIC ratio > or =32. Fifty-six and 44 of the Enterococcus strains were identified as E. faecium and E. faecalis, respectively. Thirty-one E. faecium and 48 E. faecalis were found to be susceptible to vancomycin and these susceptible strains were included in this study. The MICs of susceptible strains ranged from < or =1 to 4 mg/l, the MBCs were > or =512 mg/l. Tolerance was detected in all E. faecalis and E. faecium strains. The standard E. faecalis 21913 strain also exhibited tolerance according to the high MBC value and the MBC/MIC ratio. We defined the tolerant strains as having no bactericidal effect and MBC/MIC > or =32. We found that a 100% tolerance was present in susceptible strains. One of the hypotheses for tolerance is that tolerant cells fail to mobilize or create the autolysins needed for enlargement and division. Our data suggests that tolerance may compromise glycopeptide therapy of serious enterococci infections. To add an aminoglycoside to the glycopeptide therapy unless MBCs are unavailable can be useful in the effective treatment of serious Enterococcus infections.

Dispersion of the Vancomycin Resistance Genes vanA and vanC of Enterococcus Isolated from Nile Tilapia on Retail Sale: A Public Health Hazard.

PubMed

Osman, Kamelia M; Ali, Mohamed N; Radwan, Ismail; ElHofy, Fatma; Abed, Ahmed H; Orabi, Ahmed; Fawzy, Nehal M

2016-01-01

Although normally regarded harmless commensals, enterococci may cause a range of different infections in humans, including urinary tract infections, sepsis, and endocarditis. The acquisition of vancomycin resistance by enterococci (VRE) has seriously affected the treatment and infection control of these organisms. VRE are frequently resistant to all antibiotics that are effective treatment for vancomycin-susceptible enterococci, which leaves clinicians treating VRE infections with limited therapeutic options. With VRE emerging as a global threat to public health, we aimed to isolate, identify enterococci species from tilapia and their resistance to van-mediated glycopeptide (vanA and vanC) as well as the presence of enterococcal surface protein (esp) using conventional and molecular methods. The cultural, biochemical (Vitek 2 system) and polymerase chain reaction results revealed eight Enterococcus isolates from the 80 fish samples (10%) to be further identified as E. faecalis (6/8, 75%) and E gallinarum (2/8, 25%). Intraperitoneal injection of healthy Nile tilapia with the eight Enterococcus isolates caused significant morbidity (70%) within 3 days and 100% mortality at 6 days post-injection with general signs of septicemia. All of the eight Enterococcus isolates were found to be resistant to tetracycline. The 6/6 E. faecalis isolates were susceptible for penicillin, nitrofurantoin, gentamicin, and streptomycin. On the other hand 5/6 were susceptible for ampicillin, vancomycin, chloramphenicol, and ciprofloxacin. The two isolates of E. gallinarum were sensitive to rifampicin and ciprofloxacin and resistant to vancomycin, chloramphenicol, and erythromycin. Molecular characterization proved that they all presented the prototypic vanC element. On the whole, one of the two vancomycin resistance gene was present in 3/8 of the enterococci isolates, while the esp virulence gene was present in 1/8 of the enterococci isolates. The results in this study emphasize the potential role that aquatic environments are correlated to proximity to anthropogenic activities in determining the antimicrobial resistance patterns of Enterococcus spp. recovered from fish in the river Nile in Giza, Elmounib, Egypt as a continuation of our larger study on the reservoirs of antibiotic resistance in the environment.

Population pharmacokinetics of arbekacin, vancomycin, and panipenem in neonates.

PubMed

Kimura, Toshimi; Sunakawa, Keisuke; Matsuura, Nobuo; Kubo, Hiroaki; Shimada, Shigehiko; Yago, Kazuo

2004-04-01

Immature renal function in neonates requires antibiotic dosage adjustment. Population pharmacokinetic studies were performed to determine the optimal dosage regimens for three types of antibiotics: an aminoglycoside, arbekacin; a glycopeptide, vancomycin; and a carbapenem, panipenem. Eighty-three neonates received arbekacin (n = 41), vancomycin (n = 19), or panipenem (n = 23). The postconceptional ages (PCAs) were 24.1 to 48.4 weeks, and the body weights (BWs) ranged from 458 to 5,200 g. A one-compartment open model with first-order elimination was applied and evaluated with a nonlinear mixed-effect model for population pharmacokinetic analysis. In the fitting process, the fixed effects significantly related to clearance (CL) were PCA, postnatal age, gestational age, BW, and serum creatinine level; and the fixed effect significantly related to the volume of distribution (V) was BW. The final formulas for the population pharmacokinetic parameters are as follows: CL(arbekacin) = 0.0238 x BW/serum creatinine level for PCAs of <33 weeks and CL(arbekacin) = 0.0367 x BW/serum creatinine level for PCAs of > or = 33 weeks, V(arbekacin) = 0.54 liters/kg, CL(vancomycin) = 0.0250 x BW/serum creatinine level for PCAs of <34 weeks and CL(vancomycin) = 0.0323 x BW/serum creatinine level for PCAs of > or = 34 weeks, V(vancomycin) = 0.66 liters/kg, CL(panipenem) = 0.0832 for PCAs of <33 weeks and CL(panipenem) = 0.179 x BW for PCAs of > or = 33 weeks, and V(panipenem) = 0.53 liters/kg. When the CL of each drug was evaluated by the nonlinear mixed-effect model, we found that the mean CL for subjects with PCAs of <33 to 34 weeks was significantly smaller than those with PCAs of > or = 33 to 34 weeks, and CL showed an exponential increase with PCA. Many antibiotics are excreted by glomerular filtration, and maturation of glomerular filtration is the most important factor for estimation of antibiotic clearance. Clinicians should consider PCA, serum creatinine level, BW, and chemical features when determining the initial antibiotic dosing regimen for neonates.

Identifying the Interaction of Vancomycin With Novel pH-Responsive Lipids as Antibacterial Biomaterials Via Accelerated Molecular Dynamics and Binding Free Energy Calculations.

PubMed

Ahmed, Shaimaa; Vepuri, Suresh B; Jadhav, Mahantesh; Kalhapure, Rahul S; Govender, Thirumala

2018-06-01

Nano-drug delivery systems have proven to be an efficient formulation tool to overcome the challenges with current antibiotics therapy and resistance. A series of pH-responsive lipid molecules were designed and synthesized for future liposomal formulation as a nano-drug delivery system for vancomycin at the infection site. The structures of these lipids differ from each other in respect of hydrocarbon tails: Lipid1, 2, 3 and 4 have stearic, oleic, linoleic, and linolenic acid hydrocarbon chains, respectively. The impact of variation in the hydrocarbon chain in the lipid structure on drug encapsulation and release profile, as well as mode of drug interaction, was investigated using molecular modeling analyses. A wide range of computational tools, including accelerated molecular dynamics, normal molecular dynamics, binding free energy calculations and principle component analysis, were applied to provide comprehensive insight into the interaction landscape between vancomycin and the designed lipid molecules. Interestingly, both MM-GBSA and MM-PBSA binding affinity calculations using normal molecular dynamics and accelerated molecular dynamics trajectories showed a very consistent trend, where the order of binding affinity towards vancomycin was lipid4 > lipid1 > lipid2 > lipid3. From both normal molecular dynamics and accelerated molecular dynamics, the interaction of lipid3 with vancomycin is demonstrated to be the weakest (∆G binding  = -2.17 and -11.57, for normal molecular dynamics and accelerated molecular dynamics, respectively) when compared to other complexes. We believe that the degree of unsaturation of the hydrocarbon chain in the lipid molecules may impact on the overall conformational behavior, interaction mode and encapsulation (wrapping) of the lipid molecules around the vancomycin molecule. This thorough computational analysis prior to the experimental investigation is a valuable approach to guide for predicting the encapsulation ability, drug release and further development of novel liposome-based pH-responsive nano-drug delivery system with refined structural and chemical features of potential lipid molecule for formulation development.

Comparative Pharmacodynamics of Telavancin and Vancomycin in the Neutropenic Murine Thigh and Lung Infection Models against Staphylococcus aureus

PubMed Central

Lepak, Alexander J.; Zhao, Miao

2017-01-01

ABSTRACT The pharmacodynamics of telavancin and vancomycin were compared using neutropenic murine thigh and lung infection models. Four Staphylococcus aureus strains were included. The telavancin MIC ranged from 0.06 to 0.25 mg/liter, and the vancomycin MIC ranged from 1 to 4 mg/liter. The plasma pharmacokinetics of escalating doses (1.25, 5, 20, and 80 mg/kg of body weight) of telavancin and vancomycin were linear over the dose range. Epithelial lining fluid (ELF) pharmacokinetics for each drug revealed that penetration into the ELF mirrored the percentage of the free fraction (the fraction not protein bound) in plasma for each drug. Telavancin (0.3125 to 80 mg/kg/6 h) and vancomycin (0.3125 to 1,280 mg/kg/6 h) were administered by the subcutaneous route in treatment studies. Dose-dependent bactericidal activity against all four strains was observed in both models. A sigmoid maximum-effect model was used to determine the area under the concentration-time curve (AUC)/MIC exposure associated with net stasis and 1-log10 kill relative to the burden at the start of therapy. The 24-h plasma free drug AUC (fAUC)/MIC values associated with stasis and 1-log kill were remarkably congruent. Net stasis for telavancin was noted at fAUC/MIC values of 83 and 40.4 in the thigh and lung, respectively, and 1-log kill was noted at fAUC/MIC values of 215 and 76.4, respectively. For vancomycin, the fAUC/MIC values for stasis were 77.9 and 45.3, respectively, and those for 1-log kill were 282 and 113, respectively. The 24-h ELF total drug AUC/MIC targets in the lung model were very similar to the 24-h plasma free drug AUC/MIC targets for each drug. Integration of human pharmacokinetic data for telavancin, the results of the MIC distribution studies, and the pharmacodynamic targets identified in this study suggests that the current dosing regimen of telavancin is optimized to obtain drug exposures sufficient to treat S. aureus infections. PMID:28416551

Cost-Effectiveness Comparison of Fidaxomicin and Vancomycin for Treatment of Clostridium difficile Infection: A Markov Model Based on Data from a South West Balkan Country in Socioeconomic Transition.

PubMed

Marković, Veroljub; Kostić, Marina; Iličković, Ivana; Janković, Slobodan M

2014-09-01

Recent studies have shown that fidaxomicin, a novel antibiotic, can reduce the rate of complications and mortality in patients with colitis induced by Clostridium difficile. Introduction of fidaxomicin in clinical practice is limited by its high costs. The purpose of this study was to estimate the cost effectiveness of using fidaxomicin versus vancomycin in patients with colitis induced by C. difficile who did not respond to oral metronidazole. We constructed a Markov model that was than simulated by Monte-Carlo simulation using 1000 virtual patients with colitis induced by C. difficile. The perspective in our model was institutional. The time horizon was 3 months. Values of transition probabilities and therapy outcomes were estimated from the available literature, the prices of health services were obtained from the Republic Institute for Health Insurance Tariff Book, and the price of fidaxomicin was derived from data gained from the drug manufacturer. The total costs of treating one statistical patient for 3 months with fidaxomicin were higher (48,106.19 ± 118.07 Republic of Serbia dinars [RSD]; 95% confidence interval 47,988.12-48,224.27) than the total costs of treating with vancomycin (25,872.85 ± 41.44 RSD; 95% confidence interval 25,831.41-25,914.29). Our results showed that the treatment of infections induced by C. difficile with fidaxomicin correlated with a lower rate of mortality and with a smaller number of colectomies. The incremental cost-effectiveness ratio of fidaxomicin versus vancomycin for colitis induced by C. difficile per saved life was estimated at 2.97 million RSD and for one avoided colectomy at 10.07 million RSD. Results of our model indicate that fidaxomicin is a cost-effective therapy compared with vancomycin in patients with colitis induced by C. difficile if the outcome is life-year saved. However, if the outcome is the number of avoided colectomies, then fidaxomycin is not a cost-effective option compared with vancomycin. Copyright © 2014 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

CAMERA2 - combination antibiotic therapy for methicillin-resistant Staphylococcus aureus infection: study protocol for a randomised controlled trial.

PubMed

Tong, Steven Y C; Nelson, Jane; Paterson, David L; Fowler, Vance G; Howden, Benjamin P; Cheng, Allen C; Chatfield, Mark; Lipman, Jeffrey; Van Hal, Sebastian; O'Sullivan, Matthew; Robinson, James O; Yahav, Dafna; Lye, David; Davis, Joshua S

2016-03-31

Methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia is a serious infection resulting in 20-50 % 90-day mortality. The limitations of vancomycin, the current standard therapy for MRSA, make treatment difficult. The only other approved drug for treatment of MRSA bacteraemia, daptomycin, has not been shown to be superior to vancomycin. Surprisingly, there has been consistent in-vitro and in-vivo laboratory data demonstrating synergy between vancomycin or daptomycin and an anti-staphylococcal β-lactam antibiotic. There is also growing clinical data to support such combinations, including a recent pilot randomised controlled trial (RCT) that demonstrated a trend towards a reduction in the duration of bacteraemia in patients treated with vancomycin plus flucloxacillin compared to vancomycin alone. Our aim is to determine whether the addition of an anti-staphylococcal penicillin to standard therapy results in improved clinical outcomes in MRSA bacteraemia. We will perform an open-label, parallel-group, randomised (1:1) controlled trial at 29 sites in Australia, New Zealand, Singapore, and Israel. Adults (aged 18 years or older) with MRSA grown from at least one blood culture and able to be randomised within 72 hours of the index blood culture collection will be eligible for inclusion. Participants will be randomised to vancomycin or daptomycin (standard therapy) given intravenously or to standard therapy plus 7 days of an anti-staphylococcal β-lactam (flucloxacillin, cloxacillin, or cefazolin). The primary endpoint will be a composite outcome at 90 days of (1) all-cause mortality, (2) persistent bacteraemia at day 5 or beyond, (3) microbiological relapse, or (4) microbiological treatment failure. The recruitment target of 440 patients is based on an expected failure rate for the primary outcome of 30 % in the control arm and the ability to detect a clinically meaningful absolute decrease of 12.5 %, with a two-sided alpha of 0.05, a power of 80 %, and assuming 10 % of patients will not be evaluable for the primary endpoint. Key potential advantages of adding anti-staphylococcal β-lactams to standard therapy for MRSA bacteraemia include their safety profile, low cost, and wide availability. ClinicalTrials.gov Identifier: NCT02365493 . Registered 24 February 2015.

Vancomycin-Associated Hemorrhagic Occlusive Retinal Vasculitis: Clinical Characteristics of 36 Eyes.

PubMed

Witkin, Andre J; Chang, David F; Jumper, J Michael; Charles, Steve; Eliott, Dean; Hoffman, Richard S; Mamalis, Nick; Miller, Kevin M; Wykoff, Charles C

2017-05-01

To expand understanding of presentation, diagnosis, and outcomes of hemorrhagic occlusive retinal vasculitis (HORV). Retrospective case series. Thirty-six eyes of 23 patients. The American Society of Cataract and Refractive Surgery (ASCRS) and the American Society of Retina Specialists (ASRS) formed a joint task force to define clinical characteristics of HORV and to study its prevalence, cause, treatment, and outcomes. An online registry was established on both societies' web sites. Surveys were e-mailed to members of both societies soliciting cases of suspected HORV. A literature search was performed to uncover additional cases. Historical data including intraoperative characteristics, images, treatment regimens, and visual and anatomic outcomes. Characteristic findings of HORV included unremarkable postoperative day 1 undilated examination, delayed-onset painless vision loss, mild anterior chamber and vitreous inflammation, sectoral retinal hemorrhages in areas of ischemia, and predilection for venules and peripheral involvement. Based on predetermined diagnostic criteria, 36 eyes of 23 patients were diagnosed with HORV. All eyes received intraocular vancomycin via intracameral bolus (33/36), via intravitreal injection (1/36), or through the irrigation bottle (2/36). Patients sought treatment with HORV 1 to 21 days after surgery or intravitreal injection. Visual results usually were poor: 22 of 36 eyes (61%) had 20/200 or worse visual acuity and 8 of 36 eyes (22%) had no light perception (NLP). Neovascular glaucoma developed in 20 of 36 eyes (56%). Seven eyes received additional intravitreal vancomycin after surgery; 5 of these 7 eyes had NLP visual acuity at the most recent examination. Three eyes received intravitreal corticosteroids and had final visual acuities of 20/40, 20/70, and hand movements. Hemorrhagic occlusive retinal vasculitis is a rare, potentially devastating condition that can develop after cataract surgery or intraocular injection. All cases in this series were associated with intraocular vancomycin. Disease course and findings suggest that HORV is caused by a delayed hypersensitivity reaction to vancomycin. Early treatment with corticosteroids likely is beneficial. Subsequently, anti-vascular endothelial growth factor injections and panretinal photocoagulation are important to prevent neovascular glaucoma, a common complication. Avoidance of additional intravitreal vancomycin is recommended if HORV is suspected. Published by Elsevier Inc.

Prospective Randomized Double-blinded Trial Comparing 2 Anti-MRSA Agents With Supplemental Coverage of Cefazolin Before Lower Extremity Revascularization

PubMed Central

Stone, Patrick A.; AbuRahma, Ali F.; Campbell, James R.; Hass, Stephen M.; Mousa, Albeir Y.; Nanjundappa, Aravinda; Srivastiva, Mohit; Modak, Asmita; Emmett, Mary

2015-01-01

Objective To compare with antibiotics with methicillin-resistant microbial coverage in a prospective fashion. Background Current antibiotic prophylaxis for vascular procedures includes a first generation cephalosporin. No changes in recommendations have occurred despite changes in reports of incidence of MRSA related surgical site infections. Does supplemental anti-MRSA prophylactic coverage provide a significant reduction in Gram-positive or MRSA infections? Methods Single center prospective double blinded randomized study of patients undergoing lower extremity vascular procedures from 2011 to 2014. One hundred seventy-eight (178) patients were evaluated at 90 days for surgical site infection. Infections were categorized as early infections less than 30 days of the index procedure and late after 90 days. Results Early vascular surgical site infection occurred in 7(8.24%) of patients in the Vancomycin arm, and 11 (11.83%) in the Daptomycin arm (P = 0.43). Gram-positive related infections and MRSA infections occurred in 1(1.18%)/0(0%) of Vancomycin patients and 9 (9.68%)/1 (1.08%) of Daptomycin patients, respectively (P < 0.02 and P = 1.00). Readmissions related to surgical site infections occurred in 4(4.71%) in the Vancomycin group and 11 (11.8%) in the Daptomycin group (P = 0.11). Patients undergoing operative exploration occurred in 5 (5.88%) in the Vancomycin group and 10 (10.75%) of the Daptomycin group (P = 0.17). Late infections were reported in 3 patients, 2 of which were in the combined Daptomycin group. Median hospital charges related to readmissions due to a surgical site infection was $50,823 in the combination Vancomycin arm and $110,920 in the combination Daptomycin group; however, no statistical significance was appreciated (P = 0.11). Conclusions Vancomycin supplemental prophylaxis seems to reduce the incidence of Gram-positive infection compared with adding supplemental Daptomycin prophylaxis. The Incidence of MRSA-related surgical site infections is low with the addition of either anti-MRSA agents compared with historical incidence of MRSA-related infection. PMID:26258318

Outcomes of Aminopenicillin Therapy for Vancomycin-Resistant Enterococcal Urinary Tract Infections.

PubMed

Cole, Kelli A; Kenney, Rachel M; Perri, Mary Beth; Dumkow, Lisa E; Samuel, Linoj P; Zervos, Marcus J; Davis, Susan L

2015-12-01

Vancomycin-resistant urinary tract infections are often challenging to treat. This retrospective cohort study compared outcomes between patients treated for vancomycin-resistant enterococcal urinary tract infection with an aminopenicillin and those treated with a non-β-lactam antibiotic. Inpatients treated with an enterococcus-active agent for their first symptomatic vancomycin-resistant enterococcal urinary tract infection between 1 January 2012 and 31 December 2013 were considered for inclusion. Patients with colonization, on hospice, or receiving comfort care only were excluded. The primary endpoint of clinical cure was defined as resolution of clinical symptoms, or symptom improvement to the extent that no additional antibacterial drug therapy was necessary, and lack of microbiologic persistence. Secondary endpoints of 30-day readmission or retreatment and 30-day all-cause mortality were also compared. A total of 316 urinary isolates were screened, and 61 patients with symptomatic urinary tract infection were included. Twenty (35%) of the 57 isolates tested were ampicillin susceptible. Thirty-one patients received an aminopenicillin, and 30 received a non-β-lactam. Rates of clinical cure for aminopenicillin versus non-β-lactam treatment were 26/31 (83.9%) and 22/30 (73.3%) (P = 0.315), respectively. Rates of 30-day readmission (6/31, or 19.4%, versus 9/30, or 30%, respectively; P = 0.334), 30-day retreatment (4/31, or 12.9%, versus 4/30, 13.3%, respectively; P = 0.960), and 30-day all-cause mortality (2/31, or 6.5%, versus 1/30, or 3.3%, respectively; P = 0.573) were also not significantly different between groups. Aminopenicillins may be a viable option for treating vancomycin-resistant urinary tract infection regardless of the organism's ampicillin susceptibility. Prospective validation with larger cohorts of patients should be considered. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

A comparison of the efficacy and safety of intravenous followed by oral delafloxacin with vancomycin plus aztreonam for the treatment of acute bacterial skin and skin structure infections: a phase 3, multinational, double-blind, randomized study.

PubMed

O'Riordan, William; McManus, Alison; Teras, Juri; Poromanski, Ivan; Cruz-Saldariagga, Maria; Quintas, Megan; Lawrence, Laura; Liang, ShuJui; Cammarata, Sue

2018-03-06

Delafloxacin is an IV/oral anionic fluoroquinolone with activity against Gram-positive (including MRSA), Gram-negative, atypical and anaerobic organisms. It is approved in the US for acute bacterial skin and skin structure infections caused by designated susceptible Gram-positive and Gram-negative organisms, and is in development for the treatment of community-acquired bacterial pneumonia. A multicenter, randomized, double-blind trial of 850 adults with ABSSSI compared delafloxacin 300 mg IV Q12h for 3 days with a switch to 450 mg oral delafloxacin, to vancomycin 15 mg/kg IV with aztreonam for 5-14 days. The primary endpoint was objective response (OR) at 48-72 hours. Investigator‑assessed response based on resolution of signs and symptoms at Follow up (FU [Day 14±1]), and Late Follow up (LFU [Day 21- 28]) were secondary endpoints. In the intent-to-treat analysis set, the OR was 83.7% in the delafloxacin arm and 80.6% in the comparator arm. Investigator-assessed success was similar at FU (87.2% versus 84.4%) and LFU (83.5% versus 82.2%). Delafloxacin was comparable to vancomycin + aztreonam in eradication of MRSA at 96.0% vs 97.0% at FU. Frequency of treatment-emergent adverse events (TEAEs) between the groups was similar. TEAEs leading to study drug discontinuation was higher in the vancomycin + aztreonam group (1.2% vs 2.4%). In ABSSSI patients, IV/oral delafloxacin monotherapy was noninferior to IV vancomycin + aztreonam combination therapy for both the OR and the investigator-assessed response at FU and LFU. Delafloxacin was well tolerated as monotherapy in treatment of ABSSSI.

Clostridium difficile Infection and Patient-Specific Antimicrobial Resistance Testing Reveals a High Metronidazole Resistance Rate.

PubMed

Barkin, Jodie A; Sussman, Daniel A; Fifadara, Nimita; Barkin, Jamie S

2017-04-01

Clostridium difficile (CD) infection (CDI) causes marked morbidity and mortality, accounting for large healthcare expenditures annually. Current CDI treatment guidelines focus on clinical markers of patient severity to determine the preferred antibiotic regimen of metronidazole versus vancomycin. The antimicrobial resistance patterns for patients with CD are currently unknown. The aim of this study was to define the antimicrobial resistance patterns for CD. This study included all patients with stools sent for CD testing to a private laboratory (DRG Laboratory, Alpharetta, Georgia) in a 6-month period from across the USA. Patient data was de-identified, with only age, gender, and zip-code available per laboratory protocol. All samples underwent PCR testing followed by hybridization for CD toxin regions A and B. Only patients with CD-positive PCR were analyzed. Antimicrobial resistance testing using stool genomic DNA evaluated presence of imidazole- and vancomycin-resistant genes using multiplex PCR gene detection. Of 2743, 288 (10.5%) stool samples were positive for CD. Six were excluded per protocol. Of 282, 193 (69.4%) were women, and average age was 49.4 ± 18.7 years. Of 282, 62 were PCR positive for toxins A and B, 160 for toxin A positive alone, and 60 for toxin B positive alone. Antimicrobial resistance testing revealed 134/282 (47.5%) patients resistant to imidazole, 17 (6.1%) resistant to vancomycin, and 9 (3.2%) resistant to imidazole and vancomycin. CD-positive patients with presence of imidazole-resistant genes from stool DNA extract was a common phenomenon, while vancomycin resistance was uncommon. Similar to treatment of other infections, antimicrobial resistance testing should play a role in CDI clinical decision-making algorithms to enable more expedited and cost-effective delivery of patient care.

Case of antibiotic-associated diarrhea caused by Staphylococcus aureus enterocolitis.

PubMed

Avery, Lisa M; Zempel, Matt; Weiss, Erich

2015-06-01

A case of Staphylococcus aureus enterocolitis (SEC) misdiagnosed as toxin-negative Clostridium difficile is reported. An 82-year-old white man weighing 50 kg (body mass index, 16.8 kg/m(2)) was transported from an assisted living facility to the emergency department with the chief complaints of weakness, nausea, and diarrhea for one week and one bright-red stool on the morning of admission. Before hospital admission, he was treated for a urinary tract infection with ciprofloxacin 500 mg twice daily for 10 days. Stool cultures were negative for C. difficile but positive for S. aureus. The antimicrobial stewardship pharmacist recommended treatment with vancomycin 125 mg orally every 6 hours for staphylococcal colitis. Oral vancomycin was discontinued after three doses on the morning of hospital day 8 after a gastroenterology consultation. Within 48 hours of the discontinuation of oral vancomycin, the patient had eight stools per day. Vancomycin was reinitiated and the patient's symptoms began to again improve. On hospital day 19, the patient was discharged with a prescription for 7 more days of therapy with vancomycin (to complete a 15-day course) and a diagnosis of toxin-negative C. difficile, despite having symptoms consistent with SEC and an enteric culture positive for S. aureus. An 82-year-old man was transferred from an assisted living facility to the hospital with profuse diarrhea and dehydration. Enteric cultures were positive for methicillin-resistant S. aureus with multiple negative C. difficile toxin B assays. Appropriate therapy was delayed and the patient potentially misdiagnosed with toxin-negative C. difficile when the clinical symptoms and diagnostic testing were consistent with SEC. Copyright © 2015 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Economic evaluation of fecal microbiota transplantation for the treatment of recurrent Clostridium difficile infection in Australia.

