Antibiotic resistance in Pseudomonas aeruginosa biofilms: towards the development of novel anti-biofilm therapies.

PubMed

Taylor, Patrick K; Yeung, Amy T Y; Hancock, Robert E W

2014-12-10

The growth of bacteria as structured aggregates termed biofilms leads to their protection from harsh environmental conditions such as physical and chemical stresses, shearing forces, and limited nutrient availability. Because of this highly adapted ability to survive adverse environmental conditions, bacterial biofilms are recalcitrant to antibiotic therapies and immune clearance. This is particularly problematic in hospital settings where biofilms are a frequent cause of chronic and device-related infections and constitute a significant burden on the health-care system. The major therapeutic strategy against infections is the use of antibiotics, which, due to adaptive resistance, are often insufficient to clear biofilm infections. Thus, novel biofilm-specific therapies are required. Specific features of biofilm development, such as surface adherence, extracellular matrix formation, quorum sensing, and highly regulated biofilm maturation and dispersal are currently being studied as targets to be exploited in the development of novel biofilm-specific treatments. Using Pseudomonas aeruginosa for illustrative purposes, this review highlights the antibiotic resistance mechanisms of biofilms, and discusses current research into novel biofilm-specific therapies. Copyright © 2014 Elsevier B.V. All rights reserved.

[Interventions by clinical pharmacists on surgical wards - impact on antibiotic therapy].

PubMed

Weber, A; Schneider, C; Grill, E; Strobl, R; Vetter-Kerkhoff, C; Jauch, K-W

2011-02-01

Antibiotics are undeniably beneficial. However, inappropriate or incorrect use puts patients at risk for avoidable adverse drug reactions, promotes emergence of resistance and potentially increases overall health-care costs. The objective of this study was to assess the impact of pharmaceutical consulting on the quality and costs of antibiotic use in surgical wards. From February 2007 to February 2008 a total of 638 patients were enrolled in the controlled intervention study. Within the control period (n = 317) the current pattern of anti-biotic use was monitored without intervening, in the intervention period (n = 321) the pharmacist gave advice with regard to optimised antibiotic therapy. In 216 patients 331 antibiotic-related problems were identified; 232 interventions resulted in a modification of therapy (acceptance 70 %). The most common interventions were those regarding the duration of therapy and the choice of agent. The intervention with the greatest acceptance (91 %) was dosing recommendations. The pharmaceutical intervention resulted in a shorter duration of therapy (9.9 vs. 11.2 days, p < 0.001) and an increased adherence to the surgical department's guidelines (64 % vs. 71 %, p = 0.03). Intravenous therapy was switched to oral therapy earlier and more often (p = 0.006). As a result, the total cost for intravenous antibiotics decreased from € 96 500.- to € 81 600.- (p = 0.001). Dosage recommendations (e. g. in impaired organ function) or information on interaction and side effects increased drug -safety. Using the example of antibiotic therapy we showed that pharmaceutical counselling on surgical wards influences various aspects of antibiotic therapy, increases drug safety and reduces cost by having an effect on duration of therapy and timely switch from intravenous to oral preparations. © Georg Thieme Verlag Stuttgart ˙ New York.

Antibiotic Therapy for Very Low Birth Weigh Newborns in NICU

PubMed Central

Afjeh, Seyyed-Abolfazl; Sabzehei, Mohammad-Kazem; Fahimzad, Seyyed-Ali-Reza; Shiva, Farideh; Shamshiri, Ahmad-Reza; Esmaili, Fatemeh

2016-01-01

Background Prolonged empiric antibiotics therapy in neonates results in several adverse consequences including widespread antibiotic resistance, late onset sepsis (LOS), necrotizing enterocolitis (NEC), prolonged hospital course (HC) and increase in mortality rates. Objectives To assess the risk factors and the outcome of prolonged empiric antibiotic therapy in very low birth weight (VLBW) newborns. Materials and Methods Prospective study in VLBW neonates admitted to NICU and survived > 2 W, from July 2011 - June 2012. All relevant perinatal and postnatal data including duration of antibiotics therapy (Group I < 2W vs Group II > 2W) and outcome up to the time of discharge or death were documented and compared. Results Out of 145 newborns included in the study, 62 were in group I, and 83 in Group II. Average duration of antibiotic therapy was 14 days (range 3 - 62 days); duration in Group I and Group II was 10 ± 2.3 vs 25.5 ± 10.5 days. Hospital stay was 22.3 ± 11.5 vs 44.3 ± 14.7 days, respectively. Multiple regression analysis revealed following risk factors as significant for prolonged empiric antibiotic therapy: VLBW especially < 1000 g, (P < 0.001), maternal Illness (P = 0.003), chorioamnionitis (P = 0.048), multiple pregnancy (P = 0.03), non-invasive ventilation (P < 0.001) and mechanical ventilation (P < 0.001). Seventy (48.3%) infants developed LOS; 5 with NEC > stage II, 12 (8.3%) newborns died. Infant mortality alone and with LOS/NEC was higher in group II as compared to group I (P < 0.002 and < 0.001 respectively). Conclusions Prolonged empiric antibiotic therapy caused increasing rates of LOS, NEC, HC and infant mortality. PMID:27307961

Antibiotic and Anti-Inflammatory Therapies for Cystic Fibrosis

PubMed Central

Chmiel, James F.; Konstan, Michael W.; Elborn, J. Stuart

2013-01-01

Cystic fibrosis (CF) lung disease is characterized by chronic bacterial infection and an unremitting inflammatory response, which are responsible for most of CF morbidity and mortality. The median expected survival has increased from <6 mo in 1940 to >38 yr now. This dramatic improvement, although not great enough, is due to the development of therapies directed at secondary disease pathologies, especially antibiotics. The importance of developing treatments directed against the vigorous inflammatory response was realized in the 1990s. New therapies directed toward the basic defect are now visible on the horizon. However, the impact of these drugs on downstream pathological consequences is unknown. It is likely that antibiotics and anti-inflammatory drugs will remain an important part of the maintenance regimen for CF in the foreseeable future. Current and future antibiotic and anti-inflammatory therapies for CF are reviewed. PMID:23880054

Duration of antibiotic therapy in the intensive care unit.

PubMed

Zilahi, Gabor; McMahon, Mary Aisling; Povoa, Pedro; Martin-Loeches, Ignacio

2016-12-01

There are certain well defined clinical situations where prolonged therapy is beneficial, but prolonged duration of antibiotic therapy is associated with increased resistance, medicalising effects, high costs and adverse drug reactions. The best way to decrease antibiotic duration is both to stop antibiotics when not needed (sterile invasive cultures with clinical improvement), not to start antibiotics when not indicated (treating colonization) and keep the antibiotic course as short as possible. The optimal duration of antimicrobial treatment for ventilator-associated pneumonia (VAP) is unknown, however, there is a growing evidence that reduction in the length of antibiotic courses to 7-8 days can minimize the consequences of antibiotic overuse in critical care, including antibiotic resistance, adverse effects, collateral damage and costs. Biomarkers like C-reactive protein (CRP) and procalcitonin (PCT) do have a valuable role in helping guide antibiotic duration but should be interpreted cautiously in the context of the clinical situation. On the other hand, microbiological criteria alone are not reliable and should not be used to justify a prolonged antibiotic course, as clinical cure does not equate to microbiological eradication. We do not recommend a 'one size fits all' approach and in some clinical situations, including infection with non-fermenting Gram-negative bacilli (NF-GNB) clinical evaluation is needed but shortening the antibiotic course is an effective and safe way to decrease inappropriate antibiotic exposure.

CONSORT: May stereotactic intracavity administration of antibiotics shorten the course of systemic antibiotic therapy for brain abscesses?

PubMed

Yu, Xin; Liu, Rui; Wang, Yaming; Zhao, Hulin; Chen, Jinhui; Zhang, Jianning; Hu, Chenhao

2017-05-01

Despite advances in surgical techniques in the management of the brain abscess, continuous systemic long-term antibiotics are necessary and crucial. This study was designed to evaluate the effect of intracavity administration of high-dose antibiotics on the course of antibiotic therapy. Between 2003 and 2013, 55 patients with bacterial brain abscesses (83 abscesses) were treated with stereotactic aspiration and intracavity injection of high-dose antibiotics combined with a short course systemic antibiotic therapy. Antibiotics of one-eighth daily systemic dosage were injected into the abscess cavity after stereotactic aspiration and intravenous antibiotics were given in all patients for 3 to 4 weeks. The results of the group treated with stereotactic aspiration and intracavity injection of antibiotic solution were compared to the results of our previous patients treated by stereotactic aspiration only. Thirty-nine males and 16 females (age ranging from 1.5 to 76 years; mean age 38.7 years) were included in this study. During the follow-up (mean 26.2 months, ranging from 6 to 72 months), all the abscesses subsided with no recurrence. No adverse effects related to topical use of antibiotics occurred. At the end of follow-up, 38 patients had good outcomes, 11 had mild neurological deficits, 3 had moderate deficits, 1 was in vegetative state, and 2 died of accidents not related to brain abscesses. Compared with conventional stereotactic aspiration and drainage, intracavity injection of antibiotics shorted the course of consecutive systemic intravenous antibiotics by average 10.8 days without an increase of the recurrence rate of abscesses. Our results indicate that topical application of antibiotics into the brain abscess cavity helps to reduce the length of systemic antibiotic therapy, decreases the abscess recurrence rate, avoids the side effects of long-term high dose antibiotics, shortens the hospitalization and reduces treatment costs.

Antibiotic Desensitization Therapy in Secondary Syphilis and Listeria Infection: Case Reports and Review of Desensitization Therapy

PubMed Central

Magpantay, Gil; Madar, Cristian S; Hsue, Gunther; Belnap, Conrad

2011-01-01

Two adult cases, one of secondary syphilis and one of Listeria monocytogenes bacteremia, in which antibiotic desensitization therapy was utilized to assist treatment of active infection in the face of severe penicillin allergy. Clinical considerations are discussed that led to the decision to employ a formal desensitization procedure. Antibiotic desensitization protocols can facilitate optimal and safe antibiotic therapy in the appropriate clinical setting. PMID:22187514

Role of biomarkers in the management of antibiotic therapy: an expert panel review II: clinical use of biomarkers for initiation or discontinuation of antibiotic therapy

PubMed Central

2013-01-01

Biomarker-guided initiation of antibiotic therapy has been studied in four conditions: acute pancreatitis, lower respiratory tract infection (LRTI), meningitis, and sepsis in the ICU. In pancreatitis with suspected infected necrosis, initiating antibiotics best relies on fine-needle aspiration and demonstration of infected material. We suggest that PCT be measured to help predict infection; however, available data are insufficient to decide on initiating antibiotics based on PCT levels. In adult patients suspected of community-acquired LRTI, we suggest withholding antibiotic therapy when the serum PCT level is low (<0.25 ng/mL); in patients having nosocomial LRTI, data are insufficient to recommend initiating therapy based on a single PCT level or even repeated measurements. For children with suspected bacterial meningitis, we recommend using a decision rule as an aid to therapeutic decisions, such as the Bacterial Meningitis Score or the Meningitest®; a single PCT level ≥0.5 ng/mL also may be used, but false-negatives may occur. In adults with suspected bacterial meningitis, we suggest integrating serum PCT measurements in a clinical decision rule to help distinguish between viral and bacterial meningitis, using a 0.5 ng/mL threshold. For ICU patients suspected of community-acquired infection, we do not recommend using a threshold serum PCT value to help the decision to initiate antibiotic therapy; data are insufficient to recommend using PCT serum kinetics for the decision to initiate antibiotic therapy in patients suspected of ICU-acquired infection. In children, CRP can probably be used to help discontinue therapy, although the evidence is limited. In adults, antibiotic discontinuation can be based on an algorithm using repeated PCT measurements. In non-immunocompromised out- or in- patients treated for RTI, antibiotics can be discontinued if the PCT level at day 3 is < 0.25 ng/mL or has decreased by >80-90%, whether or not microbiological documentation has

Comparative outcomes of β-lactam antibiotics in outpatient parenteral antibiotic therapy: treatment success, readmissions and antibiotic switches.

PubMed

Lee, Boeun; Tam, Idy; Weigel, Bernard; Breeze, Janis L; Paulus, Jessica K; Nelson, Jason; Allison, Genève M

2015-08-01

β-Lactam antibiotics are commonly used in outpatient parenteral antimicrobial therapy (OPAT), but data regarding outcomes of long-term therapy are limited. The purpose of this study was to compare treatment success, readmission and antibiotic switch rates in patients treated with β-lactam antibiotics as OPAT. We carried out a retrospective review of all patients, discharged from Tufts Medical Center with cefazolin, ceftriaxone, ertapenem or oxacillin, between January 2009 and June 2013. A competing risks analysis was used to compare the cumulative incidence of first occurrence of treatment success, antibiotic switch and 30 day readmission for each drug. Four hundred patients were identified (cefazolin n = 38, ceftriaxone n = 104, ertapenem n = 128 and oxacillin n = 130). Baseline demographics were similar. Treatment success rates were higher for ceftriaxone and ertapenem (cefazolin 61%, ceftriaxone 81%, ertapenem 73% and oxacillin 58%; P < 0.001). Thirty-day all-cause readmissions were similar (cefazolin 21%, ceftriaxone 14%, ertapenem 20% and oxacillin 15%; P = 0.46). In 400 OPAT courses, 37 out of 50 antibiotic switches were accomplished without readmission. Adverse drug events (ADEs) were the most common reason for outpatient antibiotic switches (31/37, 84%). The ADE rate was higher for the oxacillin group (cefazolin 2.0 versus ceftriaxone 1.5 versus ertapenem 2.9 versus oxacillin 8.4 per 1000 OPAT days; P < 0.001). OPAT with β-lactam antibiotics is effective, but antibiotic switches for adverse events were more frequent with oxacillin use. Clinicians should be cognizant of the risk of readmissions and ADEs in OPAT patients, as the value of OPAT lies in reducing patient morbidity and readmissions by managing ADEs and preventing clinical failures. © The Author 2015. 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.

A Multicenter Evaluation of Prolonged Empiric Antibiotic Therapy in Adult ICUs in the United States.

PubMed

Thomas, Zachariah; Bandali, Farooq; Sankaranarayanan, Jayashri; Reardon, Tom; Olsen, Keith M

2015-12-01

The purpose of this study is to determine the rate of prolonged empiric antibiotic therapy in adult ICUs in the United States. Our secondary objective is to examine the relationship between the prolonged empiric antibiotic therapy rate and certain ICU characteristics. Multicenter, prospective, observational, 72-hour snapshot study. Sixty-seven ICUs from 32 hospitals in the United States. Nine hundred ninety-eight patients admitted to the ICU between midnight on June 20, 2011, and June 21, 2011, were included in the study. None. Antibiotic orders were categorized as prophylactic, definitive, empiric, or prolonged empiric antibiotic therapy. Prolonged empiric antibiotic therapy was defined as empiric antibiotics that continued for at least 72 hours in the absence of adjudicated infection. Standard definitions from the Centers for Disease Control and Prevention were used to determine infection. Prolonged empiric antibiotic therapy rate was determined as the ratio of the total number of empiric antibiotics continued for at least 72 hours divided by the total number of empiric antibiotics. Univariate analysis of factors associated with the ICU prolonged empiric antibiotic therapy rate was conducted using Student t test. A total of 660 unique antibiotics were prescribed as empiric therapy to 364 patients. Of the empiric antibiotics, 333 of 660 (50%) were continued for at least 72 hours in instances where Centers for Disease Control and Prevention infection criteria were not met. Suspected pneumonia accounted for approximately 60% of empiric antibiotic use. The most frequently prescribed empiric antibiotics were vancomycin and piperacillin/tazobactam. ICUs that utilized invasive techniques for the diagnosis of ventilator-associated pneumonia had lower rates of prolonged empiric antibiotic therapy than those that did not, 45.1% versus 59.5% (p = 0.03). No other institutional factor was significantly associated with prolonged empiric antibiotic therapy rate. Half of all

Factors associated with suitability of empiric antibiotic therapy in hospitalized patients with bloodstream infections.

PubMed

Grossman, Chagai; Keller, Nathan; Bornstein, Gil; Ben-Zvi, Ilan; Koren-Morag, Nira; Rahav, Galia

2017-06-01

Bacteremia is associated with high morbidity and mortality rates. Initiation of inadequate empiric antibiotic therapy is associated with a worse outcome. The aim of this study was to establish the prevalence and the factors associated with inappropriate empiric antibiotic therapy in patients hospitalized with bacteremia. A cross-sectional study was conducted during January 2010-December 2011 at the medical wards of the Chaim Sheba Medical Center, Israel. The records of all patients with bacteremia were reviewed. Clinical and laboratory characteristics, bacteremic pathogens and antimicrobial agents were retrieved from the medical records. Factors associated with appropriateness of empiric antibiotic therapy were assessed. A total of 681 eligible adults were included in the study. Antibiotic therapy was found to be inappropriate in 138 (20.2%) patients (95% C.I. 17.2-23.2). The rate of appropriateness was not related to the type of antibiotic regimen and the type of bacteria. Patients with healthcare-associated infections were more likely to be administrated inappropriate antibiotic therapy. Patients with primary bloodstream infections were also more likely to be administrated inappropriate antibiotic therapy. Empiric combination therapy was more likely to be appropriate than monotherapy, except for an aminoglycosides-based combination. Combination empiric antibiotic therapy should be considered in patients with healthcare-associated infections and in those with primary bloodstream infections.

Appropriateness of antibiotic prescription for targeted therapy of infections caused by multidrug-resistant bacteria: assessment of the most common improper uses in a tertiary hospital in southern Italy.

PubMed

Viceconte, Giulio; Maraolo, Alberto Enrico; Iula, Vita Dora; Catania, Maria Rosaria; Tosone, Grazia; Orlando, Raffaele

2017-09-01

A huge proportion of antibiotic therapies for infections caused by multidrug-resistant bacteria (MDR) are inappropriate. In this study, we described the most common causes of inappropriateness of definitive antibiotic regimes in a large university hospital in southern Italy and we evaluated the impact on microbial eradication, length of stay, 30-day readmission and mortality. We retrospectively assessed 45 patients who received a definitive antibiotic therapy after isolation of multidrug-resistant Staphylococcus aureus, Enterococcus spp., Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter spp. strains between 2014 and 2015. From the literature, we set a series of criteria to retrospectively determine the appropriateness of the therapy. In all, 61% of the prescribed antibiotic regimes were found to be inappropriate, especially due to incorrect drug dosage. It emerged that meropenem was the antibiotic most frequently inappropriately used. In 46% of infections caused by MDR but not extended-spectrum β-lactamase-producing Enterobacteriaceae, carbapenems were inappropriately administered. Microbial eradication was achieved in 87% of the appropriate therapy group compared to 31% of the inappropriate therapy group (chi-square=6.750, p<0.027). No statistically significant association was found between inappropriate therapy and the length of stay (chi-square=3.084, p=0.101) and 30-day readmission (p=0.103). Definitive antibiotic therapy in infections caused by multidrug-resistant bacteria in a large university hospital is often inappropriate, especially due to the drug dosing regimen, particularly in the case of meropenem and colistin. This inappropriateness has a significant impact on post-treatment microbial eradication in specimens collected after antibiotic therapy.

[LOCAL ANTIBIOTIC THERAPY OF OSTEOMYELITIS USING NONABSORBABLE IMPLANT (REVIEW)].

PubMed

Tuleubaev, B; Saginova, D; Abiyev, T; Davletbaev, M; Koshanova, A

2016-06-01

Despite the variety of treatments available, including surgical procedures and antimicrobial therapy, bone infections is still a medical problem, because they are difficult to treat. Optimal treatment should stabilize the bone, promote the biological recovery of bone defects and destroy bacterial infection. Systemic antibiotics are part of the standard therapy after surgical treatment of infected bone, but their effectiveness is limited due to malnutrition and low absorption at the site of infection. Moreover, long-term treatment and higher doses are associated with serious side effects. In contrast, the antibiotic impregnated bone cements or fillers can act as a local anti-infective drug delivery system, which not only fills the dead space after debridement, but also provide high concentrations of antibiotics in a potential site of infection, no increase levels of antibiotics in serum. The review analyzed the use of antibiotic-impregnated cement as local delivery of antibiotics systems. Gentamycin impregnated polymethylmethacrylate (PMMA) beads, for the topical treatment of orthopedic infections clinically used for over 30 years. Application of antibiotic delivery systems using cement in the infected region is common method of treatment that continues to improve. On the downside of PMMA is that the material does not biodegradable requires subsequent invasive procedures necessary to remove the implant.

[Health economics and antibiotic therapy].

PubMed

Leclercq, P; Bigdéli, M

1995-01-01

In the field of antibiotic therapy, particularly the methods of economic evaluation hold one's attention within the wide range of health economics' applications. Several tools allow a comparison of the outcomes of alternative strategies and thereby guide choices to the most appropriate solutions. After a brief recall of the methods classically used to evaluate health care strategy, the authors stress the importance and difficulty of fixing and applying a correct and satisfactory procedure for evaluation. An evaluation example of antibiotic therapy allows to illustrate the application of the principles confronting a field in which competition is intense and economic stakes stay large--a fact which naturally yields to seek after objective decision making criteria. The health care policies drawn by public authorities as well as the marketing strategies of the health sector trade are partly based on such evaluations. If these techniques are not intended for the practitioner in the first place, they should not be indifferent to him since they influence health authorities and thereby indirectly affect the therapeutic freedom of the physician.

Antibiotic prophylaxis in transarterial therapy of hepatocellular carcinoma: A meta-analysis

PubMed Central

Wang, Jun; He, Xiao Dong; Zhang, You Cheng

2012-01-01

BACKGROUND: The use of prophylactic antibiotics against postprocedure infection in patients undergoing transarterial therapy for hepatocellular carcinoma is controversial. AIM: To compare the effects of prophylactic antibiotic treatment and no prophylactic antibiotic treatment on infectious complications following transarterial procedures. METHODS: Clinical trials fulfilling predefined selection criteria were identified by searching several bibliographic databases; a meta-analysis was performed where appropriate. RESULTS: Four trials of inadequate quality consisting of 210 patients were included in the analysis. Only one case of possible postprocedure infection in each group was reported. The rate of patients developing fever (RR 0.91 [95% CI 0.61 to 1.35]), changes in peripheral white blood cell count or serum C-reactive protein levels, and the mean length of hospital stay (mean difference 0.20 [95% CI 0.75 to 1.14]) showed no significant intergroup differences between antibiotic and no antibiotic treatment. Furthermore, the results of the present study indicated that the incidence of bacteremia, septicemia, sepsis or hepatic abscess after transarterial therapy was rare. CONCLUSION: Antibiotic prophylaxis in patients undergoing transarterial therapy for hepatocellular carcinoma may not be routinely necessary. However, a more judicious use of antibiotics is recommended for patients who are at an increased risk of infection. Nevertheless, prospective trials on a larger scale are clearly needed. PMID:22312607

Antibiotic prophylaxis in transarterial therapy of hepatocellular carcinoma: a meta-analysis.

PubMed

Wang, Jun; He, Xiao Dong; Zhang, You Cheng

2012-02-01

The use of prophylactic antibiotics against postprocedure infection in patients undergoing transarterial therapy for hepatocellular carcinoma is controversial. To compare the effects of prophylactic antibiotic treatment and no prophylactic antibiotic treatment on infectious complications following transarterial procedures. Clinical trials fulfilling predefined selection criteria were identified by searching several bibliographic databases; a meta-analysis was performed where appropriate. Four trials of inadequate quality consisting of 210 patients were included in the analysis. Only one case of possible postprocedure infection in each group was reported. The rate of patients developing fever (RR 0.91 [95% CI 0.61 to 1.35]), changes in peripheral white blood cell count or serum C-reactive protein levels, and the mean length of hospital stay (mean difference 0.20 [95% CI 0.75 to 1.14]) showed no significant intergroup differences between antibiotic and no antibiotic treatment. Furthermore, the results of the present study indicated that the incidence of bacteremia, septicemia, sepsis or hepatic abscess after transarterial therapy was rare. Antibiotic prophylaxis in patients undergoing transarterial therapy for hepatocellular carcinoma may not be routinely necessary. However, a more judicious use of antibiotics is recommended for patients who are at an increased risk of infection. Nevertheless, prospective trials on a larger scale are clearly needed.

Evaluation of genome-wide expression profiles of blood and sputum neutrophils in cystic fibrosis patients before and after antibiotic therapy.

PubMed

Conese, Massimo; Castellani, Stefano; Lepore, Silvia; Palumbo, Orazio; Manca, Antonio; Santostasi, Teresa; Polizzi, Angela Maria; Copetti, Massimiliano; Di Gioia, Sante; Casavola, Valeria; Guerra, Lorenzo; Diana, Anna; Montemurro, Pasqualina; Mariggiò, Maria Addolorata; Gallo, Crescenzio; Maffione, Angela Bruna; Carella, Massimo

2014-01-01

In seeking more specific biomarkers of the cystic fibrosis (CF) lung inflammatory disease that would be sensitive to antibiotic therapy, we sought to evaluate the gene expression profiles of neutrophils in CF patients before treatment in comparison with non-CF healthy individuals and after antibiotic treatment. Genes involved in neutrophil-mediated inflammation, i.e. chemotaxis, respiratory burst, apoptosis, and granule exocytosis, were the targets of this study. Microarray analysis was carried out in blood and airway neutrophils from CF patients and in control subjects. A fold change (log) threshold of 1.4 and a cut-off of p<0.05 were utilized to identify significant genes. Community networks and principal component analysis were used to distinguish the groups of controls, pre- and post-therapy patients. Control subjects and CF patients before therapy were readily separated, whereas a clear distinction between patients before and after antibiotic therapy was not possible. Blood neutrophils before therapy presented 269 genes down-regulated and 56 up-regulated as compared with control subjects. Comparison between the same patients before and after therapy showed instead 44 genes down-regulated and 72 up-regulated. Three genes appeared to be sensitive to therapy and returned to "healthy" condition: phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1), hydrogen voltage-gated channel 1 (HVCN1), and β-arrestin 1 (ARRB1). The up-regulation of these genes after therapy were confirmed by real time PCR. In airway neutrophils, 1029 genes were differentially expressed post- vs pre-therapy. Of these, 30 genes were up-regulated and 75 down-regulated following antibiotic treatment. However, biological plausibility determined that only down-regulated genes belonged to the gene classes studied for blood neutrophils. Finally, it was observed that commonly expressed genes showed a greater variability in airway neutrophils than that found in blood neutrophils, both before and

Evaluation of Genome-Wide Expression Profiles of Blood and Sputum Neutrophils in Cystic Fibrosis Patients Before and After Antibiotic Therapy

PubMed Central

Conese, Massimo; Castellani, Stefano; Lepore, Silvia; Palumbo, Orazio; Manca, Antonio; Santostasi, Teresa; Polizzi, Angela Maria; Copetti, Massimiliano; Di Gioia, Sante; Casavola, Valeria; Guerra, Lorenzo; Diana, Anna; Montemurro, Pasqualina; Mariggiò, Maria Addolorata; Gallo, Crescenzio; Maffione, Angela Bruna; Carella, Massimo

2014-01-01

In seeking more specific biomarkers of the cystic fibrosis (CF) lung inflammatory disease that would be sensitive to antibiotic therapy, we sought to evaluate the gene expression profiles of neutrophils in CF patients before treatment in comparison with non-CF healthy individuals and after antibiotic treatment. Genes involved in neutrophil-mediated inflammation, i.e. chemotaxis, respiratory burst, apoptosis, and granule exocytosis, were the targets of this study. Microarray analysis was carried out in blood and airway neutrophils from CF patients and in control subjects. A fold change (log) threshold of 1.4 and a cut-off of p<0.05 were utilized to identify significant genes. Community networks and principal component analysis were used to distinguish the groups of controls, pre- and post-therapy patients. Control subjects and CF patients before therapy were readily separated, whereas a clear distinction between patients before and after antibiotic therapy was not possible. Blood neutrophils before therapy presented 269 genes down-regulated and 56 up-regulated as compared with control subjects. Comparison between the same patients before and after therapy showed instead 44 genes down-regulated and 72 up-regulated. Three genes appeared to be sensitive to therapy and returned to “healthy” condition: phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1), hydrogen voltage-gated channel 1 (HVCN1), and β-arrestin 1 (ARRB1). The up-regulation of these genes after therapy were confirmed by real time PCR. In airway neutrophils, 1029 genes were differentially expressed post- vs pre-therapy. Of these, 30 genes were up-regulated and 75 down-regulated following antibiotic treatment. However, biological plausibility determined that only down-regulated genes belonged to the gene classes studied for blood neutrophils. Finally, it was observed that commonly expressed genes showed a greater variability in airway neutrophils than that found in blood neutrophils, both before

Two-stage revision of infected hip arthroplasty using an antibiotic-loaded spacer: retrospective comparison between short-term and prolonged antibiotic therapy.

PubMed

Hsieh, Pang-Hsin; Huang, Kuo-Chin; Lee, Po-Cheng; Lee, Mel S

2009-08-01

The optimal duration of systemic antibiotic therapy in patients with prosthetic hip infection (PHI) undergoing staged exchange arthroplasty (SEA) has not been determined. We hypothesized that with an antibiotic-loaded cement spacer (ALCS), in the interim, short-term antibiotic therapy is as effective as a conventional prolonged treatment course. We reviewed 99 patients with PHI who were managed with SEA using an ALCS from February 2002 to October 2005. A standard (4-6 week) antibiotic treatment course was administered in the first 46 patients and a short-term (1 week) therapy was adopted in the subsequent 53 patients. Eight patients (four in each group) had persistent infection following the first attempt of surgery and antibiotic treatment; in three of them the infection was cured by additional debridement prior to re-implantation. Forty-two (91%) patients in the long-term group and 47 (89%) patients in the short-term group were free of infection (P = 0.67) at an average follow-up of 43 months (range, 24-60 months). Five (11%) patients developed complications related to prolonged antibiotic therapy. The short-term treatment resulted in a shorter hospital stay (18 versus 43 days, P < 0.001) and a lower direct medical cost (US$13 732 versus US$21 756, P < 0.001). Short-term antibiotic therapy was not associated with a higher rate of treatment failure. Given the higher costs and incidence of complications, protracted courses of antibiotic administration may not necessarily be routine practice in patients with PHI undergoing SEA, provided that an ALCS is used.

Randomized clinical trial of antibiotic therapy for uncomplicated appendicitis.

PubMed

Park, H C; Kim, M J; Lee, B H

2017-12-01

Uncomplicated appendicitis may resolve spontaneously or require treatment with antibiotics or appendicectomy. The aim of this randomized trial was to compare the outcome of a non-antibiotic management strategy with that of antibiotic therapy in uncomplicated appendicitis. Patients presenting to a university teaching hospital with CT-verified uncomplicated simple appendicitis (appendiceal diameter no larger than 11 mm and without any signs of perforation) were randomized to management with a no-antibiotic regimen with supportive care (intravenous fluids, analgesia and antipyretics as necessary) or a 4-day course of antibiotics with supportive care. The primary endpoint was rate of total treatment failure, defined as initial treatment failure within 1 month and recurrence of appendicitis during the follow-up period. Some 245 patients were randomized within the trial, and followed up for a median of 19 months. The duration of hospital stay was shorter (mean 3·1 versus 3·7 days; P < 0·001) and the medical costs lower (€1181 versus 1348; P < 0·001) among those randomized to therapy without antibiotics. There was no difference in total treatment failure rate between the groups: 29 of 124 (23·4 per cent) in the no-antibiotic group and 25 of 121 (20·7 per cent) in the antibiotic group (P = 0·609). Eighteen patients (9 in each group) had initial treatment failure, 15 of whom underwent appendicectomy and three received additional antibiotics. Thirty-six patients (20 in the no-antibiotic group, 16 in the antibiotic group) experienced recurrence, of whom 30 underwent appendicectomy and six received further antibiotics. Treatment failure rates in patients presenting with CT-confirmed uncomplicated appendicitis appeared similar among those receiving supportive care with either a no-antibiotic regimen or a 4-day course of antibiotics. Registration number: KCT0000124 ( http://cris.nih.go.kr). © 2017 BJS Society Ltd Published by John Wiley & Sons Ltd.

Antibiotic therapy for Shigella dysentery.

PubMed

Prince Christopher R H; David, Kirubah V; John, Sushil M; Sankarapandian, Venkatesan

2010-01-20

antibiotic superior in efficacy in treating Shigella dysentery, but heterogeneity for some comparisons limits confidence in the results. All the antibiotics studied were safe. There was inadequate evidence regarding the role of antibiotics in preventing relapses. Antibiotics reduce the duration of Shigella dysentery.Regularly updated local or regional antibiotic sensitivity patterns to different species and strains of Shigella are required to guide empiric therapy. More trials adhering to standard guidelines are required to evaluate the role of antibiotics in the treatment of severe forms of Shigella dysentery and in groups who are at high risk of complications.

Antibiotic therapy for Shigella dysentery.

PubMed

Christopher, Prince Rh; David, Kirubah V; John, Sushil M; Sankarapandian, Venkatesan

2010-08-04

antibiotic superior in efficacy in treating Shigella dysentery, but heterogeneity for some comparisons limits confidence in the results. All the antibiotics studied were safe. There was inadequate evidence regarding the role of antibiotics in preventing relapses. Antibiotics reduce the duration of Shigella dysentery.Regularly updated local or regional antibiotic sensitivity patterns to different species and strains of Shigella are required to guide empiric therapy. More trials adhering to standard guidelines are required to evaluate the role of antibiotics in the treatment of severe forms of Shigella dysentery and in groups who are at high risk of complications.

Alternatives to antibiotics-a pipeline portfolio review.

PubMed

Czaplewski, Lloyd; Bax, Richard; Clokie, Martha; Dawson, Mike; Fairhead, Heather; Fischetti, Vincent A; Foster, Simon; Gilmore, Brendan F; Hancock, Robert E W; Harper, David; Henderson, Ian R; Hilpert, Kai; Jones, Brian V; Kadioglu, Aras; Knowles, David; Ólafsdóttir, Sigríður; Payne, David; Projan, Steve; Shaunak, Sunil; Silverman, Jared; Thomas, Christopher M; Trust, Trevor J; Warn, Peter; Rex, John H

2016-02-01

Antibiotics have saved countless lives and enabled the development of modern medicine over the past 70 years. However, it is clear that the success of antibiotics might only have been temporary and we now expect a long-term and perhaps never-ending challenge to find new therapies to combat antibiotic-resistant bacteria. A broader approach to address bacterial infection is needed. In this Review, we discuss alternatives to antibiotics, which we defined as non-compound approaches (products other than classic antibacterial agents) that target bacteria or any approaches that target the host. The most advanced approaches are antibodies, probiotics, and vaccines in phase 2 and phase 3 trials. This first wave of alternatives to antibiotics will probably best serve as adjunctive or preventive therapies, which suggests that conventional antibiotics are still needed. Funding of more than £1·5 billion is needed over 10 years to test and develop these alternatives to antibiotics. Investment needs to be partnered with translational expertise and targeted to support the validation of these approaches in phase 2 trials, which would be a catalyst for active engagement and investment by the pharmaceutical and biotechnology industry. Only a sustained, concerted, and coordinated international effort will provide the solutions needed for the future. Copyright © 2016 Elsevier Ltd. All rights reserved.

Important cellular targets for antimicrobial photodynamic therapy.

PubMed

Awad, Mariam M; Tovmasyan, Artak; Craik, James D; Batinic-Haberle, Ines; Benov, Ludmil T

2016-09-01

The persistent problem of antibiotic resistance has created a strong demand for new methods for therapy and disinfection. Photodynamic inactivation (PDI) of microbes has demonstrated promising results for eradication of antibiotic-resistant strains. PDI is based on the use of a photosensitive compound (photosensitizer, PS), which upon illumination with visible light generates reactive species capable of damaging and killing microorganisms. Since photogenerated reactive species are short lived, damage is limited to close proximity of the PS. It is reasonable to expect that the larger the number of damaged targets is and the greater their variety is, the higher the efficiency of PDI is and the lower the chances for development of resistance are. Exact molecular mechanisms and specific targets whose damage is essential for microbial inactivation have not been unequivocally established. Two main cellular components, DNA and plasma membrane, are regarded as the most important PDI targets. Using Zn porphyrin-based PSs and Escherichia coli as a model Gram-negative microorganism, we demonstrate that efficient photoinactivation of bacteria can be achieved without detectable DNA modification. Among the cellular components which are modified early during illumination and constitute key PDI targets are cytosolic enzymes, membrane-bound protein complexes, and the plasma membrane. As a result, membrane barrier function is lost, and energy and reducing equivalent production is disrupted, which in turn compromises cell defense mechanisms, thus augmenting the photoinduced oxidative injury. In conclusion, high PDI antimicrobial effectiveness does not necessarily require impairment of a specific critical cellular component and can be achieved by inducing damage to multiple cellular targets.

Community-acquired pneumonia and positive urinary antigen tests: Factors associated with targeted antibiotic therapy.

PubMed

Mothes, A; Léotard, S; Nicolle, I; Smets, A; Chirio, D; Rotomondo, C; Tiger, F; Del Giudice, P; Perrin, C; Néri, D; Foucault, C; Della Guardia, M; Hyvernat, H; Roger, P-M

2016-10-01

The use of rapid microbiological tests is supported by antimicrobial stewardship policies. Targeted antibiotic therapy (TAT) for community-acquired pneumonia (CAP) with positive urinary antigen test (UAT) has been associated with a favorable impact on outcome. We aimed to determine the factors associated with TAT prescription. We conducted a retrospective multicenter study including all patients presenting with CAP and positive UAT for Streptococcus pneumoniae or Legionella pneumophila from January 2010 to December 2013. Patients presenting with aspiration pneumonia, coinfection, and neutropenia were excluded. CAP severity was assessed using the Pneumonia Severity Index (PSI). TAT was defined as the administration of amoxicillin for pneumococcal infection and either macrolides or fluoroquinolones (inactive against S. pneumoniae) for Legionella infection. A total of 861 patients were included, including 687 pneumococcal infections and 174 legionellosis from eight facilities and 37 medical departments. TAT was prescribed to 273 patients (32%). Four factors were found independently associated with a lower rate of TAT: a PSI score≥4 (OR 0.37), Hospital A (OR 0.41), hospitalization in the intensive care unit (OR 0.44), and cardiac comorbidities (OR 0.60). Four other factors were associated with a high rate of TAT: positive blood culture for S. pneumoniae (OR 2.32), Hospitals B (OR 2.34), E (OR 2.68), and H (OR 9.32). TAT in CAP with positive UAT was related to the hospitals as well as to patient characteristics. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Early transition to oral antibiotic therapy for community-acquired pneumonia: duration of therapy, clinical outcomes, and cost analysis.

PubMed

Omidvari, K; de Boisblanc, B P; Karam, G; Nelson, S; Haponik, E; Summer, W

1998-08-01

Our objective was to compare therapeutic outcome and analyse cost-benefit of a 'conventional' (7-day course of i.v. antibiotic therapy) vs. an abbreviated (2-day i.v. antibiotic course followed by 'switch' to oral antibiotics) therapy for in-patients with community-acquired pneumonia (CAP). We used a multicenter prospective, randomized, parallel group with a 28 day follow-up, at the University-based teaching hospitals: The Medical Center of Louisiana in New Orleans, LA and hospitals listed in the acknowledgement. Ninety-five patients were randomized to receive either a 'conventional' course of intravenous antibiotic therapy with cefamandole 1 g i.v. every 6 h for 7 days (n = 37), or an abbreviated course of intravenous therapy with cefamandole (1 g i.v. every 6 h for 2 days) followed by oral therapy with cefaclor (500 mg every 8 h for 5 days). No difference was found in the clinical courses, cure rates, survival or the resolution of the chest radiograph abnormalities among the two groups. The mean duration of therapy (6.88 days for the conventional group compared to 7-30 days for the early oral therapy group) and the frequencies of overall symptomatic improvement (97% vs. 95%, respectively) were similar in both groups. Patients who received early oral therapy had shorter hospital stays (7.3 vs. 9.71 days, P = 0.01), and a lower total cost of care ($2953 vs. $5002, P < 0.05). It was concluded that early transition to an oral antibiotic after an abbreviated course of intravenous therapy in CAP is substantially less expensive and has comparable efficacy to conventional intravenous therapy. Altering physicians' customary management of hospitalized patients with CAP can reduce costs with no appreciable additional risk of adverse patient outcome.

Systematic review of public-targeted communication interventions to improve antibiotic use.

PubMed

Cross, Elizabeth Louise Anne; Tolfree, Robert; Kipping, Ruth

2017-04-01

Excessive use of antibiotics accelerates the acquisition/spread of antimicrobial resistance. A systematic review was conducted to identify the components of successful communication interventions targeted at the general public to improve antibiotic use. The databases MEDLINE, EMBASE, CINAHL, Web of Science and Cochrane Library were searched. Search terms were related to the population (public, community), intervention (campaign, mass media) and outcomes (antibiotic, antimicrobial resistance). References were screened for inclusion by one author with a random subset of 10% screened by a second author. No date restrictions were applied and only articles in the English language were considered. Studies had to have a control group or be an interrupted time-series. Outcomes had to measure change in antibiotic-related prescribing/consumption and/or the public's knowledge, attitudes or behaviour. Two reviewers assessed the quality of studies. Narrative synthesis was performed. Fourteen studies were included with an estimated 74-75 million participants. Most studies were conducted in the United States or Europe and targeted both the general public and clinicians. Twelve of the studies measured changes in antibiotic prescribing. There was quite strong ( P  < 0·05 to ≥ 0·01) to very strong ( P  < 0·001) evidence that interventions that targeted prescribing for RTIs were associated with decreases in antibiotic prescribing; the majority of these studies reported reductions of greater than -14% with the largest effect size reaching -30%. Multi-faceted communication interventions that target both the general public and clinicians can reduce antibiotic prescribing in high-income countries but the sustainability of reductions in antibiotic prescribing is unclear. © 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.

Antibiotic therapy for preventing infections in people with acute stroke.

PubMed

Vermeij, Jan-Dirk; Westendorp, Willeke F; Dippel, Diederik Wj; van de Beek, Diederik; Nederkoorn, Paul J

2018-01-22

Stroke is the main cause of disability in high-income countries and ranks second as a cause of death worldwide. Infections occur frequently after stroke and may adversely affect outcome. Preventive antibiotic therapy in the acute phase of stroke may reduce the incidence of infections and improve outcome. In the previous version of this Cochrane Review, published in 2012, we found that antibiotics did reduce the risk of infection but did not reduce the number of dependent or deceased patients. However, included studies were small and heterogeneous. In 2015, two large clinical trials were published, warranting an update of this Review. To assess the effectiveness and safety of preventive antibiotic therapy in people with ischaemic or haemorrhagic stroke. We wished to determine whether preventive antibiotic therapy in people with acute stroke:• reduces the risk of a poor functional outcome (dependency and/or death) at follow-up;• reduces the occurrence of infections in the acute phase of stroke;• reduces the occurrence of elevated body temperature (temperature ≥ 38° C) in the acute phase of stroke;• reduces length of hospital stay; or• leads to an increased rate of serious adverse events, such as anaphylactic shock, skin rash, or colonisation with antibiotic-resistant micro-organisms. We searched the Cochrane Stroke Group Trials Register (25 June 2017); the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 5; 25 June 2017) in the Cochrane Library; MEDLINE Ovid (1950 to 11 May 2017), and Embase Ovid (1980 to 11 May 2017). In an effort to identify further published, unpublished, and ongoing trials, we searched trials and research registers, scanned reference lists, and contacted trial authors, colleagues, and researchers in the field. Randomised controlled trials (RCTs) of preventive antibiotic therapy versus control (placebo or open control) in people with acute ischaemic or haemorrhagic stroke. Two review authors independently selected

Empiric Antibiotic Therapy of Nosocomial Bacterial Infections.

PubMed

Reddy, Pramod

2016-01-01

Broad-spectrum antibiotics are commonly used by physicians to treat various infections. The source of infection and causative organisms are not always apparent during the initial evaluation of the patient, and antibiotics are often given empirically to patients with suspected sepsis. Fear of attempting cephalosporins and carbapenems in penicillin-allergic septic patients may result in significant decrease in the spectrum of antimicrobial coverage. Empiric antibiotic therapy should sufficiently cover all the suspected pathogens, guided by the bacteriologic susceptibilities of the medical center. It is important to understand the major pharmacokinetic properties of antibacterial agents for proper use and to minimize the development of resistance. In several septic patients, negative cultures do not exclude active infection and positive cultures may not represent the actual infection. This article will review the important differences in the spectrum of commonly used antibiotics for nosocomial bacterial infections with a particular emphasis on culture-negative sepsis and colonization.