PubMed

Merlo, Gregory; Graves, Nicholas; Brain, David; Connelly, Luke B

2016-12-01

Clostridium difficile is the most common cause of hospital-acquired diarrhea in Australia. In 2013, a randomized controlled trial demonstrated the effectiveness of fecal microbiota transplantation (FMT) for the treatment of recurrent Clostridium difficile infection (CDI). The aim of this study is to evaluate the cost-effectiveness of fecal microbiota transplantation-via either nasoduodenal or colorectal delivery-compared with vancomycin for the treatment of recurrent CDI in Australia. A Markov model was developed to compare the cost-effectiveness of fecal microbiota transplantation compared with standard antibiotic therapy. A literature review of clinical evidence informed the structure of the model and the choice of parameter values. Clinical effectiveness was measured in terms of quality-adjusted life years. Uncertainty in the model was explored using probabilistic sensitivity analysis. Both nasoduodenal and colorectal FMT resulted in improved quality of life and reduced cost compared with vancomycin. The incremental effectiveness of either FMT delivery compared with vancomycin was 1.2 (95% CI: 0.1, 2.3) quality-adjusted life years, or 1.4 (95% CI: 0.4, 2.4) life years saved. Treatment with vancomycin resulted in an increased cost of AU$4094 (95% CI: AU$26, AU$8161) compared with nasoduodenal delivery of FMT and AU$4045 (95% CI: -AU$33, AU$8124) compared with colorectal delivery. The mean difference in cost between colorectal and nasoduodenal FMT was not significant. If FMT, rather than vancomycin, became standard care for recurrent CDI in Australia, the estimated national healthcare savings would be over AU$4000 per treated person, with a substantial increase in quality of life. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

New liquid chromatography-tandem mass spectrometry method for routine TDM of vancomycin in patients with both normal and impaired renal functions and comparison with results of polarization fluoroimmunoassay in light of varying creatinine concentrations.

PubMed

Brozmanová, Hana; Kacířová, Ivana; Uřinovská, Romana; Šištík, Pavel; Grundmann, Milan

2017-06-01

A new LC-MS/MS method with simple sample extraction and a relatively short period of vancomycin analysis for routine therapeutic drug monitoring was developed and validated. 50μL serum was precipitated using 20μL 33% trichloroacetic acid and 0.5mol/L NH 4 OH was added to increase pH before analysis. A RP BEH C18, 1.7μm, 2.1×50mm column maintained at 30°C and tobramycin as internal standard were used. Mass detection was performed in positive electrospray mode. The results obtained with LC-MS/MS method were correlated with an FPIA assay (Abbott AxSYM) using mouse monoclonal antibody. Subjects were divided into three groups according to creatinine levels (53.5±19.1, 150.2±48.4, 471.7±124.7μmol/L) and Passing-Bablok regression analysis and Bland-Altman analysis were used to compare vancomycin concentrations. The results of subjects with both normal and higher creatinine levels correlated very well and the linear regression model equations were near ideal (LC-MS VAN =0.947×Abbott VAN +0.192 and LC-MS VAN =0.973×Abbott VAN -0.411 respectively). Dialyzed patients with the highest creatinine levels showed about 14% greater vancomycin concentration with the FPIA assay (LC-MS VAN =0.866×Abbott VAN +2.127). This overestimation probably due to the presence of the metabolite CDP ought not to be of clinical relevance owing to the wide range of recommended vancomycin concentration. Copyright © 2017 Elsevier B.V. All rights reserved.

Vancomycin-resistant gene identification from live bacteria on an integrated microfluidic system by using low temperature lysis and loop-mediated isothermal amplification

PubMed Central

Chang, Wen-Hsin; Yu, Ju-ching; Yang, Sung-Yi; Lin, Yi-Cheng; Wang, Chih-Hung; You, Huey-Ling; Wu, Jiunn-Jong; Lee, Gwo-Bin

2017-01-01

Vancomycin-resistant Enterococcus (VRE) is a kind of enterococci, which shows resistance toward antibiotics. It may last for a long period of time and meanwhile transmit the vancomycin-resistant gene (vanA) to other bacteria. In the United States alone, the resistant rate of Enterococcus to vancomycin increased from a mere 0.3% to a whopping 40% in the past two decades. Therefore, timely diagnosis and control of VRE is of great need so that clinicians can prevent patients from becoming infected. Nowadays, VRE is diagnosed by antibiotic susceptibility test or molecular diagnosis assays such as matrix-assisted laser desorption ionization/time-of-flight mass spectrometry and polymerase chain reaction. However, the existing diagnostic methods have some drawbacks, for example, time-consumption, no genetic information, or high false-positive rate. This study reports an integrated microfluidic system, which can automatically identify the vancomycin resistant gene (vanA) from live bacteria in clinical samples. A new approach using ethidium monoazide, nucleic acid specific probes, low temperature chemical lysis, and loop-mediated isothermal amplification (LAMP) has been presented. The experimental results showed that the developed system can detect the vanA gene from live Enterococcus in joint fluid samples with detection limit as low as 10 colony formation units/reaction within 1 h. This is the first time that an integrated microfluidic system has been demonstrated to detect vanA gene from live bacteria by using the LAMP approach. With its high sensitivity and accuracy, the proposed system may be useful to monitor antibiotic resistance genes from live bacteria in clinical samples in the near future. PMID:28798845

The Influence of the Route of Antibiotic Administration, Methicillin Susceptibility, Vancomycin Duration and Serum Trough Concentration on Outcomes of Pediatric Staphylococcus aureus Bacteremic Osteoarticular Infection.

PubMed

McNeil, J Chase; Kaplan, Sheldon L; Vallejo, Jesus G

2017-06-01

Bacteremia is often one factor used in deciding the need for prolonged intravenous antimicrobial therapy in osteoarticular infections (OAIs). We examined treatment practices and outcomes of Staphylococcus aureus bacteremic osteoarticular infections (BOAIs) evaluated at Texas Children's Hospital. Cases of acute hematogenous OAI in children with positive blood cultures for S. aureus at Texas Children's Hospital between 2011 and 2014 were reviewed. Orthopedic complications included chronic osteomyelitis, growth arrest, pathologic fracture, avascular necrosis and chronic dislocation. Acute kidney injury was defined as a doubling of the baseline creatinine. One hundred and ninety-two cases of S. aureus OAI were identified with 102 cases of BOAI included [35 methicillin-resistant S. aureus (MRSA)]. Twenty-five patients were discharged home on oral antibiotics. Patients discharged on oral antibiotics had a shorter duration of fever, had a more rapid decline in C-reactive protein and were less likely to have MRSA. The frequency of orthopedic complications did not increase in patients who received early transition to oral antibiotics. For patients with MRSA bacteremia, the rates of complications between those who received ≥7 days versus <7 days of vancomycin did not differ. Vancomycin serum troughs >15 µg/mL were not associated with a decreased duration of fever, bacteremia or hospitalization, need for repeat operation or orthopedic complications but were associated with acute kidney injury. S. aureus BOAIs are associated with substantial morbidity. Early transition to oral therapy may be a safe option for select patients with S. aureus BOAI, including those due to MRSA. Prolonged courses of vancomycin and vancomycin troughs >15 μg/mL were not associated with improved outcomes for MRSA OAI.

Measuring the Adhesion Forces for the Multivalent Binding of Vancomycin-Conjugated Dendrimer to Bacterial Cell-Wall Peptide.

PubMed

Peterson, Elizabeth; Joseph, Christine; Peterson, Hannah; Bouwman, Rachael; Tang, Shengzhuang; Cannon, Jayme; Sinniah, Kumar; Choi, Seok Ki

2018-06-19

Multivalent ligand-receptor interaction provides the fundamental basis for the hypothetical notion that high binding avidity relates to the strong force of adhesion. Despite its increasing importance in the design of targeted nanoconjugates, an understanding of the physical forces underlying the multivalent interaction remains a subject of urgent investigation. In this study, we designed three vancomycin (Van)-conjugated dendrimers G5(Van) n ( n = mean valency = 0, 1, 4) for bacterial targeting with generation 5 (G5) poly(amidoamine) dendrimer as a multivalent scaffold and evaluated both their binding avidity and physical force of adhesion to a bacterial model surface by employing surface plasmon resonance (SPR) spectroscopy and atomic force microscopy. The SPR experiment for these conjugates was performed in a biosensor chip surface immobilized with a bacterial cell-wall peptide Lys-d-Ala-d-Ala. Of these, G5(Van) 4 bound most tightly with a K D of 0.34 nM, which represents an increase in avidity by 2 or 3 orders of magnitude relative to a monovalent conjugate G5(Van) 1 or free vancomycin, respectively. By single-molecule force spectroscopy, we measured the adhesion force between G5(Van) n and the same cell-wall peptide immobilized on the surface. The distribution of adhesion forces increased in proportion to vancomycin valency with the mean force of 134 pN at n = 4 greater than 96 pN at n = 1 at a loading rate of 5200 pN/s. In summary, our results are strongly supportive of the positive correlation between the avidity and adhesion force in the multivalent interaction of vancomycin nanoconjugates.

Impact of accessory gene regulator (agr) dysfunction on vancomycin pharmacodynamics among Canadian community and health-care associated methicillin-resistant Staphylococcus aureus

PubMed Central

2011-01-01

Background The accessory gene regulator (agr) is a quorum sensing cluster of genes which control colonization and virulence in Staphylococcus aureus. We evaluated agr function in community- (CA) and healthcare-associated (HA) MRSA, to compare the pharmacodynamics and bactericidal activity of vancomycin against agr functional and dysfunctional HA-MRSA and CA-MRSA. Methods 40 clinical isolates of MRSA from the Canadian Nosocomial Infection Surveillance Program were evaluated for delta-haemolysin production, as a surrogate marker of agr function. Time kill experiments were performed for vancomycin at 0 to 64 times the MIC against an initial inoculum of 106 and 108 cfu/ml of agr functional and dysfunctional CA-MRSA and HA-MRSA and these data were fit to a hill-type pharmacodynamic model. Results 15% isolates were agr dysfunctional, which was higher among HA-MRSA (26.3%) versus CA-MRSA (4.76%). Against a low initial inoculum of 106 cfu/ml of CA-MRSA, vancomycin pharmacodynamics were similar among agr functional and dysfunctional strains. However, against a high initial inoculum of 108 cfu/ml, killing activity was notably attenuated against agr dysfunctional CA-MRSA (USA400) and HA-MRSA (USA100). CA-MRSA displayed a 20.0 fold decrease in the maximal reduction in bacterial counts (Emax) which was 3.71 log10 CFU/ml for agr functional vs. 2.41 log10 CFU/ml for agr dysfunctional MRSA (p = 0.0007). Conclusions Dysfunction in agr was less common among CA-MRSA vs. HA-MRSA. agr dysfunction demonstrated an impact on vancomycin bactericidal activity and pharmacodynamics against a high initial inoculum of CA-MRSA and HA-MRSA, which may have implications for optimal antimicrobial therapy against persistent, difficult to treat MRSA infections. PMID:21599878

Impact of accessory gene regulator (agr) dysfunction on vancomycin pharmacodynamics among Canadian community and health-care associated methicillin-resistant Staphylococcus aureus.

PubMed

Tsuji, Brian T; MacLean, Robert D; Dresser, Linda D; McGavin, Martin J; Simor, Andrew E

2011-05-20

The accessory gene regulator (agr) is a quorum sensing cluster of genes which control colonization and virulence in Staphylococcus aureus. We evaluated agr function in community- (CA) and healthcare-associated (HA) MRSA, to compare the pharmacodynamics and bactericidal activity of vancomycin against agr functional and dysfunctional HA-MRSA and CA-MRSA. 40 clinical isolates of MRSA from the Canadian Nosocomial Infection Surveillance Program were evaluated for delta-haemolysin production, as a surrogate marker of agr function. Time kill experiments were performed for vancomycin at 0 to 64 times the MIC against an initial inoculum of 10(6) and 10(8) cfu/ml of agr functional and dysfunctional CA-MRSA and HA-MRSA and these data were fit to a hill-type pharmacodynamic model. 15% isolates were agr dysfunctional, which was higher among HA-MRSA (26.3%) versus CA-MRSA (4.76%). Against a low initial inoculum of 10(6) cfu/ml of CA-MRSA, vancomycin pharmacodynamics were similar among agr functional and dysfunctional strains. However, against a high initial inoculum of 10(8) cfu/ml, killing activity was notably attenuated against agr dysfunctional CA-MRSA (USA400) and HA-MRSA (USA100). CA-MRSA displayed a 20.0 fold decrease in the maximal reduction in bacterial counts (Emax) which was 3.71 log(10) CFU/ml for agr functional vs. 2.41 log(10) CFU/ml for agr dysfunctional MRSA (p = 0.0007). Dysfunction in agr was less common among CA-MRSA vs. HA-MRSA. agr dysfunction demonstrated an impact on vancomycin bactericidal activity and pharmacodynamics against a high initial inoculum of CA-MRSA and HA-MRSA, which may have implications for optimal antimicrobial therapy against persistent, difficult to treat MRSA infections.

Disease Progression and Resolution in Rodent Models of Clostridium difficile Infection and Impact of Antitoxin Antibodies and Vancomycin.

PubMed

Warn, Peter; Thommes, Pia; Sattar, Abdul; Corbett, David; Flattery, Amy; Zhang, Zuo; Black, Todd; Hernandez, Lorraine D; Therien, Alex G

2016-11-01

Clostridium difficile causes infections of the colon in susceptible patients. Specifically, gut dysbiosis induced by treatment with broad-spectrum antibiotics facilitates germination of ingested C. difficile spores, expansion of vegetative cells, and production of symptom-causing toxins TcdA and TcdB. The current standard of care for C. difficile infections (CDI) consists of administration of antibiotics such as vancomycin that target the bacterium but also perpetuate gut dysbiosis, often leading to disease recurrence. The monoclonal antitoxin antibodies actoxumab (anti-TcdA) and bezlotoxumab (anti-TcdB) are currently in development for the prevention of recurrent CDI. In this study, the effects of vancomycin or actoxumab/bezlotoxumab treatment on progression and resolution of CDI were assessed in mice and hamsters. Rodent models of CDI are characterized by an early severe phase of symptomatic disease, associated with high rates of morbidity and mortality; high intestinal C. difficile burden; and a disrupted intestinal microbiota. This is followed in surviving animals by gradual recovery of the gut microbiota, associated with clearance of C. difficile and resolution of disease symptoms over time. Treatment with vancomycin prevents disease initially by inhibiting outgrowth of C. difficile but also delays microbiota recovery, leading to disease relapse following discontinuation of therapy. In contrast, actoxumab/bezlotoxumab treatment does not impact the C. difficile burden but rather prevents the appearance of toxin-dependent symptoms during the early severe phase of disease, effectively preventing disease until the microbiota (the body's natural defense against C. difficile) has fully recovered. These data provide insight into the mechanism of recurrence following vancomycin administration and into the mechanism of recurrence prevention observed clinically with actoxumab/bezlotoxumab. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Fidaxomicin for the treatment of Clostridium difficile infections.

PubMed

Whitman, Craig B; Czosnowski, Quinn A

2012-02-01

To evaluate the pharmacology, microbiology, safety, and efficacy of fidaxomicin for treatment of Clostridium difficile infections (CDI). Literature was identified through Ovid MEDLINE (1948-December 2011) and International Pharmaceutical Abstracts (1970-December 2011) using the search terms fidaxomicin, OPT-80, PAR-101, OP-118, difimicin, tiacumicin, lipiarmycin, Clostridium difficile, Clostridium difficile infection, Clostridium difficile-associated diarrhea, and cost. Drug monographs were retrieved from manufacturers' Web pages, and the Red Book component of Micromedex was used for cost information. All pertinent Phase 1, 2, and 3 studies published in English were included. Fidaxomicin is a macrocyclic compound bactericidal against C. difficile and inhibits toxin and spore production. It has poor oral absorption with high fecal concentrations. Available Phase 2 and 3 data with fidaxomicin 200 mg orally every 12 hours demonstrate similar effectiveness in treating CDI compared to oral vancomycin. Fidaxomicin was shown to have less frequency of recurrent infections. Adverse effects are uncommon and occur at similar rates as with oral vancomycin. The most frequently reported adverse effects are gastrointestinal, hematologic, and electrolyte disorders. Available data are lacking in several areas, including the efficacy and safety of fidaxomicin compared to established regimens for mild-to-moderate, life-threatening, and recurrent CDIs. The cost of a 10-day course of fidaxomicin is significantly more than that of metronidazole and vancomycin for treatment of mild-to-moderate CDI. Fidaxomicin appears to be an effective and safe alternative to oral vancomycin for treatment of mild-to-moderate and severe CDI. Data on its use compared to guideline-recommended therapies for mild-to-moderate and life-threatening CDI are needed. Further data assessing the cost-effectiveness of fidaxomicin are needed. Currently, it cannot be recommended over vancomycin for treatment of CDI. However, it may be considered for treatment of recurrent infections.

Stimulated phase-shift acoustic nanodroplets enhance vancomycin efficacy against methicillin-resistant Staphylococcus aureus biofilms.

PubMed

Guo, Hao; Wang, Ziming; Du, Quanyin; Li, Pan; Wang, Zhigang; Wang, Aimin

2017-01-01

Bacterial biofilms on the surface of prostheses are becoming a rising concern in managing prosthetic joint infections. The inherent resistant features of biofilms render traditional antimicrobial therapy unproductive and revision surgery outcomes uncertain. This situation has prompted the exploration of novel antimicrobial strategies. The synergy of ultrasound microbubbles and vancomycin has been proposed as an efficient alternative for biofilm eradication. The purpose of this study was to evaluate the anti-biofilm effect of stimulated phase-shift acoustic nanodroplets (NDs) combined with vancomycin. We fabricated lipid phase-shift NDs with a core of liquid perfluoropentane. A new phase change mode for NDs incorporating an initial unfocused low-intensity pulsed ultrasound for 5 minutes and a subsequent incubation at 37°C into a 24-hour duration was developed. Methicillin-resistant Staphylococcus aureus (MRSA) biofilms were incubated with vancomycin and NDs under the hybrid stimulation. Biofilm morphology following treatment was determined using confocal laser scanning microscopy and scanning electron microscopy. Resazurin assay was used to quantify bactericidal efficacy against MRSA biofilm bacteria. NDs treated sequentially with ultrasound and heating at 37°C achieved gradual and substantial ND vaporization and cavitation in a successive process. NDs after stimulation were capable of generating stronger destruction on biofilm structure which was best characterized by residual circular arc margins and more dead bacteria. Furthermore, NDs combined with vancomycin contributed to significantly decreasing the metabolic activity of bacteria in MRSA biofilms ( P <0.05). Phase-shift acoustic NDs could exert a significant bactericidal effect against MRSA biofilms through a new stimulation mode. Acoustic NDs present advantages over microbubbles for biofilm damage. This anti-biofilm strategy could be used either alone or as an enhancer of traditional antibiotics in the control of prosthetic joint infections.

Comprehensive identification of mutations responsible for heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA)-to-VISA conversion in laboratory-generated VISA strains derived from hVISA clinical strain Mu3.

PubMed

Matsuo, Miki; Cui, Longzhu; Kim, Jeeyoung; Hiramatsu, Keiichi

2013-12-01

Heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) spontaneously produces VISA cells within its cell population at a frequency of 10(-6) or greater. We established a total of 45 VISA mutant strains independently obtained from hVISA Mu3 and its related strains by one-step vancomycin selection. We then performed high-throughput whole-genome sequencing of the 45 strains and their parent strains to identify the genes involved in the hVISA-to-VISA phenotypic conversion. A comparative genome study showed that all the VISA strains tested carried a unique set of mutations. All of the 45 VISA strains carried 1 to 4 mutations possibly affecting the expression of a total of 48 genes. Among them, 32 VISA strains carried only one gene affected by a single mutation. As many as 20 genes in more than eight functional categories were affected in the 32 VISA strains, which explained the extremely high rates of the hVISA-to-VISA phenotypic conversion. Five genes, rpoB, rpoC, walK, pbp4, and pp2c, were previously reported as being involved in vancomycin resistance. Fifteen remaining genes were newly identified as associated with vancomycin resistance in this study. The gene most frequently affected (6 out of 32 strains) was cmk, which encodes cytidylate kinase, followed closely by rpoB (5 out of 32), encoding the β subunit of RNA polymerase. A mutation prevalence study also revealed a sizable number of cmk mutants among clinical VISA strains (7 out of 38 [18%]). Reduced cytidylate kinase activity in cmk mutant strains is proposed to contribute to the hVISA-to-VISA phenotype conversion by thickening the cell wall and reducing the cell growth rate.

Dissecting Vancomycin-Intermediate Resistance in Staphylococcus aureus Using Genome-Wide Association

PubMed Central

Alam, Md Tauqeer; Petit, Robert A.; Crispell, Emily K.; Thornton, Timothy A.; Conneely, Karen N.; Jiang, Yunxuan; Satola, Sarah W.; Read, Timothy D.

2014-01-01

Vancomycin-intermediate Staphylococcus aureus (VISA) is currently defined as having minimal inhibitory concentration (MIC) of 4–8 µg/ml. VISA evolves through changes in multiple genetic loci with at least 16 candidate genes identified in clinical and in vitro-selected VISA strains. We report a whole-genome comparative analysis of 49 vancomycin-sensitive S. aureus and 26 VISA strains. Resistance to vancomycin was determined by broth microdilution, Etest, and population analysis profile-area under the curve (PAP-AUC). Genome-wide association studies (GWAS) of 55,977 single-nucleotide polymorphisms identified in one or more strains found one highly significant association (P = 8.78E-08) between a nonsynonymous mutation at codon 481 (H481) of the rpoB gene and increased vancomycin MIC. Additionally, we used a database of public S. aureus genome sequences to identify rare mutations in candidate genes associated with VISA. On the basis of these data, we proposed a preliminary model called ECM+RMCG for the VISA phenotype as a benchmark for future efforts. The model predicted VISA based on the presence of a rare mutation in a set of candidate genes (walKR, vraSR, graSR, and agrA) and/or three previously experimentally verified mutations (including the rpoB H481 locus) with an accuracy of 81% and a sensitivity of 73%. Further, the level of resistance measured by both Etest and PAP-AUC regressed positively with the number of mutations present in a strain. This study demonstrated 1) the power of GWAS for identifying common genetic variants associated with antibiotic resistance in bacteria and 2) that rare mutations in candidate gene, identified using large genomic data sets, can also be associated with resistance phenotypes. PMID:24787619

An economic model to compare linezolid and vancomycin for the treatment of confirmed methicillin-resistant Staphylococcus aureus nosocomial pneumonia in Germany.

PubMed

Patel, Dipen A; Michel, Andre; Stephens, Jennifer; Weber, Bertram; Petrik, Christian; Charbonneau, Claudie

2014-01-01

Across Europe, methicillin-resistant Staphylococcus aureus (MRSA) is considered to be the primary cause of nosocomial pneumonia (NP). In Germany alone, approximately 14,000 cases of MRSA-associated NP occur annually, which may have a significant impact on health care resource use and associated economic costs. The objective of this study was to investigate the economic impact of linezolid compared with that of vancomycin in the treatment of hospitalized patients with MRSA-confirmed NP in the German health care system. A 4-week decision tree model incorporated published data and expert opinion on clinical parameters, resource use, and costs (2012 euros) was constructed. The base case first-line treatment duration for patients with MRSA-confirmed NP was 10 days. Treatment success (survival), failure due to lack of efficacy, serious adverse events, and mortality were possible outcomes that could impact costs. Alternate scenarios were analyzed, such as varying treatment duration (7 or 14 days) or treatment switch due to a serious adverse event/treatment failure (at day 5 or 10). The model calculated total base case inpatient costs of €15,116 for linezolid and €15,239 for vancomycin. The incremental cost-effectiveness ratio favored linezolid (versus vancomycin), with marginally lower costs (by €123) and greater efficacy (+2.7% absolute difference in the proportion of patients successfully treated for MRSA NP). Approximately 85%-87% of the total treatment costs were attributed to hospital stay (primarily in the intensive care unit). Sensitivity analysis yielded similar results. The model results show that linezolid is a cost-effective alternative to vancomycin for MRSA-confirmed NP, largely attributable to the higher clinical response rate of patients treated with linezolid.

Chlorhexidine Induces VanA-Type Vancomycin Resistance Genes in Enterococci

PubMed Central

Bhardwaj, Pooja; Ziegler, Elizabeth

2016-01-01

Chlorhexidine is a bisbiguanide antiseptic used for infection control. Vancomycin-resistant E. faecium (VREfm) is among the leading causes of hospital-acquired infections. VREfm may be exposed to chlorhexidine at supra- and subinhibitory concentrations as a result of chlorhexidine bathing and chlorhexidine-impregnated central venous catheter use. We used RNA sequencing to investigate how VREfm responds to chlorhexidine gluconate exposure. Among the 35 genes upregulated ≥10-fold after 15 min of exposure to the MIC of chlorhexidine gluconate were those encoding VanA-type vancomycin resistance (vanHAX) and those associated with reduced daptomycin susceptibility (liaXYZ). We confirmed that vanA upregulation was not strain or species specific by querying other VanA-type VRE. VanB-type genes were not induced. The vanH promoter was found to be responsive to subinhibitory chlorhexidine gluconate in VREfm, as was production of the VanX protein. Using vanH reporter experiments with Bacillus subtilis and deletion analysis in VREfm, we found that this phenomenon is VanR dependent. Deletion of vanR did not result in increased chlorhexidine susceptibility, demonstrating that vanHAX induction is not protective against chlorhexidine. As expected, VanA-type VRE is more susceptible to ceftriaxone in the presence of sub-MIC chlorhexidine. Unexpectedly, VREfm is also more susceptible to vancomycin in the presence of subinhibitory chlorhexidine, suggesting that chlorhexidine-induced gene expression changes lead to additional alterations in cell wall synthesis. We conclude that chlorhexidine induces expression of VanA-type vancomycin resistance genes and genes associated with daptomycin nonsusceptibility. Overall, our results indicate that the impacts of subinhibitory chlorhexidine exposure on hospital-associated pathogens should be further investigated in laboratory studies. PMID:26810654

Feasibility studies of concomitant administration of optimized formulation of probiotic-loaded Vancomycin hydrochloride pellets for colon delivery.