Recurrent uncomplicated cystitis in women: allowing patients to self-initiate antibiotic therapy.

PubMed

2014-02-01

Acute uncomplicated cystitis is a lower urinary tract infection occurring in the absence of anatomic or functional abnormalities of the urinary tract or any other complicating factors.The organism responsible is often an enterobacterium, especially Escherichia coli. What is the role of antibiotic therapy for non-pregnant women with recurrent acute uncomplicated cystitis? We reviewed the available evidence using the standard Prescrire methodology. A single oral dose of fosfomycin trometamol is the antibiotic of choice for treating an episode of acute uncomplicated cystitis. Alternative antibiotics are certain fluoroquinolones or co-trimoxazole (a fixed-dose combination of sulfamethoxazole and trimethoprim). For recurrent acute uncomplicated cystitis, cranberry juice has modest efficacy in reducing the frequency of episodes. A number of non-drug measures are typically proposed, although their effects are unproven: drinking sufficient fluids and urinating regularly; urinating after sexual intercourse; and avoiding spermicides. The strategy that results in the lowest antibiotic exposure is a short course of antibiotics for each episode of urinary tract infection, initiated as soon as clinical symptoms appear. Long-term antibiotic therapy is sometimes offered. According to one systematic review, women taking long-term prophylactic antibiotic therapy had about 6 times fewer clinical recurrences than with placebo. According to one randomised trial, 3 g of fosfomycin trometamol taken as a single dose every ten days reduced the frequency of recurrence, resulting in 0.14 episodes of infection per year on average versus about 3 episodes with placebo (p < 0.001). The amount of antibiotic used when fosfomycin trometamol is taken every 10 days for 6 months is equivalent to treatment of 18 acute episodes of cystitis. When cystitis appears to be associated with sexual intercourse, two small randomised trials suggest that routine postcoital antibiotic treatment is more effective

DNA topoisomerase I and DNA gyrase as targets for TB therapy.

PubMed

Nagaraja, Valakunja; Godbole, Adwait A; Henderson, Sara R; Maxwell, Anthony

2017-03-01

Tuberculosis (TB) is the deadliest bacterial disease in the world. New therapeutic agents are urgently needed to replace existing drugs for which resistance is a significant problem. DNA topoisomerases are well-validated targets for antimicrobial and anticancer chemotherapies. Although bacterial topoisomerase I has yet to be exploited as a target for clinical antibiotics, DNA gyrase has been extensively targeted, including the highly clinically successful fluoroquinolones, which have been utilized in TB therapy. Here, we review the exploitation of topoisomerases as antibacterial targets and summarize progress in developing new agents to target DNA topoisomerase I and DNA gyrase from Mycobacterium tuberculosis. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Educational Effectiveness, Target, and Content for Prudent Antibiotic Use

PubMed Central

Lee, Chang-Ro; Lee, Jung Hun; Kang, Lin-Woo; Jeong, Byeong Chul; Lee, Sang Hee

2015-01-01

Widespread antimicrobial use and concomitant resistance have led to a significant threat to public health. Because inappropriate use and overuse of antibiotics based on insufficient knowledge are one of the major drivers of antibiotic resistance, education about prudent antibiotic use aimed at both the prescribers and the public is important. This review investigates recent studies on the effect of interventions for promoting prudent antibiotics prescribing. Up to now, most educational efforts have been targeted to medical professionals, and many studies showed that these educational efforts are significantly effective in reducing antibiotic prescribing. Recently, the development of educational programs to reduce antibiotic use is expanding into other groups, such as the adult public and children. The investigation of the contents of educational programs for prescribers and the public demonstrates that it is important to develop effective educational programs suitable for each group. In particular, it seems now to be crucial to develop appropriate curricula for teaching medical and nonmedical (pharmacy, dentistry, nursing, veterinary medicine, and midwifery) undergraduate students about general medicine, microbial virulence, mechanism of antibiotic resistance, and judicious antibiotic prescribing. PMID:25945327

Multifaceted antibiotic treatment analysis of methicillin-sensitive Staphylococcus aureus bloodstream infections.

PubMed

Weber, Zhanni; Ariano, Robert; Lagacé-Wiens, Philippe; Zelenitsky, Sheryl

2016-12-01

Given the overall prevalence and poor prognosis of Staphylococcus aureus bloodstream infections (BSIs), the study of treatment strategies to improve patient outcomes is important. The aim of this study was to conduct a multifaceted antibiotic treatment analysis of methicillin-sensitive S. aureus (MSSA) BSI and to characterise optimal early antibiotic therapy (within the first 7 days of drawing the index blood culture) for this serious infection. Antibiotic selection was categorised as optimal targeted (intravenous cloxacillin or cefazolin), optimal broad (piperacillin/tazobactam or meropenem), adequate (vancomycin) or inadequate (other antibiotics or oral therapy). A TSE (timing, selection, exposure) score was developed to comprehensively characterise early antibiotic therapy, where higher points corresponded to prompt initiation, optimal antibiotic selection and longer exposure (duration). Amongst 71 cases of complicated MSSA-BSI, end-of-treatment (EOT) response (i.e. clinical cure) was improved when at least adequate antibiotic therapy was initiated within 24 h [71.7% (33/46) vs. 48.0% (12/25); P = 0.047]. Clinical cure was also more likely when therapy included ≥4 days of optimal targeted antibiotics within the first 7 days [74.4% (29/39) vs. 50.0% (16/32); P = 0.03]. The TSE score was an informative index of early antibiotic therapy, with EOT cure documented in 72.0% (36/50) compared with 42.9% (9/21) of cases with scores above and below 15.2, respectively (P = 0.02). In multivariable analysis, lower Charlson comorbidity index, presence of BSI on admission, and optimising early antibiotic therapy, as described above, were associated with clinical cure in patients with MSSA-BSI. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Inhaled Antibiotic Therapy in Chronic Respiratory Diseases

PubMed Central

Maselli, Diego J.; Keyt, Holly; Restrepo, Marcos I.

2017-01-01

The management of patients with chronic respiratory diseases affected by difficult to treat infections has become a challenge in clinical practice. Conditions such as cystic fibrosis (CF) and non-CF bronchiectasis require extensive treatment strategies to deal with multidrug resistant pathogens that include Pseudomonas aeruginosa, Methicillin-resistant Staphylococcus aureus, Burkholderia species and non-tuberculous Mycobacteria (NTM). These challenges prompted scientists to deliver antimicrobial agents through the pulmonary system by using inhaled, aerosolized or nebulized antibiotics. Subsequent research advances focused on the development of antibiotic agents able to achieve high tissue concentrations capable of reducing the bacterial load of difficult-to-treat organisms in hosts with chronic respiratory conditions. In this review, we focus on the evidence regarding the use of antibiotic therapies administered through the respiratory system via inhalation, nebulization or aerosolization, specifically in patients with chronic respiratory diseases that include CF, non-CF bronchiectasis and NTM. However, further research is required to address the potential benefits, mechanisms of action and applications of inhaled antibiotics for the management of difficult-to-treat infections in patients with chronic respiratory diseases. PMID:28509852

Inhaled Antibiotic Therapy in Chronic Respiratory Diseases.

PubMed

Maselli, Diego J; Keyt, Holly; Restrepo, Marcos I

2017-05-16

The management of patients with chronic respiratory diseases affected by difficult to treat infections has become a challenge in clinical practice. Conditions such as cystic fibrosis (CF) and non-CF bronchiectasis require extensive treatment strategies to deal with multidrug resistant pathogens that include Pseudomonas aeruginosa , Methicillin-resistant Staphylococcus aureus , Burkholderia species and non-tuberculous Mycobacteria (NTM). These challenges prompted scientists to deliver antimicrobial agents through the pulmonary system by using inhaled, aerosolized or nebulized antibiotics. Subsequent research advances focused on the development of antibiotic agents able to achieve high tissue concentrations capable of reducing the bacterial load of difficult-to-treat organisms in hosts with chronic respiratory conditions. In this review, we focus on the evidence regarding the use of antibiotic therapies administered through the respiratory system via inhalation, nebulization or aerosolization, specifically in patients with chronic respiratory diseases that include CF, non-CF bronchiectasis and NTM. However, further research is required to address the potential benefits, mechanisms of action and applications of inhaled antibiotics for the management of difficult-to-treat infections in patients with chronic respiratory diseases.

Triple combination antibiotic therapy for carbapenemase-producing Klebsiella pneumoniae: a systematic review.

PubMed

Jacobs, David M; Safir, M Courtney; Huang, Dennis; Minhaj, Faisal; Parker, Adam; Rao, Gauri G

2017-11-25

The spread of carbapenemase-producing K. pneumoniae (CPKP) has become a significant problem worldwide. Combination therapy for CPKP is encouraging, but polymyxin resistance to many antibiotics is hampering effective treatment. Combination therapy with three or more antibiotics is being increasingly reported, therefore we performed a systematic review of triple combination cases in an effort to evaluate their clinical effectiveness for CPKP infections. The PubMed database was searched to identify all published clinical outcomes of CPKP infections treated with triple combination therapy. Articles were stratified into two tiers depending on the level of clinical detail provided. A tier 1 study included: antibiotic regimen, regimen-specific outcome, patient status at onset of infection, and source of infection. Articles not reaching these criteria were considered tier 2. Thirty-three studies were eligible, 23 tier 1 and ten tier 2. Among tier 1 studies, 53 cases were included in this analysis. The most common infection was pneumonia (31%) followed by primary or catheter-related bacteremia (21%) and urinary tract infection (17%). Different combinations of antibiotic classes were utilized in triple combinations, the most common being a polymyxin (colistin or polymyxin B, 86.8%), tigecycline (73.6%), aminoglycoside (43.4%), or carbapenem (43.4%). Clinical and microbiological failure occurred in 14/39 patients (35.9%) and 22/42 patients (52.4%), respectively. Overall mortality for patients treated with triple combination therapy was 35.8% (19/53 patients). Triple combination therapy is being considered as a treatment option for CPKP. Polymyxin-based therapy is the backbone antibiotic in these regimens, but its effectiveness needs establishing in prospective clinical trials.

Prophylactic broad spectrum antibiotics as a new anti-myeloma therapy.

PubMed

Valkovic, Toni; Nacinovic, Antica Duletic; Petranovic, Duska

2013-12-01

Multiple myeloma is a common, yet incurable, haematological neoplasm. The reciprocal communication between malignant plasma cells, other cell types, and the extracellular matrix in the bone marrow micro-eco system is mediated by cell-cell and cell-matrix adhesion, as well as the production of different soluble factors, and is crucial for tumour growth and drug resistance. Inflammation and pro-inflammatory cytokines contribute to the clonal expansion of neoplastic plasmacytes. This extremely complex pathogenesis of multiple myeloma gives us the opportunity to promote numerous novel drugs and approaches based on the paradigm of targeted therapy. Immune dysfunction is a hallmark of multiple myeloma. Intrinsic and therapy-related immunosuppression leads to an increased risk of recurrent infection, the major cause of mortality. However, little data is available regarding the possible influence of infection on the biology and progression of multiple myeloma. Some authors have shown that pathogenic microorganisms can activate tool-like receptors on myeloma cells, as well as the robust production of pro-inflammatory cytokines; together these factors can contribute to myeloma growth, survival, and progression. Therefore, we proposed a simple, inexpensive, and new approach for anti-myeloma therapy that, to the best of our knowledge, is the first one concerning the prophylactic, long-term use of broad-spectrum antibiotics during the course of disease regardless of the chosen concomitant regimens. Prophylactic treatment with antibiotics should suppress the pro-inflammatory milieu produced during recurrent bacterial infections and prevent the activation of tool-like receptors on tumour cells, which are important factors responsible for tumour growth and survival in patients with multiple myeloma. Copyright © 2013 Elsevier Ltd. All rights reserved.

Subinhibitory antibiotic therapy alters recurrent urinary tract infection pathogenesis through modulation of bacterial virulence and host immunity.

PubMed

Goneau, Lee W; Hannan, Thomas J; MacPhee, Roderick A; Schwartz, Drew J; Macklaim, Jean M; Gloor, Gregory B; Razvi, Hassan; Reid, Gregor; Hultgren, Scott J; Burton, Jeremy P

2015-03-31

The capacity of subinhibitory levels of antibiotics to modulate bacterial virulence in vitro has recently been brought to light, raising concerns over the appropriateness of low-dose therapies, including antibiotic prophylaxis for recurrent urinary tract infection management. However, the mechanisms involved and their relevance in influencing pathogenesis have not been investigated. We characterized the ability of antibiotics to modulate virulence in the uropathogens Staphylococcus saprophyticus and Escherichia coli. Several antibiotics were able to induce the expression of adhesins critical to urothelial colonization, resulting in increased biofilm formation, colonization of murine bladders and kidneys, and promotion of intracellular niche formation. Mice receiving subinhibitory ciprofloxacin treatment were also more susceptible to severe infections and frequent recurrences. A ciprofloxacin prophylaxis model revealed this strategy to be ineffective in reducing recurrences and worsened infection by creating larger intracellular reservoirs at higher frequencies. Our study indicates that certain agents used for antibiotic prophylaxis have the potential to complicate infections. Antibiotics are the mainstay treatment for bacterial infections; however, evidence is emerging that argues these agents may have off-target effects if sublethal concentrations are present. Most studies have focused on changes occurring in vitro, leaving questions regarding the clinical relevance in vivo. We utilized a murine urinary tract infection model to explore the potential impact of low-dose antibiotics on pathogenesis. Using this model, we showed that subinhibitory antibiotics prime uropathogens for adherence and invasion of murine urothelial tissues. These changes in initial colonization promoted the establishment of chronic infection. Furthermore, treatment of chronically infected mice with subtherapeutic ciprofloxacin served to exacerbate infection. A part of these changes was

Effects of Long Term Antibiotic Therapy on Human Oral and Fecal Viromes

PubMed Central

Abeles, Shira R.; Ly, Melissa; Santiago-Rodriguez, Tasha M.; Pride, David T.

2015-01-01

Viruses are integral members of the human microbiome. Many of the viruses comprising the human virome have been identified as bacteriophage, and little is known about how they respond to perturbations within the human ecosystem. The intimate association of phage with their cellular hosts suggests their communities may change in response to shifts in bacterial community membership. Alterations to human bacterial biota can result in human disease including a reduction in the host's resilience to pathogens. Here we report the ecology of oral and fecal viral communities and their responses to long-term antibiotic therapy in a cohort of human subjects. We found significant differences between the viral communities of each body site with a more heterogeneous fecal virus community compared with viruses in saliva. We measured the relative diversity of viruses, and found that the oral viromes were significantly more diverse than fecal viromes. There were characteristic changes in the membership of oral and fecal bacterial communities in response to antibiotics, but changes in fecal viral communities were less distinguishing. In the oral cavity, an abundance of papillomaviruses found in subjects on antibiotics suggests an association between antibiotics and papillomavirus production. Despite the abundance of papillomaviruses identified, in neither the oral nor the fecal viromes did antibiotic therapy have any significant impact upon overall viral diversity. There was, however, an apparent expansion of the reservoir of genes putatively involved in resistance to numerous classes of antibiotics in fecal viromes that was not paralleled in oral viromes. The emergence of antibiotic resistance in fecal viromes in response to long-term antibiotic therapy in humans suggests that viruses play an important role in the resilience of human microbial communities to antibiotic disturbances. PMID:26309137

Effects of Long Term Antibiotic Therapy on Human Oral and Fecal Viromes.

PubMed

Abeles, Shira R; Ly, Melissa; Santiago-Rodriguez, Tasha M; Pride, David T

2015-01-01

Viruses are integral members of the human microbiome. Many of the viruses comprising the human virome have been identified as bacteriophage, and little is known about how they respond to perturbations within the human ecosystem. The intimate association of phage with their cellular hosts suggests their communities may change in response to shifts in bacterial community membership. Alterations to human bacterial biota can result in human disease including a reduction in the host's resilience to pathogens. Here we report the ecology of oral and fecal viral communities and their responses to long-term antibiotic therapy in a cohort of human subjects. We found significant differences between the viral communities of each body site with a more heterogeneous fecal virus community compared with viruses in saliva. We measured the relative diversity of viruses, and found that the oral viromes were significantly more diverse than fecal viromes. There were characteristic changes in the membership of oral and fecal bacterial communities in response to antibiotics, but changes in fecal viral communities were less distinguishing. In the oral cavity, an abundance of papillomaviruses found in subjects on antibiotics suggests an association between antibiotics and papillomavirus production. Despite the abundance of papillomaviruses identified, in neither the oral nor the fecal viromes did antibiotic therapy have any significant impact upon overall viral diversity. There was, however, an apparent expansion of the reservoir of genes putatively involved in resistance to numerous classes of antibiotics in fecal viromes that was not paralleled in oral viromes. The emergence of antibiotic resistance in fecal viromes in response to long-term antibiotic therapy in humans suggests that viruses play an important role in the resilience of human microbial communities to antibiotic disturbances.

Targeting Antibiotic Resistance

PubMed Central

Chellat, Mathieu F.; Raguž, Luka

2016-01-01

Abstract Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human‐pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last‐resort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled “Combat drug resistance: no action today means no cure tomorrow” triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens. PMID:27000559

Implementation of treatment guidelines to support judicious use of antibiotic therapy.

PubMed

Deuster, S; Roten, I; Muehlebach, S

2010-02-01

Judicious use of antibiotics is essential considering the growth of antimicrobial resistance and escalating costs in health care. This intervention study used treatment guidelines to improve antibiotic therapy by changing prescribing practice. A before-after intervention study was performed in a 550-bed tertiary care teaching hospital in Switzerland, with an additional follow-up analysis 1 year later. The pre-intervention phase included chart analysis of current antibiotic use in 100 consecutive patients from the representative medical and surgical wards included in the study. Treatment guidelines were defined, taking into account published guidelines, the local antibacterial sensitivity of the pathogens, and the hospital antibiotic formulary defined by the drug and therapeutics committee. The guidelines were presented to the medical residents on a pocket card. They were informed and educated by the pharmacist (intervention). In the post-intervention phase immediately after the instruction, and in the follow-up phase 1 year later, a prospective analysis of antibiotic prescription was performed by chart review of 100 antibacterial treatments in consecutive patients to detect changes in antibiotic prescribing (treatment) and to determine whether these changes were sustained. The pre-intervention review of antibiotic use showed the need for therapy improvements in urinary tract infections (UTI) and hospital-acquired pneumonia (HAP). In the post-intervention phase 100% of UTI were treated as recommended, compared to 30% before the intervention (P < 0.001). The follow-up analysis showed a decrease in guideline adherence to 39% in patients with UTI. Before implementation of the clinical guidelines, HAP was inappropriately treated like community-acquired pneumonia (CAP). Immediately after the intervention, 50% of HAP patients were treated as recommended, and 1 year later (follow-up phase) 56% of HAP patients received the recommended antibiotic medication. This change in

Effect of an Undergraduate Special Problems Elective upon Student Knowledge of Antibiotic Therapy.

ERIC Educational Resources Information Center

MacCosbe, Paul E.; Segelman, Alvin B.

1984-01-01

The knowledge of antibiotic therapy among students taking an elective course in antibiotic prescription following a course in antibiotics and infectious diseases was compared with those not taking the follow-up elective course, and it was determined that the elective course reinforced existing knowledge. (MSE)

Streamlining antibiotic therapy with procalcitonin protocols: consensus and controversies.

PubMed

Haubitz, Sebastian; Mueller, Beat; Schuetz, Philipp

2013-04-01

Accumulating evidence supports procalcitonin (PCT) as an accurate surrogate biomarker for likelihood and severity of bacterial infections. In community-acquired pneumonia and other respiratory infections, PCT-guided antibiotic therapy algorithms resulted in reduced antibiotic exposure while maintaining a similar or even better level of safety compared with standard care. Reductions in antibiotic use translate into lower treatment costs, decreased risk of side effects and decreased bacterial multiresistance. This is especially important, as acute respiratory infections represent the most frequent reason for antibiotic prescriptions worldwide. Still, there is some controversy about the benefits of PCT measurement in sepsis patients in the intensive care unit and for nonrespiratory infections. Highly sensitive PCT assays are readily available in many hospitals today, and point-of-care assays with high enough sensitivity for antibiotic guidance are expected to be available soon. Herein, the authors provide an overview of recent studies evaluating PCT in different clinical situations and an outlook of currently enrolling or upcoming interventional trials.

Evaluation of an antibiotic intravenous to oral sequential therapy program.

PubMed

Pablos, Ana I; Escobar, Ismael; Albiñana, Sandra; Serrano, Olga; Ferrari, José M; Herreros de Tejada, Alberto

2005-01-01

This study was designed to analyse the drug consumption difference and economic impact of an antibiotic sequential therapy focused on quinolones. We studied the consumption of quinolones (ofloxacin/levofloxacin and ciprofloxacin) 6 months before and after the implementation of a sequential therapy program in hospitalised patients. It was calculated for each antibiotic, in its oral and intravenous forms, in defined daily dose (DDD/100 stays per day) and economical terms (drug acquisition cost). At the beginning of the program ofloxacin was replaced by levofloxacin and, since their clinical uses are similar, the consumption of both drugs was compared during the period. In economic terms, the consumption of intravenous quinolones decreased 60% whereas the consumption of oral quinolones increased 66%. In DDD/100 stays per day, intravenous forms consumption decreased 53% and oral forms consumption increased 36%. Focusing on quinolones, the implementation of a sequential therapy program based on promoting an early switch from intravenous to oral regimen has proved its capacity to alter the utilisation profile of these antibiotics. The program has permitted the hospital a global saving of 41420 dollars for these drugs during the period of time considered. Copyright (c) 2004 John Wiley & Sons, Ltd.

An office model of outpatient parenteral antibiotic therapy.