PubMed

Avachat, Amelia M; Shinde, Amol S

2016-01-01

Objective of this study was to develop Vancomycin HCl pellets loaded with Saccharomyces boulardii (S.b.) for pH-dependent system and CODES™ for augmenting the efficacy of Vancomycin HCl in the treatment of colitis. Pellets were prepared by extrusion-spheronization. In the pH-dependent system, the pellets were coated with Eudragit FS 30D. These pellets exhibited spherical form and a uniform surface coating. The CODES™ system consisted of three components: core containing mannitol, drug and probiotic, an inner acid-soluble coating layer, and an outer layer of enteric coating material. Statistical factorial design was used to optimize both formulations. Scanning electron micrographs of coated pellets revealed uniform coating. In vitro drug release of these coated pellets was studied sequentially in various buffers with (2%) and without rat cecal content for a period of 12 h. From the optimized pH-dependent formulation, F6 (20% w/w coating level and 15% w/v concentration of polymer), higher amount of probiotic was released in earlier time phase (first 5 h) as compared to the CODES™ and so R5 [containing acid-soluble inner coating layer (15% w/w coating level and 12% w/v concentration of Eudragit E100), and an outer layer of enteric coating material (12% w/w coating level and 10% w/v concentration of Eudragit L100)] was considered as the best formulation after confirming in vivo X-ray studies conducted on rabbits, suggesting that Vancomycin HCl and S.b. may be co-administered as pellets [CODES™] to enhance the effectiveness of Vancomycin HCl in the treatment of colitis without its associated side effects, which can only be confirmed after clinical trials.

Emergence of vancomycin resistance in the genus Streptococcus: characterization of a vanB transferable determinant in Streptococcus bovis.

PubMed Central

Poyart, C; Pierre, C; Quesne, G; Pron, B; Berche, P; Trieu-Cuot, P

1997-01-01

Streptococcus bovis NEM760 was isolated from a stool swab collected on admission from a patient as surveillance for vancomycin-resistant enterococci. Strain NEM760 was identified as S. bovis by conventional biochemical methods and partial sequence analysis of its 16S rRNA. This strain was resistant to a low level of vancomycin (MIC, 64 micrograms/ml) but was susceptible to teicoplanin (MIC, 1 micrograms/ml), and vancomycin induced resistance to both glycopeptides. The presence of a vanB-related gene in NEM760 was demonstrated in a PCR assay which enabled specific amplification of a 635-hp internal segment of vanB. Sequence analysis of the corresponding PCR product revealed that it was highly homologous (96% identity) to the prototype vanB sequence of Enterococcus faecalis V583. The VanB resistance of determinant of S. bovis NEM760 was transferred by conjugation to E. faecalis and Enterococcus faecium at a similar frequency of 2 x 10(-5) per donor. SmaI-digested genomic DNAs of independently obtained transconjugants of E. faecalis and E. faecium were analyzed by pulsed-field gel electrophoresis and Southern hybridization with a vanB DNA probe. The electrophoretic and hybridization patterns obtained with all transconjugants of the same species were indistinguishable and revealed vanB-containing chromosomal insertions of approximately 100 kb. These results suggest that the genes mediating VanB-type resistance in S. bovis NEM760 are part of large transferable genetic elements. The results presented in the report demonstrate for the first time the role of streptococci in the dissemination of vancomycin resistance among gram-positive bacteria. PMID:8980749

Molecular Epidemiology of Vancomycin-Resistant Enterococcus faecalis and Enterococcus faecium Isolated from Clinical Specimens in the Northwest of Iran.

PubMed

Jahansepas, Ali; Ahangarzadeh Rezaee, Mohammad; Hasani, Alka; Sharifi, Yaeghob; Rahnamaye Farzami, Marjan; Dolatyar, Alireza; Aghazadeh, Mohammad

2018-04-30

This study was conducted to investigate the phenotypic and genotypic characteristics of vancomycin-resistant Enterococcus faecalis and Enterococcus faecium. Antibiotic resistance and virulence genes in the aforementioned resistant isolates were studied using the epsilometer (E)-test and polymerase chain reaction (PCR). These isolates were subjected to typing by pulsed-field gel electrophoresis (PFGE). Thirty vancomycin-resistant enterococci (VRE; 18.75%) were isolated from a total of 160 various clinical specimens cultured for any bacterial growth. Of these, 11 (36.7%) isolates were identified as E. faecalis and 19 (63.3%) as E. faecium. Minimum inhibitory concentrations (MICs) of vancomycin, teicoplanin, and three alternative therapeutic options (linezolid, daptomycin, and quinupristin/dalfopristin) were determined using the E-test. Multiplex PCR was done for confirming species, identification of the resistant genotypes, and the detection of the virulence genes. Finally, the clonal relationship of all VRE strains was studied by PFGE. All VRE strains showed vancomycin MIC ≥256 μg/mL, and 27 (90%) isolates carried the vanA gene, whereas none of the isolates carried vanB. The most common resistance antibiotic pattern observed was toward rifampicin (n = 30 [100%]). Among all virulence genes studied, gelE (n = 28 [93.33%]) was found as the most prevalent virulent gene. VRE isolates exhibited 90%, 46.67%, 100%, and 66.67% resistance to teicoplanin, linezolid, quinupristin/dalfopristin, and daptomycin, respectively. Molecular typing demonstrated 16 PFGE types of VRE isolates (A-P). Although vanA was carried by most of the isolates, PFGE displayed small clonal dissemination among VR E. faecium and VR E. faecalis species.

Impact of Molecular Epidemiology and Reduced Susceptibility to Glycopeptides and Daptomycin on Outcomes of Patients with Methicillin-Resistant Staphylococcus aureus Bacteremia

PubMed Central

Lee, Hao-Yuan; Chen, Chyi-Liang; Liu, Shu-Ying; Yan, Yu-Shan; Chang, Chee-Jen; Chiu, Cheng-Hsun

2015-01-01

Background Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia was associated with high mortality, but the risk factors associated with mortality remain controversial. Methods A retrospective cohort study was designed. All patients with MRSA bacteremia admitted were screened and collected for their clinical presentations and laboratory characteristics. Minimum inhibitory concentration (MIC) and staphylococcal cassette chromosome mec (SCCmec) type of bacterial isolates were determined. Risk factors for mortality were analyzed. Results Most MRSA isolates from the 189 enrolled patients showed reduced susceptibility to antibiotics, including MIC of vancomycin ≥ 1.5 mg/L (79.9%), teicoplanin ≥ 2 mg/L (86.2%), daptomycin ≥ 0.38 mg/L (73.0%) and linezolid ≥ 1.5 mg/L (64.0%). MRSA with vancomycin MIC ≥ 1.5 mg/L and inappropriate initial therapy were the two most important risk factors for mortality (both P < 0.05; odds ratio = 7.88 and 6.78). Hospital-associated MRSA (HA-MRSA), carrying SCCmec type I, II, or III, was associated with reduced susceptibility to vancomycin, teicoplanin or daptomycin and also with higher attributable mortality (all P < 0.05). Creeping vancomycin MIC was linked to higher MIC of teicoplanin and daptomycin (both P < 0.001), but not linezolid (P = 0.759). Conclusions Giving empirical broad-spectrum antibiotics for at least 5 days to treat catheter-related infections, pneumonia, soft tissue infection and other infections was the most important risk factor for acquiring subsequent HA-MRSA infection. Choice of effective anti-MRSA agents for treating MRSA bacteremia should be based on MIC of vancomycin, teicoplanin and daptomycin. Initiation of an effective anti-MRSA agent without elevated MIC in 2 days is crucial for reducing mortality. PMID:26295150

Inhibition of MRSA and of Clostridium difficile by durancin 61A: synergy with bacteriocins and antibiotics.

PubMed

Hanchi, Hasna; Hammami, Riadh; Gingras, Hélène; Kourda, Rim; Bergeron, Michel G; Ben Hamida, Jeannette; Ouellette, Marc; Fliss, Ismail

2017-03-01

The aim of this study was to evaluate the efficacy of durancin 61A alone or in combination with nisin, pediocin PA-1, reuterin, microcin J25, vancomycin or tetracycline as an inhibitor of resistant clinical pathogens and to shed light on its mode of action. Durancin and reuterin were effective inhibitors of Clostridium difficile, vancomycin-resistant Enterococcus faecium and methicillin-resistant Staphylococcus aureus. The combination of durancin and reuterin was highly synergistic against C. difficile (fractional inhibitory concentration index = 0.2). Durancin/vancomycin combination was synergistic against S. aureus ATCC ® 700699 (fractional inhibitory concentration index = 0.3). Conclusion & future perspective: Durancin 61A alone or combined with other bacteriocins or antibiotics may therefore provide a possible therapeutic option for the treatment of infections by these pathogens.

Increase in IS256 transposition in invasive vancomycin heteroresistant Staphylococcus aureus isolate belonging to ST100 and its derived VISA mutants.

PubMed

Di Gregorio, Sabrina; Fernandez, Silvina; Perazzi, Beatriz; Bello, Natalia; Famiglietti, Angela; Mollerach, Marta

2016-09-01

In Staphylococcus aureus, transposition of IS256 has been described to play an important role in biofilm formation and antibiotic resistance. This study describes the molecular characterization of two clinical heterogeneous vancomycin-intermediate S. aureus (hVISA) isolates recovered from the same patient (before and after antibiotic treatment) and two VISA derivatives obtained by serial passages in the presence of vancomycin. Our results showed that antibiotic treatment (in vivo and in vitro) could enhance IS256 transposition, being responsible for the eventual loss of agr function. As far as we know this is the first study that reports the increase of IS256 transposition in isogenic strains after antibiotic treatment in a clinical setting. Copyright © 2016 Elsevier B.V. All rights reserved.

Vancomycin-Resistance Enterococci Infections in the Department of the Defense: Annual Report 2013

DTIC Science & Technology

2014-08-01

str.r.:lioos, S€’ £l "r:’hi fl!’:: lil<i~lin ,:l ddc ~o.r-c.;s, !]:l:ho:>r rr:, aY. nflinttlirir~ :he !::f;, ·nod c ol ’ HO: Io ~:·rnhlir’U ;;· ;d ro...16. Morris JG, et al. Enterococci resistant to multiple antimicrobial agents, including vancomycin: establishment of endemicity in a university

Detection of Fusobacterium nucleatum in two cases of empyema and lung abscess using paromomycin-vancomycin supplemented Brucella HK agar.

PubMed

Nagaoka, Kentaro; Yanagihara, Katsunori; Morinaga, Yoshitomo; Kohno, Shigeru

2017-02-01

Fusobacterium nucleatum was found in patients with empyema or pulmonary abscess, using paromomycin-vancomycin Brucella HK agar. In vitro examination revealed that growth of the strains differed significantly in different media. Clinicians should be aware that suboptimal F. nucleatum cultivation methods may result in an underestimation of its frequency. Copyright © 2016 Elsevier Ltd. All rights reserved.

The Risk of Microbial Contamination in Multiple-Dose Preservative-Free Ophthalmic Preparations.

PubMed

Saisyo, Atsuyuki; Shimono, Rima; Oie, Shigeharu; Kimura, Kazuhiro; Furukawa, Hiroyuki

2017-01-01

Multiple-dose ophthalmic preparations that do not contain preservatives carry high risks of microbial contamination. However, there are various types of hospital preparations, with different physicochemical properties. In the present study, we evaluated the association between physicochemical properties and microbial contamination in ophthalmic preparations. The investigated hospital preparations included ophthalmic preparations of physiological saline, 0.2% fluconazole, 0.5% vancomycin hydrochloride, and 2% cyclosporine. We investigated the microbial dynamics of each ophthalmic preparation and microbial contamination in ophthalmic preparations used by patients. Remarkable growth of Pseudomonas aeruginosa, Burkholderia cepacia, and Serratia marcescens was observed in ophthalmic preparations of physiological saline and 0.2% fluconazole. All tested microorganisms displayed decreased counts after inoculation in 0.5% vancomycin hydrochloride. In 2% cyclosporine, all investigated microorganisms were below the limit of detection after inoculation for 6 h. The microbial contamination rates of ophthalmic preparations used by patients were 16.7% (3/18 samples) for 0.5% vancomycin hydrochloride and 0% (0/30 samples) for 2% cyclosporine. All detected contaminants in 0.5% vancomycin hydrochloride were Candida spp., one of which was present at a level of 1×10 4 colony-forming units/mL. The storage method for in-use ophthalmic preparations should be considered on the basis of their physicochemical properties.

Oral care with vancomycin paste for reduction in incidence of alpha-hemolytic streptococcal sepsis.

PubMed

Barker, G J; Call, S K; Gamis, A S

1995-05-01

alpha-Hemolytic streptococcal (AHS) sepsis is increasing in oncology patients receiving myelosuppressive chemotherapy. In response to a high rate of AHS sepsis in this population at our institution, an oral care protocol was instituted, including vancomycin 0.5% in flavored methylcellulose (vanc paste) applied orally t.i.d. at the oncologists' discretion. A retrospective cohort study of 239 neutropenic episodes among 42 children receiving myelosuppressive chemotherapy between 1988 and 1991 compared the incidence of septicemia based on the prophylactic use of vanc paste. A total of 236 consecutive neutropenic episodes were evaluable, 121 with vanc paste and 115 without. AHS sepsis occurred in one child using vanc paste and in six children not using vanc paste (p = 0.06). Excluding staph-only positive blood cultures, which would not be reduced with a topical oral antibiotic drug, there were 6 and 13 positive blood cultures in the vanc-paste and nonvanc-paste patients, respectively (p = 0.09). There was no increase in incidence of gram-negative bacteremia among vanc-paste recipients. Vancomycin resistance was not encountered. This analysis suggests that vanc paste effectively reduces AHS sepsis, does not increase gram-negative bacteremia, and is not associated with vancomycin resistance. A multicentered, placebo-controlled, double-blind study is currently planned.

Biodegradable drug-eluting nanofiber-enveloped implants for sustained release of high bactericidal concentrations of vancomycin and ceftazidime: in vitro and in vivo studies

PubMed Central

Hsu, Yung-Heng; Chen, Dave Wei-Chih; Tai, Chun-Der; Chou, Ying-Chao; Liu, Shih-Jung; Ueng, Steve Wen-Neng; Chan, Err-Cheng

2014-01-01

We developed biodegradable drug-eluting nanofiber-enveloped implants that provided sustained release of vancomycin and ceftazidime. To prepare the biodegradable nanofibrous membranes, poly(D,L)-lactide-co-glycolide and the antibiotics were first dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol. They were electrospun into biodegradable drug-eluting membranes, which were then enveloped on the surface of stainless plates. An elution method and a high-performance liquid chromatography assay were employed to characterize the in vivo and in vitro release rates of the antibiotics from the nanofiber-enveloped plates. The results showed that the biodegradable nanofiber-enveloped plates released high concentrations of vancomycin and ceftazidime (well above the minimum inhibitory concentration) for more than 3 and 8 weeks in vitro and in vivo, respectively. A bacterial inhibition test was carried out to determine the relative activity of the released antibiotics. The bioactivity ranged from 25% to 100%. In addition, the serum creatinine level remained within the normal range, suggesting that the high vancomycin concentration did not affect renal function. By adopting the electrospinning technique, we will be able to manufacture biodegradable drug-eluting implants for the long-term drug delivery of different antibiotics. PMID:25246790

In Vitro Assessment of Electric Currents Increasing the Effectiveness of Vancomycin Against Staphylococcus epidermidis Biofilms.

PubMed

Haddad, Peter A; Mah, Thien-Fah; Mussivand, Tofy

2016-08-01

Biofilms are communities of bacteria that can cause infections which are resistant to the immune system and antimicrobial treatments, posing a significant threat for patients with implantable and indwelling medical devices. The purpose of our research was to determine if utilizing specific parameters for electric currents in conjunction with antibiotics could effectively treat a highly resistant biofilm. Our study evaluated the impact of 16 μg/mL of vancomycin with or without 22 or 333 μA of direct electric current (DC) generated by stainless steel electrodes against 24-, 48-, and 72-h-old Staphylococcus epidermidis biofilms formed on titanium coupons. An increase in effectiveness of vancomycin was observed with the combination of 333 μA of electric current against 48-h-old biofilms (P value = 0.01) as well as in combination with 22 μA of electric current against 72-h-old biofilms (P value = 0.04); 333 μA of electric current showed the most significant impact on the effectiveness of vancomycin against S. epidermidis biofilms demonstrating a bioelectric effect previously not observed against this strain of bacteria. © 2015 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

In vitro evaluation of the antibiotic lock technique (ALT) for the treatment of catheter-related infections caused by staphylococci.

PubMed

Lee, Ji-Young; Ko, Kwan Soo; Peck, Kyong Ran; Oh, Won Sup; Song, Jae-Hoon

2006-06-01

To investigate appropriate antimicrobial agents, the optimal concentration and treatment duration for the antibiotic lock technique (ALT) to treat catheter-related infections caused by Staphylococcus epidermidis and Staphylococcus aureus. We evaluated the bacterial killing activity of vancomycin, teicoplanin, ciprofloxacin, rifampicin, cefazolin, gentamicin, nafcillin and erythromycin against biofilms formed by two strains of S. aureus and two strains of S. epidermidis. The effectiveness of the antibiotic lock was assayed after exposure to antibiotics (1, 5 and 10 mg/mL) for 1, 3, 5, 7, 10 or 14 days using an in vitro model of biofilms on polyurethane film. The biofilms were completely sterile after exposure to vancomycin (5 mg/mL) for 5 days and teicoplanin (5 and 10 mg/mL) for 7 days. Ciprofloxacin and rifampicin (both 5 mg/mL) achieved eradication of the biofilms of both staphylococcal species more rapidly than vancomycin or teicoplanin. Significant biofilm eradication was not achieved with cefazolin, nafcillin, gentamicin and erythromycin at any of the time exposures examined. The data suggest that 5 mg/mL vancomycin, ciprofloxacin or rifampicin can eradicate S. epidermidis and S. aureus biofilms within 5 days. These findings warrant prospective clinical trials for the evaluation of the clinical efficacy of ALT for less than 10 days.

The position of a key tyrosine in dTDP-4-Keto-6-deoxy-D-glucose-5-epimerase (EvaD) alters the substrate profile for this RmlC-like enzyme.

PubMed

Merkel, Alexandra B; Major, Louise L; Errey, James C; Burkart, Michael D; Field, Robert A; Walsh, Christopher T; Naismith, James H

2004-07-30

Vancomycin, the last line of defense antibiotic, depends upon the attachment of the carbohydrate vancosamine to an aglycone skeleton for antibacterial activity. Vancomycin is a naturally occurring secondary metabolite that can be produced by bacterial fermentation. To combat emerging resistance, it has been proposed to genetically engineer bacteria to produce analogues of vancomycin. This requires a detailed understanding of the biochemical steps in the synthesis of vancomycin. Here we report the 1.4 A structure and biochemical characterization of EvaD, an RmlC-like protein that is required for the C-5' epimerization during synthesis of dTDP-epivancosamine. EvaD, although clearly belonging to the RmlC class of enzymes, displays very low activity in the archetypal RmlC reaction (double epimerization of dTDP-6-deoxy-4-keto-D-glucose at C-3' and C-5'). The high resolution structure of EvaD compared with the structures of authentic RmlC enzymes indicates that a subtle change in the enzyme active site repositions a key catalytic Tyr residue. A mutant designed to re-establish the normal position of the Tyr increases the RmlC-like activity of EvaD.

Genome Sequence of Staphylococcus aureus VC40, a Vancomycin- and Daptomycin-Resistant Strain, To Study the Genetics of Development of Resistance to Currently Applied Last-Resort Antibiotics

PubMed Central

Berscheid, Anne; Jansen, Andrea; Oedenkoven, Marion; Szekat, Christiane; Strittmatter, Axel; Gottschalk, Gerhard; Bierbaum, Gabriele

2012-01-01

The increasing emergence of multidrug-resistant Staphylococcus aureus is a problem of global importance. Here, we report the genome of S. aureus VC40, which is resistant to the last-resort antibiotics vancomycin and daptomycin. Its genome sequence will allow insights into the mechanisms that convey full resistance to these compounds. PMID:22461548

Silver(I)-promoted conversion of thioamides to amidines: divergent synthesis of a key series of vancomycin aglycon residue 4 amidines that clarify binding behavior to model ligands.

PubMed

Okano, Akinori; James, Robert C; Pierce, Joshua G; Xie, Jian; Boger, Dale L

2012-05-30

Development of a general Ag(I)-promoted reaction for the conversion of thioamides to amidines is disclosed. This reaction was employed to prepare a key series of vancomycin aglycon residue 4 substituted amidines that were used to clarify their interaction with model ligands of peptidoglycan precursors and explore their resulting impact on antimicrobial properties.

Simultaneous determination of vancomycin and ceftazidime in cerebrospinal fluid in craniotomy patients by high-performance liquid chromatography.

PubMed

Ye, Guangming; Cai, Xuejian; Wang, Biao; Zhou, Zhongxian; Yu, Xiaohua; Wang, Weibin; Zhang, Jiandong; Wang, Yuhai; Dong, Jierong; Jiang, Yunyun

2008-11-04

A simple, accurate and rapid method for simultaneous analysis of vancomycin and ceftazidime in cerebrospinal fluid (CSF), utilizing high-performance liquid chromatography (HPLC), has been developed and thoroughly validated to satisfy strict FDA guidelines for bioanalytical methods. Protein precipitation was used as the sample pretreatment method. In order to increase the accuracy, tinidazole was chosen as the internal standard. Separation was achieved on a Diamonsil C18 column (200 mm x 4.6mm I.D., 5 microm) using a mobile phase composed of acetonitrile and acetate buffer (pH 3.5) (8:92, v/v) at room temperature (25 degrees C), and the detection wavelength was 240 nm. All the validation data, such as accuracy, precision, and inter-day repeatability, were within the required limits. The method was applied to determine vancomycin and ceftazidime concentrations in CSF in five craniotomy patients.

Bromomethylthioindole Inspired Carbazole Hybrids as Promising Class of Anti-MRSA Agents.

PubMed

Cheng, Chia-Yi; Chang, Chun-Ping; Lauderdale, Tsai-Ling Yang; Yu, Guann-Yi; Lee, Jinq-Chyi; Jhang, Yi-Wun; Wu, Chien-Huang; Ke, Yi-Yu; Sadani, Amit A; Yeh, Ching-Fang; Huang, I-Wen; Kuo, Yi-Ping; Tsai, De-Jiun; Yeh, Teng-Kuang; Tseng, Chen-Tso; Song, Jen-Shin; Liu, Yu-Wei; Tsou, Lun K; Shia, Kak-Shan

2016-12-08

Series of N -substituted carbazole analogues bearing an indole ring were synthesized as anti-methicillin-resistant Staphylococcus aureus (MRSA) agents from a molecular hybridization approach. The representative compound 19 showed an MIC = 1 μg/mL against a panel of MRSA clinical isolates as it possessed comparable in vitro activities to that of vancomycin. Moreover, compound 19 also exhibited MIC = 1 μg/mL activities against a recent identified Z172 MRSA strain (vancomycin-intermediate and daptomycin-nonsusceptible phenotype) and the vancomycin-resistant Enterococcus faecalis (VRE) strain. In a mouse model with lethal infection of MRSA (4N216), a 75% survival rate was observed after a single dose of compound 19 was intravenously administered at 20 mg/kg. In light of their equipotent activities against different MRSA isolates and VRE strain, the data underscore the importance of designed hybrid series for the development of new N -substituted carbazoles as potential anti-MRSA agents.

Cyclosporine and Vancomycin + Amikacin Induced Hot Kidney Appearance in a Young Adult and a Pediatric Patient.

PubMed

Çayır, Derya; Araz, Mine; Filik, Mustafa; Erdoğan, Mehmet

2017-10-03

The appearance of a hot kidney on bone scintigraphy is rare and can be seen due to various factors. In our clinic, we observed hot kidney appearance in two patients to whom technetium-99m methylene diphosphonate (Tc-99m MDP) whole body scan has been performed: a young male adult at the age of 18 who was diagnosed with acute lymphocytic leukemia with a presumptive diagnosis of avascular necrosis, and a 9-year-old girl with cystitis for a pre-diagnosis of osteomyelitis. The first patient had a history of cyclosporine usage and the second patient was being treated with amikacin + vancomycin. To the best of our knowledge, we present the first cases where hot-kidney appearance on Tc-99m MDP whole body scan due to the use of cyclosporin and amikacin + vancomycin is demonstrated.

Detection of vancomycin resistances in enterococci within 3 1/2 hours

NASA Astrophysics Data System (ADS)

Schröder, U. -Ch.; Beleites, C.; Assmann, C.; Glaser, U.; Hübner, U.; Pfister, W.; Fritzsche, W.; Popp, J.; Neugebauer, U.

2015-02-01

Vancomycin resistant enterococci (VRE) constitute a challenging problem in health care institutions worldwide. Novel methods to rapidly identify resistances are highly required to ensure an early start of tailored therapy and to prevent further spread of the bacteria. Here, a spectroscopy-based rapid test is presented that reveals resistances of enterococci towards vancomycin within 3.5 hours. Without any specific knowledge on the strain, VRE can be recognized with high accuracy in two different enterococci species. By means of dielectrophoresis, bacteria are directly captured from dilute suspensions, making sample preparation very easy. Raman spectroscopic analysis of the trapped bacteria over a time span of two hours in absence and presence of antibiotics reveals characteristic differences in the molecular response of sensitive as well as resistant Enterococcus faecalis and Enterococcus faecium. Furthermore, the spectroscopic fingerprints provide an indication on the mechanisms of induced resistance in VRE.

Analysis of the world epidemiological situation among vancomycin-resistant Enterococcus faecium infections and the current situation in Poland

PubMed

Talaga-Ćwiertnia, Katarzyna; Bulanda, Małgorzata

2018-01-01

Vancomycin-resistant Enterococcus faecium (VREfm) strains have become an important hospital pathogen due to their rapid spread, high mortality rate associated with infections and limited therapeutic options. Vancomycin resistance is predominantly mediated by VanA or VanB phenotypes, which differ as regards maintaining sensitivity to teicoplanin in the VanB phenotype. The majority of VREfm cases in the United States, Europe, Korea, South America and Africa are currently caused by the VanA phenotype. However, the epidemics in Australia and Singapore are chiefly brought about by the VanB phenotype. The rate of VREfm isolate spread varies greatly. The greatest percentage of VREfm is now recorded in the USA, Ireland and Australia. Supervision of VRE is implemented to varying degrees. Therefore, the epidemiological situation in some countries is difficult to assess due to limited data or lack thereof.