PubMed

Tice, A D

1991-01-01

This office-based program for parenteral therapy began with the im administration of therapy to outpatients in 1981. Since then it has expanded in scope and staff and has provided more than 1,200 courses of i.v. antibiotics. The success of the program is dependent on patients' ability to provide i.v. medication to themselves. These patients are trained and cared for by a team consisting of a physician who specializes in infectious diseases, nurses trained in i.v. techniques, a pharmacist, and microbiologists who are all part of a practice of the subspecialty of infectious diseases. This office model has resulted in excellent quality of care for patients who have experienced few adverse effects or complications. The cost savings of an office program are significant compared to hospitalization for i.v. administration of antibiotics, but issues related to reimbursement are a constant issue.

[Rational antibiotic therapy in the dental office: Practical guidelines for decision-making].

PubMed

Zadik, Y

2016-04-01

Although most dental and periodontal diseases are caused by bacteria, the usual therapy is mechanical/surgical rather than antimicrobial medications. However, sometimes antibiotic administration may be necessary in addition to or as an alternative to the surgical/mechanical treatment. Many studies have shown that the misuse of antibiotics by dentists may be mostly attributed to unnecessity or inefficient regimen, and could contribute to bacterial resistance to antibiotics. The article presents practical guidelines to the administration of antibiotics in the dental office.

Predicting the dynamics of bacterial growth inhibition by ribosome-targeting antibiotics

NASA Astrophysics Data System (ADS)

Greulich, Philip; Doležal, Jakub; Scott, Matthew; Evans, Martin R.; Allen, Rosalind J.

2017-12-01

Understanding how antibiotics inhibit bacteria can help to reduce antibiotic use and hence avoid antimicrobial resistance—yet few theoretical models exist for bacterial growth inhibition by a clinically relevant antibiotic treatment regimen. In particular, in the clinic, antibiotic treatment is time-dependent. Here, we use a theoretical model, previously applied to steady-state bacterial growth, to predict the dynamical response of a bacterial cell to a time-dependent dose of ribosome-targeting antibiotic. Our results depend strongly on whether the antibiotic shows reversible transport and/or low-affinity ribosome binding (‘low-affinity antibiotic’) or, in contrast, irreversible transport and/or high affinity ribosome binding (‘high-affinity antibiotic’). For low-affinity antibiotics, our model predicts that growth inhibition depends on the duration of the antibiotic pulse, and can show a transient period of very fast growth following removal of the antibiotic. For high-affinity antibiotics, growth inhibition depends on peak dosage rather than dose duration, and the model predicts a pronounced post-antibiotic effect, due to hysteresis, in which growth can be suppressed for long times after the antibiotic dose has ended. These predictions are experimentally testable and may be of clinical significance.

Predicting the dynamics of bacterial growth inhibition by ribosome-targeting antibiotics

PubMed Central

Greulich, Philip; Doležal, Jakub; Scott, Matthew; Evans, Martin R; Allen, Rosalind J

2017-01-01

Understanding how antibiotics inhibit bacteria can help to reduce antibiotic use and hence avoid antimicrobial resistance—yet few theoretical models exist for bacterial growth inhibition by a clinically relevant antibiotic treatment regimen. In particular, in the clinic, antibiotic treatment is time-dependent. Here, we use a theoretical model, previously applied to steady-state bacterial growth, to predict the dynamical response of a bacterial cell to a time-dependent dose of ribosome-targeting antibiotic. Our results depend strongly on whether the antibiotic shows reversible transport and/or low-affinity ribosome binding (‘low-affinity antibiotic’) or, in contrast, irreversible transport and/or high affinity ribosome binding (‘high-affinity antibiotic’). For low-affinity antibiotics, our model predicts that growth inhibition depends on the duration of the antibiotic pulse, and can show a transient period of very fast growth following removal of the antibiotic. For high-affinity antibiotics, growth inhibition depends on peak dosage rather than dose duration, and the model predicts a pronounced post-antibiotic effect, due to hysteresis, in which growth can be suppressed for long times after the antibiotic dose has ended. These predictions are experimentally testable and may be of clinical significance. PMID:28714461

Procalcitonin versus C-reactive protein for guiding antibiotic therapy in sepsis: a randomized trial.

PubMed

Oliveira, Carolina F; Botoni, Fernando A; Oliveira, Clara R A; Silva, Camila B; Pereira, Helena A; Serufo, José C; Nobre, Vandack

2013-10-01

We sought to evaluate whether procalcitonin was superior to C-reactive protein in guiding antibiotic therapy in intensive care patients with sepsis. Randomized open clinical trial. Two university hospitals in Brazil. Patients with severe sepsis or septic shock. Patients were randomized in two groups: the procalcitonin group and the C-reactive protein group. Antibiotic therapy was discontinued following a protocol based on serum levels of these markers, according to the allocation group. The procalcitonin group was considered superior if the duration of antibiotic therapy was at least 25% shorter than in the C-reactive protein group. For both groups, at least seven full-days of antibiotic therapy were ensured in patients with Sequential Organ Failure Assessment greater than 10 and/or bacteremia at inclusion, and patients with evident resolution of the infectious process had antibiotics stopped after 7 days, despite biomarkers levels. Ninety-four patients were randomized: 49 patients to the procalcitonin group and 45 patients to the C-reactive protein group. The mean age was 59.8 (SD, 16.8) years. The median duration of antibiotic therapy for the first episode of infection was 7.0 (Q1-Q3, 6.0-8.5) days in the procalcitonin group and 6.0 (Q1-Q3, 5.0-7.0) days in the C-reactive protein group (p=0.13), with a hazard ratio of 1.206 (95% CI, 0.774-1.3; p=0.13). Overall, protocol overruling occurred in only 13 (13.8%) patients. Twenty-one patients died in each group (p=0.836). C-reactive protein was as useful as procalcitonin in reducing antibiotic use in a predominantly medical population of septic patients, causing no apparent harm.

Membrane-active macromolecules kill antibiotic-tolerant bacteria and potentiate antibiotics towards Gram-negative bacteria

PubMed Central

Uppu, Divakara S. S. M.; Konai, Mohini M.; Sarkar, Paramita; Samaddar, Sandip; Fensterseifer, Isabel C. M.; Farias-Junior, Celio; Krishnamoorthy, Paramanandam; Shome, Bibek R.; Franco, Octávio L.

2017-01-01

Chronic bacterial biofilms place a massive burden on healthcare due to the presence of antibiotic-tolerant dormant bacteria. Some of the conventional antibiotics such as erythromycin, vancomycin, linezolid, rifampicin etc. are inherently ineffective against Gram-negative bacteria, particularly in their biofilms. Here, we report membrane-active macromolecules that kill slow dividing stationary-phase and antibiotic tolerant cells of Gram-negative bacteria. More importantly, these molecules potentiate antibiotics (erythromycin and rifampicin) to biofilms of Gram-negative bacteria. These molecules eliminate planktonic bacteria that are liberated after dispersion of biofilms (dispersed cells). The membrane-active mechanism of these molecules forms the key for potentiating the established antibiotics. Further, we demonstrate that the combination of macromolecules and antibiotics significantly reduces bacterial burden in mouse burn and surgical wound infection models caused by Acinetobacter baumannii and Carbapenemase producing Klebsiella pneumoniae (KPC) clinical isolate respectively. Colistin, a well-known antibiotic targeting the lipopolysaccharide (LPS) of Gram-negative bacteria fails to kill antibiotic tolerant cells and dispersed cells (from biofilms) and bacteria develop resistance to it. On the contrary, these macromolecules prevent or delay the development of bacterial resistance to known antibiotics. Our findings emphasize the potential of targeting the bacterial membrane in antibiotic potentiation for disruption of biofilms and suggest a promising strategy towards developing therapies for topical treatment of Gram-negative infections. PMID:28837596

DRESS syndrome due to antibiotic therapy of osteoarticular infections in children: two case reports.

PubMed

Ramírez, A; Abril, J C; Cano, J

2015-01-01

Osteoarticular infection in children frequently occurs before 10 years of age. Surgical drainage is sometimes required, whereas acute osteomyelitis can be treated with antibiotic therapy alone. The duration of antibiotic therapy varies, 2 weeks is sufficient for septic arthritis, whereas 6 weeks is often required for complicated cases. Some of these antibiotic drugs present direct complications with low clinical impact in certain individuals. Hypersensitivity to these drugs causes different reactions in children. DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) is a severe and potentially life-threatening drug reaction. It is characterised by high fever, malaise, lymphadenopathy and skin rash. From a clinical perspective, these symptoms can lead to an exacerbation of the initial infectious process for which treatment was commenced. The liver is the organ most often affected in DRESS syndrome associated with haematological changes, potentially similar to sepsis. We present two cases of children with osteoarticular infections who developed DRESS syndrome after antibiotic therapy. Both patients made a complete recovery after cessation of the antibiotic drugs used. Copyright © 2014 SECOT. Published by Elsevier Espana. All rights reserved.

Increase in interleukin-8 production from circulating neutrophils upon antibiotic therapy in cystic fibrosis patients.

PubMed

Montemurro, Pasqualina; Mariggiò, Maria A; Barbuti, Giovanna; Cassano, Amalia; Vincenti, Alessandra; Serio, Gabriella; Guerra, Lorenzo; Diana, Anna; Santostasi, Teresa; Polizzi, Angela; Fumarulo, Ruggiero; Casavola, Valeria; Manca, Antonio; Conese, Massimo

2012-12-01

It is not known whether antibiotic therapy for lung disease in cystic fibrosis (CF) has an influence on circulating polymorphonuclear neutrophil (PMN) function and apoptosis. Blood PMNs were obtained from 14 CF patients before and after antibiotic treatment for an acute exacerbation, and from 10 healthy controls. PMNs were evaluated for production of reactive oxygen species (ROS) by spectrophotometry, of cytokines in the conditioned medium by ELISA, and apoptotic response by cytofluorimetry. ROS and interleukin (IL)-8 were produced at higher levels by CF PMNs pre-therapy than control PMNs under basal conditions. IL-8 levels further increased after therapy. Early apoptotic response was higher in CF PMNs pre-therapy than in control PMNs, and this pattern did not change after antibiotic treatment. Circulating PMNs are primed in CF acute patients. Further studies are needed to consider PMN-produced IL-8 as a biomarker to evaluate response to antibiotic therapy in CF patients. Copyright © 2012 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Impact of antibiotic restrictions: the ethical perspective.

PubMed

Garau, J

2006-08-01

Antibiotic restrictions present difficult choices for physicians, patients and payors. Physicians must choose between the welfare of the patient and the directive of healthcare systems to restrict antibiotics. These may be supported with incentives or penalties, causing a conflict of interest. The patient has an expectation of best care, but will often be unaware of antibiotic restriction policies and is therefore not fully informed about his/her treatment. For payors, reducing the volume of antibiotic prescribing and/or prescribing less expensive antibiotics are apparently attractive targets for cost savings. However, we are only now beginning to understand the downstream consequences of restricting antibiotics on outcomes and costs. We are hampered by the lack of a universal ethical framework and information on outcomes. In addition, the concept of 'effective' or 'best' therapy will vary among different groups. Balancing the risks of treating or not treating with antibiotics is complex. Suboptimal therapy, that fails to eradicate the bacterial infection, exposes the patient to the risk of poor outcome, adverse events and the wider risk of antimicrobial resistance. Failure to treat where the risk of a poor outcome exceeds the risk of an adverse event is also ethically unacceptable. The key to rational antibiotic prescribing is to identify those patients who need antibiotic therapy and optimise therapy to achieve the fastest bacterial and clinical cure. We are only now beginning to assemble the information and tools to be able to make such decisions. Above all, we should treat on the basis of knowledge.

Targeted Therapy for Cancer

Cancer.gov

Targeted therapy is a type of cancer treatment that targets the changes in cancer cells that help them grow, divide, and spread. Learn how targeted therapy works against cancer and about side effects that may occur.

Synergistic Photothermal and Antibiotic Killing of Biofilm-Associated Staphylococcus aureus Using Targeted Antibiotic-Loaded Gold Nanoconstructs.

PubMed

Meeker, Daniel G; Jenkins, Samir V; Miller, Emily K; Beenken, Karen E; Loughran, Allister J; Powless, Amy; Muldoon, Timothy J; Galanzha, Ekaterina I; Zharov, Vladimir P; Smeltzer, Mark S; Chen, Jingyi

2016-04-08

Resistance to conventional antibiotics is a growing public health concern that is quickly outpacing the development of new antibiotics. This has led the Infectious Diseases Society of America (IDSA) to designate Enterococcus faecium , Staphylococcus aureus , Klebsiella pneumoniae , Acinetobacter baumannii , Pseudomonas aeruginosa , and Enterobacter species as "ESKAPE pathogens" on the basis of the rapidly decreasing availability of useful antibiotics. This emphasizes the urgent need for alternative therapeutic strategies to combat infections caused by these and other bacterial pathogens. In this study, we used Staphylococcus aureus ( S. aureus ) as a proof-of-principle ESKAPE pathogen to demonstrate that an appropriate antibiotic (daptomycin) can be incorporated into polydopamine-coated gold nanocages (AuNC@PDA) and that daptomycin-loaded AuNC@PDA can be conjugated to antibodies targeting a species-specific surface protein (staphylococcal protein A; Spa) as a means of achieving selective delivery of the nanoconstructs directly to the bacterial cell surface. Targeting specificity was confirmed by demonstrating a lack of binding to mammalian cells, reduced photothermal and antibiotic killing of the Spa-negative species Staphylococcus epidermidis , and reduced killing of S. aureus in the presence of unconjugated anti-Spa antibodies. We demonstrate that laser irradiation at levels within the current safety standard for use in humans can be used to achieve both a lethal photothermal effect and controlled release of the antibiotic, thus resulting in a degree of therapeutic synergy capable of eradicating viable S. aureus cells. The system was validated using planktonic bacterial cultures of both methicillin-sensitive and methicillin-resistant S. aureus strains and subsequently shown to be effective in the context of an established biofilm, thus indicating that this approach could be used to facilitate the effective treatment of intrinsically resistant biofilm infections.

Photo-activated porphyrin in combination with antibiotics: therapies against Staphylococci

PubMed Central

Dastgheyb, Sana S.; Eckmann, David M.; Composto, Russell J.

2013-01-01

Staphylococcal infections have become difficult to treat due to antibiotic insensitivity and resistance. Antimicrobial combination therapies may minimize acquisition of resistance and photodynamic therapy is an attractive candidate for these combinations. In this manuscript, we explore combined use of antibiotics and meso-tetra (4-aminophenyl) porphine (TAPP), a cationic porphyrin, for treatment of Staphylococcus aureus contamination. We characterize the antimicrobial activity of photoactivated TAPP and show that activity is largely lost in the presence of a radical scavenger. Importantly, TAPP can be reactivated with continued, albeit attenuated, antibacterial activity. We then show that the antimicrobial activity of illuminated TAPP is additive with chloramphenicol and tobramycin for Staphylococcus aureus and Escherichia coli, and synergistic for MRSA and Staphylococcus epidermidis. Chloramphenicol + methylene blue, another photosensitizer, also show additivity against Staphylococcus aureus. In contrast, ceftriaxone and vancomycin do not strongly augment the low level effects of TAPP against S. aureus. Eukaryotic cells exhibit a dose-dependent toxicity with illuminated TAPP. Our results suggest that even sub-minimum inhibitory concentration levels of photo-activated TAPP could be used to boost the activity of waning antibiotics. This may play an important role in treatments reliant on antibiotic controlled release systems where augmentation with photo-active agents could extend their efficacy. PMID:24148969

An assessment of antibiotic therapy of urinary tract infection in elderly, hospitalised patients.

PubMed

McCaig, D J; Stewart, D; Harvey, Y; Downie, G; Scott, C J

1995-11-01

The aim of the study was to compare the antibiotic treatment actually received by elderly, hospitalised patients with urinary tract infection (UTI) with 'optimal' therapy (as gauged by compliance with antibiotic policy, infecting organism, sensitivity data, patient renal function and cost). UTI was more common in females and in catheterised patients and E.Coli was the commonest pathogen. Trimethoprim and co-amoxiclav were the drugs used most frequently for either empirical or sensitivity data-based treatment. In 96% of infections a drug with appropriate action was administered. Often, however, treatment could have been optimised by substituting a cheaper suitable antibiotic, by standardising duration of therapy and ensuring that doses were adjusted for renal impairment. Savings from the use of 'optimal' therapy were estimated at 17%. There is clearly considerable scope for positive input from the clinical pharmacist in this area.

Practical Considerations and the Intestinal Microbiome in Disease: Antibiotics for IBD Therapy.

PubMed

Fedorak, Richard N; Ismond, Kathleen P

2016-01-01

The inflammatory bowel diseases, Crohn's and ulcerative colitis, have been treated with a range of antibiotics for inducing and maintaining remission, as well as the prevention of post-operative symptoms. To date, many studies have been performed assessing the efficacy of antibiotics when used alone, in combination with other antibiotics, or as an adjunctive therapy to other pharmaceutical treatments. Literature evidence supporting the use of antibiotics in IBD can be ambiguous, especially when considering the potential role of dysbiosis in the gastrointestinal tract. The review considers the systemic effect of antibiotics and the evidence base for their efficacy in the treatment of IBD. © 2016 S. Karger AG, Basel.

Consensus on diagnosis and empiric antibiotic therapy of febrile neutropenia

PubMed Central

Giurici, Nagua; Zanazzo, Giulio A.

2011-01-01

Controversial issues on the management of empiric therapy and diagnosis of febrile neutropenia (FN) were faced by a Consensus Group of the Italian Association of Pediatric Hematology-Oncology (AIEOP). In this paper we report the suggestions of the consensus process regarding the role of aminoglycosides, glycopeptides and oral antibiotics in empiric therapy of FN, the rules for changing or discontinuing the therapy as well as the timing of the blood cultures. PMID:21647277

Every antibiotic, every day: Maximizing the impact of prospective audit and feedback on total antibiotic use

PubMed Central

Decloe, Melissa; Gill, Suzanne; Ho, Grace; McCready, Janine; Powis, Jeff

2017-01-01

Background The success of antimicrobial stewardship is dependent on how often it is completed and which antimicrobials are targeted. We evaluated the impact of an antimicrobial stewardship program (ASP) in three non-ICU settings where all systemic antibiotics, regardless of spectrum, were targeted on the first weekday after initiation. Methods Prospective audit and feedback (PAAF) was initiated on the surgical, respiratory, and medical wards of a community hospital on July 1, 2010, October 1, 2010, and April 1, 2012, respectively. We evaluated rates of total antibiotic use, measured in days on therapy (DOTs), among all patients admitted to the wards before and after PAAF initiation using an interrupted time series analysis. Changes in antibiotic costs, rates of C. difficile infection (CDI), mortality, readmission, and length of stay were evaluated using univariate analyses. Results Time series modelling demonstrated that total antibiotic use decreased (± standard error) by 100 ± 51 DOTs/1,000 patient-days on the surgical wards (p = 0.049), 100 ± 46 DOTs/1,000 patient-days on the respiratory ward (p = 0.029), and 91 ± 33 DOTs/1,000 patient-days on the medical wards (p = 0.006) immediately following PAAF initiation. Reductions in antibiotic use were sustained up to 50 months after intervention initiation, and were accompanied by decreases in antibiotic costs. There were no significant changes to patient outcomes on the surgical and respiratory wards following intervention initiation. On the medical wards, however, readmission increased from 4.6 to 5.6 per 1,000 patient-days (p = 0.043), while mortality decreased from 7.4 to 5.0 per 1,000 patient-days (p = 0.001). CDI rates showed a non-significant declining trend after PAAF initiation. Conclusions ASPs can lead to cost-effective, sustained reductions in total antibiotic use when interventions are conducted early in the course of therapy and target all antibiotics. Shifting to such a model may help strengthen the

Every antibiotic, every day: Maximizing the impact of prospective audit and feedback on total antibiotic use.

PubMed

Campbell, Tonya J; Decloe, Melissa; Gill, Suzanne; Ho, Grace; McCready, Janine; Powis, Jeff

2017-01-01

The success of antimicrobial stewardship is dependent on how often it is completed and which antimicrobials are targeted. We evaluated the impact of an antimicrobial stewardship program (ASP) in three non-ICU settings where all systemic antibiotics, regardless of spectrum, were targeted on the first weekday after initiation. Prospective audit and feedback (PAAF) was initiated on the surgical, respiratory, and medical wards of a community hospital on July 1, 2010, October 1, 2010, and April 1, 2012, respectively. We evaluated rates of total antibiotic use, measured in days on therapy (DOTs), among all patients admitted to the wards before and after PAAF initiation using an interrupted time series analysis. Changes in antibiotic costs, rates of C. difficile infection (CDI), mortality, readmission, and length of stay were evaluated using univariate analyses. Time series modelling demonstrated that total antibiotic use decreased (± standard error) by 100 ± 51 DOTs/1,000 patient-days on the surgical wards (p = 0.049), 100 ± 46 DOTs/1,000 patient-days on the respiratory ward (p = 0.029), and 91 ± 33 DOTs/1,000 patient-days on the medical wards (p = 0.006) immediately following PAAF initiation. Reductions in antibiotic use were sustained up to 50 months after intervention initiation, and were accompanied by decreases in antibiotic costs. There were no significant changes to patient outcomes on the surgical and respiratory wards following intervention initiation. On the medical wards, however, readmission increased from 4.6 to 5.6 per 1,000 patient-days (p = 0.043), while mortality decreased from 7.4 to 5.0 per 1,000 patient-days (p = 0.001). CDI rates showed a non-significant declining trend after PAAF initiation. ASPs can lead to cost-effective, sustained reductions in total antibiotic use when interventions are conducted early in the course of therapy and target all antibiotics. Shifting to such a model may help strengthen the effectiveness of ASPs in non

Is there an improvement of antibiotic use in China? Evidence from the usage analysis of combination antibiotic therapy for type I incisions in 244 hospitals.

PubMed

Zhou, Wen-Juan; Luo, Zhen-Ni; Tang, Chang-Min; Zou, Xiao-Xu; Zhao, Lu; Fang, Peng-Qian

2016-10-01

The improvement of antibiotic rational use in China was studied by usage analysis of combination antibiotic therapy for type I incisions in 244 hospitals. Five kinds of hospitals, including general hospital, maternity hospital, children's hospital, stomatological hospital and cancer hospital, from 30 provinces were surveyed. A systematic random sampling strategy was employed to select outpatient prescriptions and inpatient cases in 2011 and 2012. A total of 29 280 outpatient prescriptions and 73 200 inpatient cases from 244 hospitals in each year were analyzed. Data were collected with regards to the implementation of the national antibiotic stewardship program (NASP), the overall usage and the prophylactic use of antibiotic for type I incisions. Univariate analysis was used for microbiological diagnosis rate before antimicrobial therapy, prophylactic use of antibiotics for type I incision operation, and so on. For multivariate analysis, the use of antibiotics was dichotomized according to the guidelines, and entered as binary values into logistic regression analysis. The results were compared with the corresponding criteria given by the guidelines of this campaign. The antibiotic stewardship in China was effective in that more than 80% of each kind of hospitals achieved the criteria of recommended antibiotics varieties. Hospital type appeared to be a factor statistically associated with stewardship outcome. The prophylactic use of antibiotics on type I incision operations decreased by 16.22% (P<0.05). The usage of combination antibiotic therapy for type I incisions was also decreased. Region and bed size were the main determinants on surgical prophylaxis for type I incision. This national analysis of hospitals on antibiotic use and stewardship allows relevant comparisons for bench marking. More efforts addressing the root cause of antibiotics abuse would continue to improve the rational use of antibiotics in China.

Early antibiotic administration but not antibody therapy directed against IL-6 improves survival in septic mice predicted to die based upon high IL-6 levels

PubMed Central

Vyas, Dinesh; Javadi, Pardis; DiPasco, Peter J; Buchman, Timothy G; Hotchkiss, Richard S; Coopersmith, Craig M

2005-01-01

Elevated interleukin (IL)-6 levels correlate with increased mortality following sepsis. IL-6 levels >14,000 pg/ml drawn 6 hours following cecal ligation and puncture (CLP) are associated with 100% mortality in ND4 mice, even if antibiotic therapy is initiated 12 hours after the septic insult. The first aim of this study was to see if earlier institution of antibiotic therapy could improve overall survival in septic mice and rescue the subset of animals predicted to die based upon high IL-6 levels. Mice (n=184) were subjected to CLP, had IL-6 levels drawn six hours later and then were randomized to receive imipenem, a broad spectrum antimicrobial agent, beginning six or twelve hours post-operatively. Overall one-week survival improved from 25.5% to 35.9% with earlier administration of antibiotics (p<0.05). In mice with IL-6 levels >14,000 pg/ml, 25% survived if imipenem was started at 6 hours, while none survived if antibiotics were started later (p<0.05). Based upon these results, we examined whether targeted antibody therapy could improve survival in mice with elevated IL-6 levels. A different cohort of mice (n=54) had their blood drawn six hours after CLP and then were randomized to receive either monoclonal anti-IL-6 IgG or irrelevant rat IgG. Anti-IL-6 antibody failed to improve either overall survival or outcome in mice with IL-6 levels >14,000 pg/ml. These results demonstrate that earlier systemic therapy can improve outcome in a subset of mice predicted to die in sepsis, but we are unable to demonstrate any benefit in similar animals using targeted therapy directed at IL-6. PMID:15947070

Ligand design for riboswitches, an emerging target class for novel antibiotics.

PubMed

Rekand, Illimar Hugo; Brenk, Ruth

2017-09-01

Riboswitches are cis-acting gene regulatory elements and constitute potential targets for new antibiotics. Recent studies in this field have started to explore these targets for drug discovery. New ligands found by fragment screening, design of analogs of the natural ligands or serendipitously by phenotypic screening have shown antibacterial effects in cell assays against a range of bacteria strains and in animal models. In this review, we highlight the most advanced drug design work of riboswitch ligands and discuss the challenges in the field with respect to the development of antibiotics with a new mechanism of action.

Using Chemical Reaction Kinetics to Predict Optimal Antibiotic Treatment Strategies.

PubMed

Abel Zur Wiesch, Pia; Clarelli, Fabrizio; Cohen, Ted

2017-01-01

Identifying optimal dosing of antibiotics has proven challenging-some antibiotics are most effective when they are administered periodically at high doses, while others work best when minimizing concentration fluctuations. Mechanistic explanations for why antibiotics differ in their optimal dosing are lacking, limiting our ability to predict optimal therapy and leading to long and costly experiments. We use mathematical models that describe both bacterial growth and intracellular antibiotic-target binding to investigate the effects of fluctuating antibiotic concentrations on individual bacterial cells and bacterial populations. We show that physicochemical parameters, e.g. the rate of drug transmembrane diffusion and the antibiotic-target complex half-life are sufficient to explain which treatment strategy is most effective. If the drug-target complex dissociates rapidly, the antibiotic must be kept constantly at a concentration that prevents bacterial replication. If antibiotics cross bacterial cell envelopes slowly to reach their target, there is a delay in the onset of action that may be reduced by increasing initial antibiotic concentration. Finally, slow drug-target dissociation and slow diffusion out of cells act to prolong antibiotic effects, thereby allowing for less frequent dosing. Our model can be used as a tool in the rational design of treatment for bacterial infections. It is easily adaptable to other biological systems, e.g. HIV, malaria and cancer, where the effects of physiological fluctuations of drug concentration are also poorly understood.

Using Chemical Reaction Kinetics to Predict Optimal Antibiotic Treatment Strategies

PubMed Central

Abel zur Wiesch, Pia; Cohen, Ted

2017-01-01

Identifying optimal dosing of antibiotics has proven challenging—some antibiotics are most effective when they are administered periodically at high doses, while others work best when minimizing concentration fluctuations. Mechanistic explanations for why antibiotics differ in their optimal dosing are lacking, limiting our ability to predict optimal therapy and leading to long and costly experiments. We use mathematical models that describe both bacterial growth and intracellular antibiotic-target binding to investigate the effects of fluctuating antibiotic concentrations on individual bacterial cells and bacterial populations. We show that physicochemical parameters, e.g. the rate of drug transmembrane diffusion and the antibiotic-target complex half-life are sufficient to explain which treatment strategy is most effective. If the drug-target complex dissociates rapidly, the antibiotic must be kept constantly at a concentration that prevents bacterial replication. If antibiotics cross bacterial cell envelopes slowly to reach their target, there is a delay in the onset of action that may be reduced by increasing initial antibiotic concentration. Finally, slow drug-target dissociation and slow diffusion out of cells act to prolong antibiotic effects, thereby allowing for less frequent dosing. Our model can be used as a tool in the rational design of treatment for bacterial infections. It is easily adaptable to other biological systems, e.g. HIV, malaria and cancer, where the effects of physiological fluctuations of drug concentration are also poorly understood. PMID:28060813

Systematic review of duration and choice of systemic antibiotic therapy for acute haematogenous bacterial osteomyelitis in children.

PubMed

Howard-Jones, Annaleise R; Isaacs, David

2013-09-01

Historically, children with acute osteomyelitis received 4-6 weeks of parenteral antibiotics; however, evidence to guide optimal duration of therapy is limited. This study aims to summarise the available evidence on the duration and choice of antimicrobial therapy for acute haematogenous osteomyelitis in children. We systematically reviewed the literature on children with acute osteomyelitis to determine if shorter durations of antibiotic treatment compared with protracted treatment gave different cure rates. We also analysed studies for choice of antibiotics to determine differences in success rates. Randomised controlled trials, cohort studies, case-control studies and case series were eligible for inclusion. We identified six randomised controlled trials, three of which addressed duration of antibiotic use and three choice of antibiotic for acute osteomyelitis in children. We found 28 observational studies, 20 of which focused on duration and 22 of which allowed analysis of choice of antibiotic. A range of therapy durations and types of antibiotics were assessed. Only one small study looked at treatment of neonates. The quality of evidence on antibiotic treatment for acute osteomyelitis is limited, allowing only weak (GRADE 2B) recommendations. Our review suggests that early transition from intravenous to oral therapy, after 3-4 days in patients responding well, followed by oral therapy to a total of 3 weeks may be as effective as longer courses for uncomplicated acute osteomyelitis. This recommendation does not apply to neonates. © 2013 The Authors. Journal of Paediatrics and Child Health © 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

Systemic antibiotics in periodontics.

PubMed

Slots, Jørgen

2004-11-01

This position paper addresses the role of systemic antibiotics in the treatment of periodontal disease. Topical antibiotic therapy is not discussed here. The paper was prepared by the Research, Science and Therapy Committee of the American Academy of Periodontology. The document consists of three sections: 1) concept of antibiotic periodontal therapy; 2) efficacy of antibiotic periodontal therapy; and 3) practical aspects of antibiotic periodontal therapy. The conclusions drawn in this paper represent the position of the American Academy of Periodontology and are intended for the information of the dental profession.

Antibiotic therapy in ventilator-associated tracheobronchitis: a literature review.

PubMed

Alves, Abel Eduardo; Pereira, José Manuel

2018-03-01

The concept of ventilator-associated tracheobronchitis is controversial; its definition is not unanimously accepted and often overlaps with ventilator-associated pneumonia. Ventilator-associated tracheobronchitis has an incidence similar to that of ventilator-associated pneumonia, with a high prevalence of isolated multiresistant agents, resulting in an increase in the time of mechanical ventilation and hospitalization but without an impact on mortality. The performance of quantitative cultures may allow better diagnostic definition of tracheobronchitis associated with mechanical ventilation, possibly avoiding the overdiagnosis of this condition. One of the major difficulties in differentiating between ventilator-associated tracheobronchitis and ventilator-associated pneumonia is the exclusion of a pulmonary infiltrate by chest radiography; thoracic computed tomography, thoracic ultrasonography, or invasive specimen collection may also be required. The institution of systemic antibiotic therapy does not improve the clinical impact of ventilator-associated tracheobronchitis, particularly in reducing time of mechanical ventilation, hospitalization or mortality, despite the possible reduced progression to ventilator-associated pneumonia. However, there are doubts regarding the methodology used. Thus, considering the high prevalence of tracheobronchitis associated with mechanical ventilation, routine treatment of this condition would result in high antibiotic usage without clear benefits. However, we suggest the institution of antibiotic therapy in patients with tracheobronchitis associated with mechanical ventilation and septic shock and/or worsening of oxygenation, and other auxiliary diagnostic tests should be simultaneously performed to exclude ventilator-associated pneumonia. This review provides a better understanding of the differentiation between tracheobronchitis associated with mechanical ventilation and pneumonia associated with mechanical ventilation, which

Early antibiotic administration but not antibody therapy directed against IL-6 improves survival in septic mice predicted to die on basis of high IL-6 levels.

PubMed

Vyas, Dinesh; Javadi, Pardis; Dipasco, Peter J; Buchman, Timothy G; Hotchkiss, Richard S; Coopersmith, Craig M

2005-10-01

Elevated interleukin (IL)-6 levels correlate with increased mortality following sepsis. IL-6 levels >14,000 pg/ml drawn 6 h after cecal ligation and puncture (CLP) are associated with 100% mortality in ND4 mice, even if antibiotic therapy is initiated 12 h after septic insult. Our first aim was to see whether earlier institution of antibiotic therapy could improve overall survival in septic mice and rescue the subset of animals predicted to die on the basis of high IL-6 levels. Mice (n = 184) were subjected to CLP, had IL-6 levels drawn 6 h later, and then were randomized to receive imipenem, a broad spectrum antimicrobial agent, beginning 6 or 12 h postoperatively. Overall 1-wk survival improved from 25.5 to 35.9% with earlier administration of antibiotics (P < 0.05). In mice with IL-6 levels >14,000 pg/ml, 25% survived if imipenem was started at 6 h, whereas none survived if antibiotics were started later (P < 0.05). On the basis of these results, we examined whether targeted antibody therapy could improve survival in mice with elevated IL-6 levels. A different cohort of mice (n = 54) had blood drawn 6 h after CLP, and then they were randomized to receive either monoclonal anti-IL-6 IgG or irrelevant rat IgG. Anti-IL-6 antibody failed to improve either overall survival or outcome in mice with IL-6 levels >14,000 pg/ml. These results demonstrate that earlier systemic therapy can improve outcome in a subset of mice predicted to die in sepsis, but we are unable to demonstrate any benefit in similar animals using targeted therapy directed at IL-6.

The analysis of the antibiotic resistome offers new opportunities for therapeutic intervention.

PubMed

Corona, Fernando; Blanco, Paula; Alcalde-Rico, Manuel; Hernando-Amado, Sara; Lira, Felipe; Bernardini, Alejandra; Sánchez, María B; Martínez, José L

2016-06-01

Most efforts in the development of antimicrobials have focused on the screening of lethal targets. Nevertheless, the constant expansion of antimicrobial resistance makes the antibiotic resistance determinants themselves suitable targets for finding inhibitors to be used in combination with antibiotics. Among them, inhibitors of antibiotic inactivating enzymes and of multidrug efflux pumps are suitable candidates for improving the efficacy of antibiotics. In addition, the application of systems biology tools is helping to understand the changes in bacterial physiology associated to the acquisition of resistance, including the increased susceptibility to other antibiotics displayed by some antibiotic-resistant mutants. This information is useful for implementing novel strategies based in metabolic interventions or combination of antibiotics for improving the efficacy of antibacterial therapy.

Antibiotic dosing in critically ill patients receiving CRRT: underdosing is overprevalent.

PubMed

Lewis, Susan J; Mueller, Bruce A

2014-01-01

Published CRRT drug dosing algorithms and other dosing guidelines appear to result in underdosed antibiotics, leading to failure to attain pharmacodynamic targets. High mortality rates persist with inadequate antibiotic therapy as the most important risk factor for death. Reasons for unintended antibiotic underdosing in patients receiving CRRT are many. Underdosing may result from lack of the recognition that better hepatic function in AKI patients yields higher nonrenal antibiotic clearance compared to ESRD patients. Other factors include the variability in body size and fluid composition of patients, the serious consequence of delayed achievement of antibiotic pharmacodynamic targets in septic patients, potential subtherapeutic antibiotic concentrations at the infection site, and the influence of RRT intensity on antibiotic concentrations. Too often, clinicians weigh the benefits of overcautious antibiotic dosing to avoid antibiotic toxicity too heavily against the benefits of rapid attainment of therapeutic antibiotic concentrations in critically ill patients receiving CRRT. We urge clinicians to prescribe antibiotics aggressively for these vulnerable patients. © 2014 Wiley Periodicals, Inc.

Ticarcillin in Combination with Cephalothin or Gentamicin as Empiric Antibiotic Therapy in Granulocytopenic Cancer Patients

PubMed Central

Schimpff, Stephen C.; Landesman, Sheldon; Hahn, Davis M.; Standiford, Harold C.; Fortner, Clarence L.; Young, Viola Mae; Wiernik, Peter H.

1976-01-01

Ticarcillin was used in combination with either cephalothin or gentamicin as initial empiric antibiotic therapy for 127 patient trials of suspected infection in granulocytopenic cancer patients. Bacteremia was present in 20%, nonbacteremic microbiologically documented infections in 21%, clinically documented infections in 23%, and possible infections in 5%; infection was doubtful in 31%. Although Staphylococcus aureus was the most common single organism isolated (23%), gram-negative bacilli accounted for 54% of all pathogens. Both antibiotic regimens were highly efficacious, with complete resolution in 46% of bacteremias, 88% of nonbacteremic microbiologically documented infections, and 95% of clinically documented infections. Among bacteremias, 8 of 9 caused by S. aureus but only 4 of 15 (27%) caused by gram-negative bacilli were completely resolved with these antibiotic combinations. Reasons for nonresponse in bacteremias were persistent granulocytopenia, mixed infection and, in two patients, antibiotic-resistant organisms. Toxicities other than hypokalemia were minimal. Although the rate of further infections was high overall (18/127), only one occurred among the 39 patients with <4 days of antibiotic therapy. Ticarcillin in combination with either cephalothin or gentamicin was effective as initial empiric therapy of suspected infection in granulocytopenic cancer patients. PMID:795372

Non-adherence to antibiotic therapy in patients visiting community pharmacies.

PubMed

Fernandes, Milene; Leite, Andreia; Basto, Maria; Nobre, Miguel Araújo; Vieira, Nuno; Fernandes, Rui; Nogueira, Paulo; Nicola, Paulo Jorge; Jorge, Paulo

2014-02-01

Patient non-adherence to antibiotic therapy may lead to therapeutic failure, re-infection, and bacterial resistance. Assessing the factors associated with this problem is important for promoting rational use of antibiotics. This study aimed to measure prevalence and reasons for non-adherence to antibiotic treatment and to identify associated factors. Patients were recruited for the study in community pharmacies in Lisbon, Portugal, from February to April, 2009. Data from prescriptions for oral antibiotics were collected for adult subjects. Adherence to treatment was assessed with a modified Portuguese version of the Morisky scale. Factors associated with non-adherence were identified through bivariate analysis and logistic regression models. A total of 243 patients were included in the study. They had a mean age 46.5 ± 16.6 years and 74.5 % of the sample was female. The prevalence of non-adherence was 57.7 % and was related to delays and failures in taking the prescribed medicine. Increasing age (OR 0.97), difficulty in buying the antibiotic (OR 2.34), duration of treatment (OR 1.28), difficulty with ingestion (OR 3.08), and satisfaction with the information given by physician (OR 0.33) were identified as independent factors associated with non-adherence. Non-adherence to antibiotics is common in the community setting. Factors related to the antibiotic, the patient, and the patient-physician relationship should be addressed to promote adherence. Pharmacists should provide information to patients about correct use of antibiotics and address barriers to adherence.

Effectiveness of oral antibiotics for definitive therapy of Gram-negative bloodstream infections.

PubMed

Kutob, Leila F; Justo, Julie Ann; Bookstaver, P Brandon; Kohn, Joseph; Albrecht, Helmut; Al-Hasan, Majdi N

2016-11-01

There is paucity of data evaluating intravenous-to-oral antibiotic switch options for Gram-negative bloodstream infections (BSIs). This retrospective cohort study examined the effectiveness of oral antibiotics for definitive treatment of Gram-negative BSI. Patients with Gram-negative BSI hospitalised for <14 days at Palmetto Health Hospitals in Columbia, SC, from 1 January 2010 through 31 December 2013 and discharged on oral antibiotics were included in this study. The cohort was stratified into three groups based on bioavailability of oral antibiotics prescribed (high, ≥95%; moderate, 75-94%; and low, <75%). Kaplan-Meier analysis and multivariate Cox proportional hazards regression were used to examine treatment failure. Among the 362 patients, high, moderate and low bioavailability oral antibiotics were prescribed to 106, 179 and 77 patients, respectively, for definitive therapy of Gram-negative BSI. Mean patient age was 63 years, 217 (59.9%) were women and 254 (70.2%) had a urinary source of infection. Treatment failure rates were 2%, 12% and 14% in patients receiving oral antibiotics with high, moderate and low bioavailability, respectively (P = 0.02). Risk of treatment failure in the multivariate Cox model was higher in patients receiving antibiotics with moderate [adjusted hazard ratio (aHR) = 5.9, 95% CI 1.6-38.5; P = 0.005] and low bioavailability (aHR = 7.7, 95% CI 1.9-51.5; P = 0.003) compared with those receiving oral antimicrobial agents with high bioavailability. These data demonstrate the effectiveness of oral antibiotics with high bioavailability for definitive therapy of Gram-negative BSI. Risk of treatment failure increases as bioavailability of the oral regimen declines. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Spotlight on the microbes that produce heat shock protein 90-targeting antibiotics.

PubMed

Piper, Peter W; Millson, Stefan H

2012-12-12

Heat shock protein 90 (Hsp90) is a promising cancer drug target as a molecular chaperone critical for stabilization and activation of several of the oncoproteins that drive cancer progression. Its actions depend upon its essential ATPase, an activity fortuitously inhibited with a very high degree of selectivity by natural antibiotics: notably the actinomycete-derived benzoquinone ansamycins (e.g. geldanamycin) and certain fungal-derived resorcyclic acid lactones (e.g. radicicol). The molecular interactions made by these antibiotics when bound within the ADP/ATP-binding site of Hsp90 have served as templates for the development of several synthetic Hsp90 inhibitor drugs. Much attention now focuses on the clinical trials of these drugs. However, because microbes have evolved antibiotics to target Hsp90, it is probable that they often exploit Hsp90 inhibition when interacting with each other and with plants. Fungi known to produce Hsp90 inhibitors include mycoparasitic, as well as plant-pathogenic, endophytic and mycorrhizal species. The Hsp90 chaperone may, therefore, be a prominent target in establishing a number of mycoparasitic (interfungal), fungal pathogen-plant and symbiotic fungus-plant relationships. Furthermore the Hsp90 family proteins of the microbes that produce Hsp90 inhibitor antibiotics are able to reveal how drug resistance can arise by amino acid changes in the highly conserved ADP/ATP-binding site of Hsp90.

Pharmacological Targeting of the Host-Pathogen Interaction: Alternatives to Classical Antibiotics to Combat Drug-Resistant Superbugs

PubMed Central

Munguia, Jason; Nizet, Victor

2017-01-01

The rise of multidrug-resistant pathogens and the dearth of new antibiotic development place an existential strain on successful infectious disease therapy. Breakthrough strategies that go beyond classical antibiotic mechanisms are needed to combat this looming public health catastrophe. Reconceptualizing antibiotic therapy in the richer context of the host-pathogen interaction is required for innovative solutions. By defining specific virulence factors, the essence of a pathogen, and pharmacologically neutralizing their activities, one can block disease progression and sensitize microbes to immune clearance. Likewise, host-directed strategies to boost phagocyte bactericidal activity, enhance leukocyte recruitment, or reverse pathogen-induced immunosuppression seek to replicate the success of cancer immunotherapy in the field of infectious diseases. The answer to the threat of multidrug-resistant pathogens lies “outside-the-box” of current antibiotic paradigms. PMID:28283200

Dynamic energy budget approach to evaluate antibiotic effects on biofilms

NASA Astrophysics Data System (ADS)

Birnir, Bjorn; Carpio, Ana; Cebrián, Elena; Vidal, Perfecto

2018-01-01

Quantifying the action of antibiotics on biofilms is essential to devise therapies against chronic infections. Biofilms are bacterial communities attached to moist surfaces, sheltered from external aggressions by a polymeric matrix. Coupling a dynamic energy budget based description of cell metabolism to surrounding concentration fields, we are able to approximate survival curves measured for different antibiotics. We reproduce numerically stratified distributions of cell types within the biofilm and introduce ways to incorporate different resistance mechanisms. Qualitative predictions follow that are in agreement with experimental observations, such as higher survival rates of cells close to the substratum when employing antibiotics targeting active cells or enhanced polymer production when antibiotics are administered. The current computational model enables validation and hypothesis testing when developing therapies.