Efficacy of oral vancomycin in recurrent primary sclerosing cholangitis following liver transplantation

PubMed Central

Hey, Penelope; Lokan, Julie; Johnson, Paul; Gow, Paul

2017-01-01

Primary sclerosing cholangitis (PSC) is a liver disease that leads to progressive destruction and stricturing of the biliary tree. Unfortunately, apart from orthotopic liver transplantation (OLT), there are no universally accepted therapies to treat this disease. Even following transplantation, recurrence of PSC is seen in approximately one quarter of patients and leads to high rates of graft failure. Oral vancomycin, through possible immunomodulatory and anti-inflammatory mechanisms, has been shown in small-scale studies to be successful in improving liver function tests in patients with pretransplant PSC. We report the first case of an adult patient diagnosed with recurrent PSC 4 years after OLT who was treated with oral vancomycin leading to complete normalisation of his liver biochemistry. This case adds to the growing literature of a potential therapeutic role for this antibiotic in PSC and highlights interesting questions regarding mechanisms of disease. PMID:28951512

Selective vancomycin detection using optical fibre long period gratings functionalised with molecularly imprinted polymer nanoparticles.

PubMed

Korposh, Sergiy; Chianella, Iva; Guerreiro, Antonio; Caygill, Sarah; Piletsky, Sergey; James, Stephen W; Tatam, Ralph P

2014-05-07

An optical fibre long period grating (LPG) sensor modified with molecularly imprinted polymer nanoparticles (nanoMIPs) for the specific detection of antibiotics is presented. The operation of the sensor is based on the measurement of changes in refractive index induced by the interaction of nanoMIPs deposited onto the cladding of the LPG with free vancomycin (VA). The binding of nanoMIPs to vancomycin was characterised by a binding constant of 4.3 ± 0.1 × 10(-8) M. The lowest concentration of analyte measured by the fibre sensor was 10 nM. In addition, the sensor exhibited selectivity, as much smaller responses were obtained for high concentrations (∼700 μM) of other commonly prescribed antibiotics such as amoxicillin, bleomycin and gentamicin. In addition, the response of the sensor was characterised in a complex matrix, porcine plasma, spiked with 10 μM of VA.

Selective vancomycin detection using optical fibre long period gratings functionalised with molecularly imprinted polymer nanoparticles

PubMed Central

Korposh, Sergiy; Chianella, Iva; Guerreiro, Antonio; Caygill, Sarah; Piletsky, Sergey; James, Stephen W.; Tatam, Ralph P.

2015-01-01

An optical fibre long period grating (LPG) sensor modified with molecularly imprinted polymer nanoparticles (nanoMIPs) for the specific detection of antibiotics is presented. The operation of the sensor is based on the measurement of changes in refractive index induced by the interaction of nanoMIPs deposited onto the cladding of the LPG with free vancomycin (VA). The binding of nanoMIPs to vancomycin was characterised by a binding constant of 4.3±0.1×10−8 M. The lowest concentration of analyte measured by the fibre sensor was 10 nM. In addition, the sensor exhibited selectivity, as much smaller responses were obtained for high concentrations (~ 700 μM) of other commonly prescribed antibiotics such as amoxicillin, bleomycin and gentamicin. In addition, the response of the sensor was characterised in a complex matrix, porcine plasma, spiked with 10 μM of VA. PMID:24634909

Structural and Functional Adaptation of Vancomycin Resistance VanT Serine Racemases.

PubMed

Meziane-Cherif, Djalal; Stogios, Peter J; Evdokimova, Elena; Egorova, Olga; Savchenko, Alexei; Courvalin, Patrice

2015-08-11

Vancomycin resistance in Gram-positive bacteria results from the replacement of the D-alanyl-D-alanine target of peptidoglycan precursors with D-alanyl-D-lactate or D-alanyl-D-serine (D-Ala-D-Ser), to which vancomycin has low binding affinity. VanT is one of the proteins required for the production of D-Ala-D-Ser-terminating precursors by converting L-Ser to D-Ser. VanT is composed of two domains, an N-terminal membrane-bound domain, likely involved in L-Ser uptake, and a C-terminal cytoplasmic catalytic domain which is related to bacterial alanine racemases. To gain insight into the molecular function of VanT, the crystal structure of the catalytic domain of VanTG from VanG-type resistant Enterococcus faecalis BM4518 was determined. The structure showed significant similarity to type III pyridoxal 5'-phosphate (PLP)-dependent alanine racemases, which are essential for peptidoglycan synthesis. Comparative structural analysis between VanTG and alanine racemases as well as site-directed mutagenesis identified three specific active site positions centered around Asn696 which are responsible for the L-amino acid specificity. This analysis also suggested that VanT racemases evolved from regular alanine racemases by acquiring additional selectivity toward serine while preserving that for alanine. The 4-fold-lower relative catalytic efficiency of VanTG against L-Ser versus L-Ala implied that this enzyme relies on its membrane-bound domain for L-Ser transport to increase the overall rate of d-Ser production. These findings illustrate how vancomycin pressure selected for molecular adaptation of a housekeeping enzyme to a bifunctional enzyme to allow for peptidoglycan remodeling, a strategy increasingly observed in antibiotic-resistant bacteria. Vancomycin is one of the drugs of last resort against Gram-positive antibiotic-resistant pathogens. However, bacteria have evolved a sophisticated mechanism which remodels the drug target, the D-alanine ending precursors in cell wall synthesis, into precursors terminating with D-lactate or D-serine, to which vancomycin has less affinity. D-Ser is synthesized by VanT serine racemase, which has two unusual characteristics: (i) it is one of the few serine racemases identified in bacteria and (ii) it contains a membrane-bound domain involved in L-Ser uptake. The structure of the catalytic domain of VanTG showed high similarity to alanine racemases, and we identified three specific active site substitutions responsible for L-Ser specificity. The data provide the molecular basis for VanT evolution to a bifunctional enzyme coordinating both transport and racemization. Our findings also illustrate the evolution of the essential alanine racemase into a vancomycin resistance enzyme in response to antibiotic pressure. Copyright © 2015 Meziane-Cherif et al.

Fidaxomicin: A novel agent for the treatment of Clostridium difficile infection

PubMed Central

Zhanel, George G; Walkty, Andrew J; Karlowsky, James A

2015-01-01

BACKGROUND: Due to the limitations of existing treatment options for Clostridium difficile infection (CDI), new therapies are needed. OBJECTIVE: To review the available data on fidaxomicin regarding chemistry, mechanisms of action and resistance, in vitro activity, pharmacokinetic and pharmacodynamic properties, efficacy and safety in clinical trials, and place in therapy. METHODS: A search of PubMed using the terms “fidaxomicin”, “OPT-80”, “PAR-101”, “OP-1118”, “difimicin”, “tiacumicin” and “lipiarmycin” was performed. All English-language articles from January 1983 to November 2014 were reviewed, as well as bibliographies of all articles. RESULTS: Fidaxomicin is the first macrocyclic lactone antibiotic with activity versus C difficile. It inhibits RNA polymerase, therefore, preventing transcription. Fidaxomicin (and its active metabolite OP-1118) is bactericidal against C difficile and exhibits a prolonged postantibiotic effect (approximately 10 h). Other than for C difficile, fidaxomicin demonstrated only moderate inhibitory activity against Gram-positive bacteria and was a poor inhibitor of normal colonic flora, including anaerobes and enteric Gram-negative bacilli. After oral administration (200 mg two times per day for 10 days), fidaxomicin achieved low serum concentration levels but high fecal concentration levels (mean approximately 1400 μg/g stool). Phase 3 clinical trials involving adults with CDI demonstrated that 200 mg fidaxomicin twice daily for 10 days was noninferior to 125 mg oral vancomycin four times daily for 10 days in regard to clinical response at the end of therapy. Fidaxomicin was, however, reported to be superior to oral vancomycin in reducing recurrent CDI and achieving a sustained clinical response (assessed at day 28) for patients infected with non-BI/NAP1/027 strains. CONCLUSION: Fidaxomicin was noninferior to oral vancomycin with regard to clinical response at the end of CDI therapy. Fidaxomicin has been demonstated to be as safe as oral vancomycin, but superior to vancomycin in achieving a sustained clinical response for CDI in patients infected with non-BI/NAP1/027 strains. Caution should be exercised in using fidaxomicin monotherapy for treatment of severe complicated CDI because limited data are available. Whether fidaxomicin is cost effective (due to its significantly higher acquisition cost versus oral vancomycin) depends on the acceptable willingness to pay threshold per quality-adjusted life year as a measure of assessing cost effectiveness. PMID:26744587

Antistaphylococcal activity of DX-619, a new des-F(6)-quinolone, compared to those of other agents.

PubMed

Bogdanovich, Tatiana; Esel, Duygu; Kelly, Linda M; Bozdogan, Bülent; Credito, Kim; Lin, Gengrong; Smith, Kathy; Ednie, Lois M; Hoellman, Dianne B; Appelbaum, Peter C

2005-08-01

The in vitro activity of DX-619, a new des-F(6)-quinolone, was tested against staphylococci and compared to those of other antimicrobials. DX-619 had the lowest MIC ranges/MIC(50)s/MIC(90)s (microg/ml) against 131 Staphylococcus aureus strains (32), and ciprofloxacin (>32/>32). Raised quinolone MICs were associated with mutations in GyrA (S84L) and single or double mutations in GrlA (S80F or Y; E84K, G, or V) in all S. aureus strains tested. A recent vancomycin-resistant S. aureus (VRSA) strain (Hershey) was resistant to available quinolones and was inhibited by DX-619 at 0.25 microg/ml and sitafloxacin at 1.0 microg/ml. Vancomycin (except VRSA), linezolid, ranbezolid, tigecycline, and quinupristin-dalfopristin were active against all strains, and teicoplanin was active against S. aureus but less active against coagulase-negative staphylococci. DX-619 produced resistant mutants with MICs of 1 to >32 microg/ml after <50 days of selection compared to 16 to >32 microg/ml for ciprofloxacin, sitafloxacin, moxifloxacin, and gatifloxacin. DX-619 and sitafloxacin were also more active than other tested drugs against selected mutants and had the lowest mutation frequencies in single-step resistance selection. DX-619 and sitafloxacin were bactericidal against six quinolone-resistant (including the VRSA) and seven quinolone-susceptible strains tested, whereas gatifloxacin, moxifloxacin, levofloxacin, and ciprofloxacin were bactericidal against 11, 10, 7, and 5 strains at 4x MIC after 24 h, respectively. DX-619 was also bactericidal against one other VRSA strain, five vancomycin-intermediate S. aureus strains, and four vancomycin-intermediate coagulase-negative staphylococci. Linezolid, ranbezolid, and tigecycline were bacteriostatic and quinupristin-dalfopristin, teicoplanin, and vancomycin were bactericidal against two, eight, and nine strains, and daptomycin and oritavancin were rapidly bactericidal against all strains, including the VRSA. DX-619 has potent in vitro activity against staphylococci, including methicillin-, ciprofloxacin-, and vancomycin-resistant strains.

Fidaxomicin: A novel agent for the treatment of Clostridium difficile infection.

PubMed

Zhanel, George G; Walkty, Andrew J; Karlowsky, James A

2015-01-01

Due to the limitations of existing treatment options for Clostridium difficile infection (CDI), new therapies are needed. To review the available data on fidaxomicin regarding chemistry, mechanisms of action and resistance, in vitro activity, pharmacokinetic and pharmacodynamic properties, efficacy and safety in clinical trials, and place in therapy. A search of PubMed using the terms "fidaxomicin", "OPT-80", "PAR-101", "OP-1118", "difimicin", "tiacumicin" and "lipiarmycin" was performed. All English-language articles from January 1983 to November 2014 were reviewed, as well as bibliographies of all articles. Fidaxomicin is the first macrocyclic lactone antibiotic with activity versus C difficile. It inhibits RNA polymerase, therefore, preventing transcription. Fidaxomicin (and its active metabolite OP-1118) is bactericidal against C difficile and exhibits a prolonged postantibiotic effect (approximately 10 h). Other than for C difficile, fidaxomicin demonstrated only moderate inhibitory activity against Gram-positive bacteria and was a poor inhibitor of normal colonic flora, including anaerobes and enteric Gram-negative bacilli. After oral administration (200 mg two times per day for 10 days), fidaxomicin achieved low serum concentration levels but high fecal concentration levels (mean approximately 1400 μg/g stool). Phase 3 clinical trials involving adults with CDI demonstrated that 200 mg fidaxomicin twice daily for 10 days was noninferior to 125 mg oral vancomycin four times daily for 10 days in regard to clinical response at the end of therapy. Fidaxomicin was, however, reported to be superior to oral vancomycin in reducing recurrent CDI and achieving a sustained clinical response (assessed at day 28) for patients infected with non-BI/NAP1/027 strains. Fidaxomicin was noninferior to oral vancomycin with regard to clinical response at the end of CDI therapy. Fidaxomicin has been demonstated to be as safe as oral vancomycin, but superior to vancomycin in achieving a sustained clinical response for CDI in patients infected with non-BI/NAP1/027 strains. Caution should be exercised in using fidaxomicin monotherapy for treatment of severe complicated CDI because limited data are available. Whether fidaxomicin is cost effective (due to its significantly higher acquisition cost versus oral vancomycin) depends on the acceptable willingness to pay threshold per quality-adjusted life year as a measure of assessing cost effectiveness.

Treatment of experimental pneumonia due to penicillin-resistant Streptococcus pneumoniae in immunocompetent rats.

PubMed Central

Gavaldà, J; Capdevila, J A; Almirante, B; Otero, J; Ruiz, I; Laguarda, M; Allende, H; Crespo, E; Pigrau, C; Pahissa, A

1997-01-01

A model of pneumonia due to Streptococcus pneumoniae resistant to penicillin was developed in immunocompetent Wistar rats and was used to evaluate the efficacies of different doses of penicillin, cefotaxime, cefpirome, and vancomycin. Adult Wistar rats were challenged by intratracheal inoculation with 3 x 10(9) CFU of one strain of S. pneumoniae resistant to penicillin (MICs of penicillin, cefotaxime, cefpirome, and vancomycin, 2, 1, 0.5, and 0.5 microg/ml, respectively) suspended in brain heart broth supplemented with 0.7% agar. The rats experienced a fatal pneumonia, dying within 5 days and with peak mortality (70 to 80%) occurring 48 to 72 h after infection, and the bacterial counts in the lungs persisted from 8.87 +/- 0.3 log10 CFU/g of lung at 24 h of the infection to 9.1 +/- 0.3 log10 CFU/g at 72 h. Four hours after infection the animals were randomized into the following treatment groups: (i) control without treatment, (ii) penicillin G at 100,000 IU/kg of body weight every 2 h, (iii) penicillin G at 250,000 IU/kg every 2 h, (iv) cefotaxime at 100 mg/kg every 2 h, (v) cefpirome at 200 mg/kg every 2 h, and (vi) vancomycin at 50 mg/kg every 8 h. Two different protocols were used for the therapeutic efficacy studies: four doses of beta-lactams and one dose of vancomycin or eight doses of beta-lactams and two doses of vancomycin. Results of the therapy for experimental pneumonia caused by penicillin-resistant S. pneumoniae showed that initially, all the antimicrobial agents tested had similar efficacies, but when we prolonged the treatment, higher doses of penicillin, cefotaxime, and cefpirome were more effective than penicillin at lower doses in decreasing the residual bacterial titers in the lungs. Also, when we extended the treatment, vancomycin was more efficacious than penicillin at lower doses but was less efficacious than higher doses of penicillin or cefpirome. The model that we have developed is simple and amenable for inducing pneumonia in immunocompetent rats and could be used to explore the pathophysiology and to evaluate optimal therapy of this infection in the immunocompetent host. PMID:9087492

A review of the economics of treating Clostridium difficile infection.

PubMed

Mergenhagen, Kari A; Wojciechowski, Amy L; Paladino, Joseph A

2014-07-01

Clostridium difficile infection (CDI) is a costly result of antibiotic use, responsible for an estimated 14,000 deaths annually in the USA according to the Centers for Disease Control and Prevention. Annual costs attributable to CDI are in excess of $US 1 billion. This review summarizes appropriate utilization of prevention and treatment methods for CDI that have the potential to reduce the economic and humanistic costs of the disease. Some cost-effective strategies to prevent CDI include screening and isolation of hospital admissions based on C. difficile carriage to reduce transmission in the inpatient setting, and probiotics, which are potentially efficacious in preventing CDI in the appropriate patient population. The most extensively studied agents for treatment of CDI are metronidazole, vancomycin, and fidaxomicin. Most economic comparisons between metronidazole and vancomycin favor vancomycin, especially with the emergence of metronidazole-resistant C. difficile strains. Metronidazole can only be recommended for mild disease. Moderate to severe CDI should be treated with vancomycin, preferably the compounded oral solution, which provides the most cost-effective therapeutic option. Fidaxomicin offers a clinically effective and potentially cost-effective alternative for treating moderate CDI in patients who do not have the NAP1/BI/027 strain of C. difficile. Probiotics and fecal microbiota transplant have variable efficacy and the US FDA does not currently regulate the content; the potential economic advantages of these treatment modalities are currently unknown.

Comparative Analysis of the First Complete Enterococcus faecium Genome

PubMed Central

Lam, Margaret M. C.; Seemann, Torsten; Bulach, Dieter M.; Gladman, Simon L.; Chen, Honglei; Haring, Volker; Moore, Robert J.; Ballard, Susan; Grayson, M. Lindsay; Johnson, Paul D. R.; Howden, Benjamin P.

2012-01-01

Vancomycin-resistant enterococci (VRE) are one of the leading causes of nosocomial infections in health care facilities around the globe. In particular, infections caused by vancomycin-resistant Enterococcus faecium are becoming increasingly common. Comparative and functional genomic studies of E. faecium isolates have so far been limited owing to the lack of a fully assembled E. faecium genome sequence. Here we address this issue and report the complete 3.0-Mb genome sequence of the multilocus sequence type 17 vancomycin-resistant Enterococcus faecium strain Aus0004, isolated from the bloodstream of a patient in Melbourne, Australia, in 1998. The genome comprises a 2.9-Mb circular chromosome and three circular plasmids. The chromosome harbors putative E. faecium virulence factors such as enterococcal surface protein, hemolysin, and collagen-binding adhesin. Aus0004 has a very large accessory genome (38%) that includes three prophage and two genomic islands absent among 22 other E. faecium genomes. One of the prophage was present as inverted 50-kb repeats that appear to have facilitated a 683-kb chromosomal inversion across the replication terminus, resulting in a striking replichore imbalance. Other distinctive features include 76 insertion sequence elements and a single chromosomal copy of Tn1549 containing the vanB vancomycin resistance element. A complete E. faecium genome will be a useful resource to assist our understanding of this emerging nosocomial pathogen. PMID:22366422

Structural and metabolic responses of Staphylococcus aureus biofilms to hyperosmotic and antibiotic stress

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kiamco, Mia M.; Mohamed, Abdelrhman; Reardon, Patrick N.

Biofilms alter their metabolism in response to environmental stress. This study explores the effect of a hyperosmotic agent–antibiotic treatment on the metabolism of Staphylococcus aureus biofilms through the use of nuclear magnetic resonance (NMR) techniques. To determine the metabolic activity of S. aureus, we quantified the concentrations of metabolites in spent medium using high-resolution NMR spectroscopy. Biofilm porosity, thickness, biovolume, and relative diffusion coefficient depth profiles were obtained using NMR microimaging. Dissolved oxygen (DO) concentration was measured to determine the availability of oxygen within the biofilm. Under vancomycin-only treatment, the biofilm communities switched to anaerobic fermentation, as evidenced by highmore » concentrations of formate, acetate, and lactate, and there was no detectable dissolved oxygen in the biofilm. Anaerobic conditions such as fermentation can signify that biofilm is combating antibiotic stress by developing resistance. In addition, we observed the highest consumption of pyruvate, the sole carbon source, under the vancomycin-only treatment. On the other hand, relative effective diffusion coefficients increased under vancomycin-only treatment but decreased under maltodextrin-only and combined treatments. No change was observed in either biofilm thickness or biovolume for biofilms treated with maltodextrin-only or in combination with vancomycin. This indicates that biofilm growth was halted during maltodextrin-only and combined treatments. Overall, we demonstrated that the metabolic activity of S. aureus biofilm is affected by hyperosmotic and antibiotic stress.« less

Short communication: β-Lactam resistance and vancomycin heteroresistance in Staphylococcus spp. isolated from bovine subclinical mastitis.

PubMed

Mello, Priscila Luiza; Pinheiro, Luiza; Martins, Lisiane de Almeida; Brito, Maria Aparecida Vasconcelos Paiva; Ribeiro de Souza da Cunha, Maria de Lourdes

2017-08-01

The use of antimicrobial agents has led to the emergence of resistant bacterial strains over a relatively short period. Furthermore, Staphylococcus spp. can produce β-lactamase, which explains the survival of these strains in a focus of infection despite the use of a β-lactam antibiotic. The aim of this study was to evaluate the resistance of Staphylococcus spp. isolated from bovine subclinical mastitis to oxacillin and vancomycin (by minimum inhibitory concentration) and to detect vancomycin heteroresistance by a screening method. We also evaluated β-lactamase production and resistance due to hyperproduction of this enzyme and investigated the mecA and mecC genes and performed staphylococcal cassette chromosome mec typing. For this purpose, 181 Staphylococcus spp. isolated from mastitis subclinical bovine were analyzed. Using the phenotypic method, 33 (18.2%) of Staphylococcus spp. were resistant to oxacillin. In contrast, all isolates were susceptible to vancomycin, and heteroresistance was detected by the screening method in 13 isolates. Production of β-lactamase was observed in 174 (96%) of the Staphylococcus spp. isolates. The mecA gene was detected in 8 isolates, all of them belonging to the species Staphylococcus epidermidis, and staphylococcal cassette chromosome mec typing revealed the presence of type I and type IV isolates. Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Prevalence of Slow-Growth Vancomycin Nonsusceptibility in Methicillin-Resistant Staphylococcus aureus

PubMed Central

Azechi, Takuya; Miyazaki, Motoyasu; Takata, Tohru; Sekine, Miwa; Matsui, Hidehito; Hanaki, Hideaki; Yahara, Koji; Sasano, Hiroshi; Asakura, Kota; Takaku, Tomoiku; Ochiai, Tomonori; Komatsu, Norio; Chambers, Henry F.

2017-01-01

ABSTRACT We previously reported a novel phenotype of vancomycin-intermediate Staphylococcus aureus (VISA), i.e., “slow VISA,” whose colonies appear only after 72 h of incubation. Slow-VISA strains can be difficult to detect because prolonged incubation is required and the phenotype is unstable. To develop a method for detection of slow-VISA isolates, we studied 23 slow-VISA isolates derived from the heterogeneous VISA (hVISA) clinical strain Mu3. We identified single nucleotide polymorphisms (SNPs) in genes involved in various pathways which have been implicated in the stringent response, such as purine/pyrimidine synthesis, cell metabolism, and cell wall peptidoglycan synthesis. We found that mupirocin, which also induces the stringent response, caused stable expression of vancomycin resistance. On the basis of these results, we developed a method for detection of slow-VISA strains by use of 0.032 μg/ml mupirocin (Yuki Katayama, 7 March 2017, patent application PCT/JP2017/008975). Using this method, we detected 53 (15.6%) slow-VISA isolates among clinical methicillin-resistant S. aureus (MRSA) isolates. In contrast, the VISA phenotype was detected in fewer than 1% of isolates. Deep-sequencing analysis showed that slow-VISA clones are present in small numbers among hVISA isolates and proliferate in the presence of vancomycin. This slow-VISA subpopulation may account in part for the recurrence and persistence of MRSA infection. PMID:28827421

Telavancin for Acute Bacterial Skin and Skin Structure Infections, a Post Hoc Analysis of the Phase 3 ATLAS Trials in Light of the 2013 FDA Guidance

PubMed Central

Pushkin, Richard; Barriere, Steven L.; Corey, G. Ralph; Stryjewski, Martin E.

2015-01-01

Two phase 3 ATLAS trials demonstrated noninferiority of telavancin compared with vancomycin for complicated skin and skin structure infections. Data from these trials were retrospectively evaluated according to 2013 U.S. Food and Drug Administration (FDA) guidance on acute bacterial skin and skin structure infections. This post hoc analysis included patients with lesion sizes of ≥75 cm2 and excluded patients with ulcers or burns (updated all-treated population; n = 1,127). Updated day 3 (early) clinical response was defined as a ≥20% reduction in lesion size from baseline and no rescue antibiotic. Updated test-of-cure (TOC) clinical response was defined as a ≥90% reduction in lesion size, no increase in lesion size since day 3, and no requirement for additional antibiotics or significant surgical procedures. Day 3 (early) clinical responses were achieved in 62.6% and 61.0% of patients receiving telavancin and vancomycin, respectively (difference, 1.7%, with a 95% confidence interval [CI] of −4.0% to 7.4%). Updated TOC visit cure rates were similar for telavancin (68.0%) and vancomycin (63.3%), with a difference of 4.8% (95% CI, −0.7% to 10.3%). Adopting current FDA guidance, this analysis corroborates previous noninferiority findings of the ATLAS trials of telavancin compared with vancomycin. PMID:26248356

Risk factors of treatment failure and 30-day mortality in patients with bacteremia due to MRSA with reduced vancomycin susceptibility.

PubMed

Yang, Chien-Chang; Sy, Cheng-Len; Huang, Yhu-Chering; Shie, Shian-Sen; Shu, Jwu-Ching; Hsieh, Pang-Hsin; Hsiao, Ching-Hsi; Chen, Chih-Jung

2018-05-18

Bacteremia caused by MRSA with reduced vancomycin susceptibility (MRSA-RVS) frequently resulted in treatment failure and mortality. The relation of bacterial factors and unfavorable outcomes remains controversial. We retrospectively reviewed clinical data of patients with bacteremia caused by MRSA with vancomycin MIC = 2 mg/L from 2009 to 2012. The significance of bacterial genotypes, agr function and heterogeneous vancomycin-intermediate S. aureus (hIVSA) phenotype in predicting outcomes were determined after clinical covariates adjustment with multivariate analysis. A total of 147 patients with mean age of 63.5 (±18.1) years were included. Seventy-nine (53.7%) patients failed treatment. Forty-seven (31.9%) patients died within 30 days of onset of MRSA bacteremia. The Charlson index, Pitt bacteremia score and definitive antibiotic regimen were independent factors significantly associated with either treatment failure or mortality. The hVISA phenotype was a potential risk factor predicting treatment failure (adjusted odds ratio 2.420, 95% confidence interval 0.946-6.191, P = 0.0652). No bacterial factors were significantly associated with 30-day mortality. In conclusion, the comorbidities, disease severity and antibiotic regimen remained the most relevant factors predicting treatment failure and 30-day mortality in patients with MRSA-RVS bacteremia. hIVSA phenotype was the only bacterial factor potentially associated with unfavorable outcome in this cohort.