Targeted enzyme prodrug therapies.

PubMed

Schellmann, N; Deckert, P M; Bachran, D; Fuchs, H; Bachran, C

2010-09-01

The cure of cancer is still a formidable challenge in medical science. Long-known modalities including surgery, chemotherapy and radiotherapy are successful in a number of cases; however, invasive, metastasized and inaccessible tumors still pose an unresolved and ongoing problem. Targeted therapies designed to locate, detect and specifically kill tumor cells have been developed in the past three decades as an alternative to treat troublesome cancers. Most of these therapies are either based on antibody-dependent cellular cytotoxicity, targeted delivery of cytotoxic drugs or tumor site-specific activation of prodrugs. The latter is a two-step procedure. In the first step, a selected enzyme is accumulated in the tumor by guiding the enzyme or its gene to the neoplastic cells. In the second step, a harmless prodrug is applied and specifically converted by this enzyme into a cytotoxic drug only at the tumor site. A number of targeting systems, enzymes and prodrugs were investigated and improved since the concept was first envisioned in 1974. This review presents a concise overview on the history and latest developments in targeted therapies for cancer treatment. We cover the relevant technologies such as antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT) as well as related therapies such as clostridial- (CDEPT) and polymer-directed enzyme prodrug therapy (PDEPT) with emphasis on prodrug-converting enzymes, prodrugs and drugs.

Antibiotic Combinations That Enable One-Step, Targeted Mutagenesis of Chromosomal Genes.

PubMed

Lee, Wonsik; Do, Truc; Zhang, Ge; Kahne, Daniel; Meredith, Timothy C; Walker, Suzanne

2018-06-08

Targeted modification of bacterial chromosomes is necessary to understand new drug targets, investigate virulence factors, elucidate cell physiology, and validate results of -omics-based approaches. For some bacteria, reverse genetics remains a major bottleneck to progress in research. Here, we describe a compound-centric strategy that combines new negative selection markers with known positive selection markers to achieve simple, efficient one-step genome engineering of bacterial chromosomes. The method was inspired by the observation that certain nonessential metabolic pathways contain essential late steps, suggesting that antibiotics targeting a late step can be used to select for the absence of genes that control flux into the pathway. Guided by this hypothesis, we have identified antibiotic/counterselectable markers to accelerate reverse engineering of two increasingly antibiotic-resistant pathogens, Staphylococcus aureus and Acinetobacter baumannii. For S. aureus, we used wall teichoic acid biosynthesis inhibitors to select for the absence of tarO and for A. baumannii, we used colistin to select for the absence of lpxC. We have obtained desired gene deletions, gene fusions, and promoter swaps in a single plating step with perfect efficiency. Our method can also be adapted to generate markerless deletions of genes using FLP recombinase. The tools described here will accelerate research on two important pathogens, and the concept we outline can be readily adapted to any organism for which a suitable target pathway can be identified.

Developing New Antimicrobial Therapies: Are Synergistic Combinations of Plant Extracts/Compounds with Conventional Antibiotics the Solution?

PubMed Central

Cheesman, Matthew J.; Ilanko, Aishwarya; Blonk, Baxter; Cock, Ian E.

2017-01-01

The discovery of penicillin nearly 90 years ago revolutionized the treatment of bacterial disease. Since that time, numerous other antibiotics have been discovered from bacteria and fungi, or developed by chemical synthesis and have become effective chemotherapeutic options. However, the misuse of antibiotics has lessened the efficacy of many commonly used antibiotics. The emergence of resistant strains of bacteria has seriously limited our ability to treat bacterial illness, and new antibiotics are desperately needed. Since the discovery of penicillin, most antibiotic development has focused on the discovery of new antibiotics derived from microbial sources, or on the synthesis of new compounds using existing antibiotic scaffolds to the detriment of other lines of discovery. Both of these methods have been fruitful. However, for a number of reasons discussed in this review, these strategies are unlikely to provide the same wealth of new antibiotics in the future. Indeed, the number of newly developed antibiotics has decreased dramatically in recent years. Instead, a reexamination of traditional medicines has become more common and has already provided several new antibiotics. Traditional medicine plants are likely to provide further new antibiotics in the future. However, the use of plant extracts or pure natural compounds in combination with conventional antibiotics may hold greater promise for rapidly providing affordable treatment options. Indeed, some combinational antibiotic therapies are already clinically available. This study reviews the recent literature on combinational antibiotic therapies to highlight their potential and to guide future research in this field. PMID:28989242

Developing New Antimicrobial Therapies: Are Synergistic Combinations of Plant Extracts/Compounds with Conventional Antibiotics the Solution?

PubMed

Cheesman, Matthew J; Ilanko, Aishwarya; Blonk, Baxter; Cock, Ian E

2017-01-01

The discovery of penicillin nearly 90 years ago revolutionized the treatment of bacterial disease. Since that time, numerous other antibiotics have been discovered from bacteria and fungi, or developed by chemical synthesis and have become effective chemotherapeutic options. However, the misuse of antibiotics has lessened the efficacy of many commonly used antibiotics. The emergence of resistant strains of bacteria has seriously limited our ability to treat bacterial illness, and new antibiotics are desperately needed. Since the discovery of penicillin, most antibiotic development has focused on the discovery of new antibiotics derived from microbial sources, or on the synthesis of new compounds using existing antibiotic scaffolds to the detriment of other lines of discovery. Both of these methods have been fruitful. However, for a number of reasons discussed in this review, these strategies are unlikely to provide the same wealth of new antibiotics in the future. Indeed, the number of newly developed antibiotics has decreased dramatically in recent years. Instead, a reexamination of traditional medicines has become more common and has already provided several new antibiotics. Traditional medicine plants are likely to provide further new antibiotics in the future. However, the use of plant extracts or pure natural compounds in combination with conventional antibiotics may hold greater promise for rapidly providing affordable treatment options. Indeed, some combinational antibiotic therapies are already clinically available. This study reviews the recent literature on combinational antibiotic therapies to highlight their potential and to guide future research in this field.

β-Lactam Antibiotics with a High Affinity for PBP2 Act Synergistically with the FtsZ-Targeting Agent TXA707 against Methicillin-Resistant Staphylococcus aureus

PubMed Central

Ferrer-González, Edgar; Kaul, Malvika; Parhi, Ajit K.; LaVoie, Edmond J.

2017-01-01

ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) is a multidrug-resistant pathogen that poses a significant risk to global health today. We have developed a promising new FtsZ-targeting agent (TXA707) with potent activity against MRSA isolates resistant to current standard-of-care antibiotics. We present here results that demonstrate differing extents of synergy between TXA707 and a broad range of β-lactam antibiotics (including six cephalosporins, two penicillins, and two carbapenems) against MRSA. To explore whether there is a correlation between the extent of synergy and the preferential antibacterial target of each β-lactam, we determined the binding affinities of the β-lactam antibiotics for each of the four native penicillin-binding proteins (PBPs) of S. aureus using a fluorescence anisotropy competition assay. A comparison of the resulting PBP binding affinities with our corresponding synergy results reveals that β-lactams with a high affinity for PBP2 afford the greatest degree of synergy with TXA707 against MRSA. In addition, we present fluorescence and electron microscopy studies that suggest a potential mechanism underlying the synergy between TXA707 and the β-lactam antibiotics. In this connection, our microscopy results show a disruption of septum formation in TXA707-treated MRSA cells, with a concomitant mislocalization of the PBPs from midcell to nonproductive peripheral sites. Viewed as a whole, our results indicate that PBP2-targeting β-lactam antibiotics are optimal synergistic partners with FtsZ-targeting agents for use in combination therapy of MRSA infections. PMID:28630190

Antimicrobial Therapy for Legionnaire's Disease: Antibiotic Stewardship Implications.

PubMed

Cunha, Cheston B; Cunha, Burke A

2017-03-01

Legionnaire's disease is a common cause of community-acquired pneumonia (CAP). Although no single clinical feature is diagnostic, if characteristic extrapulmonary findings are present a presumptive clinical syndromic diagnosis is possible. Depending on geographic location, season, and physician awareness, Legionnaire's disease may be included in the differential diagnosis of CAP. Some antibiotics effective against Legionella sp are also effective in treating the typical bacterial causes of CAP. From an antimicrobial stewardship program (ASP) perspective, monotherapy is preferred to double-drug therapy. From an ASP and pharmacoeconomic standpoint, monotherapy with doxycycline or a respiratory quinolone provides optimal cost effective therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

Continuous alternating inhaled antibiotic therapy in CF: A single center retrospective analysis.

PubMed

Van de Kerkhove, C; Goeminne, P C; Kicinski, M; Nawrot, T S; Lorent, N; Van Bleyenbergh, P; De Boeck, K; Dupont, L J

2016-11-01

The efficacy of inhaled antibiotics to treat chronic Pseudomonas aeruginosa pulmonary infection in patients with cystic fibrosis (CF) has been well established. Few data are available on the value of continuous alternating inhaled antibiotic therapy (CAIT), a strategy increasingly used in the management of CF. To investigate the effect of CAIT on clinical outcome in adult CF patients treated at the University Hospital Leuven. Patients with a documented CF diagnosis who received inhaled antibiotics between March 2010 and January 2015 were retrospectively evaluated. In patients receiving CAIT patient characteristics, recorded spirometry data and number of IV antibiotic days were collected retrospectively at fixed time intervals, from 6months before to one year after the start of the 2nd inhaled antibiotic. For patients on inhaled antibiotic monotherapy (IAMT), the same data were obtained at similar intervals during the study period. A total of 49 of 89 patients using chronic inhaled antibiotic therapy received CAIT. Patients receiving CAIT had a lower baseline FEV 1 and were more likely to be homozygous for F508del compared to patients receiving IAMT. FEV 1 deteriorated on average by a factor of 0.904 per year (95% CI: 0.851-0.960) prior to the start of CAIT. The initiation of CAIT was associated with an average improvement in FEV 1 by a factor of 1.148 per year (95% CI: 1.068-1.236, p=0.0002). The analysis of specific types of antibiotics revealed evidence of positive effects of adding COLI to TOBI and COLI to AZLI. We found no effect of the initiation of CAIT on the number of IV antibiotic days (p=0.80). CF patients with more advanced lung disease are more likely to receive CAIT. In this patient group, CAIT was associated with a significant improvement in FEV 1 . Further data are warranted to identify the value of CAIT. Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Rapid resolution of cellulitis in patients managed with combination antibiotic and anti-inflammatory therapy.

PubMed

Dall, Lawrence; Peterson, Sandford; Simmons, Tom; Dall, Amy

2005-03-01

There is some evidence to suggest that host inflammatory response has some effect on the clinical manifestations of cellulitis. The objective of this pilot study was to investigate whether the addition of oral nonsteroidal anti-inflammatory (NSAI) therapy to antibiotic treatment hastens resolution of cellulitis-related inflammation. Patients presenting in the emergency department with signs and symptoms of class II cellulitis were assigned to receive treatment with either antibiotic therapy alone (intravenous, supplemented with oral cephalexin or an equivalent) for 10 days (n = 33) or antibiotic therapy for 10 days plus an oral anti-inflammatory (ibuprofen 400 mg every 6 hours) for 5 days (n = 31). Patients were discharged as soon as possible to complete their therapy on an outpatient basis. The addition of an oral anti-inflammatory agent significantly (P < .05) shortened the time to regression of inflammation and complete resolution of cellulitis. Twenty-four of 29 evaluable patients (82.8%) who received supplemental anti-inflammatory treatment showed regression of inflammation within 1 to 2 days compared with only 3 of 33 patients (9.1%) treated without an anti-inflammatory in the same time frame. All patients receiving adjunctive anti-inflammatory treatment experienced complete resolution of cellulitis in 4 to 5 days or less, while 24.2% (8/33) of patients treated with antibiotic alone required 6 to 7 days, and 6.1% (2/33) required 7 days or more (P < .05). This small preliminary study provides some promising data, suggesting that the supplemental use of anti-inflammatory therapy may hasten the time to regression of inflammation and complete resolution of cellulitis.

Antibiotic Therapy in Comatose Mechanically Ventilated Patients Following Aspiration: Differentiating Pneumonia From Pneumonitis.

PubMed

Lascarrou, Jean Baptiste; Lissonde, Floriane; Le Thuaut, Aurélie; Bachoumas, Konstantinos; Colin, Gwenhael; Henry Lagarrigue, Matthieu; Vinatier, Isabelle; Fiancette, Maud; Lacherade, Jean Claude; Yehia, Aihem; Joret, Aurélie; Lebert, Christine; Bourdon, Sandra; Martin Lefèvre, Laurent; Reignier, Jean

2017-08-01

To determine the proportion of patients with documented bacterial aspiration pneumonia among comatose ICU patients with symptoms suggesting either bacterial aspiration pneumonia or non-bacterial aspiration pneumonitis. Prospective observational study. University-affiliated 30-bed ICU. Prospective cohort of 250 patients admitted to the ICU with coma (Glasgow Coma Scale score ≤ 8) and treated with invasive mechanical ventilation. None. The primary outcome was the proportion of patients with microbiologically documented bacterial aspiration pneumonia. Patients meeting predefined criteria for aspiration syndrome routinely underwent telescopic plugged catheter sampling during bronchoscopy before starting probabilistic antibiotic treatment. When cultures were negative, the antibiotic treatment was stopped. Of 250 included patients, 98 (39.2%) had aspiration syndrome, including 92 before mechanical ventilation discontinuation. Telescopic plugged catheter in these 92 patients showed bacterial aspiration pneumonia in 43 patients (46.7%). Among the remaining 49 patients, 16 continued to receive antibiotics, usually for infections other than pneumonia; of the 33 patients whose antibiotics were discontinued, only two subsequently showed signs of lung infection. In the six patients with aspiration syndrome after mechanical ventilation, and therefore without telescopic plugged catheter, antibiotic treatment was continued for 7 days. Mechanical ventilation duration, ICU length of stay, and mortality did not differ between the 43 patients with bacterial aspiration pneumonia and the 49 patients with non-bacterial aspiration pneumonitis. The 152 patients without aspiration syndrome did not receive antibiotics. Among comatose patients receiving mechanical ventilation, those without clinical, laboratory, or radiologic evidence of bacterial aspiration pneumonia did not require antibiotics. In those with suspected bacterial aspiration pneumonia, stopping empirical antibiotic therapy

Pharmacological Targeting of the Host-Pathogen Interaction: Alternatives to Classical Antibiotics to Combat Drug-Resistant Superbugs.

PubMed

Munguia, Jason; Nizet, Victor

2017-05-01

The rise of multidrug-resistant pathogens and the dearth of new antibiotic development place an existential strain on successful infectious disease therapy. Breakthrough strategies that go beyond classical antibiotic mechanisms are needed to combat this looming public health catastrophe. Reconceptualizing antibiotic therapy in the richer context of the host-pathogen interaction is required for innovative solutions. By defining specific virulence factors, the essence of a pathogen, and pharmacologically neutralizing their activities, one can block disease progression and sensitize microbes to immune clearance. Likewise, host-directed strategies to boost phagocyte bactericidal activity, enhance leukocyte recruitment, or reverse pathogen-induced immunosuppression seek to replicate the success of cancer immunotherapy in the field of infectious diseases. The answer to the threat of multidrug-resistant pathogens lies 'outside the box' of current antibiotic paradigms. Copyright © 2017 Elsevier Ltd. All rights reserved.

Comparison of Antibiotic Therapy and Appendectomy for Acute Uncomplicated Appendicitis in Children

PubMed Central

Huang, Libin; Yin, Yuan; Yang, Lie; Wang, Cun; Zhou, Zongguang

2017-01-01

Importance Antibiotic therapy for acute uncomplicated appendicitis is effective in adult patients, but its application in pediatric patients remains controversial. Objective To compare the safety and efficacy of antibiotic treatment vs appendectomy as the primary therapy for acute uncomplicated appendicitis in pediatric patients. Data Sources The PubMed, MEDLINE, EMBASE, and Cochrane Library databases and the Cochrane Controlled Trials Register for randomized clinical trials were searched through April 17, 2016. The search was limited to studies published in English. Search terms included appendicitis, antibiotics, appendectomy, randomized controlled trial, controlled clinical trial, randomized, placebo, drug therapy, randomly, and trial. Study Selection Randomized clinical trials and prospective clinical controlled trials comparing antibiotic therapy with appendectomy for acute uncomplicated appendicitis in pediatric patients (aged 5-18 years) were included in the meta-analysis. The outcomes included at least 2 of the following terms: success rate of antibiotic treatment and appendectomy, complications, readmissions, length of stay, total cost, and disability days. Data Extraction and Synthesis Data were independently extracted by 2 reviewers. The quality of the included studies was examined in accordance with the Cochrane guidelines and the Newcastle-Ottawa criteria. Data were pooled using a logistic fixed-effects model, and the subgroup pooled risk ratio with or without appendicolith was estimated. Main Outcomes and Measures The primary outcome was the success rate of treatment. The hypothesis was formulated before data collection. Results A total of 527 articles were screened. In 5 unique studies, 404 unique patients with uncomplicated appendicitis (aged 5-15 years) were enrolled. Nonoperative treatment was successful in 152 of 168 patients (90.5%), with a Mantel-Haenszel fixed-effects risk ratio of 8.92 (95% CI, 2.67-29.79; heterogeneity, P = .99; I2�

[Domiciliary parenteral antibiotic therapy: a prospective analysis of the last 12 years].

PubMed

Peláez Cantero, M J; Madrid Rodríguez, A; Urda Cardona, A L; Jurado Ortiz, A

2014-08-01

Parenteral antibiotic treatment has been classically developed in hospitals and is considered as a hospital procedure. The development of Hospital at Home Units (HHU) has led to an increase in outpatient parenteral antibiotic therapy (OPAT) in paediatrics patients. The objective of this study is to describe our experience, as an HHU integrated within a Paediatric Department, in home antimicrobial therapy over a period of 12 years. This prospective and descriptive study included every patient with a disease requiring parenteral antimicrobial therapy who was admitted to our HHU from January 2000 to December 2012. During the study there were 163 cases on OPAT. The mean age of the patients was 11.1 years, and the sample group was comprised of 33 males and 22 feamales. The main sources of the treated infections were respiratory tract (76%), catheter-related bloodstream (9.2%), and urinary tract infections (5.5%). Amikacin was the most widely used antibiotic. Almost all treatments (96.6%) were via an intravenous route. Catheter-associated complications were more common than drug-associated complications. Successful at-home treatment was observed in 90.2% of cases. OPAT is a good and safe alternative in many paediatric diseases. Copyright © 2013 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

A PCT algorithm for discontinuation of antibiotic therapy is a cost-effective way to reduce antibiotic exposure in adult intensive care patients with sepsis.

PubMed

Kip, Michelle M A; Kusters, Ron; IJzerman, Maarten J; Steuten, Lotte M G

2015-01-01

Procalcitonin (PCT) is a specific marker for differentiating bacterial from non-infective causes of inflammation. It can be used to guide initiation and duration of antibiotic therapy in intensive care unit (ICU) patients with suspected sepsis, and might reduce the duration of hospital stay. Limiting antibiotic treatment duration is highly important because antibiotic over-use may cause patient harm, prolonged hospital stay, and resistance development. Several systematic reviews show that a PCT algorithm for antibiotic discontinuation is safe, but upfront investment required for PCT remains an important barrier against implementation. The current study investigates to what extent this PCT algorithm is a cost-effective use of scarce healthcare resources in ICU patients with sepsis compared to current practice. A decision tree was developed to estimate the health economic consequences of the PCT algorithm for antibiotic discontinuation from a Dutch hospital perspective. Input data were obtained from a systematic literature review. When necessary, additional information was gathered from open interviews with clinical chemists and intensivists. The primary effectiveness measure is defined as the number of antibiotic days, and cost-effectiveness is expressed as incremental costs per antibiotic day avoided. The PCT algorithm for antibiotic discontinuation is expected to reduce hospital spending by circa € 3503 per patient, indicating savings of 9.2%. Savings are mainly due to reductions in length of hospital stay, number of blood cultures performed, and, importantly, days on antibiotic therapy. Probabilistic and one-way sensitivity analyses showed the model outcome to be robust against changes in model inputs. Proven safe, a PCT algorithm for antibiotic discontinuation is a cost-effective means of reducing antibiotic exposure in adult ICU patients with sepsis, compared to current practice. Additional resources required for PCT are more than offset by downstream cost

[Hot rods in the ICU : What is the antibiotic mileage of your renal replacement therapy?

PubMed

Kielstein, J T; Kruse, A K; Anderson, N; Vaitiekunas, H; Scherneck, S

2017-05-08

We would neither be disappointed nor upset if the gas mileage on the sticker of a car didn't match our personal, real-life fuel consumption. Depending on our daily route to work, our style of accelerating and the number of passengers in our carpool, the gas mileage will vary. As soon as the falcon wing door of our car is closed and entrance to the ICU is granted, we tend to forget all of this, even though another hot rod is waiting there for us. Renal replacement therapy is like a car; it fulfills goals, such as the removal of uremic toxins and accumulated fluids, but it also "consumes" (removes) antibiotics. Unlike catecholamines, where we have the mean arterial pressure on our ICU dashboard, we do not have a gauge to measure antibiotic "consumption", i.e. elimination by renal replacement therapy. This manuscript describes the principles and basic knowledge to improve dosing of antibiotics in critically ill patients undergoing renal replacement therapy. As in modern cars, we briefly touch on hybrid therapies combining renal replacement therapy with extracorporeal lung support or adsorbent technologies that remove cytokines or bacteria. Further, the importance of considering body size and body composition is addressed, especially for choosing the right initial dose of antibiotics. Lastly we point out the dire need to increase the availability of timely and affordable therapeutic drug monitoring on the most commonly used antiinfectives, ideally using point-of-care devices at the bedside.

Gram-negative bacteremia: which empirical antibiotic therapy?

PubMed

Shoai Tehrani, M; Hajage, D; Fihman, V; Tankovic, J; Cau, S; Day, N; Visseaux, C; Carbonnelle, E; Kouatchet, A; Cattoir, V; Nhan, T X; Corvec, S; Jacquier, H; Jauréguy, F; Le Monnier, A; Morand, P; Zahar, J R

2014-04-01

Given the increasing frequency of cefotaxime-resistant strains, third-generation cephalosporins (3GC e.g. cefotaxime, ceftriaxone) might not be recommended any longer as empirical antibiotic therapy for community-acquired Gram-negative bacteremia (CA-GNB). We conducted a multicenter prospective descriptive study including patients with CA-GNB. Two hundred and nineteen patients were included. Escherichia coli and Pseudomonas aeruginosa were the most frequently isolated species in 63% (n=138) and 11% (n=24) of the cases, respectively. The prevalence of cefotaxime-resistance reached 18% (n=39) mostly due to intrinsic resistance (27 cases, 12%). The presence of invasive material (P<0.001), the origin of the patient (Paris region or West of France) (P=0.006), and home health care (P<0.001) were variables predicting resistant GNB. The negative predictive value for resistance in patients with invasive material coming from the West of France, or without invasive material and with home health care was 94%. The positive predictive value for patients with invasive material living in Paris, or without invasive material and with home health care only reached 58 and 54%, respectively. Using 3GC for CA-GNB due to cefotaxime-resistant strains was relatively frequent, ESBL-producing Enterobacteriaceae being rarely involved. Our study highlights the role of local epidemiology; before any changes to first-line antibiotic therapy, local epidemiological data should be taken into account. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Time to Guideline-Based Empiric Antibiotic Therapy in the Treatment of Pneumonia in a Community Hospital: A Retrospective Review.

PubMed

Erwin, Beth L; Kyle, Jeffrey A; Allen, Leland N

2016-08-01

The 2005 American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines for hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and health care-associated pneumonia (HCAP) stress the importance of initiating prompt appropriate empiric antibiotic therapy. This study's purpose was to determine the percentage of patients with HAP, VAP, and HCAP who received guideline-based empiric antibiotic therapy and to determine the average time to receipt of an appropriate empiric regimen. A retrospective chart review of adults with HAP, VAP, or HCAP was conducted at a community hospital in suburban Birmingham, Alabama. The hospital's electronic medical record system utilized International Classification of Diseases, Ninth Revision (ICD-9) codes to identify patients diagnosed with pneumonia. The percentage of patients who received guideline-based empiric antibiotic therapy was calculated. The mean time from suspected diagnosis of pneumonia to initial administration of the final antibiotic within the empiric regimen was calculated for patients who received guideline-based therapy. Ninety-three patients met the inclusion criteria. The overall guideline adherence rate for empiric antibiotic therapy was 31.2%. The mean time to guideline-based therapy in hours:minutes was 7:47 for HAP and 28:16 for HCAP. For HAP and HCAP combined, the mean time to appropriate therapy was 21:55. Guideline adherence rates were lower and time to appropriate empiric therapy was greater for patients with HCAP compared to patients with HAP. © The Author(s) 2015.

How to measure the impacts of antibiotic resistance and antibiotic development on empiric therapy: new composite indices.

PubMed

Hughes, Josie S; Hurford, Amy; Finley, Rita L; Patrick, David M; Wu, Jianhong; Morris, Andrew M

2016-12-16

We aimed to construct widely useable summary measures of the net impact of antibiotic resistance on empiric therapy. Summary measures are needed to communicate the importance of resistance, plan and evaluate interventions, and direct policy and investment. As an example, we retrospectively summarised the 2011 cumulative antibiogram from a Toronto academic intensive care unit. We developed two complementary indices to summarise the clinical impact of antibiotic resistance and drug availability on empiric therapy. The Empiric Coverage Index (ECI) measures susceptibility of common bacterial infections to available empiric antibiotics as a percentage. The Empiric Options Index (EOI) varies from 0 to 'the number of treatment options available', and measures the empiric value of the current stock of antibiotics as a depletable resource. The indices account for drug availability and the relative clinical importance of pathogens. We demonstrate meaning and use by examining the potential impact of new drugs and threatening bacterial strains. In our intensive care unit coverage of device-associated infections measured by the ECI remains high (98%), but 37-44% of treatment potential measured by the EOI has been lost. Without reserved drugs, the ECI is 86-88%. New cephalosporin/β-lactamase inhibitor combinations could increase the EOI, but no single drug can compensate for losses. Increasing methicillin-resistant Staphylococcus aureus (MRSA) prevalence would have little overall impact (ECI=98%, EOI=4.8-5.2) because many Gram-positives are already resistant to β-lactams. Aminoglycoside resistance, however, could have substantial clinical impact because they are among the few drugs that provide coverage of Gram-negative infections (ECI=97%, EOI=3.8-4.5). Our proposed indices summarise the local impact of antibiotic resistance on empiric coverage (ECI) and available empiric treatment options (EOI) using readily available data. Policymakers and drug developers can use the

[Adequacy of antibiotic therapy for urinary tract infection in a Medical Department from the university hospital of Lille: A retrospective cohort study].

PubMed

Deconinck, L; Maillard, H; Lemaitre, M; Barbottin, E; Bakhache, E; Galperine, T; Puisieux, F; Hatron, P-Y; Lambert, M

2015-11-01

The main objective of the study was to assess the adequacy of antibiotic therapy for urinary tract infections (UTI) in a French hospital medical department. The secondary objective was to identify factors associated with inadequacy of the antibiotic therapy. A retrospective single centre cohort study was performed in the Post-Emergency Medicine Department (PEMD) of the university hospital of Lille. All patients presenting with an UTI from May 2012 to April 2014 were included. Adequacy of antibiotic therapy was assessed with reference to local guidelines. Factors associated with inadequacy of antibiotic prescription were determined using a multivariate logistic regression model. Two hundred and twenty-eight patients were included. The antibiotic prescription was fully adequate in 173 patients (76%) with appropriate use of a single or a combination antibiotic therapy in 96%, appropriate drug in 80%, appropriate dosage in 89% and appropriate route of administration in 95%. The risk for antibiotic inadequacy was significantly higher in patients with cystitis than in those with pyelonephritis (OR 12.01; 95% CI 4.17-34.65), when antibiotics were prescribed in the Emergency Department (OR 6.84; 95% CI 2.29-20.47) or before hospital admission (OR 382.46; 95% CI 19.61≥999.99) compared to when antibiotics were first administered in the PEMD, and in patients with severe UTI (OR 19.55; 95% CI 2.79-137.01). Adequacy of antibiotic therapy for UTI is relatively high in our study, reflecting the effective dissemination of antibiotic guidelines. However, antibiotic therapy is still inappropriate in cystitis, severe UTI and in case of prescription before the admission in the PEMD. Copyright © 2015 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

Bioengineering Strategies for Designing Targeted Cancer Therapies

PubMed Central

Wen, Xuejun

2014-01-01

The goals of bioengineering strategies for targeted cancer therapies are (1) to deliver a high dose of an anticancer drug directly to a cancer tumor, (2) to enhance drug uptake by malignant cells, and (3) to minimize drug uptake by nonmalignant cells. Effective cancer-targeting therapies will require both passive- and active targeting strategies and a thorough understanding of physiologic barriers to targeted drug delivery. Designing a targeted therapy includes the selection and optimization of a nanoparticle delivery vehicle for passive accumulation in tumors, a targeting moiety for active receptor-mediated uptake, and stimuli-responsive polymers for control of drug release. The future direction of cancer targeting is a combinatorial approach, in which targeting therapies are designed to use multiple targeting strategies. The combinatorial approach will enable combination therapy for delivery of multiple drugs and dual ligand targeting to improve targeting specificity. Targeted cancer treatments in development and the new combinatorial approaches show promise for improving targeted anticancer drug delivery and improving treatment outcomes. PMID:23768509

Epidemiology, antibiotic therapy and outcomes of bacteremia caused by drug-resistant ESKAPE pathogens in cancer patients.

PubMed

Bodro, Marta; Gudiol, Carlota; Garcia-Vidal, Carolina; Tubau, Fe; Contra, Anna; Boix, Lucía; Domingo-Domenech, Eva; Calvo, Mariona; Carratalà, Jordi

2014-03-01

Infection due to the six ESKAPE pathogens has recently been identified as a serious emerging problem. However, there is still a lack of information on bacteremia caused by these organisms in cancer patients. We aimed to assess the epidemiology, antibiotic therapy and outcomes of bacteremia due to drug-resistant ESKAPE pathogens (rESKAPE) in patients with cancer. All episodes of bacteremia prospectively documented in hospitalized adults with cancer from 2006 to 2011 were analyzed. Of 1,148 episodes of bacteremia, 392 (34 %) were caused by ESKAPE pathogens. Fifty-four episodes (4.7 %) were due to rESKAPE strains (vancomycin-resistant Enterococcus faecium 0, methicillin-resistant Staphylococcus aureus (MRSA) 13, extended-spectrum beta-lactamase (ESLB)-producing Klebsiella pneumoniae 7, carbapenem-resistant Acinetobacter baumannii 4, carbapenem- and quinolone-resistant Pseudomonas aeruginosa 18 and derepression chromosomic ß-lactam and ESBL-producing Enterobacter species 12. Risk factors independently associated with rESKAPE bacteremia were comorbidities, prior antibiotic therapy, urinary catheter and urinary tract source. Inappropriate empirical antibiotic therapy was more frequent in patients with rESKAPE bacteremia than in the other cases (55.6 % vs. 21.5 %, p < 0.001). Persistence of bacteremia (25 % vs. 9.7 %), septic metastasis (8 % vs. 4 %) and early case-fatality rate (23 % vs. 11 %) were more frequent in patients with rESKAPE bacteremia than in patients with other etiologies (p < 0.05). Bacteremia due to rESKAPE pathogens in cancer patients occurs mainly among those with comorbidities who have received prior antibiotic therapy and have a urinary tract source. These patients often receive inappropriate empirical antibiotic therapy and have a poor outcome.

Bacterial cytoskeleton and implications for new antibiotic targets.

PubMed

Wang, Huan; Xie, Longxiang; Luo, Hongping; Xie, Jianping

2016-01-01

Traditionally eukaryotes exclusive cytoskeleton has been found in bacteria and other prokaryotes. FtsZ, MreB and CreS are bacterial counterpart of eukaryotic tubulin, actin filaments and intermediate filaments, respectively. FtsZ can assemble to a Z-ring at the cell division site, regulate bacterial cell division; MreB can form helical structure, and involve in maintaining cell shape, regulating chromosome segregation; CreS, found in Caulobacter crescentus (C. crescentus), can form curve or helical filaments in intracellular membrane. CreS is crucial for cell morphology maintenance. There are also some prokaryotic unique cytoskeleton components playing crucial roles in cell division, chromosome segregation and cell morphology. The cytoskeleton components of Mycobacterium tuberculosis (M. tuberculosis), together with their dynamics during exposure to antibiotics are summarized in this article to provide insights into the unique organization of this formidable pathogen and druggable targets for new antibiotics.

De-escalation, adequacy of antibiotic therapy and culture positivity in septic patients: an observational study.

PubMed

Moraes, Rafael Barberena; Guillén, Julián Alberto Viteri; Zabaleta, William Javier Castillo; Borges, Flavia Kessler

2016-09-01

To evaluate the prevalence of antibiotic de-escalation in patients diagnosed with severe sepsis or septic shock at a public academic tertiary hospital and to evaluate antibiotic adequacy and culture positivity. The prevalence of antibiotic de-escalation, the adequacy of antibiotic treatment and the rates of culture positivity were analyzed in patients with severe sepsis and septic shock between April and December 2013 at an intensive care unit in a tertiary university hospital. Among the 224 patients included in the study, de-escalation was appropriate in 66 patients (29.4%) but was implemented in 44 patients (19.6%). Among the patients who underwent de-escalation, half experienced narrowing of the antimicrobial spectrum. The mortality rate was 56.3%, with no differences between the patients with or without de-escalation (56.8% versus 56.1%; p = 0.999) nor in the length of hospital stay. Empirical antibiotic therapy was appropriate in 89% of cases. Microorganisms were isolated from total cultures in 30% of cases and from blood cultures in 26.3% of cases. The adequacy rate of empirical antibiotic therapy was high, reflecting an active institutional policy of monitoring epidemiological profiles and institutional protocols on antimicrobial use. However, antibiotic de-escalation could have been implemented in a greater number of patients. De-escalation did not affect mortality rates.

The Efficacy of Perioperative Antibiotic Therapy in Tonsillectomy Patients.

PubMed

Orłowski, Krzysztof; Lisowska, Grażyna; Misiołek, Hanna; Paluch, Zbigniew; Misiołek, Maciej

2016-01-01

While the results of early research suggested that perioperative antibiotic prophylaxis in tonsillectomy patients is associated with many benefits, these data were not confirmed by further studies and meta-analyses. The aim of this study was to investigate the usefulness and efficacy of antibiotic monotherapy in the healing of surgical wounds of patients undergoing bilateral resection of the palatine tonsils, based on an analysis of selected objective and subjective characteristics of wound healing during the postoperative period. The study included 50 men and women who underwent routine resection of the palatine tonsils. The patients were randomized into two groups: Group I, undergoing tonsillectomy with cefuroxime prophylaxis (n = 25), and Group II, who were not given perioperative antibiotic therapy (n = 25). The severity of signs and complaints recorded on postoperative days 1-10 was scored on 3- and 10-item scales. The only significant intergroup differences pertained to problems with swallowing food and fluids on postoperative days 4-6, 8 and 9 (less prevalent in Group II), postoperative use of analgesics on postoperative day 9 (less frequent in Group II), the degree of mucosal swelling in the operated area on postoperative days 3 and 7 (less severe in Group II), and the amount of fibrin covering the tonsillar niches on the third postoperative day (significantly higher in Group I). The administration of antibiotics for prevention or control of infection should be preceded by a comprehensive analysis of the potential benefits and risks. Perioperative use of antibiotics is justified only in selected cases, i.e. in individuals with comorbidities.

Antibiotic loaded nanocapsules functionalized with aptamer gates for targeted destruction of pathogens.

PubMed

Kavruk, M; Celikbicak, O; Ozalp, V C; Borsa, B A; Hernandez, F J; Bayramoglu, G; Salih, B; Arica, M Y

2015-05-18

In this study, we designed aptamer-gated nanocapsules for the specific targeting of cargo to bacteria with controlled release of antibiotics based on aptamer-receptor interactions. Aptamer-gates caused a specific decrease in minimum inhibitory concentration (MIC) values of vancomycin for Staphylococcus aureus when mesoporous silica nanoparticles (MSNs) were used for bacteria-targeted delivery.

Surface mediated cooperative interactions of drugs enhance mechanical forces for antibiotic action

NASA Astrophysics Data System (ADS)

Ndieyira, Joseph W.; Bailey, Joe; Patil, Samadhan B.; Vögtli, Manuel; Cooper, Matthew A.; Abell, Chris; McKendry, Rachel A.; Aeppli, Gabriel

2017-02-01

The alarming increase of pathogenic bacteria that are resistant to multiple antibiotics is now recognized as a major health issue fuelling demand for new drugs. Bacterial resistance is often caused by molecular changes at the bacterial surface, which alter the nature of specific drug-target interactions. Here, we identify a novel mechanism by which drug-target interactions in resistant bacteria can be enhanced. We examined the surface forces generated by four antibiotics; vancomycin, ristomycin, chloroeremomycin and oritavancin against drug-susceptible and drug-resistant targets on a cantilever and demonstrated significant differences in mechanical response when drug-resistant targets are challenged with different antibiotics although no significant differences were observed when using susceptible targets. Remarkably, the binding affinity for oritavancin against drug-resistant targets (70 nM) was found to be 11,000 times stronger than for vancomycin (800 μM), a powerful antibiotic used as the last resort treatment for streptococcal and staphylococcal bacteria including methicillin-resistant Staphylococcus aureus (MRSA). Using an exactly solvable model, which takes into account the solvent and membrane effects, we demonstrate that drug-target interactions are strengthened by pronounced polyvalent interactions catalyzed by the surface itself. These findings further enhance our understanding of antibiotic mode of action and will enable development of more effective therapies.

Liposomes as potential carrier system for targeted delivery of polyene antibiotics.

PubMed

Naik, Suresh R; Desai, Sandhya K; Shah, Priyank D; Wala, Santosh M

2013-09-01

The development of new therapeutic modalities involves the use of drug carrier, such as liposomes, which can modify pharmacokinetic and bio-distribution of drug profile. Polyene antibiotics incorporation into liposomes improves its availability at the site, bio-distribution and therapeutic index mainly through the engulfment of liposomes by circulating monocytes/macrophages and transportation to the site of infection. Polyene antibiotics (AmB, SJA-95, HA-1-92) and other antibiotics (streptomycin, tobramycin, quinolones, anti-tubercular and anti-cancer drugs), liposomal preparations are described with possible advantages from therapeutic efficacy and toxicity point of view. The polyene macrolide antibiotics liposomal preparations proved to be more effective in the treatment of systemic mycosis. The AmB-cyclodextrin derivatives inclusion complex is a major breakthrough in liposomal preparation which can be converted into aqueous phase of liposome. Liposomal drug incorporated preparation has been one of the important areas of research for developing the existing polyene antibiotics into useful chemotherapeutic agents in clinical medicine. In recent past other antibiotics have also been incorporated into liposomes using wide variety of materials, phosphatidylethanolamine derivatives (pegylated liposomes, enzyme sensitive conjugates, fluidosomes of anti-cancer drugs and poly lactic/glycolic acid microspheres for anti-tuberculosis drugs). In addition, attempts were also made to extend the receptor mediated drug targeting and to review some relevant patents.

Targets for Antibiotic and Health Care Resource Stewardship in Inpatient Community-Acquired Pneumonia: A Comparison of Management Practices with National Guideline Recommendations

PubMed Central

Jenkins, Timothy C.; Stella, Sarah A.; Cervantes, Lilia; Knepper, Bryan C.; Sabel, Allison L.; Price, Connie S.; Shockley, Lee; Hanley, Michael E.; Mehler, Philip S.; Burman, William J.

2012-01-01

Purpose Community-acquired pneumonia (CAP) is the most common infection leading to hospitalization in the U.S. The objective of this study was to evaluate management practices for inpatient CAP in relation to IDSA/ATS guidelines to identify opportunities for antibiotic and health care resource stewardship. Methods This was a retrospective cohort study of adults hospitalized for CAP at a single institution from April 15, 2008 – May 31, 2009. Results Of 209 cases, 166 (79%) were admitted to a medical ward and 43 (21%) to the intensive care unit (ICU). 61 (29%) cases were candidates for outpatient therapy per IDSA/ATS guidance with a CURB-65 score of 0 or 1 and absence of hypoxemia. 110 sputum cultures were ordered; however, an evaluable sample was obtained in 49 (45%) cases, median time from antibiotic initiation to specimen collection was 11 (IQR 6–19) hours, and a potential pathogen was identified in only 18 (16%). Blood cultures were routinely obtained for both non-ICU (81%) and ICU (95%) cases, but 15 of 36 (42%) positive cultures were false-positive results. The most common antibiotic regimen was ceftriaxone plus azithromycin (182, 87% cases). Discordant with IDSA/ATS recommendations, oral step-down therapy consisted of a new antibiotic class in 120 (66%), most commonly levofloxacin (101, 55%). Treatment durations were typically longer than suggested with a median of 10 (IQR 8 – 12) days. Conclusions In this cohort of patients hospitalized for CAP, management was frequently inconsistent with IDSA/ATS guideline recommendations revealing potential targets to reduce unnecessary antibiotic and health care resource utilization. PMID:23160837

Targets for antibiotic and healthcare resource stewardship in inpatient community-acquired pneumonia: a comparison of management practices with National Guideline Recommendations.

PubMed

Jenkins, T C; Stella, S A; Cervantes, L; Knepper, B C; Sabel, A L; Price, C S; Shockley, L; Hanley, M E; Mehler, P S; Burman, W J

2013-02-01

Community-acquired pneumonia (CAP) is the most common infection leading to hospitalization in the USA. The objective of this study was to evaluate management practices for inpatient CAP in relation to Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) guidelines to identify opportunities for antibiotic and health care resource stewardship. This was a retrospective cohort study of adults hospitalized for CAP at a single institution from 15 April 2008 to 31 May 2009. Of the 209 patients with CAP who presented to Denver Health Medical Center during the study period and were hospitalized, 166 (79 %) and 43 (21 %) were admitted to a medical ward and the intensive care unit (ICU), respectively. Sixty-one (29 %) patients were candidates for outpatient therapy per IDSA/ATS guidance with a CURB-65 score of 0 or 1 and absence of hypoxemia. Sputum cultures were ordered for 110 specimens; however, an evaluable sample was obtained in only 49 (45 %) cases. Median time from antibiotic initiation to specimen collection was 11 [interquartile range (IQR) 6-19] h, and a potential pathogen was identified in only 18 (16 %) cultures. Blood cultures were routinely obtained for both non-ICU (81 %) and ICU (95 %) cases, but 15 of 36 (42 %) positive cultures were false-positive results. The most common antibiotic regimen was ceftriaxone + azithromycin (182, 87 % cases). Discordant with IDSA/ATS recommendations, oral step-down therapy consisted of a new antibiotic class in 120 (66 %), most commonly levofloxacin (101, 55 %). Treatment durations were typically longer than suggested with a median of 10 (IQR 8-12) days. In this cohort of patients hospitalized for CAP, management was frequently inconsistent with IDSA/ATS guideline recommendations, revealing potential targets to reduce unnecessary antibiotic and healthcare resource utilization.

Targeted therapy in esophageal cancer.

PubMed

Zhang, Lei; Ma, Jiaojiao; Han, Yu; Liu, Jinqiang; Zhou, Wei; Hong, Liu; Fan, Daiming

2016-01-01

An increasing number of patients are diagnosed with esophageal cancer at an advanced stages, and only a small group of them can benefit from the traditional chemotherapy and radiotherapy. So far, multiple monoclonal antibodies and tyrosine kinase inhibitors have been developed, alone or in combination with traditional therapy, to improve the prognosis of patients with advanced esophageal cancer. This review summarizes the recent advances of targeted therapies against EGFR, HER2, VEGFR and c-MET in esophageal cancer. More clinical trials should be performed to evaluate the efficacy and safety of various targeted therapy regimens. Future basic research should focus on investigating the molecular mechanisms of therapeutic targets in esophageal cancer.