Comparison of the antibiotic activities of Daptomycin, Vancomycin, and the investigational Fluoroquinolone Delafloxacin against biofilms from Staphylococcus aureus clinical isolates.

PubMed

Siala, Wafi; Mingeot-Leclercq, Marie-Paule; Tulkens, Paul M; Hallin, Marie; Denis, Olivier; Van Bambeke, Françoise

2014-11-01

Biofilm-related infections remain a scourge. In an in vitro model of biofilms using Staphylococcus aureus reference strains, delafloxacin and daptomycin were found to be the most active among the antibiotics from 8 different pharmacological classes (J. Bauer, W. Siala, P. M. Tulkens, and F. Van Bambeke, Antimicrob. Agents Chemother. 57:2726-2737, 2013, doi:10.1128/AAC.00181-13). In this study, we compared delafloxacin to daptomycin and vancomycin using biofilms produced by 7 clinical strains (S. aureus epidemic clones CC5 and CC8) in order to rationalize the differences observed between the antibiotics and strains. The effects of the antibiotics on bacterial viability (resazurin reduction assay) and biomass (crystal violet staining) were measured and correlated with the proportion of polysaccharides in the matrix, the local microenvironmental pH (micro-pH), and the antibiotic penetration in the biofilm. At clinically meaningful concentrations, delafloxacin, daptomycin, and vancomycin caused a ≥25% reduction in viability against the biofilms formed by 5, 4, and 3 strains, respectively. The antibiotic penetration within the biofilms ranged from 0.6 to 52% for delafloxacin, 0.2 to 10% for daptomycin, and 0.2 to 1% for vancomycin; for delafloxacin, this was inversely related to the polysaccharide proportion in the matrix. Six biofilms were acidic, explaining the high potency of delafloxacin (lower MICs at acidic pH). Norspermidine and norspermine (disassembling the biofilm matrix) drastically increased delafloxacin potency and efficacy (50% reduction in viability for 6 biofilms at clinically meaningful concentrations) in direct correlation with its increased penetration within the biofilm, while they only modestly improved daptomycin efficacy (50% reduction in viability for 2 biofilms) and penetration, and they showed marginal effects with vancomycin. Delafloxacin potency and efficacy against biofilms are benefited by its penetration into the matrix and the local acidic micro-pH. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Comparison of the Antibiotic Activities of Daptomycin, Vancomycin, and the Investigational Fluoroquinolone Delafloxacin against Biofilms from Staphylococcus aureus Clinical Isolates

PubMed Central

Siala, Wafi; Mingeot-Leclercq, Marie-Paule; Tulkens, Paul M.; Hallin, Marie; Denis, Olivier

2014-01-01

Biofilm-related infections remain a scourge. In an in vitro model of biofilms using Staphylococcus aureus reference strains, delafloxacin and daptomycin were found to be the most active among the antibiotics from 8 different pharmacological classes (J. Bauer, W. Siala, P. M. Tulkens, and F. Van Bambeke, Antimicrob. Agents Chemother. 57:2726–2737, 2013, doi:10.1128/AAC.00181-13). In this study, we compared delafloxacin to daptomycin and vancomycin using biofilms produced by 7 clinical strains (S. aureus epidemic clones CC5 and CC8) in order to rationalize the differences observed between the antibiotics and strains. The effects of the antibiotics on bacterial viability (resazurin reduction assay) and biomass (crystal violet staining) were measured and correlated with the proportion of polysaccharides in the matrix, the local microenvironmental pH (micro-pH), and the antibiotic penetration in the biofilm. At clinically meaningful concentrations, delafloxacin, daptomycin, and vancomycin caused a ≥25% reduction in viability against the biofilms formed by 5, 4, and 3 strains, respectively. The antibiotic penetration within the biofilms ranged from 0.6 to 52% for delafloxacin, 0.2 to 10% for daptomycin, and 0.2 to 1% for vancomycin; for delafloxacin, this was inversely related to the polysaccharide proportion in the matrix. Six biofilms were acidic, explaining the high potency of delafloxacin (lower MICs at acidic pH). Norspermidine and norspermine (disassembling the biofilm matrix) drastically increased delafloxacin potency and efficacy (50% reduction in viability for 6 biofilms at clinically meaningful concentrations) in direct correlation with its increased penetration within the biofilm, while they only modestly improved daptomycin efficacy (50% reduction in viability for 2 biofilms) and penetration, and they showed marginal effects with vancomycin. Delafloxacin potency and efficacy against biofilms are benefited by its penetration into the matrix and the local acidic micro-pH. PMID:25114142

In Vitro and In Vivo Activities of Nitazoxanide against Clostridium difficile

PubMed Central

McVay, Catherine S.; Rolfe, Rial D.

2000-01-01

We have used the hamster model of antibiotic-induced Clostridium difficile intestinal disease to evaluate nitazoxanide (NTZ), a nitrothiazole benzamide antimicrobial agent. The following in vitro and in vivo activities of NTZ in the adult hamster were examined and compared to those of metronidazole and vancomycin: (i) MICs and minimum bactericidal concentrations (MBCs) against C. difficile, (ii) toxicity, (iii) ability to prevent C. difficile-associated ileocecitis, and (iv) propensity to induce C. difficile-associated ileocecitis. The MICs and MBCs of NTZ against 15 toxigenic strains of C. difficile were comparable to those of vancomycin or metronidazole. C. difficile-associated ileocecitis was induced with oral clindamycin and toxigenic C. difficile in a group of 60 hamsters. Subgroups of 10 hamsters were given six daily intragastric treatments of NTZ (15, 7.5, and 3.0 mg/100 g of body weight [gbw]), metronidazole (15 mg/100 gbw), vancomycin (5 mg/100 gbw), or saline (1 ml/100 gbw). Animals receiving saline died 3 days post-C. difficile challenge. During the treatment period, NTZ (≥7.5 mg/100 gbw), like metronidazole and vancomycin, prevented outward manifestations of clindamycin-induced C. difficile intestinal disease. Six of ten hamsters on a scheduled dose of 3.0 mg of NTZ/100 gbw survived for the complete treatment period. Of these surviving animals, all but three died of C. difficile disease by between 3 and 12 days following discontinuation of antibiotic therapy. Another group of hamsters received six similar daily doses of the three antibiotics, followed by an inoculation with toxigenic C. difficile. All of the NTZ-treated animals survived the 15-day postinfection period. Upon necropsy, all hamsters appeared normal: there were no gross signs of toxicity or C. difficile intestinal disease, nor was C. difficile detected in the cultures of the ceca of these animals. By contrast, vancomycin and metronidazole treatment induced fatal C. difficile intestinal disease in 20 and 70% of recipients, respectively. PMID:10952564

Implications of serum creatinine measurements on GFR estimation and vancomycin dosing in children.

PubMed

Neuman, Gal; Nulman, Irena; Adeli, Khosrow; Koren, Gideon; Colantonio, David A; Helldén, Anders

2014-07-01

Different serum creatinine (sCr) assays may obtain different values in the same patient, causing discrepancies in estimated glomerular filtration rate (eGFR) and sCr-based vancomycin dosing calculations. To identify potential discrepancies in sCr concentrations obtained by different assays, the compensated Jaffe (sCr-Jaffe) and the enzymatic (sCr-enz), and to compare between the eGFR and vancomycin daily dose, based on these sCr values. sCr-Jaffe and, sCr-enz concentrations of 890 healthy children, aged 1-18 years, were available from the Canadian Laboratory Initiative in Pediatric Reference Intervals study in Ontario. For each subject, eGFR (eGFR-Jaffe, eGFR-enz) was calculated using the revised Schwartz equation, and vancomycin daily dose (Vdose-Jaffe, Vdose-enz) was calculated using a sCr-based pharmacokinetic model. Significant, age-related differences were found in sCr concentrations, and in subsequent eGFR and Vdose, between the two assays. In children aged 1-5 years, mean sCr-Jaffe was higher than sCr-enz (44.0 ± 5.0 vs. 27.7 ± 7.3 μmol/L, P < 0.001), leading to lower eGFR-Jaffe (83.2 ± 9.0 vs. 137.9 ± 27.1 mL/min/1.73m2, P < 0.001) and lower Vdose-Jaffe (44.7 ± 2.5 vs. 53.5 ± 5.1 mg/kg/24 h, P < 0.001). Based on these findings, young children may be at risk for vancomycin under-treatment. Further research is needed to define the more accurate sCr assay in young children treated with renally excreted drugs. © 2014, The American College of Clinical Pharmacology.

Vancomycin AUC/MIC and Corresponding Troughs in a Pediatric Population

PubMed Central

Lardieri, Allison B.; Heil, Emily L.; Morgan, Jill A.

2017-01-01

OBJECTIVES Adult guidelines suggest an area under the curve/minimum inhibitory concentration (AUC/MIC) > 400 corresponds to a vancomycin trough serum concentration of 15 to 20 mg/L for methicillin-resistant Staphylococcus aureus infections, but obtaining these troughs in children are difficult. The primary objective of this study was to assess the likelihood that 15 mg/kg of vancomycin every 6 hours in a child achieves an AUC/MIC > 400. METHODS This retrospective chart review included pediatric patients >2 months to <18 years with a positive S aureus blood culture and documented MIC who received at least two doses of vancomycin with corresponding trough. Patients were divided into two groups: group 1 initially receiving ≥15 mg/kg every 6 hours, and group 2 initially receiving any other dosing ranges or intervals. AUCs were calculated four times using three pharmacokinetic methods. RESULTS A total of 36 patients with 99 vancomycin trough serum concentrations were assessed. Baseline characteristics were similar between groups. For troughs in group 1 (n = 55), the probability of achieving an AUC/MIC > 400 ranged from 16.4% to 90.9% with a median trough concentration of 11.4 mg/L, while in group 2 (n = 44) the probability of achieving AUC/MIC > 400 ranged from 15.9% to 54.5% with mean trough concentration of 9.2 mg/L. The AUC/MICs were not similar between the different pharmacokinetic methods used; however, a trapezoidal equation (Method A) yielded the highest correlation coefficient (r2 = 0.59). When dosing every 6 hours, an AUC/MIC of 400 correlated to a trough serum concentration of 11 mg/L. CONCLUSIONS The probability of achieving an AUC/MIC > 400 using only a trough serum concentration and an MIC with patients receiving 15 mg/kg every 6 hours is variable based on the method used to calculate the AUC. An AUC/MIC of 400 in children correlated to a trough concentration of 11 mg/L using a trapezoidal Method to calculate AUC. PMID:28337080

Vancomycin AUC/MIC and Corresponding Troughs in a Pediatric Population.

PubMed

Kishk, Omayma A; Lardieri, Allison B; Heil, Emily L; Morgan, Jill A

2017-01-01

Adult guidelines suggest an area under the curve/minimum inhibitory concentration (AUC/MIC) > 400 corresponds to a vancomycin trough serum concentration of 15 to 20 mg/L for methicillin-resistant Staphylococcus aureus infections, but obtaining these troughs in children are difficult. The primary objective of this study was to assess the likelihood that 15 mg/kg of vancomycin every 6 hours in a child achieves an AUC/MIC > 400. This retrospective chart review included pediatric patients >2 months to <18 years with a positive S aureus blood culture and documented MIC who received at least two doses of vancomycin with corresponding trough. Patients were divided into two groups: group 1 initially receiving ≥15 mg/kg every 6 hours, and group 2 initially receiving any other dosing ranges or intervals. AUCs were calculated four times using three pharmacokinetic methods. A total of 36 patients with 99 vancomycin trough serum concentrations were assessed. Baseline characteristics were similar between groups. For troughs in group 1 (n = 55), the probability of achieving an AUC/MIC > 400 ranged from 16.4% to 90.9% with a median trough concentration of 11.4 mg/L, while in group 2 (n = 44) the probability of achieving AUC/MIC > 400 ranged from 15.9% to 54.5% with mean trough concentration of 9.2 mg/L. The AUC/MICs were not similar between the different pharmacokinetic methods used; however, a trapezoidal equation (Method A) yielded the highest correlation coefficient (r 2 = 0.59). When dosing every 6 hours, an AUC/MIC of 400 correlated to a trough serum concentration of 11 mg/L. The probability of achieving an AUC/MIC > 400 using only a trough serum concentration and an MIC with patients receiving 15 mg/kg every 6 hours is variable based on the method used to calculate the AUC. An AUC/MIC of 400 in children correlated to a trough concentration of 11 mg/L using a trapezoidal Method to calculate AUC.

Vancomycin-resistance phenotypes, vancomycin-resistance genes, and resistance to antibiotics of enterococci isolated from food of animal origin.

PubMed

Gousia, Panagiota; Economou, Vangelis; Bozidis, Petros; Papadopoulou, Chrissanthy

2015-03-01

In the present study, 500 raw beef, pork, and chicken meat samples and 100 pooled egg samples were analyzed for the presence of vancomycin-resistant enterococci, vancomycin-resistance phenotypes, and resistance genes. Of 141 isolates of enterococci, 88 strains of Enterococcus faecium and 53 strains of E. faecalis were identified. The most prevalent species was E. faecium. Resistance to ampicillin (n = 93, 66%), ciprofloxacin (n = 74, 52.5%), erythromycin (n = 73, 51.8%), penicillin (n = 59, 41.8%) and tetracycline (n = 52, 36.9%) was observed, while 53.2% (n = 75) of the isolates were multiresistant and 15.6% (n = 22) were susceptible to all antibiotics. Resistance to vancomycin was exhibited in 34.1% (n = 30) of the E. faecium isolates (n = 88) and 1.9% (n = 1) of the E. faecalis isolates (n = 53) using the disc-diffusion test and the E-test. All isolates were tested for vanA and vanB using real-time polymerase chain reaction (PCR) and multiplex PCR, and for vanC, vanD, vanE, vanG genes using multiplex PCR only. Among E. faecalis isolates, no resistance genes were identified. Among the E. faecium isolates, 28 carried the vanA gene when tested by multiplex PCR and 29 when tested with real-time PCR. No isolate carrying the vanC, vanD, vanE, or vanG genes was identified. Melting-curve analysis of the positive real-time PCR E. faecium isolates showed that 22 isolates carried the vanA gene only, 2 isolates the vanB2,3 genes only, and seven isolates carried both the vanA and vanB2,3 genes. Enterococci should be considered a significant zoonotic pathogen and a possible reservoir of genes encoding resistance potentially transferred to other bacterial species.

Comprehensive Identification of Mutations Responsible for Heterogeneous Vancomycin-Intermediate Staphylococcus aureus (hVISA)-to-VISA Conversion in Laboratory-Generated VISA Strains Derived from hVISA Clinical Strain Mu3

PubMed Central

Matsuo, Miki; Cui, Longzhu; Kim, Jeeyoung

2013-01-01

Heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) spontaneously produces VISA cells within its cell population at a frequency of 10−6 or greater. We established a total of 45 VISA mutant strains independently obtained from hVISA Mu3 and its related strains by one-step vancomycin selection. We then performed high-throughput whole-genome sequencing of the 45 strains and their parent strains to identify the genes involved in the hVISA-to-VISA phenotypic conversion. A comparative genome study showed that all the VISA strains tested carried a unique set of mutations. All of the 45 VISA strains carried 1 to 4 mutations possibly affecting the expression of a total of 48 genes. Among them, 32 VISA strains carried only one gene affected by a single mutation. As many as 20 genes in more than eight functional categories were affected in the 32 VISA strains, which explained the extremely high rates of the hVISA-to-VISA phenotypic conversion. Five genes, rpoB, rpoC, walK, pbp4, and pp2c, were previously reported as being involved in vancomycin resistance. Fifteen remaining genes were newly identified as associated with vancomycin resistance in this study. The gene most frequently affected (6 out of 32 strains) was cmk, which encodes cytidylate kinase, followed closely by rpoB (5 out of 32), encoding the β subunit of RNA polymerase. A mutation prevalence study also revealed a sizable number of cmk mutants among clinical VISA strains (7 out of 38 [18%]). Reduced cytidylate kinase activity in cmk mutant strains is proposed to contribute to the hVISA-to-VISA phenotype conversion by thickening the cell wall and reducing the cell growth rate. PMID:24018261

The evolution of vancomycin intermediate Staphylococcus aureus (VISA) and heterogenous-VISA.

PubMed

Howden, Benjamin P; Peleg, Anton Y; Stinear, Timothy P

2014-01-01

Resistance to new antimicrobials is generally recognized in Staphylococcus aureus soon after they are released for clinical use. In the case of vancomycin, which was first released in the 1950s, resistance was not reported until the mid 1990s, with the description of vancomycin-intermediate S. aureus (VISA), and heterogenous-VISA (hVISA). Unraveling the complex genetic and cell wall structural changes conferring low-level vancomycin resistance in S. aureus has proved challenging. However the recent advances in high throughput whole-genome sequencing has played a key role in determining the breadth of bacterial chromosomal changes linked with resistance. Diverse mutations in a small number of staphylococcal regulatory genes, in particular walKR, graRS, vraSR and rpoB, have been associated with hVISA and VISA. Only a small number of these mutations have been experimentally proven to confer the resistance phenotype and some of these only partially contribute to resistance. It also appears that the evolution of VISA from VSSA is a step-wise process. Transcriptomics studies, and analysis of host pathogen interactions, indicate that the evolution of vancomycin-susceptible S. aureus to VISA is associated not only with antibiotic resistance, but with other changes likely to promote persistent infection. These include predicted alterations in central metabolism, altered expression of virulence associated factors, attenuated virulence in vivo, and alterations in susceptibility to host innate immune responses, together with reduced susceptibility to other antibiotics. In fact, current data suggests that hVISA and VISA represent a bacterial evolutionary state favoring persistence in the face of not only antibiotics, but also the host environment. The additional knowledge of staphylococcal biology that has been uncovered during the study of hVISA and VISA is significant. The present review will detail the current understanding of the evolutionary process in the generation of hVISA and VISA, and explore the diverse additional changes that occur in these strains. Copyright © 2013 Elsevier B.V. All rights reserved.

Clinical and Microbiological Characteristics of Heteroresistant and Vancomycin-Intermediate Staphylococcus aureus from Bloodstream Infections in a Brazilian Teaching Hospital

PubMed Central

da Costa, Thaina Miranda; Morgado, Priscylla Guimarães Migueres; Cavalcante, Fernanda Sampaio; Damasco, Andreia Paredes; Nouér, Simone Aranha; dos Santos, Kátia Regina Netto

2016-01-01

This study analyzed clinical and microbiological characteristics of heteroresistant (hVISA) and vancomycin-intermediate Staphylococcus aureus (VISA) from bloodstream infections (BSI) in a Brazilian teaching hospital, between 2011 and 2013. Minimum inhibitory concentrations (MIC) of antimicrobials were determined by broth microdilution method and SCCmec was detected by PCR. Isolates with a vancomycin MIC ≥ 2mg/L were cultured on BHI agar with 3, 4 or 6 mg/L (BHIa3, BHIa4 or BHIa6) of vancomycin and BHIa4 with casein (BHIa4ca). Macromethod Etest® and Etest® Glicopeptides Resistance Detection were also used. VISA and hVISA isolates were confirmed by the population analysis profile then typed by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing. Medical data from the patients were obtained from their medical records. Among 110 consecutive isolates, 31 (28%) were MRSA and carried the SCCmec type II (15 isolates) or IV (16 isolates). Vancomycin MIC50 and MIC90 were 1 and 2 mg/L, respectively. MRSA isolates had increased non-susceptibility to daptomycin (p = 0.0003). Six (5%) isolates were VISA, four of which were MRSA, three SCCmec type II/USA100/ST5 and one type IV/USA800/ST3192. One MRSA SCCmec II isolate grew on agar BHIa3, BHIa4 and BHIa4ca, and it was confirmed as hVISA. Among the six VISA isolates, five (83%) grew on BHIa3 and three (50%) on BHI4ca. Four of the six VISA isolates and the one hVISA isolate were from patients who had undergone dialysis. Thus, a possible dissemination of the SCCmec II/USA100/ST5 lineage may have occurred in the hospital comprising the VISA, hVISA and daptomycin non-susceptible S. aureus Brazilian isolates from health care associated bloodstream infections. PMID:27575698

Clinical and Microbiological Characteristics of Heteroresistant and Vancomycin-Intermediate Staphylococcus aureus from Bloodstream Infections in a Brazilian Teaching Hospital.

PubMed

da Costa, Thaina Miranda; Morgado, Priscylla Guimarães Migueres; Cavalcante, Fernanda Sampaio; Damasco, Andreia Paredes; Nouér, Simone Aranha; Dos Santos, Kátia Regina Netto

2016-01-01

This study analyzed clinical and microbiological characteristics of heteroresistant (hVISA) and vancomycin-intermediate Staphylococcus aureus (VISA) from bloodstream infections (BSI) in a Brazilian teaching hospital, between 2011 and 2013. Minimum inhibitory concentrations (MIC) of antimicrobials were determined by broth microdilution method and SCCmec was detected by PCR. Isolates with a vancomycin MIC ≥ 2mg/L were cultured on BHI agar with 3, 4 or 6 mg/L (BHIa3, BHIa4 or BHIa6) of vancomycin and BHIa4 with casein (BHIa4ca). Macromethod Etest® and Etest® Glicopeptides Resistance Detection were also used. VISA and hVISA isolates were confirmed by the population analysis profile then typed by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing. Medical data from the patients were obtained from their medical records. Among 110 consecutive isolates, 31 (28%) were MRSA and carried the SCCmec type II (15 isolates) or IV (16 isolates). Vancomycin MIC50 and MIC90 were 1 and 2 mg/L, respectively. MRSA isolates had increased non-susceptibility to daptomycin (p = 0.0003). Six (5%) isolates were VISA, four of which were MRSA, three SCCmec type II/USA100/ST5 and one type IV/USA800/ST3192. One MRSA SCCmec II isolate grew on agar BHIa3, BHIa4 and BHIa4ca, and it was confirmed as hVISA. Among the six VISA isolates, five (83%) grew on BHIa3 and three (50%) on BHI4ca. Four of the six VISA isolates and the one hVISA isolate were from patients who had undergone dialysis. Thus, a possible dissemination of the SCCmec II/USA100/ST5 lineage may have occurred in the hospital comprising the VISA, hVISA and daptomycin non-susceptible S. aureus Brazilian isolates from health care associated bloodstream infections.

The effects of amoxicillin and vancomycin on parameters reflecting cholesterol metabolism.

PubMed

Baumgartner, S; Reijnders, D; Konings, M C J M; Groen, A K; Lütjohann, D; Goossens, G H; Blaak, E E; Plat, J

2017-10-01

Changes in the microbiota composition have been implicated in the development of obesity and type 2 diabetes. However, not much is known on the involvement of gut microbiota in lipid and cholesterol metabolism. In addition, the gut microbiota might also be a potential source of plasma oxyphytosterol and oxycholesterol concentrations (oxidation products of plant sterols and cholesterol). Therefore, the aim of this study was to modulate the gut microbiota by antibiotic therapy to investigate effects on parameters reflecting cholesterol metabolism and oxyphytosterol concentrations. A randomized, double blind, placebo-controlled trial was performed in which 55 obese, pre-diabetic men received oral amoxicillin (broad-spectrum antibiotic), vancomycin (antibiotic directed against Gram-positive bacteria) or placebo (microcrystalline cellulose) capsules for 7days (1500mg/day). Plasma lipid and lipoprotein, non-cholesterol sterol, bile acid and oxy(phyto)sterol concentrations were determined at baseline and after 1-week intervention. Plasma secondary bile acids correlated negatively with cholestanol (marker for cholesterol absorption, r=-0.367; P<0.05) and positively with lathosterol concentrations (marker for cholesterol synthesis, r=0.430; P<0.05). Fasting plasma secondary bile acid concentrations were reduced after vancomycin treatment as compared to placebo treatment (-0.24±0.22μmol/L vs. -0.08±0.29μmol/L; P<0.01). Vancomycin and amoxicillin treatment did not affect markers for cholesterol metabolism, plasma TAG, total cholesterol, LDL-C or HDL-C concentrations as compared to placebo. In addition, both antibiotic treatments did not affect individual isoforms or total plasma oxyphytosterol or oxycholesterol concentrations. Despite strong correlations between plasma bile acid concentrations and cholesterol metabolism (synthesis and absorption), amoxicillin and vancomycin treatment for 7days did not affect plasma lipid and lipoprotein, plasma non-cholesterol sterol and oxy(phyto)sterol concentrations in obese, pre-diabetic men. Copyright © 2017 Elsevier B.V. All rights reserved.

Presence of the resistance genes vanC1 and pbp5 in phenotypically vancomycin and ampicillin susceptible Enterococcus faecalis.

PubMed

Schwaiger, Karin; Bauer, Johann; Hörmansdorfer, Stefan; Mölle, Gabriele; Preikschat, Petra; Kämpf, Peter; Bauer-Unkauf, Ilse; Bischoff, Meike; Hölzel, Christina

2012-08-01

Ampicillin and vancomycin are important antibiotics for the therapy of Enterococcus faecalis infections. The ampicillin resistance gene pbp5 is intrinsic in Enterococcus faecium. The vanC1 gene confers resistance to vancomycin and serves as a species marker for Enterococcus gallinarum. Both genes are chromosomally located. Resistance to ampicillin and vancomycin was determined in 484 E. faecalis of human and porcine origin by microdilution. Since E. faecalis are highly skilled to acquire resistance genes, all strains were investigated for the presence of pbp5 (and, in positive strains, for the penicillin-binding protein synthesis repressor gene psr) and vanC1 (and, in positive strains, for vanXYc and vanT) by using polymerase chain reaction (PCR). One porcine and one human isolate were phenotypically resistant to ampicillin; no strain was vancomycin resistant. Four E. faecalis (3/1 of porcine/human origin) carried pbp5 (MIC=1 mg/L), and four porcine strains were vanC1 positive (minimum inhibitory concentration [MIC]=1 mg/L). Real-time reverse transcriptase (RT)-PCR revealed that the genes were not expressed. The psr gene was absent in the four pbp5-positive strains; the vanXYc gene was absent in the four vanC1-positive strains. However, vanT of the vanC gene cluster was detected in two vanC1-positive strains. To our knowledge, this is the first report on the presence of pbp5, identical with the "E. faecium pbp5 gene," and of vanC1/vanT in E. faecalis. Even if resistance is not expressed in these strains, this study shows that E. faecalis have a strong ability to acquire resistance genes-and potentially to spread them to other bacteria. Therefore, close monitoring of this species should be continued.

A Comparison of Environmental Contamination by Patients Infected or Colonized with Methicillin-Resistant Staphylococcus aureus or Vancomycin-Resistant Enterococci: A Multicenter Study

PubMed Central

Knelson, Lauren P.; Williams, David A.; Gergen, Maria F.; Rutala, William A.; Weber, David J.; Sexton, Daniel J.; Anderson, Deverick J.

2014-01-01

A total of 1,023 environmental surfaces were sampled from 45 rooms with patients infected or colonized with methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant enterococci (VRE) before terminal room cleaning. Colonized patients had higher median total target colony-forming units (CFU) of MRSA or VRE than did infected patients (median, 25 CFU [interquartile range, 0–106 CFU] vs 0 CFU [interquartile range, 0–29 CFU]; P = .033). PMID:24915217

Bio-inspired synthetic receptor molecules towards mimicry of vancomycin.

PubMed

Monnee, M C; Brouwer, A J; Verbeek, L M; van Wageningen, A M; Liskamp, R M

2001-06-18

A 512-member library of bio-inspired synthetic receptor molecules was prepared featuring a triazacyclophane scaffold. The purpose of this scaffold was to orient three (identical) peptide 'binding arms' in order to mimic an antibiotic binding cavity as is present in the vancomycin antibiotics. The library was screened with D-Ala-D-Ala and D-Ala-D-Lac containing ligands, which are present in the cell wall precursors of pathogenic bacteria. Screening and validation led to identification of a synthetic receptor capable of binding these ligands.

Treatment of Vancomycin-Resistant Enterococcal Infections in the Immunocompromised Host: Quinupristin-Dalfopristin in Combination with Minocycline

PubMed Central

Raad, Issam; Hachem, Ray; Hanna, Hend; Girgawy, Essam; Rolston, Kenneth; Whimbey, Estella; Husni, Rola; Bodey, Gerald

2001-01-01

Between February 1994 and November 1998, 56 oncology patients infected with vancomycin-resistant enterococci (VRE) were treated with quinopristin-dalfopristin (Q-D) plus minocycline (MIN). Infections included bacteremia, urinary tract infection, pneumonia, and wound infection. The response rate was 68%, and the most frequent adverse event was arthralgia or myalgia (36%). Q-D–MIN is effective for VRE infection in cancer patients but is associated with a substantial frequency of arthralgia or myalgia. PMID:11600379

Complete Genome Sequence of Staphylococcus aureus XN108, an ST239-MRSA-SCCmec III Strain with Intermediate Vancomycin Resistance Isolated in Mainland China

PubMed Central

Zhang, Xia; Xu, Xiaomeng; Yuan, Wenchang; Hu, Qiwen; Shang, Weilong; Hu, Xiaomei

2014-01-01

ST239-MRSA-SCCmec III (ST239, sequence type 239; MRSA, methicillin-resistant Staphylococcus aureus; SCCmec III, staphylococcal cassette chromosome mec type III) is the most predominant clone of hospital-acquired methicillin-resistant S. aureus in mainland China. We report here the complete genome sequence of XN108, the first vancomycin-intermediate S. aureus strain isolated from a steam-burned patient with a wound infection. PMID:25059856

Molecular Characterization of Enterococcus faecalis N06-0364 with Low-Level Vancomycin Resistance Harboring a Novel d-Ala-d-Ser Gene Cluster, vanL▿

PubMed Central

Boyd, David A.; Willey, Barbara M.; Fawcett, Darlene; Gillani, Nazira; Mulvey, Michael R.

2008-01-01

Enterococcus faecalis N06-0364, exhibiting a vancomycin MIC of 8 μg/ml, was found to harbor a novel d-Ala-d-Ser gene cluster, designated vanL. The vanL gene cluster was similar in organization to the vanC operon, but the VanT serine racemase was encoded by two separate genes, vanTmL (membrane binding) and vanTrL (racemase). PMID:18458129

Synthesis and study of antibacterial activities of antibacterial glycopeptide antibiotics conjugated with benzoxaboroles.

PubMed

Printsevskaya, S S; Reznikova, M I; Korolev, A M; Lapa, G B; Olsufyeva, E N; Preobrazhenskaya, M N; Plattner, J J; Zhang, Y K

2013-04-01

The ability of boron-containing compounds to undergo a number of novel binding interactions with drug target functional groups has recently been described. In an extension of this work, we have incorporated a boron-containing scaffold, the benzoxaborole, into several glycopeptides antibiotics. The aim of this work is to exploit the inherent reactivity of boron to gain additional interactions with the bacterial cell wall components to improve binding affinity and to thereby overcome resistance. Three antibacterial glycopeptides (vancomycin, eremomycin and teicoplanin aglycone) have been selected for the construction of a series of 12 new benzoxaborole-glycopeptide conjugates. The hybrid antibiotics, in which the benzoxaborole and glycopeptide moieties were separated by a linker, exhibited excellent antibacterial activity against Gram-positive bacteria, including those with intermediate susceptibility to glycopeptides. Some analogs also demonstrated activity against vancomycin-resistant enterococci. Conjugation of antibiotics with benzoxaborole derivatives provides antibiotics with new and useful properties. Teicoplanin aglycone-benzoxaborole derivatives overcome resistance of Gram-positive bacteria to vancomycin.

Staphylococcus haemolyticus endocarditis: clinical and microbiologic analysis of 4 cases.

PubMed

Falcone, Marco; Campanile, Floriana; Giannella, Maddalena; Borbone, Sonia; Stefani, Stefania; Venditti, Mario

2007-03-01

Only 3 cases of infective endocarditis (IE) due to methicillin-resistant Staphylococcus haemolyticus (MRSH) have been reported in English literature. Here we report 4 cases of IE due to MRSH encountered in a single university hospital. Population analysis of the strains was performed to assess the presence of vancomycin/teicoplanin heteroresistant subpopulations. Pulsed-field gel electrophoresis was used for molecular typing of isolates. IE was defined in 3 cases as health care associated, and in 1 case, as community acquired. A causative strain was lost. Two strains were heteroresistant to teicoplanin, and 1 also to vancomycin. Genome macrorestriction profile studies demonstrated that 2 MRSH isolates belonged to clones A and E, possessing a class C1 mecDNA, whereas 1 clone was sporadic. All patients were treated with vancomycin plus rifampin. Two patients were cured with antibiotic therapy alone, 1 patient needed surgery, and 1 patient died. Methicillin-resistant multiresistant S. haemolyticus may represent a difficult-to-treat cause of both community and nosocomially acquired IE.

Gut microbiota modulates adoptive cell therapy via CD8α dendritic cells and IL-12.

PubMed

Uribe-Herranz, Mireia; Bittinger, Kyle; Rafail, Stavros; Guedan, Sonia; Pierini, Stefano; Tanes, Ceylan; Ganetsky, Alex; Morgan, Mark A; Gill, Saar; Tanyi, Janos L; Bushman, Frederic D; June, Carl H; Facciabene, Andrea

2018-02-22

Adoptive T cell therapy (ACT) is a promising new modality for malignancies. Here, we report that adoptive T cell efficacy in tumor-bearing mice is significantly affected by differences in the native composition of the gut microbiome or treatment with antibiotics, or by heterologous fecal transfer. Depletion of bacteria with vancomycin decreased the rate of tumor growth in mice from The Jackson Laboratory receiving ACT, whereas treatment with neomycin and metronidazole had no effect, indicating the role of specific bacteria in host response. Vancomycin treatment induced an increase in systemic CD8α+ DCs, which sustained systemic adoptively transferred antitumor T cells in an IL-12-dependent manner. In subjects undergoing allogeneic hematopoietic cell transplantation, we found that oral vancomycin also increased IL-12 levels. Collectively, our findings demonstrate an important role played by the gut microbiota in the antitumor effectiveness of ACT and suggest potentially new avenues to improve response to ACT by altering the gut microbiota.

Lactobacillus Species Identification, H2O2 Production, and Antibiotic Resistance and Correlation with Human Clinical Status

PubMed Central

Felten, Annie; Barreau, Claude; Bizet, Chantal; Lagrange, Philippe Henri; Philippon, Alain

1999-01-01

Lactobacilli recovered from the blood, cerebrospinal fluid, respiratory tract, and gut of 20 hospitalized immunocompromised septic patients were analyzed. Biochemical carbohydrate fermentation and total soluble cell protein profiles were used to identify the species. Hydrogen peroxide production was measured. Susceptibility to 19 antibiotics was tested by a diffusion method, and the MICs of benzylpenicillin, amoxicillin, imipenem, erythromycin, vancomycin, gentamicin, and levofloxacin were determined. A small number of species produced H2O2, and antibiotic susceptibilities were species related. Eighteen (90%) of the isolates were L. rhamnosus, one was L. paracasei subsp. paracasei, and one was L. crispatus. L. rhamnosus, L. paracasei subsp. paracasei isolates, and the type strains were neither H2O2 producers nor vancomycin susceptible (MICs, ≥256 μg/ml). L. crispatus, as well as most of the type strains of lactobacilli which belong to the L. acidophilus group, was an H2O2 producer and vancomycin susceptible (MICs, <4 μg/ml). PMID:9986841

Evaluation of [(201)Tl](III) Vancomycin in normal rats.

PubMed

Jalilian, Amir Reza; Hosseini, Mohammad Amin; Majdabadi, Abbas; Saddadi, Fariba

2008-01-01

Tl-201 has potential in the preparation of radiolabelled compounds similar to its homologues, like In-111 and radiogallium. In this paper, recently prepared [(201)Tl](III) vancomycin complex ([(201)Tl](III)VAN) has been evaluated for its biological properties. [(201)Tl](III)VAN was prepared according to the optimized conditions followed by biodistribution studies in normal rats for up to 52 h. The Staphylococcus aurous specific binding was checked in vitro. The complex was finally injected to normal rats. Tracer SPECT images were obtained in normal animals and compared to those of (67)Ga-citrate. Freshly-prepared [(201)Tl](III)VAN batches (radiochemical yield > 99%, radiochemical purity > 98%, specific activity approximately 1.2 Ci/mmol) showed a similar biodistribution to that of unlabeled vancomycin. The microorganism binding ratios were 3 and 9 for tracer (201)Tl(3+) and tracer (201)Tl(III)DTPA, respectively, suggesting the preservation of the tracer bioactivity. As a nonspecific cell penetrating tracer, [(201)Tl](III)DTPA was used.

Efficacy and safety of fidaxomicin compared with oral vancomycin for the treatment of adults with Clostridium difficile-associated diarrhea: data from the OPT-80-003 and OPT-80-004 studies.

PubMed

Chen, Luke F; Anderson, Deverick J

2012-06-01

Clostridium difficile is emerging as one of the most important and devastating pathogens affecting hospitalized populations around the world. The incidence of C. difficile infection is increasing and disease severity is worsening. Thus, an effective alternative to metronidazole and oral vancomycin is urgently needed. Two Phase III trials, OPT-80-003 and OPT-80-004, showed that oral fidaxomicin for 10 days was noninferior compared with treatment with oral vancomycin among adult patients with toxin-positive C. difficile-associated diarrhea (CDAD). Furthermore, fidaxomicin was associated with a lower rate of recurrence of CDAD within 4 weeks of completion of therapy. The safety and tolerability of fidaxomicin was consistent with earlier studies and established that fidaxomicin is an efficacious and well-tolerated treatment option for CDAD. Despite these potential advantages, the cost-effectiveness of this expensive agent remains poorly understood.

Efficacy of oral vancomycin in recurrent primary sclerosing cholangitis following liver transplantation.

PubMed

Hey, Penelope; Lokan, Julie; Johnson, Paul; Gow, Paul

2017-09-25

Primary sclerosing cholangitis (PSC) is a liver disease that leads to progressive destruction and stricturing of the biliary tree. Unfortunately, apart from orthotopic liver transplantation (OLT), there are no universally accepted therapies to treat this disease. Even following transplantation, recurrence of PSC is seen in approximately one quarter of patients and leads to high rates of graft failure. Oral vancomycin, through possible immunomodulatory and anti-inflammatory mechanisms, has been shown in small-scale studies to be successful in improving liver function tests in patients with pretransplant PSC. We report the first case of an adult patient diagnosed with recurrent PSC 4 years after OLT who was treated with oral vancomycin leading to complete normalisation of his liver biochemistry. This case adds to the growing literature of a potential therapeutic role for this antibiotic in PSC and highlights interesting questions regarding mechanisms of disease. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Gut microbiota modulates adoptive cell therapy via CD8α dendritic cells and IL-12

PubMed Central

Bittinger, Kyle; Rafail, Stavros; Pierini, Stefano; Tanes, Ceylan; Ganetsky, Alex; Morgan, Mark A.; Gill, Saar; Tanyi, Janos L.; Bushman, Frederic D.; June, Carl H.

2018-01-01

Adoptive T cell therapy (ACT) is a promising new modality for malignancies. Here, we report that adoptive T cell efficacy in tumor-bearing mice is significantly affected by differences in the native composition of the gut microbiome or treatment with antibiotics, or by heterologous fecal transfer. Depletion of bacteria with vancomycin decreased the rate of tumor growth in mice from The Jackson Laboratory receiving ACT, whereas treatment with neomycin and metronidazole had no effect, indicating the role of specific bacteria in host response. Vancomycin treatment induced an increase in systemic CD8α+ DCs, which sustained systemic adoptively transferred antitumor T cells in an IL-12–dependent manner. In subjects undergoing allogeneic hematopoietic cell transplantation, we found that oral vancomycin also increased IL-12 levels. Collectively, our findings demonstrate an important role played by the gut microbiota in the antitumor effectiveness of ACT and suggest potentially new avenues to improve response to ACT by altering the gut microbiota. PMID:29467322

Novel quercetin glycosides as potent anti-MRSA and anti-VRE agents.

PubMed

Hossion, Abugafar M L; Sasaki, Kenji

2013-12-01

Each year in the United States, at least 2 million people become infected with bacteria that are resistant to antibiotics and at least 23,000 people die each year as a direct result of these infections (Threat report 2013). Vancomycin is an FDA approved antibiotic and is growing importance in the treatment of hospital infections, with particular emphasis on its value to fight against methicillin-resistant Staphylococcus aureus (MRSA). The increasing use of vancomycin to treat infections caused by the Gram-positive MRSA in the 1970s selected for drug-resistant enterococci, less potent than staphylococci but opportunistic in the space vacated by other bacteria and in patients with compromised immune systems. The dramatic rise of antibiotic-resistant bacteria over the past two decades has stressed the need for completely novel classes of antibacterial agents. This paper reports the recent patent review on the strategy for finding novel quercetinglycoside type antibacterial agents against vancomycin-resistant bacterial strains.

Bromomethylthioindole Inspired Carbazole Hybrids as Promising Class of Anti-MRSA Agents

PubMed Central

2016-01-01

Series of N-substituted carbazole analogues bearing an indole ring were synthesized as anti-methicillin-resistant Staphylococcus aureus (MRSA) agents from a molecular hybridization approach. The representative compound 19 showed an MIC = 1 μg/mL against a panel of MRSA clinical isolates as it possessed comparable in vitro activities to that of vancomycin. Moreover, compound 19 also exhibited MIC = 1 μg/mL activities against a recent identified Z172 MRSA strain (vancomycin-intermediate and daptomycin-nonsusceptible phenotype) and the vancomycin-resistant Enterococcus faecalis (VRE) strain. In a mouse model with lethal infection of MRSA (4N216), a 75% survival rate was observed after a single dose of compound 19 was intravenously administered at 20 mg/kg. In light of their equipotent activities against different MRSA isolates and VRE strain, the data underscore the importance of designed hybrid series for the development of new N-substituted carbazoles as potential anti-MRSA agents. PMID:27994762

Can dalbavancin be used as a catheter lock solution?

PubMed

Díaz-Ruíz, Cristina; Alonso, Beatriz; Cercenado, Emilia; Cruces, Raquel; Bouza, Emilio; Muñoz, Patricia; Guembe, María

2018-05-17

The new lipoglycopeptide dalbavancin has only been approved for acute bacterial skin and skin structure infections. However, its alternative use as a catheter lock solution could facilitate the conservative management of catheter-related bloodstream infection. Our objective was to assess the stability and activity of dalbavancin alone and in combination with heparin against methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE) biofilms. We also compared the results with those obtained with vancomycin alone and in combination with heparin. We used a 96-well plate in vitro model based on 24 h biofilms of MRSA and MRSE (ATCC 43300, ATCC 35984 and one clinical strain of each). The biofilms were exposed to dalbavancin (0.128 mg ml -1 ) and vancomycin (5 mg ml -1 ) alone and in combination with heparin (60 IU). The median percentage reductions in metabolic activity, biomass, bacterial load, and cell viability for each solution were compared. Dalbavancin combined with heparin significantly reduced the median [interquartile range (IQR)] percentage of metabolic activity in MRSA biofilms compared with vancomycin [90.0 % (70.4-92.9 %) versus 35.0 % (14.8-59.6 %), P=0.006]. For the remaining variables studied, the combination was not inferior to vancomycin for MRSA and MRSE. Dalbavancin proved to be active against MRSA and MRSE biofilms. The combination of dalbavancin with heparin is a promising catheter lock solution that has the advantage of locking the catheter at home for 7 days.

Assessment of treatment patterns and patient outcomes before vs after implementation of a severity-based Clostridium difficile infection treatment policy.

PubMed

Jardin, C G M; Palmer, H R; Shah, D N; Le, F; Beyda, N D; Jiang, Z; Garey, K W

2013-09-01

National guidelines recommend oral vancomycin for severe Clostridium difficile infection (CDI) based on results from recent clinical trials demonstrating improved clinical outcomes. However, real-world data to support these clinical trials are scant. To compare treatment patterns and patient outcomes of those treated for CDI before and after implementation of a severity-based CDI treatment policy at a tertiary teaching hospital. This study evaluated adult patients with a positive C. difficile toxin before and after implementation of a policy where patients with severe CDI given metronidazole were switched to oral vancomycin unless contra-indicated. Patients were stratified according to disease severity using a modified published severity score. Treatment patterns based on CDI severity and rates of refractory CDI were assessed. In total, 256 patients with CDI (mean age 66 years, standard deviation 17, 52% female) were evaluated (before implementation: N = 144; after implementation: N = 112). Use of oral vancomycin for severe CDI increased significantly from 14% (N = 8) to 91% (N = 48) following implementation of the policy (P < 0.0001). Refractory disease in patients with severe CDI decreased significantly from 37% to 15% following implementation of the policy (P = 0.035). No significant differences were noted among patients with mild to moderate CDI. A severity-based CDI treatment policy at a tertiary teaching hospital increased the use of oral vancomycin and was associated with decreased rates of refractory CDI. Copyright © 2013 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

Treatment of osteomyelitis and repair of bone defect by degradable bioactive borate glass releasing vancomycin.

PubMed

Xie, Zongping; Liu, Xin; Jia, Weitao; Zhang, Changqing; Huang, Wenhai; Wang, Jianqiang

2009-10-15

The effectiveness of a degradable and bioactive borate glass has been compared with the clinically used calcium sulfate in the treatment of osteomyelitis of rabbits, as a carrier for vancomycin. The bone infections were induced in the tibias of 65 rabbits by injecting methicillin-resistant Staphylococcus aureus (MRSA). After 3 weeks, these rabbits were distributed into 4 groups and treated by debridement. Pure borate glass (BG), vancomycin-loaded calcium sulfate (VCS) and vancomycin-loaded borate glass (VBG) were implanted into the infection sites of groups 2 to 4 respectively. After 8 weeks, the effectiveness of treatment was assessed radiographically, bacteriologically, and histopathologically. The results showed that the negative rates of MRSA examination for rabbits were 36.36%, 18.18%, 73.33% and 81.25% respectively for groups 1 to 4. Significant differences were observed radiographically, bacteriologically, and histopathologically between groups 1 and 4, groups 2 and 3, and between groups 2 and 4. The best result of treatment was observed in group 4. Radiographically, VBG was found to be mostly reabsorbed and replaced by lots of new bones, whereas, VCS was completely reabsorbed and replaced by modest new bones. Histopathologically, there were lots of newly formed bones around VBG without any foreign body response, and only modest new bones around VCS with obvious foreign body response. VBG proved to have excellent biocompatibility and to be very effective in eradicating osteomyelitis and simultaneously stimulating bone regeneration, avoiding the disadvantages of VCS.

A Transposon Screen Identifies Genetic Determinants of Vibrio cholerae Resistance to High-Molecular-Weight Antibiotics

PubMed Central

Delgado, Fernanda; Umans, Benjamin D.; Gerding, Matthew A.; Davis, Brigid M.

2016-01-01

Gram-negative bacteria are notoriously resistant to a variety of high-molecular-weight antibiotics due to the limited permeability of their outer membrane (OM). The basis of OM barrier function and the genetic factors required for its maintenance remain incompletely understood. Here, we employed transposon insertion sequencing to identify genes required for Vibrio cholerae resistance to vancomycin and bacitracin, antibiotics that are thought to be too large to efficiently penetrate the OM. The screen yielded several genes whose protein products are predicted to participate in processes important for OM barrier functions and for biofilm formation. In addition, we identified a novel factor, designated vigA (for vancomycin inhibits growth), that has not previously been characterized or linked to outer membrane function. The vigA open reading frame (ORF) codes for an inner membrane protein, and in its absence, cells became highly sensitive to glycopeptide antibiotics (vancomycin and ramoplanin) and bacitracin but not to other large antibiotics or detergents. In contrast to wild-type (WT) cells, the vigA mutant was stained with fluorescent vancomycin. These observations suggest that VigA specifically prevents the periplasmic accumulation of certain large antibiotics without exerting a general role in the maintenance of OM integrity. We also observed marked interspecies variability in the susceptibilities of Gram-negative pathogens to glycopeptides and bacitracin. Collectively, our findings suggest that the OM barrier is not absolute but rather depends on specific OM-antibiotic interactions. PMID:27216069

Synergistic effect of Carum copticum and Mentha piperita essential oils with ciprofloxacin, vancomycin, and gentamicin on Gram-negative and Gram-positive bacteria

PubMed Central

Talei, Gholam-Reza; Mohammadi, Mohsen; Bahmani, Mahmoud; Kopaei, Mahmoud Rafieian

2017-01-01

Background: Infectious diseases have always been an important health issue in human communities. In the recent years, much research has been conducted on antimicrobial effects of nature-based compounds because of increased prevalence of antibiotic resistance. The present study was conducted to investigate synergistic effect of Carum copticum and Mentha piperita essential oils with ciprofloxacin, vancomycin, and gentamicin on Gram-negative and Gram-positive bacteria. Materials and Methods: In this experimental study, the synergistic effects of C. copticum and M. piperita essential oils with antibiotics on Staphylococcus aureus (ATCC 25923), Enterococcus faecalis (ATCC 29212), Escherichia coli (ATCC 8739), Pseudomonas aeruginosa (ATCC 9027), Staphylococcus epidermidis (ATCC 14990), and Listeria monocytogenes (ATCC 7644) were studied according to broth microdilution and the MIC and fractional inhibitory concentration (FIC) of these two essential oils determined. Results: C. copticum essential oil at 30 μg/ml could inhibit S. aureus, and in combination with vancomycin, decreased MIC from 0.5 to 0.12 μg/ml. Moreover, the FIC was derived 0.24 μg/ml which represents a potent synergistic effect with vancomycin against S. aureus growth. C. copticum essential oil alone or combined with other antibiotics is effective in treating bacterial infections. Conclusions: In addition, C. copticum essential oil can strengthen the activities of certain antibiotics, which makes it possible to use this essential oil, especially in drug resistance or to lower dosage or toxicity of the drugs. PMID:28929050

A polyclonal outbreak of bloodstream infections by Enterococcus faecium in patients with hematologic malignancies.

PubMed

Alatorre-Fernández, Pamela; Mayoral-Terán, Claudia; Velázquez-Acosta, Consuelo; Franco-Rodríguez, Cecilia; Flores-Moreno, Karen; Cevallos, Miguel Ángel; López-Vidal, Yolanda; Volkow-Fernández, Patricia

2017-03-01

Enterococcus faecium causes bloodstream infection (BSI) in patients with hematologic malignancies (HMs). We studied the clinical features and outcomes of patients with HM with vancomycin-sensitive E faecium (VSE) and vancomycin-resistant E faecium (VRE) BSI and determined the genetic relatedness of isolates and circumstances associated with the upsurge of E faecium BSI. Case-control study of patients with HM and E faecium-positive blood culture from January 2008-December 2012; cases were patients with VRE and controls were VSE isolates. The strains were tested for Van genes by polymerase chain reaction amplification and we performed pulsed-field gel electrophoresis to determine genetic relatedness. Fifty-eight episodes of E faecium BSI occurred: 35 sensitive and 23 resistant to vancomycin. Mortality was 46% and 57%, attributable 17% and 40%, respectively. Early stage HM was associated with VSE (P = .044), whereas an episode of BSI within the 3 months before the event (P = .039), prophylactic antibiotics (P = .013), and vancomycin therapy during the previous 3 months (P = .001) was associated with VRE. The VanA gene was identified in 97% of isolates studied. E faecium isolates were not clonal. E faecium BSI was associated with high mortality. This outbreak of VRE was not clonal; it was associated with antibiotic-use pressure and highly myelosuppressive chemotherapy. Copyright © 2017 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.

COMPARISON BETWEEN AUTOMATED SYSTEM AND PCR-BASED METHOD FOR IDENTIFICATION AND ANTIMICROBIAL SUSCEPTIBILITY PROFILE OF CLINICAL Enterococcus spp

PubMed Central

Furlaneto-Maia, Luciana; Rocha, Kátia Real; Siqueira, Vera Lúcia Dias; Furlaneto, Márcia Cristina

2014-01-01

Enterococci are increasingly responsible for nosocomial infections worldwide. This study was undertaken to compare the identification and susceptibility profile using an automated MicrosScan system, PCR-based assay and disk diffusion assay of Enterococcus spp. We evaluated 30 clinical isolates of Enterococcus spp. Isolates were identified by MicrosScan system and PCR-based assay. The detection of antibiotic resistance genes (vancomycin, gentamicin, tetracycline and erythromycin) was also determined by PCR. Antimicrobial susceptibilities to vancomycin (30 µg), gentamicin (120 µg), tetracycline (30 µg) and erythromycin (15 µg) were tested by the automated system and disk diffusion method, and were interpreted according to the criteria recommended in CLSI guidelines. Concerning Enterococcus identification the general agreement between data obtained by the PCR method and by the automatic system was 90.0% (27/30). For all isolates of E. faecium and E. faecalis we observed 100% agreement. Resistance frequencies were higher in E. faecium than E. faecalis. The resistance rates obtained were higher for erythromycin (86.7%), vancomycin (80.0%), tetracycline (43.35) and gentamicin (33.3%). The correlation between disk diffusion and automation revealed an agreement for the majority of the antibiotics with category agreement rates of > 80%. The PCR-based assay, the van(A) gene was detected in 100% of vancomycin resistant enterococci. This assay is simple to conduct and reliable in the identification of clinically relevant enterococci. The data obtained reinforced the need for an improvement of the automated system to identify some enterococci. PMID:24626409

Bactericidal micron-thin sol-gel films prevent pin tract and periprosthetic infection.

PubMed

Qu, Haibo; Knabe, Christine; Burke, Megan; Radin, Shula; Garino, Jonathan; Schaer, Thomas; Ducheyne, Paul

2014-08-01

Orthopedic injuries constitute the majority of wounds sustained by U.S. soldiers in recent conflicts. The risk of infection is considerable with fracture fixation devices. In this pilot study, we examined the use of unique bactericidal micron-thin sol-gel films on fracture fixation devices and their ability to prevent and eradicate infections. External fixation was studied with micron-thin sol-gel coated percutaneous pins releasing triclosan and inserted medially into rabbit tibiae. A total of 11 rabbits received percutaneous pins that were either uncoated or sol-gel/triclosan coated. Internal fracture fixation was also studied using sol-gel coated intramedullary (IM) nails releasing vancomycin in the intramedullary tibiae. Six sheep received IM nails that were coated with a sol-gel film that either contained vancomycin or did not contain vancomycin. All animals were challenged with Staphylococcus aureus around the implant. Animals were euthanized at 1 month postoperative. Rabbits receiving triclosan/sol-gel coated percutaneous pins did not show signs of infection. Uncoated percutaneous pins had a significantly higher infection rate. In the sheep study, there were no radiographic signs of osteomyelitis with vancomycin/sol-gel coated IM nails, in contrast to the observations in the control cohort. Hence, the nanostructured sol-gel controlled release technology offers the promise of a reliable and continuous delivery system of bactericidals from orthopedic devices to prevent and treat infection. Reprint & Copyright © 2014 Association of Military Surgeons of the U.S.

Topical Rifampin Powder for Orthopaedic Trauma Part I: Rifampin powder reduces recalcitrant infection in a delayed treatment musculoskeletal trauma model.

PubMed

Shiels, Stefanie M; Tennent, David J; Wenke, Joseph C

2018-05-21

Open fractures become infected despite meticulous debridement and care. Locally applied antibiotics, commonly embedded in polymethylmethacrylate, deliver high doses of drug directly to the fracture site. Direct application of antibiotic powder, which is being applied prophylactically in spine surgery, is a recent interest in the trauma sector, where bacterial biofilms are more prevalent. Traditional antibiotics, such as vancomycin, are poor performers against bacterial biofilms thus are ineffective in delayed treatment. Rifampin is an effective eradicator of Staphylococcal biofilms. Here, a rat model of musculoskeletal trauma was used to evaluate the utility of locally applied rifampin powder for reducing established orthopaedic Staphylococcal infections in a delayed treatment scenario that previously indicated the limited use of local vancomycin. By applying rifampin powder directly to the contaminated segmental defect, the number of bacteria, as well as clinical indications of infection, were significantly reduced compared to vancomycin and daptomycin. Considering the Infectious Disease Society of America's recommendation to use rifampin in combination with another antibiotic to reduce the onset of rifampin resistance, rifampin powder was also applied in combination with vancomycin or daptomycin with insignificant changes in eradication performance. No indications of rifampin resistance were identified. Statement of Clinical Significance: The use of locally applied rifampin is a promising therapy for mature and tolerant musculoskeletal infections. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Misidentification of methicillin-resistant Staphylococcus aureus (MRSA) in hospitals in Tripoli, Libya

PubMed Central

Ahmed, Mohamed O.; Abuzweda, Abdulbaset R.; Alghazali, Mohamed H.; Elramalli, Asma K.; Amri, Samira G.; Aghila, Ezzeddin Sh.; Abouzeed, Yousef M.

2010-01-01

Background Methicillin-resistant Staphylococcus aureus (MRSA) is a nosocomial (hospital-acquired) pathogen of exceptional concern. It is responsible for life-threatening infections in both the hospital and the community. Aims To determine the frequency of MRSA misidentification in hospitals in Tripoli, Libya using current testing methods. Methods One hundred and seventy S. aureus isolates previously identified as MRSA were obtained from three hospitals in Tripoli. All isolates were reidentified by culturing on mannitol salt agar, API 20 Staph System and retested for resistance to methicillin using the cefoxitin disk diffusion susceptibility test and PBP2a. D-tests and vancomycin E-tests (Van-E-tests) were also performed for vancomycin-resistant isolates. Results Of the 170 isolates examined, 86 (51%) were confirmed as MRSA (i.e. 49% were misidentified as MRSA). Fifteen (17%) of the confirmed MRSA strains exhibited inducible clindamycin resistance. Of the 86 confirmed MRSA isolates, 13 (15%) were resistant to mupirocin, 53 (62%) were resistant to ciprofloxacin, 41 (48%) were resistant to trimethoprim-sulfamethoxazole, and none were resistant to linezolid. Although disc-diffusion testing indicated that 23 (27%) of the isolates were resistant to vancomycin, none of the isolates were vancomycin-resistant by Van-E-test. Conclusions Misidentification of nosocomial S. aureus as MRSA is a serious problem in Libyan hospitals. There is an urgent need for the proper training of microbiology laboratory technicians in standard antimicrobial susceptibility procedures and the implementation of quality control programs in microbiology laboratories of Libyan hospitals. PMID:21483574

Bioactive borate glass scaffolds: in vitro and in vivo evaluation for use as a drug delivery system in the treatment of bone infection.

PubMed

Liu, Xin; Xie, Zongping; Zhang, Changqing; Pan, Haobo; Rahaman, Mohamed N; Zhang, Xin; Fu, Qiang; Huang, Wenhai

2010-02-01

The objective of this work was to evaluate borate bioactive glass scaffolds (with a composition in the system Na(2)O-K(2)O-MgO-CaO-B(2)O(3)-P(2)O(5)) as devices for the release of the drug Vancomycin in the treatment of bone infection. A solution of ammonium phosphate, with or without dissolved Vancomycin, was used to bond borate glass particles into the shape of pellets. The in vitro degradation of the pellets and their conversion to a hydroxyapatite-type material in a simulated body fluid (SBF) were investigated using weight loss measurements, chemical analysis, X-ray diffraction, and scanning electron microscopy. The results showed that greater than 90% of the glass in the scaffolds degraded within 1 week, to form poorly crystallized hydroxyapatite (HA). Pellets loaded with Vancomycin provided controlled release of the drug over 4 days. Vancomycin-loaded scaffolds were implanted into the right tibiae of rabbits infected with osteomyelitis. The efficacy of the treatment was assessed using microbiological examination and histology. The HA formed in the scaffolds in vivo, resulting from the conversion of the glass, served as structure to support the growth of new bone and blood vessels. The results in this work indicate that bioactive borate glass could provide a promising biodegradable and bioactive material for use as both a drug delivery system and a scaffold for bone repair.

Randomized clinical trial to evaluate the effect of fecal microbiota transplant for initial Clostridium difficile infection in intestinal microbiome.

PubMed

Camacho-Ortiz, Adrián; Gutiérrez-Delgado, Eva María; Garcia-Mazcorro, Jose F; Mendoza-Olazarán, Soraya; Martínez-Meléndez, Adrián; Palau-Davila, Laura; Baines, Simon D; Maldonado-Garza, Héctor; Garza-González, Elvira

2017-01-01

The aim of this study was to evaluate the impact of fecal donor-unrelated donor mix (FMT-FURM) transplantation as first-line therapy for C. difficile infection (CDI) in intestinal microbiome. We designed an open, two-arm pilot study with oral vancomycin (250mg every 6 h for 10-14 days) or FMT-FURM as treatments for the first CDI episode in hospitalized adult patients in Hospital Universitario "Dr. Jose Eleuterio Gonzalez". Patients were randomized by a closed envelope method in a 1: 1 ratio to either oral vancomycin or FMT-FURM. CDI resolution was considered when there was a reduction on the Bristol scale of at least 2 points, a reduction of at least 50% in the number of bowel movements, absence of fever, and resolution of abdominal pain (at least two criteria). From each patient, a fecal sample was obtained at days 0, 3, and 7 after treatment. Specimens were cultured to isolate C. difficile, and isolates were characterized by PCR. Susceptibility testing of isolates was performed using the agar dilution method. Fecal samples and FMT-FURM were analyzed by 16S rRNA sequencing. We included 19 patients; 10 in the vancomycin arm and 9 in the FMT-FURM arm. However, one of the patients in the vancomycin arm and two patients in the FMT-FURM arm were eliminated. Symptoms resolved in 8/9 patients (88.9%) in the vancomycin group, while symptoms resolved in 4/7 patients (57.1%) after the first FMT-FURM dose (P = 0.26) and in 5/7 patients (71.4%) after the second dose (P = 0.55). During the study, no adverse effects attributable to FMT-FURM were observed in patients. Twelve isolates were recovered, most isolates carried tcdB, tcdA, cdtA, and cdtB, with an 18-bp deletion in tcdC. All isolates were resistant to ciprofloxacin and moxifloxacin but susceptible to metronidazole, linezolid, fidaxomicin, and tetracycline. In the FMT-FURM group, the bacterial composition was dominated by Firmicutes, Bacteroidetes, and Proteobacteria at all-time points and the microbiota were remarkably stable over time. The vancomycin group showed a very different pattern of the microbial composition when comparing to the FMT-FURM group over time. The results of this preliminary study showed that FMT-FURM for initial CDI is associated with specific bacterial communities that do not resemble the donors' sample.

Antistaphylococcal Activity of DX-619, a New Des-F(6)-Quinolone, Compared to Those of Other Agents

PubMed Central

Bogdanovich, Tatiana; Esel, Duygu; Kelly, Linda M.; Bozdogan, Bülent; Credito, Kim; Lin, Gengrong; Smith, Kathy; Ednie, Lois M.; Hoellman, Dianne B.; Appelbaum, Peter C.

2005-01-01

The in vitro activity of DX-619, a new des-F(6)-quinolone, was tested against staphylococci and compared to those of other antimicrobials. DX-619 had the lowest MIC ranges/MIC50s/MIC90s (μg/ml) against 131 Staphylococcus aureus strains (≤0.002 to 2.0/0.06/0.5) and 128 coagulase-negative staphylococci (0.004 to 0.25/0.016/0.125). Among strains tested, 76 S. aureus strains and 51 coagulase-negative staphylococci were resistant to ciprofloxacin. DX-619 had the lowest MIC50/MIC90 values against 127 quinolone-resistant staphylococci (0.125/0.5), followed by sitafloxacin (0.5/4), moxifloxacin (2/8), gatifloxacin (4/16), levofloxacin (16/>32), and ciprofloxacin (>32/>32). Raised quinolone MICs were associated with mutations in GyrA (S84L) and single or double mutations in GrlA (S80F or Y; E84K, G, or V) in all S. aureus strains tested. A recent vancomycin-resistant S. aureus (VRSA) strain (Hershey) was resistant to available quinolones and was inhibited by DX-619 at 0.25 μg/ml and sitafloxacin at 1.0 μg/ml. Vancomycin (except VRSA), linezolid, ranbezolid, tigecycline, and quinupristin-dalfopristin were active against all strains, and teicoplanin was active against S. aureus but less active against coagulase-negative staphylococci. DX-619 produced resistant mutants with MICs of 1 to >32 μg/ml after <50 days of selection compared to 16 to >32 μg/ml for ciprofloxacin, sitafloxacin, moxifloxacin, and gatifloxacin. DX-619 and sitafloxacin were also more active than other tested drugs against selected mutants and had the lowest mutation frequencies in single-step resistance selection. DX-619 and sitafloxacin were bactericidal against six quinolone-resistant (including the VRSA) and seven quinolone-susceptible strains tested, whereas gatifloxacin, moxifloxacin, levofloxacin, and ciprofloxacin were bactericidal against 11, 10, 7, and 5 strains at 4× MIC after 24 h, respectively. DX-619 was also bactericidal against one other VRSA strain, five vancomycin-intermediate S. aureus strains, and four vancomycin-intermediate coagulase-negative staphylococci. Linezolid, ranbezolid, and tigecycline were bacteriostatic and quinupristin-dalfopristin, teicoplanin, and vancomycin were bactericidal against two, eight, and nine strains, and daptomycin and oritavancin were rapidly bactericidal against all strains, including the VRSA. DX-619 has potent in vitro activity against staphylococci, including methicillin-, ciprofloxacin-, and vancomycin-resistant strains. PMID:16048943

Enterococcus faecalis endocarditis following percutaneous manipulation of a biliary tract calculus and ERCP

PubMed Central

Ronald, Allan R; Pattullo, Andrew LS

1990-01-01

A case of Enterococcus faecalis endocarditis followed endoscopic retrograde cholangiopancreatography and percutaneous extraction of a biliary calculus is reported. The most likely cause of endocarditis, though unproven, is the latter procedure, as the bile is often infected during biliary tract obstruction, and bacteremia is frequent during percutaneous manipulations. Initial therapy with vancomycin was unsuccessful in clearing the bacteremia, possibly due to vancomycin tolerance of the isolate and lack of an aminoglycoside in the initial regimen. Cure was obtained when therapy with ampicillin and gentamicin was undertaken. PMID:22553458

Impact of Serum Vancomycin Trough Levels in the Treatment of Central Nervous System Shunt Infections Caused by Coagulase-Negative Staphylococci.

PubMed

Gibson, Ashley; Kaplan, Sheldon L; Vallejo, Jesus G

2018-04-26

Coagulase-negative staphylococci (CoNS) are a common cause of pediatric ventricular shunt infections. The Infectious Diseases Society of America recommends vancomycin serum troughs of 15-20 µg/mL when treating CoNS shunt infections in adult patients. We report a series of pediatric cases of CoNS shunt infections in which clinical cure was obtained with troughs < 15 µg/mL. These findings question the relevance of this recommendation in pediatric patients. © 2018 S. Karger AG, Basel.

Biosynthesis of Enterobacterial Common Antigen: The ECA-Trace Phenotype of Salmonella Typhimurium and The Role of the rfe Gene in 08 Side-Chain Synthesis in Escherichia Coli

DTIC Science & Technology

1993-03-18

malachite green, 2mg/ml; erythromycin, 2mg/ml; bacitracin, 20mg/ml; streptomycin, 50mg/ml; crystal violet, 100mg/ml; novobiocin, Smg/ml; rifamycin...cephalosporin C, ISug/ml; actinomycin D, 37Sug/ml; kanamycin, S.6ug/ml; chlorotetracycline, 3.8ug/ml; vancomycin, 900ug/ml; malachite green, 60ug...carbenicillin; Ceph, cephalosporin C; AcID, actinomycin D; ((an, kanamycin; Ctet, chlorotetracycline; Van, vancomycin; MalG, malachite green; Eryth

Photobactericidal activity of methylene blue derivatives against vancomycin-resistant Enterococcus spp.

PubMed

Wainwright, M; Phoenix, D A; Gaskell, M; Marshall, B

1999-12-01

The toxicities and phototoxicities of methylene blue and its two methylated derivatives were measured against one standard and three vancomycin-resistant pathogenic strains of Enterococcus spp. Each of the compounds was bactericidal and the derivatives exhibited photobactericidal activity on illumination at a 'light' dose of 6.3 J/cm(2) against one or more of the strains. Increased bactericidal and photobactericidal activity in the methylated derivatives is thought to be due to their higher hydrophobicities allowing greater interaction with the bacterial cell wall. In addition, the derivatives exhibited higher inherent photosensitizing efficacies.

Serum Vancomycin Levels Resulting from Continuous or Intermittent Infusion in Critically Ill Burn Patients With or Without Continuous Renal Replacement Therapy

DTIC Science & Technology

2012-12-01

associated with higher vancomycin levels in gen- eral and fewer levels of ᝺ μg/mL, significant nephrotoxicity or neutropenia was not observed. Fifty...therapeutic course. An absolute neutrophil count (ANC) of ≤500 cells/μL was used to define neutropenia .11 As a standardized definition for drug-induced...150,000 plate- lets/μL (Table 3, data not shown). The lowest ANC at the end of therapy was 1800 cells/μL. No patients had neutropenia (defined as 

Recent progress toward the clinical development of new anti-MRSA antibiotics.

PubMed

Long, Timothy E

2003-04-01

The escalation in drug resistance is well documented for methicillin-resistant Staphylococcus aureus (MRSA) and the urgency to discover new antibiotic treatments is more apparent with the growing incidences of vancomycin-intermediate and vancomycin-resistant S aureus. Much of the current research into finding new remedies focuses on chemical modification of existing antibiotics (ie, glycopeptides and cephalosporins) and developing synthetic molecules with novel mechanisms of action (ie, oxazolidinones and N-thiolated b-lactams). This review describes recent progress toward the clinical development of new drug therapies for MRSA.

Ceftobiprole: a review of a broad-spectrum and anti-MRSA cephalosporin.

PubMed

Zhanel, George G; Lam, Ashley; Schweizer, Frank; Thomson, Kristjan; Walkty, Andrew; Rubinstein, Ethan; Gin, Alfred S; Hoban, Daryl J; Noreddin, Ayman M; Karlowsky, James A

2008-01-01

Ceftobiprole, an investigational cephalosporin, is currently in phase III clinical development. Ceftobiprole is a broad-spectrum cephalosporin with demonstrated in vitro activity against Gram-positive cocci, including meticillin-resistant Staphylococcus aureus (MRSA) and meticillin-resistant S. epidermidis, penicillin-resistant S. pneumoniae, Enterococcus faecalis, Gram-negative bacilli including AmpC-producing Escherichia coli and Pseudomonas aeruginosa, but excluding extended-spectrum beta-lactamase-producing strains. Like cefotaxime, ceftriaxone, ceftazidime, and cefepime, ceftobiprole demonstrates limited activity against anaerobes such as Bacteroides fragilis and non-fragilis Bacteroides spp. In single-step and serial passage in vitro resistance development studies, ceftobiprole demonstrated a low propensity to select for resistant subpopulations. Ceftobiprole, like cefepime, is a weak inducer and a poor substrate for AmpC beta-lactamases.Ceftobiprole medocaril, the prodrug of ceftobiprole, is converted by plasma esterases to ceftobiprole in <30 minutes. Peak serum concentrations of ceftobiprole observed at the end of a single 30-minute infusion were 35.5 mug/mL for a 500-mg dose and 59.6 mug/mL for a 750-mg dose. The volume of distribution of ceftobiprole is 0.26 L/kg ( approximately 18 L), protein binding is 16%, and its serum half-life is approximately 3.5 hours. Ceftobiprole is renally excreted ( approximately 70% in the active form) and systemic clearance correlates with creatinine clearance, meaning that dosage adjustment is required in patients with renal dysfunction. Ceftobiprole has a modest post-antibiotic effect (PAE) of approximately 0.5 hours for MRSA and a longer PAE of approximately 2 hours for penicillin-resistant pneumococci. Ceftobiprole, when administered intravenously at 500 mg once every 8 hours (2-hour infusion), has a >90% probability of achieving f T(>MIC) (free drug concentration exceeds the minimum inhibitory concentration [MIC]) for 40% and 60%, respectively, of the dosing interval for isolates with ceftobiprole MIC < or =4 and < or =2 mg/L, respectively.Currently, only limited clinical trial data are published for ceftobiprole. In a phase III trial, 784 patients with Gram-positive skin infections were randomized to treatment with either ceftobiprole 500 mg or vancomycin 1 g, each administered twice daily for 7-14 days; 93.3% of patients were clinically cured with ceftobiprole compared with 93.5% receiving vancomycin, and the eradication rate for MRSA infections was 91.8% for ceftobiprole compared with 90% for vancomycin. A phase III, randomized, double-blind, multicenter trial compared ceftobiprole 500 mg every 8 hours with vancomycin 1 g every 12 hours plus ceftazidime 1 g every 8 hours in patients with complicated skin and skin structure infections. Of the 828 patients enrolled, 31% had diabetic foot infections, 30% had abscesses, and 22% had wounds. No difference in clinical cure was reported in the clinically evaluable, intent-to-treat and microbiologically evaluable populations with cure rates of 90.5%, 81.9%, and 90.8%, respectively, in the ceftobiprole-treated patients and 90.2%, 80.8%, and 90.5%, respectively, in the vancomycin plus ceftazidime-treated group. Microbiologic eradication of Gram-positive cocci meticillin-susceptible S. aureus (MSSA) [ceftobiprole 91% vs vancomycin plus ceftazidime 92%] and MRSA (ceftobiprole 87% vs vancomycin plus ceftazidime 80%), as well as Gram-negative bacilli, E. coli (ceftobiprole 89% vs vancomycin plus ceftazidime 92%), and P. aeruginosa (ceftobiprole 87% vs vancomycin plus ceftazidime 100%), was not significantly different between groups. Similar cures rates in the microbiologically evaluable population occurred in both groups for Panton-Valentine leukocidin (PVL)-positive MSSA and PVL-positive MRSA.Currently, ceftobiprole has completed phase III trials for complicated skin and skin structure infections due to MRSA and nosocomial pneumonia due to suspected or proven MRSA; phase III trials are also ongoing in community-acquired pneumonia. Ceftobiprole has so far demonstrated a good safety profile in preliminary studies with similar tolerability to comparators. The broad-spectrum activity of ceftobiprole may allow it to be used as monotherapy in situations where a combination of antibacterials might be required. Further clinical studies are needed to determine the efficacy and safety of ceftobiprole and to define its role in patient care.

Impact of rapid methicillin-resistant Staphylococcus aureus polymerase chain reaction testing on mortality and cost effectiveness in hospitalized patients with bacteraemia: a decision model.

PubMed

Brown, Jack; Paladino, Joseph A

2010-01-01

Patients hospitalized with Staphylococcus aureus bacteraemia have an unacceptably high mortality rate. Literature available to date has shown that timely selection of the most appropriate antibacterial may reduce mortality. One tool that may help with this selection is a polymerase chain reaction (PCR) assay that distinguishes methicillin (meticillin)-resistant S. aureus (MRSA) from methicillin-susceptible S. aureus (MSSA) in less than 1 hour. To date, no information is available evaluating the impact of this PCR technique on clinical or economic outcomes. To evaluate the effect of a rapid PCR assay on mortality and economics compared with traditional empiric therapy, using a literature-derived model. A literature search for peer-reviewed European (EU) and US publications regarding treatment regimens, outcomes and costs was conducted. Information detailing the rates of infection, as well as the specificity and sensitivity of a rapid PCR assay (Xpert MRSA/SA Blood Culture PCR) were obtained from the peer-reviewed literature. Sensitivity analysis varied the prevalence rate of MRSA from 5% to 80%, while threshold analysis was applied to the cost of the PCR test. Hospital and testing resource consumption were valued with direct medical costs, adjusted to year 2009 values. Adjusted life-years were determined using US and WHO life tables. The cost-effectiveness ratio was defined as the cost per life-year saved. Incremental cost-effectiveness ratios (ICERs) were calculated to determine the additional cost necessary to produce additional effectiveness. All analyses were performed using TreeAge Software (2008). The mean mortality rates were 23% for patients receiving empiric vancomycin subsequently switched to semi-synthetic penicillin (SSP) for MSSA, 36% for patients receiving empiric vancomycin treatment for MRSA, 59% for patients receiving empiric SSP subsequently switched to vancomycin for MRSA and 12% for patients receiving empiric SSP for MSSA. Furthermore, with an MRSA prevalence of 30%, the numbers of patients needed to test in order to save one life were 14 and 16 compared with empiric vancomycin and SSP, respectively. The absolute mortality difference for MRSA prevalence rates of 80% and 5% favoured the PCR testing group at 2% and 10%, respectively, compared with empiric vancomycin and 18% and 1%, respectively, compared with empiric SSP. In the EU, the cost-effectiveness ratios for empiric vancomycin- and SSP-treated patients were Euro 695 and Euro 687 per life-year saved, respectively, compared with Euro 636 per life-year saved for rapid PCR testing. In the US, the cost-effectiveness ratio was $US 898 per life-year saved for empiric vancomycin and $US 820 per life-year saved for rapid PCR testing. ICERs demonstrated dominance of the PCR test in all instances. Threshold analysis revealed that PCR testing would be less costly overall, even at greatly inflated assay prices. Rapid PCR testing for MRSA appears to have the potential to reduce mortality rates while being less costly than empiric therapy in the EU and US, across a wide range of MRSA prevalence rates and PCR test costs.

[Vancomycin-loaded bioactive borate glass for treatment of chronic osteomyelitis in rabbits].

PubMed

Xie, Zongping; Liu, Xin; Jia, Weitao; Zhang, Changqing; Huang, Wenhai

2011-07-01

Bioactive borate glass (BG) has good biocompatibility and biodegradation. To investigate the feasibility of bioactive borate glass as a carrier of the antibiotic controlled-releasing by implanting vancomycin-loaded BG (VBG) into the focus of tibia chronic osteomyelitis after debridement. VBG and vancomycin-loaded calcium sulfate (VCS) were prepared with a vancomycin content of 80 mg/g. Sixty-five New Zealand white rabbits, weighing 2.12-3.91 kg (mean, 2.65 kg), were used. The tibia chronic osteomyelitis rabbit models were established by injecting methicillin-resistant Staphylococcus aureus (MRSA, 0.1 mL, 1 x 10(9) cfu/mL) into the right tibia of 65 rabbits. After 3 weeks of injection, 54 rabbits of successful models were randomly divided into groups A (n=11), B (n=11), C (n=16), and D (n=16). Simple debridement was performed in group A; BG, VCS, and VBG were implanted into the infection sites of groups B, C, and D respectively after thorough debridement. A sample of the debrided tissues was harvested for bacterial examination. The vancomycin serum levels were determined in groups C and D at 1, 2, 4, 10, 24, and 48 hours after operation. The boron serum levels were determined in groups B and D at 10, 24, 48, 72, and 120 hours after operation. After 8 weeks, the effectiveness was assessed radiographically, bacteriologically, and histopathologically. Ten rabbits died after operation. No vancomycin was detected in group C; the vancomycin level increased gradually, reached the highest level at 4 hours after operation, and then decreased rapidly in group D. No boron was detected in group B; the boron reached the highest serum level at 10 hours after operation, and then decreased gradually in group D. At 8 weeks, calcium sulfate degraded in group C; BG degraded partially in group D; and no obvious degradation was observed in group B. The repair effect was better in group D than in group C. There was no significant difference in radiograph scoring between groups A, B, C and D (P > 0.05) before operation, but there was significant difference between group D and groups A, B, C (P < 0.05) at 8 weeks after operation. The bacterial culture showed that all the MRSA results were positive in 4 groups. At 8 weeks, the negative rates of MRSA examination were 36.36%, 18.18%, 73.33%, and 81.25% respectively in groups A, B, C, and D, showing significant differences between group D and groups A, B (P < 0.05). The histopathological observation showed that a large number of new bones formed and no foreign body reaction occurred in group D. The histopathologic scores of groups A, B, C, and D were 6.45 +/- 3.62, 7.55 +/- 3.36, 4.27 +/- 2.91, and 3.81 +/- 3.04 respectively, showing significant differences between group D and groups A, B, and between group C and group B (P < 0.05). VBG can improve the repair of bone defect in the treatment of chronic osteomyelitis.

Occurrence of vancomycin-resistant and -susceptible Enterococcus spp. in reclaimed water used for spray irrigation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carey, Stephanie Ann; Goldstein, Rachel E. Rosenberg; Gibbs, Shawn G.

Reclaiming municipal wastewater for agricultural, environmental, and industrial purposes is increasing in the United States to combat dwindling freshwater supplies. However, there is a lack of data regarding the microbial quality of reclaimed water. In particular, no previous studies have evaluated the occurrence of vancomycin-resistant enterococci (VRE) in reclaimed water used at spray irrigation sites in the United States. To address this knowledge gap, we investigated the occurrence, concentration, and antimicrobial resistance patterns of VRE and vancomycin-susceptible enterococci at three U.S. spray irrigation sites that use reclaimed water. We collected 48 reclaimed water samples from one Mid-Atlantic and two Midwestmore » spray irrigation sites, as well as their respective wastewater treatment plants, in 2009 and 2010. Samples were analyzed for total enterococci and VRE using standard membrane filtration. Isolates were purified and then confirmed using biochemical tests and PCR. Antimicrobial susceptibility testing was conducted using the Sensititre® microbroth dilution system. Data were analyzed by two-sample proportion tests and one-way analysis of variance. We detected total enterococci and VRE in 71% (34/48) and 4% (2/48) of reclaimed water samples, respectively. Enterococcus faecalis was the most common species identified. At the Mid-Atlantic spray irrigation site, UV radiation decreased total enterococci to undetectable levels; however, subsequent storage in an open-air pond at this site resulted in increased concentrations of enterococci. E. faecalis isolates recovered from the Mid-Atlantic spray irrigation site expressed intrinsic resistance to quinupristin/dalfopristin; however, non-E. faecalis isolates expressed resistance to quinupristin/dalfopristin (52% of isolates), vancomycin (4%), tetracycline (13%), penicillin (4%) and ciprofloxacin (17%). Our findings show that VRE are present in low numbers in reclaimed water at point-of-use at the sampled spray irrigation sites; however, resistance to other antimicrobial classes is more prevalent, particularly among non-E. faecalis isolates. - Highlights: • Enterococci were recovered in 71% of reclaimed water samples. • Vancomycin-resistant enterococci were detected in 4% of reclaimed water samples. • UV radiation at irrigation sites reduced enterococci to undetectable levels. • Storage of reclaimed water in open-air ponds increased levels of enterococci.« less

Genetic Pathway in Acquisition and Loss of Vancomycin Resistance in a Methicillin Resistant Staphylococcus aureus (MRSA) Strain of Clonal Type USA300

PubMed Central

Gardete, Susana; Kim, Choonkeun; Hartmann, Boris M.; Mwangi, Michael; Roux, Christelle M.; Dunman, Paul M.; Chambers, Henry F.; Tomasz, Alexander

2012-01-01

An isolate of the methicillin-resistant Staphylococcus aureus (MRSA) clone USA300 with reduced susceptibility to vancomycin (SG-R) (i.e, vancomycin-intermediate S. aureus, VISA) and its susceptible “parental” strain (SG-S) were recovered from a patient at the end and at the beginning of an unsuccessful vancomycin therapy. The VISA phenotype was unstable in vitro generating a susceptible revertant strain (SG-rev). The availability of these 3 isogenic strains allowed us to explore genetic correlates of antibiotic resistance as it emerged in vivo. Compared to the susceptible isolate, both the VISA and revertant strains carried the same point mutations in yycH, vraG, yvqF and lspA genes and a substantial deletion within an intergenic region. The revertant strain carried a single additional frameshift mutation in vraS which is part of two component regulatory system VraSR. VISA isolate SG-R showed complex alterations in phenotype: decreased susceptibility to other antibiotics, slow autolysis, abnormal cell division and increased thickness of cell wall. There was also altered expression of 239 genes including down-regulation of major virulence determinants. All phenotypic properties and gene expression profile returned to parental levels in the revertant strain. Introduction of wild type yvqF on a multicopy plasmid into the VISA strain caused loss of resistance along with loss of all the associated phenotypic changes. Introduction of the wild type vraSR into the revertant strain caused recovery of VISA type resistance. The yvqF/vraSR operon seems to function as an on/off switch: mutation in yvqF in strain SG-R turns on the vraSR system, which leads to increase in vancomycin resistance and down-regulation of virulence determinants. Mutation in vraS in the revertant strain turns off this regulatory system accompanied by loss of resistance and normal expression of virulence genes. Down-regulation of virulence genes may provide VISA strains with a “stealth” strategy to evade detection by the host immune system. PMID:22319446

A biodegradable antibiotic-eluting PLGA nanofiber-loaded deproteinized bone for treatment of infected rabbit bone defects.

PubMed

Gao, Jianting; Huang, Guofeng; Liu, Guojun; Liu, Yan; Chen, Qi; Ren, Lei; Chen, Changqing; Ding, Zhenqi

2016-08-01

We fabricated a biodegradable antibiotic-eluting poly(d,l)-lactide-co-glycolide nanofiber-loaded deproteinized bone (ANDB) scaffold that provided sustained delivery of vancomycin to repair methicillin-resistant Staphylococcus aureus bone defects. To fabricate the biodegradable ANDB, poly(d,l)-lactide-co-glycolide and vancomycin were first dissolved in 1,1,1,3,3,3-hexafluoro-2-propano. The solution was then electrospun to produce biodegradable antibiotic-eluting membranes that were deposited on the surface of bovine deproteinized cancellous bone. We used scanning electron microscopy to determine the properties of the scaffold. Both elution and high-performance liquid chromatography assays were used to evaluate the in vitro vancomycin release rate from the ANDB scaffold. Three types of scaffolds were co-cultured with bacteria to confirm the in vitro antibacterial activity. The infected bone defect rabbit model was induced by injecting 10(7) colony forming units of a methicillin-resistant Staphylococcus aureus strain into the radial defect of rabbits. Animals were then separated into treatment groups and implanted according to the following scheme: ANDB scaffold in group A, poly(d,l)-lactide-co-glycolide nanofiber-loaded deproteinized bone (NDB) scaffold with intravenous (i.v.) vancomycin in group B, and NDB scaffold alone in group C. Treatment efficacy was evaluated after eight weeks using radiological, microbiological, and histological examinations. In vitro results revealed that biodegradable ANDB scaffolds released concentrations of vancomycin that were greater than the minimum inhibitory concentration for more than four weeks. Bacterial inhibition tests also confirmed antibacterial efficacy lasted for approximately four weeks. Radiological and histological scores obtained in vivo revealed significant differences between groups A, B and C. Importantly, group A had significantly lower bacterial load and better bone regeneration when compared to either group B or C. Collectively, these results show that our fabricated ANDB scaffolds possess: (1) effective bactericidal activity against methicillin-resistant Staphylococcus aureus, (2) the ability to promote site-specific bone regeneration, and (3) the potential for use in the treatment of infected bone defects. © The Author(s) 2016.

A randomized, blinded, multicenter trial of a gentamicin vancomycin gel (DFA-02) in patients undergoing abdominal surgery.

PubMed

Bennett-Guerrero, Elliott; Berry, Scott M; Bergese, Sergio D; Fleshner, Phillip R; Minkowitz, Harold S; Segura-Vasi, Alvaro M; Itani, Kamal M F; Henderson, Karen W; Rackowski, Felicia P; Aberle, Laura H; Stryjewski, Martin E; Corey, G Ralph; Allenby, Kent S

2017-06-01

SI is a significant medical problem. DFA-02 is an investigational bioresorbable modified release gel consisting of both gentamicin (16.8 mg/mL) and vancomycin (18.8 mg/mL). A Phase 2a study, where the drug was applied during surgical incision closure, suggested safety and tolerability but was not designed to assess its efficacy. In a Phase 2b randomized, blinded trial patients undergoing abdominal, primarily colorectal, surgery were randomized (4:1:1) to one of three study arms: DFA-02, matching placebo gel, or standard of care (SOC) involving irrigation of the wound with normal saline. The DFA-02 and placebo gel groups received up to 20 mL of study drug inserted above the fascia during wound closure, and were treated in a double-blind manner; the SOC group was treated in a single-blind manner. The primary endpoint was SSI (adjudicated centrally by a blinded committee) through postoperative day 30. Overall, 445 subjects (intention-to-treat) were randomized at 35 centers with 425 subjects completing the study and being evaluable. There were 67 SSIs (15.8%): 64.2% superficial, 7.5% deep, and 28.4% organ space. The incidence of SSI was not statistically significantly different between the DFA-02 and the placebo gel/SOC arms combined, 42/287 = 14.6% vs 25/138 = 18.1% (p = 0.36), respectively. Rehospitalization within 30 days was also similar between study groups (DFA-02 28.6%, placebo gel 21.4%, SOC 27.3%). In this multicenter, blinded, randomized trial with central adjudication, the gentamicin/vancomycin gel was not associated with a significant reduction in SSI. Patients undergoing abdominal surgery were randomized to one of three study arms: DFA-02 gel consisting of both gentamicin and vancomycin, matching placebo gel, or standard of care (SOC). Of 425 patients completing the study at 35 sites the gentamicin/vancomycin gel was not associated with a significant reduction in SSI. Copyright © 2016 Elsevier Inc. All rights reserved.

Passive immunization with Pneumovax® 23 and pneumolysin in combination with vancomycin for pneumococcal endophthalmitis.

PubMed

Sanders, Melissa E; Taylor, Sidney; Tullos, Nathan; Norcross, Erin W; Moore, Quincy C; Thompson, Hilary; King, Lauren B; Marquart, Mary E

2013-03-11

Capsule and pneumolysin (PLY) are two major virulence factors of Streptococcus pneumoniae. S. pneumoniae is one of the leading causes of bacterial endophthalmitis. The aim of this study is to determine whether passive immunization with the 23-valent pneumococcal polysaccharide vaccine (Pneumovax® 23; PPSV23) or PLY protects against pneumococcal endophthalmitis. New Zealand white rabbits were passively immunized with antiserum to PLY, PPSV23, a mixture of PPSV23/PLY, or PBS (mock). Vitreous was infected with a clinical strain of S. pneumoniae. In a separate group of experiments, vancomycin was injected 4 hours post-infection (PI) for each passively immunized group. Severity of infection, bacterial recovery, myeloperoxidase (MPO) activity and percent loss of retinal function were determined. Passive immunization with each antiserum significantly lowered clinical severity compared to mock immunization (PPSV23 = 9.19, PPSV23/PLY = 10.45, PLY = 8.71, Mock = 16.83; P = 0.0467). A significantly higher bacterial load was recovered from the vitreous of PLY passively immunized rabbits 24 hours PI (7.87 log10 CFU) compared to controls (7.10 log10 CFU; P = 0.0134). Retinas from immunized rabbits were more intact. Vitreous of PLY (2.88 MPO untis/mL) and PPSV23/PLY (2.17) passively immunized rabbits had less MPO activity compared to controls (5.64; P = 0.0480), and both passive immunizations (PLY = 31.34% loss of retinal function, PPSV23/PLY = 27.44%) helped to significantly preserve retinal function compared to controls (64.58%; P = 0.0323). When vancomycin was administered 4 hours PI, all eyes were sterile at 24 hours PI. A significantly lower clinical severity was observed for rabbits administered the combination immunization (5.29) or PPSV23 (5.29) with vancomycin treatment compared to controls (17.68; P = 0.0469). Passive immunization with antisera to these antigens is effective in reducing clinical severity of pneumococcal endophthalmitis in rabbits. Addition of vancomycin to immunization is effective at eliminating the bacteria.

Single Intravenous Dose of Oritavancin for Treatment of Acute Skin and Skin Structure Infections Caused by Gram-Positive Bacteria: Summary of Safety Analysis from the Phase 3 SOLO Studies.

PubMed

Corey, G Ralph; Loutit, Jeffery; Moeck, Greg; Wikler, Matthew; Dudley, Michael N; O'Riordan, William

2018-04-01

Oritavancin is a lipoglycopeptide with bactericidal activity against Gram-positive organisms. Its rapid concentration-dependent bactericidal activity and long elimination half-life allow single-dose treatment of acute bacterial skin and skin structure infections (ABSSSI). SOLO I and SOLO II were randomized, double-blind studies evaluating the efficacy and safety of a single 1,200-mg intravenous (i.v.) dose of oritavancin versus twice-daily i.v. vancomycin for 7 to 10 days in ABSSSI patients. Safety data from both studies were pooled for safety analysis. The database comprised pooled safety data for 976 oritavancin-treated patients and 983 vancomycin-treated patients. The incidences of adverse events, serious adverse events, and discontinuations due to adverse events were similar for oritavancin (55.3, 5.8, and 3.7%, respectively) and vancomycin (56.9, 5.9, and 4.2%, respectively). The median time to onset (3.8 days versus 3.1 days, respectively) and the duration (3.0 days for both groups) of adverse events were also similar between the two groups. The most frequently reported events were nausea, headache, and vomiting. Greater than 90% of all events were mild or moderate in severity. There were slightly more infections and infestations, abscesses or cellulitis, and hepatic and cardiac adverse events in the oritavancin group; however, more than 80% of these events were mild or moderate. Subgroup analyses did not identify clinically meaningful differences in the incidence of adverse events attributed to oritavancin. A single 1,200-mg dose of oritavancin was well tolerated and had a safety profile similar to that of twice-daily vancomycin. The long elimination half-life of oritavancin compared to that of vancomycin did not result in a clinically meaningful delay to the onset or prolongation of adverse events. (This study has been registered at ClinicalTrials.gov under registration no. NCT01252719 and NCT01252732.). Copyright © 2018 American Society for Microbiology.

[Study of marine actinomycetes isolated from the central coast of Peru and their antibacterial activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis].

PubMed

León, Jorge; Aponte, Juan José; Rojas, Rosario; Cuadra, D'Lourdes; Ayala, Nathaly; Tomás, Gloria; Guerrero, Marco

2011-06-01

To determine the antimicrobial potential of marine actinomycetes against drug-resistant pathogens represented by strains of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE). Strains of actinomycetes (29) isolated from marine sediment were evaluated by their characteristics in two culture media and by testing their inhibitory capacity by in vitro antagonism against multi-drug resistant (MDR) pathogenic bacteria for MRSA and VRE. Organic extracts of 3 selected actinomicetes were processed to determine the minimum inhibitory concentration (MIC) of the active compound. Most isolated actinomycetes belong to a homogeneous group of write-gray actinomycetes with a good growth in Marine Agar. The inhibitory rates of the isolates were above 85% for both pathogens with inhibition zones greater than 69 and 78 mm in diameter for MRSA and VRE respectively. Dichloromethane extracts of 3 isolates (I-400A, B1-T61, M10-77) showed strong inhibitory activity of both pathogens, M10-77 being the highest actinomycete strain with antibiotic activity against methicillin-resistant S. aureus ATCC 43300 and vancomycin-resistant E. faecalis ATCC 51299 with a minimum inhibitory concentrations (MIC) of 7.9 and 31.7 μg/ml respectively. Phylogenetic analysis of M10-77 strain showed 99% similarity with the marine species Streptomyces erythrogriseus. Marine sediments of the central coast of Peru, are a source of actinomycetes strains showing high capacity to produce bioactive compounds able to inhibit pathogens classified as multi-drug-resistant such as methicillin-resistant S. aureus and vancomycin-resistant E. faecalis.

Clinical and economic consequences of vancomycin and fidaxomicin for the treatment of Clostridium difficile infection in Canada.

PubMed

Wagner, Monika; Lavoie, Louis; Goetghebeur, Mireille

2014-03-01

Clostridium difficile infection (CDI) represents a public health problem with increasing incidence and severity. To evaluate the clinical and economic consequences of vancomycin compared with fidaxomicin in the treatment of CDI from the Canadian health care system perspective. A decision-tree model was developed to compare vancomycin and fidaxomicin for the treatment of severe CDI. The model assumed identical initial cure rates and included first recurrent episodes of CDI (base case). Treatment of patients presenting with recurrent CDI was examined as an alternative analysis. Costs included were for study medication, physician services and hospitalization. Cost effectiveness was measured as incremental cost per recurrence avoided. Sensitivity analyses of key input parameters were performed. In a cohort of 1000 patients with an initial episode of severe CDI, treatment with fidaxomicin led to 137 fewer recurrences at an incremental cost of $1.81 million, resulting in an incremental cost of $13,202 per recurrence avoided. Among 1000 patients with recurrent CDI, 113 second recurrences were avoided at an incremental cost of $18,190 per second recurrence avoided. Incremental costs per recurrence avoided increased with increasing proportion of cases caused by the NAP1/B1/027 strain. Results were sensitive to variations in recurrence rates and treatment duration but were robust to variations in other parameters. The use of fidaxomicin is associated with a cost increase for the Canadian health care system. Clinical benefits of fidaxomicin compared with vancomycin depend on the proportion of cases caused by the NAP1/B1/027 strain in patients with severe CDI.

Cost-effectiveness analysis of fecal microbiota transplantation for recurrent Clostridium difficile infection.

PubMed

Varier, Raghu U; Biltaji, Eman; Smith, Kenneth J; Roberts, Mark S; Kyle Jensen, M; LaFleur, Joanne; Nelson, Richard E

2015-04-01

Clostridium difficile infection (CDI) places a high burden on the US healthcare system. Recurrent CDI (RCDI) occurs frequently. Recently proposed guidelines from the American College of Gastroenterology (ACG) and the American Gastroenterology Association (AGA) include fecal microbiota transplantation (FMT) as a therapeutic option for RCDI. The purpose of this study was to estimate the cost-effectiveness of FMT compared with vancomycin for the treatment of RCDI in adults, specifically following guidelines proposed by the ACG and AGA. We constructed a decision-analytic computer simulation using inputs from the published literature to compare the standard approach using tapered vancomycin to FMT for RCDI from the third-party payer perspective. Our effectiveness measure was quality-adjusted life years (QALYs). Because simulated patients were followed for 90 days, discounting was not necessary. One-way and probabilistic sensitivity analyses were performed. Base-case analysis showed that FMT was less costly ($1,669 vs $3,788) and more effective (0.242 QALYs vs 0.235 QALYs) than vancomycin for RCDI. One-way sensitivity analyses showed that FMT was the dominant strategy (both less expensive and more effective) if cure rates for FMT and vancomycin were ≥70% and <91%, respectively, and if the cost of FMT was <$3,206. Probabilistic sensitivity analysis, varying all parameters simultaneously, showed that FMT was the dominant strategy over 10, 000 second-order Monte Carlo simulations. Our results suggest that FMT may be a cost-saving intervention in managing RCDI. Implementation of FMT for RCDI may help decrease the economic burden to the healthcare system.

Rapid and easy detection of low-level resistance to vancomycin in methicillin-resistant Staphylococcus aureus by matrix-assisted laser desorption ionization time-of-flight mass spectrometry.

PubMed

Asakura, Kota; Azechi, Takuya; Sasano, Hiroshi; Matsui, Hidehito; Hanaki, Hideaki; Miyazaki, Motoyasu; Takata, Tohru; Sekine, Miwa; Takaku, Tomoiku; Ochiai, Tomonori; Komatsu, Norio; Shibayama, Keigo; Katayama, Yuki; Yahara, Koji

2018-01-01

Vancomycin-intermediately resistant Staphylococcus aureus (VISA) and heterogeneous VISA (hVISA) are associated with treatment failure. hVISA contains only a subpopulation of cells with increased minimal inhibitory concentrations, and its detection is problematic because it is classified as vancomycin-susceptible by standard susceptibility testing and the gold-standard method for its detection is impractical in clinical microbiology laboratories. Recently, a research group developed a machine-learning classifier to distinguish VISA and hVISA from vancomycin-susceptible S. aureus (VSSA) according to matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) data. Nonetheless, the sensitivity of hVISA classification was found to be 76%, and the program was not completely automated with a graphical user interface. Here, we developed a more accurate machine-learning classifier for discrimination of hVISA from VSSA and VISA among MRSA isolates in Japanese hospitals by means of MALDI-TOF MS data. The classifier showed 99% sensitivity of hVISA classification. Furthermore, we clarified the procedures for preparing samples and obtaining MALDI-TOF MS data and developed all-in-one software, hVISA Classifier, with a graphical user interface that automates the classification and is easy for medical workers to use; it is publicly available at https://github.com/bioprojects/hVISAclassifier. This system is useful and practical for screening MRSA isolates for the hVISA phenotype in clinical microbiology laboratories and thus should improve treatment of MRSA infections.

Rapid and easy detection of low-level resistance to vancomycin in methicillin-resistant Staphylococcus aureus by matrix-assisted laser desorption ionization time-of-flight mass spectrometry

PubMed Central

Asakura, Kota; Azechi, Takuya; Sasano, Hiroshi; Matsui, Hidehito; Hanaki, Hideaki; Miyazaki, Motoyasu; Takata, Tohru; Sekine, Miwa; Takaku, Tomoiku; Ochiai, Tomonori; Komatsu, Norio; Shibayama, Keigo

2018-01-01

Vancomycin-intermediately resistant Staphylococcus aureus (VISA) and heterogeneous VISA (hVISA) are associated with treatment failure. hVISA contains only a subpopulation of cells with increased minimal inhibitory concentrations, and its detection is problematic because it is classified as vancomycin-susceptible by standard susceptibility testing and the gold-standard method for its detection is impractical in clinical microbiology laboratories. Recently, a research group developed a machine-learning classifier to distinguish VISA and hVISA from vancomycin-susceptible S. aureus (VSSA) according to matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) data. Nonetheless, the sensitivity of hVISA classification was found to be 76%, and the program was not completely automated with a graphical user interface. Here, we developed a more accurate machine-learning classifier for discrimination of hVISA from VSSA and VISA among MRSA isolates in Japanese hospitals by means of MALDI-TOF MS data. The classifier showed 99% sensitivity of hVISA classification. Furthermore, we clarified the procedures for preparing samples and obtaining MALDI-TOF MS data and developed all-in-one software, hVISA Classifier, with a graphical user interface that automates the classification and is easy for medical workers to use; it is publicly available at https://github.com/bioprojects/hVISAclassifier. This system is useful and practical for screening MRSA isolates for the hVISA phenotype in clinical microbiology laboratories and thus should improve treatment of MRSA infections. PMID:29522576

Taking an Antibiotic Time-out: Utilization and Usability of a Self-Stewardship Time-out Program for Renewal of Vancomycin and Piperacillin-Tazobactam.

PubMed

Graber, Christopher J; Jones, Makoto M; Glassman, Peter A; Weir, Charlene; Butler, Jorie; Nechodom, Kevin; Kay, Chad L; Furman, Amy E; Tran, Thuong T; Foltz, Christopher; Pollack, Lori A; Samore, Matthew H; Goetz, Matthew Bidwell

2015-11-01

Antibiotic time-outs can promote critical thinking and greater attention to reviewing indications for continuation. We pilot tested an antibiotic time-out program at a tertiary care teaching hospital where vancomycin and piperacillin-tazobactam continuation past day 3 had previously required infectious diseases service approval. The time-out program consisted of 3 components: (1) an electronic antimicrobial dashboard that aggregated infection-relevant clinical data; (2) a templated note in the electronic medical record that included a structured review of antibiotic indications and that provided automatic approval of continuation of therapy when indicated; and (3) an educational and social marketing campaign. In the first 6 months of program implementation, vancomycin was discontinued by day 5 in 93/145 (64%) courses where a time-out was performed on day 4 versus in 96/199 (48%) 1 year prior (P = .04). Seven vancomycin continuations via template (5% of time-outs) were guideline-discordant by retrospective chart review versus none 1 year prior (P = .002). Piperacillin-tazobactam was discontinued by day 5 in 70/105 (67%) courses versus 58/93 (62%) 1 year prior (P = .55); 9 continuations (9% of time-outs) were guideline-discordant versus two 1 year prior (P = .06). A usability survey completed by 32 physicians demonstrated modest satisfaction with the overall program, antimicrobial dashboard, and renewal templates. By providing practitioners with clinical informatics support and guidance, the intervention increased provider confidence in making decisions to de-escalate antimicrobial therapy in ambiguous circumstances wherein they previously sought authorization for continuation from an antimicrobial steward.

Antibiofilm and Membrane-Damaging Potential of Cuprous Oxide Nanoparticles against Staphylococcus aureus with Reduced Susceptibility to Vancomycin

PubMed Central

Singh, Avinash; Ahmed, Asar; Khanduja, Sonali; Singh, Satyendra K.; Srivastava, Janmejai K.; Gajbhiye, Namdeo S.

2015-01-01

The antimicrobial effects of copper ions and salts are well known, but the effects of cuprous oxide nanoparticles (Cu2O-NPs) on staphylococcal biofilms have not yet been clearly revealed. The present study evaluated Cu2O-NPs for their antibacterial and antibiofilm activities against heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) and vancomycin-intermediate S. aureus (VISA). Nanoscaled Cu2O, generated by solution phase technology, contained Cu2O octahedral nanoparticles. Field emission electron microscopy demonstrated particles with sizes ranging from 100 to 150 nm. Cu2O-NPs inhibited the growth of S. aureus and showed antibiofilm activity. The MICs and minimum biofilm inhibitory concentrations ranged from 625 μg/ml to 5,000 μg/ml and from 2,500 μg/ml to 10,000 μg/ml, respectively. Exposure of S. aureus to Cu2O-NPs caused leakage of the cellular constituents and increased uptake of ethidium bromide and propidium iodide. Exposure also caused a significant reduction in the overall vancomycin-BODIPY (dipyrromethene boron difluoride [4,4-difluoro-4-bora-3a,4a-diaza-s-indacene] fluorescent dye) binding and a decrease in the viable cell count in the presence of 7.5% sodium chloride. Cu2O-NP toxicity assessment by hemolysis assay showed no cytotoxicity at 625 to 10,000 μg/ml concentrations. The results suggest that Cu2O-NPs exert their action by disruption of the bacterial cell membrane and can be used as effective antistaphylococcal and antibiofilm agents in diverse medical devices. PMID:26303796