[Antibiomania: Think of the manic syndrome secondary to antibiotic therapy].

PubMed

Legendre, T; Boudebesse, C; Henry, C; Etain, B

2017-04-01

Antibiomania is characterized by the emergence of a manic episode in reaction to antibiotics. Although relatively uncommon, this kind of side effect is observed in a growing number of cases and mostly occurs in patients who do not have a history of bipolar disorder. Several dozen cases have been reported showing the onset of manic symptoms after taking antibiotics. The antibiotic most frequently involved is clarithromycin. We report the case of a 61-year-old patient who presented a manic episode after taking an antibiotic combination to treat Helicobacter pylori. Five days after the start of highly active antiretroviral therapy (HAART), behavioral problems appeared (aggressiveness, irritability, talkativeness, insomnia). At the time of hospitalization, she had an acute delusional symptomatology, with a theme of persecution, associated with intuitive, interpretive and imaginative mechanisms. Manic symptoms were obvious: psychomotor excitement, aggressiveness and irritability, flight of ideas, verbal disinhibition and a denial of problems. There was no toxic cause. Brain magnetic resonance imaging (MRI) was normal. Her condition improved very quickly and delusions disappeared in four days. Mrs. H. could critic her delirium and recovered a euthymic state. During hospitalization, treatment divalproate sodium was introduced (250mg, 3 times a day), was maintained following hospital discharge for 2 years for prevention, and then decreased to the stop. There are currently no further behavioral problems or sleep disorders two years after this episode. Facing this clinical case, several questions arise: Which drug therapy is the most suitable for this type of mental disorder? Are there predictors of antibiomania? Is there a risk of recurrence of mood episodes following an antibiomania that occurs spontaneously? What are the pathophysiological mechanisms that could explain this reaction? In all cases identified, stopping the antibiotics was decisive. However, the

[Urinary pneumococcal or Legionella antigen detection tests and low-spectrum antibiotic therapy for community-acquired pneumonia].

PubMed

Roger, P-M; Risso, K; Hyvernat, H; Landraud, L; Vassallo, M; Dellamonica, J; de Salvador, F; Cua, E; Bernardin, G

2010-06-01

We performed urinary antigen tests for pneumococcus and Legionella for patients with community-acquired pneumonia (CAP), to prescribe a documented antibiotic therapy. We report the efficiency of low-spectrum antibiotic treatment, illustrating the inappropriateness of bacteriological respiratory sampling. Patients with CAP were enrolled from three different units; the pneumonia severity index was used to assess the disease. Respiratory samples were also listed. Low-spectrum antibiotic therapy was amoxicillin for pneumococcal infection, and macrolides or non-anti-pneumococcal fluoroquinolone for legionellosis. Six hundred and seventy-five CAP were diagnosed during the study period,, 150 with positive urinary antigen tests (23%), among which 108 pneumococcal infections (73%), 40 legionellosis (26%), and two mixed infections. The pneumonia severity index was 106+/-38. Amoxicillin was prescribed in 108 cases, fluoroquinolone in 24 cases, macrolide in 18 cases. The outcome was favourable for 138 patients (92%). Eighty three respiratory samples allowed identification of a bacterium for 58 patients (39%), among which 24 strains were not in the antibiotic spectrum: Haemophilus influenzae and Pseudmomonas aeruginosa in six cases, Staphylococcus aureus in five cases, Klebsiella pneumoniae in two cases, and another Gram negative bacillus in five cases. These strains were resistant in vitro to the prescribed treatment in 19/24 cases (79%). One out of 12 patients who died had a respiratory sample positive for Enterobacter spp strain resistant to the ongoing antibiotic treatment. The low-spectrum antibiotic therapy based on urinary antigen tests is efficient, and demonstrates respiratory tract colonisation with bacteriological strains usually considered as pathogenic.

Antisense antibiotics: a brief review of novel target discovery and delivery.

PubMed

Bai, Hui; Xue, Xiaoyan; Hou, Zheng; Zhou, Ying; Meng, Jingru; Luo, Xiaoxing

2010-06-01

The nightmare of multi-drug resistant bacteria will still haunt if no panacea is ever found. Efforts on seeking desirable natural products with bactericidal property and screening chemically modified derivatives of traditional antibiotics have lagged behind the emergence of new multi-drug resistant bacteria. The concept of using antisense antibiotics, now as revolutionary as is on threshold has experienced ups and downs in the past decade. In the past five years, however, significant technology advances in the fields of microbial genomics, structural modification of oligonucleotides and efficient delivery system have led to fundamental progress in the research and in vivo application of this paradigm. The wealthy information provided in the microbial genomics era has allowed the identification and/or validation of a number of essential genes that may serve as possible targets for antisense inhibition; antisense oligodeoxynucleotides (ODNs) based on the 3rd generation of modified structures, e.g., peptide nucleic acids (PNAs) and phosphorodiamidate morpholino oligomers (PMOs) have shown great potency in gene expression inhibition in a sequence-specific and dosedependent manner at low micromolar concentrations; and cell penetrating peptide mediated delivery system has enabled the effective display of intracellular antisense inhibition of targeted genes both in vitro and in vivo. The new methods show promise in the discovery of novel gene-specific antisense antibiotics that will be useful in the future battle against drug-resistant bacterial infections. This review describes this promising paradigm, the targets that have been identified and the recent technologies on which it is delivered.

Legionella Pneumophila and Dendrimers-Mediated Antisense Therapy.

PubMed

Pashaei-Asl, Roghiyeh; Khodadadi, Khodadad; Pashaei-Asl, Fatima; Haqshenas, Gholamreza; Ahmadian, Nasser; Pashaiasl, Maryam; Hajihosseini Baghdadabadi, Reza

2017-06-01

Finding novel and effective antibiotics for treatment of Legionella disease is a challenging field. Treatment with antibiotics usually cures Legionella infection; however, if the resultant disease is not timely recognized and treated properly, it leads to poor prognosis and high case fatality rate. Legionella pneumophila DrrA protein (Defects in Rab1 recruitment protein A)/also known as SidM affects host cell vesicular trafficking through modification of the activity of cellular small guanosine triphosphatase )GTPase( Rab (Ras-related in brain) function which facilitates intracellular bacterial replication within a supporter vacuole. Also, Legionella pneumophila LepA and LepB (Legionella effector protein A and B) proteins suppress host-cell Rab1 protein's function resulting in the cell lysis and release of bacteria that subsequently infect neighbour cells. Legionella readily develops resistant to antibiotics and, therefore, new drugs with different modes of action and therapeutic strategic approaches are urgently required among antimicrobial drug therapies;gene therapy is a novel approach for Legionnaires disease treatment. On the contrary to the conventional treatment approaches that target bacterial proteins, new treatment interventions target DNA (Deoxyribonucleic acid), RNA (Ribonucleic acid) species, and different protein families or macromolecular complexes of these components. The above approaches can overcome the problems in therapy of Legionella infections caused by antibiotics resistance pathogens. Targeting Legionella genes involved in manipulating cellular vesicular trafficking using a dendrimer-mediated antisense therapy is a promising approach to inhibit bacterial replication within the target cells.

Targeted therapies: a nursing perspective.

PubMed

Kay, Polly

2006-02-01

To review the development of targeted therapies and the biology of relevant therapeutic targets. To analyze the relevance of targeted agents as part of current clinical practice. Research articles. Several targeted agents are now available for clinical use. Their mechanisms of action are more specific against tumor cells than traditional cytotoxics. Monotherapy regimens based on targeted agents tend to be better tolerated than chemotherapy, and most combination regimens with targeted agents have proven feasible. Their availability has greatly expanded cancer treatment options, especially for chemorefractory patients. Nurses involved in the care of patients with cancer can benefit from an increased understanding of targeted therapies, including their mechanisms of action, their efficacy profile, as well as prophylaxis and management of adverse events and administration procedures.

Appropriate antibiotic therapy improves Ureaplasma sepsis outcome in the neonatal mouse.

PubMed

Weisman, Leonard E; Leeming, Angela H; Kong, Lingkun

2012-11-01

Ureaplasma causes sepsis in human neonates. Although erythromycin has been the standard treatment, it is not always effective. No published reports have evaluated Ureaplasma sepsis in a neonatal model. We hypothesized that appropriate antibiotic treatment improves Ureaplasma sepsis in a neonatal mouse model. Two ATCC strains and two clinical strains of Ureaplasma were evaluated in vitro for antibiotic minimum inhibitory concentration (MIC). In addition, FVB albino mice pups infected with Ureaplasma were randomly assigned to saline, erythromycin, or azithromycin therapy and survival, quantitative blood culture, and growth were evaluated. MICs ranged from 0.125 to 62.5 µg/ml and 0.25 to 1.0 µg/ml for erythromycin and azithromycin, respectively. The infecting strain and antibiotic selected for treatment appeared to affect survival and bacteremia, but only the infecting strain affected growth. Azithromycin improved survival and bacteremia against each strain, whereas erythromycin was effective against only one of four strains. We have established a neonatal model of Ureaplasma sepsis and observed that treatment outcome is related to infecting strain and antibiotic treatment. We speculate that appropriate antibiotic selection and dosing are required for effective treatment of Ureaplasma sepsis in neonates, and this model could be used to further evaluate these relationships.

Does appropriate empiric antibiotic therapy modify intensive care unit-acquired Enterobacteriaceae bacteraemia mortality and discharge?

PubMed

Pouwels, K B; Van Kleef, E; Vansteelandt, S; Batra, R; Edgeworth, J D; Smieszek, T; Robotham, J V

2017-05-01

Conflicting results have been found regarding outcomes of intensive care unit (ICU)-acquired Enterobacteriaceae bacteraemia and the potentially modifying effect of appropriate empiric antibiotic therapy. To evaluate these associations while adjusting for potential time-varying confounding using methods from the causal inference literature. Patients who stayed more than two days in two general ICUs in England between 2002 and 2006 were included in this cohort study. Marginal structural models with inverse probability weighting were used to estimate the mortality and discharge associated with Enterobacteriaceae bacteraemia and the impact of appropriate empiric antibiotic therapy on these outcomes. Among 3411 ICU admissions, 195 (5.7%) ICU-acquired Enterobacteriaceae bacteraemia cases occurred. Enterobacteriaceae bacteraemia was associated with an increased daily risk of ICU death [cause-specific hazard ratio (HR): 1.48; 95% confidence interval (CI): 1.10-1.99] and a reduced daily risk of ICU discharge (HR: 0.66; 95% CI: 0.54-0.80). Appropriate empiric antibiotic therapy did not significantly modify ICU mortality (HR: 1.08; 95% CI: 0.59-1.97) or discharge (HR: 0.91; 95% CI: 0.63-1.32). ICU-acquired Enterobacteriaceae bacteraemia was associated with an increased daily risk of ICU mortality. Furthermore, the daily discharge rate was also lower after acquiring infection, even when adjusting for time-varying confounding using appropriate methodology. No evidence was found for a beneficial modifying effect of appropriate empiric antibiotic therapy on ICU mortality and discharge. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

[Difficulties with the prescription and administration of antibiotics in routine hospital emergency department care: a survey study].

PubMed

Monclús Cols, Ester; Nicolás Ocejo, David; Sánchez Sánchez, Miquel; Ortega Romero, Mar

2015-02-01

To detect the problems hospital emergency room staff have when prescribing and administering antibiotics. A 14-item questionnaire was designed to assess staff members' knowledge of the importance of starting antibiotic treatment promptly, assigning appropriate dosing intervals, adjusting for renal function, and switching to oral therapy. Agreement with each item was expressed on a 5-point Likert scale. Items with a rate of appropriate response of less than 75% were targeted for specific attention. Two hundred questionnaires were distributed to the staff and 150 were returned completed (response rate, 75%). The following items were targeted for attention based on rates of appropriate response of less than 75%: clear medical orders (65%), understanding the implication of early empirical antibiotic therapy on prognosis in serious infections (67%), estimation of the prevalence of renal insufficiency (42%), assumption that a creatinine serum level under < 1.6 mg/dL is safe (33%), use of glomerular filtration rate to adjust dose according to renal function (47%), and an understanding of switching from intravenous to oral treatment (60%). This study revealed the difficulties medical and nursing staff have in prescribing and administering antibiotics in a hospital emergency department. The results can facilitate improvements in antibiotic therapy by pinpointing areas to target for specific training interventions or the design of electronic prescribing aids.

[Antibiotics, azelaic acid and benzoyl peroxide in topical acne therapy].

PubMed

Fluhr, Joachim W; Degitz, Klaus

2010-03-01

Benzoyl peroxide was introduced as a basic treatment already in acne therapy 1934. The mechanism of action is the reduction of anaerobe bacteria by strong oxidation processes. No resistancies have been ever reported. BPO is available in 2.5, 5 and 10 % formulations. Its efficacy is slightly related to the strength of concentrations, but the side effect profile with burning, erythema and desquamation is increasing with concentrations. BPO 5% mostly is efficient enough to control acne of grades I to II according to the Kligman & Plewig classification. BPO my bleach clothes and hair. It is the most costeffective topical drug in acne of grades I-II. Inflammatory acne of the papular-pustular type I-II can also be treated by topical antibiotics such as erythromycin, clindamycin, and, less frequent and today not anymore recommended tetracyclines. Mechanism of action is not alone an antibacterial but anti inflammatory effect. The efficacy and penetration of the topical antibiotics between the groups are similar. Randomized studies have shown that concentrations of 2-4% are equivalent to oral tetracycline and minocycline in mild to moderate acne. Combinatory formulations with BPO and with retinoids enhance the efficacy significantly. Topical antibiotics plus BPO show less bacterial resistancies as topical antibiotics alone. Antibiotics should therefore not be used as monotherapy. Moreover gram negative folliculitis may develop. Azelaic acid is acting as an antimicrobial and can also reduce comedones. It can also be used in pregnancy and during the lactation period.

Hybrid Therapy as First-Line Regimen for Helicobacter pylori Eradication in Populations with High Antibiotic Resistance Rates.

PubMed

Song, Zhiqiang; Zhou, Liya; Zhang, Jianzhong; He, Lihua; Bai, Peng; Xue, Yan

2016-10-01

Hybrid therapy has recently attracted widespread attention. However, many issues require further exploration. For example, research in regions with high antibiotic resistance rates is limited, and the correlation between eradication efficacy and antibiotic resistance remains unclear. The aim of this study was to determine the efficacy, compliance, safety, and risk factors of hybrid therapy as first-line regimen in a region with high antibiotic resistance rates. This prospective study was conducted in a tertiary hospital between January 2014 and June 2015. A total of 196 patients with dyspepsia but without prior eradication therapy received hybrid regimen (esomeprazole 20 mg and amoxicillin 1000 mg twice daily for 14 days with the addition of clarithromycin 500 mg and tinidazole 500 mg twice daily for the final 7 days). All patients underwent Helicobacter pylori culture, antibiotic susceptibility testing and cytochrome P450 isoenzyme 2C19 polymorphism testing. Hybrid therapy achieved eradication rates of 77.0% (95% confidence interval (CI), 70.9-83.7%) in intention-to-treat (ITT), 83.9% (78.9-88.9%) in modified ITT and 86.0% (80.2-91.3%) in per-protocol analyses in a setting with high antibiotic resistance rates (amoxicillin 2.0%, clarithromycin 44.9%, metronidazole 67.3% and dual clarithromycin and metronidazole 33.3%). Adverse reactions occurred in 31.9% patients and 2.7% discontinued medications due to adverse reactions. Good compliance was achieved by 92.0%. Multivariate analyses identified clarithromycin resistance (odds ratio, 3.494; 95% CI, 1.237-9.869), metronidazole resistance (3.012; 1.013-12.054) and poor compliance (5.840; 1.126-30.296) as independent predictors of treatment failure. The eradication rate with dual clarithromycin and metronidazole resistance (70.2%) was markedly decreased compared to isolated clarithromycin resistance (87.5%), isolated metronidazole resistance (88.6%), or dual susceptibility (96.4%) (p = .014). Despite good compliance and

Trihydroxamate siderophore-fluoroquinolone conjugates are selective sideromycin antibiotics that target Staphylococcus aureus.

PubMed

Wencewicz, Timothy A; Long, Timothy E; Möllmann, Ute; Miller, Marvin J

2013-03-20

Siderophores are multidentate iron(III) chelators used by bacteria for iron assimilation. Sideromycins, also called siderophore-antibiotic conjugates, are a unique subset of siderophores that enter bacterial cells via siderophore uptake pathways and deliver the toxic antibiotic in a "Trojan horse" fashion. Sideromycins represent a novel antibiotic delivery technology with untapped potential for developing sophisticated microbe-selective antibacterial agents that limit the emergence of bacterial resistance. The chemical synthesis of a series of mono-, bis-, and trihydroxamate sideromycins are described here along with their biological evaluation in antibacterial susceptibility assays. The linear hydroxamate siderophores used for the sideromycins in this study were derived from the ferrioxamine family and inspired by the naturally occurring salmycin sideromycins. The antibacterial agents used were a β-lactam carbacepholosporin, Lorabid, and a fluoroquinolone, ciprofloxacin, chosen for the different locations of their biological targets, the periplasm (extracellular) and the cytoplasm (intracellular). The linear hydroxamate-based sideromycins were selectively toxic toward Gram-positive bacteria, especially Staphylococcus aureus SG511 (MIC = 1.0 μM for the trihydroxamate-fluoroquinolone sideromycin). Siderophore-sideromycin competition assays demonstrated that only the fluoroquinolone sideromycins required membrane transport to reach their cytoplasmic biological target and that a trihydroxamate siderophore backbone was required for protein-mediated active transport of the sideromycins into S. aureus cells via siderophore uptake pathways. This work represents a comprehensive study of linear hydroxamate sideromycins and teaches how to build effective hydroxamate-based sideromycins as Gram-positive selective antibiotic agents.

Effects of One-Week Empirical Antibiotic Therapy on the Early Development of Gut Microbiota and Metabolites in Preterm Infants.

PubMed

Zhu, Danping; Xiao, Sa; Yu, Jialin; Ai, Qing; He, Yu; Cheng, Chen; Zhang, Yunhui; Pan, Yun

2017-08-14

The early postnatal period is the most dynamic and vulnerable stage in the assembly of intestinal microbiota. Antibiotics are commonly prescribed to newborn preterm babies and are frequently used for a prolonged duration in China. We hypothesized that the prolonged antibiotic therapy would affect the early development of intestinal microbiota and their metabolites. To test this hypothesis, we analyzed the stool microbiota and metabolites in 36 preterm babies with or without antibiotic treatment. These babies were divided into three groups, including two groups treated with the combination of penicillin and moxalactam or piperacillin-tazobactam for 7 days, and the other group was free of antibiotics. Compared to the antibiotic-free group, both antibiotic-treated groups had distinct gut microbial communities and metabolites, including a reduction of bacterial diversity and an enrichment of harmful bacteria such as Streptococcus and Pseudomonas. In addition, there was a significant difference in the composition of gut microbiota and their metabolites between the two antibiotic-treated groups, where the piperacillin-tazobactam treatment group showed an overgrowth of Enterococcus. These findings suggest that prolonged antibiotic therapy affects the early development of gut microbiota in preterm infants, which should be considered when prescribing antibiotics for this population.

A Pilot Study of Quantitative Loop-mediated Isothermal Amplification-guided Target Therapies for Hospital-acquired Pneumonia.

PubMed

Wang, Fang; Li, Ran; Shang, Ying; Wang, Can; Wang, Guo-Qing; Zhou, De-Xun; Yang, Dong-Hong; Xi, Wen; Wang, Ke-Qiang; Bao, Jing; Kang, Yu; Gao, Zhan-Cheng

2016-01-20

It is important to achieve the definitive pathogen identification in hospital-acquired pneumonia (HAP), but the traditional culture results always delay the target antibiotic therapy. We assessed the method called quantitative loop-mediated isothermal amplification (qLAMP) as a new implement for steering of the antibiotic decision-making in HAP. Totally, 76 respiratory tract aspiration samples were prospectively collected from 60 HAP patients. DNA was isolated from these samples. Specific DNA fragments for identifying 11 pneumonia-related bacteria were amplified by qLAMP assay. Culture results of these patients were compared with the qLAMP results. Clinical data and treatment strategies were analyzed to evaluate the effects of qLAMP results on clinical data. McNemar test and Fisher's exact test were used for statistical analysis. The detection of Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumonia, Stenotrophomonas maltophilia, Streptococcus pneumonia, and Acinetobacter baumannii by qLAMP was consistent with sputum culture (P > 0.05). The qLAMP results of 4 samples for Haemophilus influenzae, Legionella pneumophila, or Mycoplasma pneumonia (MP) were inconsistent with culture results; however, clinical data revealed that the qLAMP results were all reliable except 1 MP positive sample due to the lack of specific species identified in the final diagnosis. The improvement of clinical condition was more significant (P < 0.001) in patients with pathogen target-driven therapy based on qLAMP results than those with empirical therapy. qLAMP is a more promising method for detection of pathogens in an early, rapid, sensitive, and specific manner than culture.

Patient and physician predictors of patient receipt of therapies recommended by a computerized decision support system when initially prescribed broad-spectrum antibiotics: a cohort study

PubMed Central

Lye, David C.; Arah, Onyebuchi A

2016-01-01

Objective Antibiotic computerized decision support systems (CDSSs) were developed to guide antibiotic decisions, yet prescriptions of CDSS-recommended antibiotics have remained low. Our aim was to identify predictors of patients' receipt of empiric antibiotic therapies recommended by a CDSS when the prescribing physician had an initial preference for using broad-spectrum antibiotics. Methods We conducted a prospective cohort study in a 1 500-bed tertiary-care hospital in Singapore. We included all patients admitted from October 1, 2011 through September 30, 2012, who were prescribed piperacillin-tazobactam or carbapenem for empiric therapy and auto-triggered to receive antibiotic recommendations by the in-house antibiotic CDSS. Relevant data on the patient, prescribing and attending physicians were collected via electronic linkages of medical records and administrative databases. To account for clustering, we used multilevel logistic regression models to explore factors associated with receipt of CDSS-recommended antibiotic therapy. Results One-quarter of the 1 886 patients received CDSS-recommended antibiotics. More patients treated for pneumonia (33.2%) than sepsis (12.1%) and urinary tract infections (7.1%) received CDSS-recommended antibiotic therapies. The prescribing physician – but not the attending physician or clinical specialty – accounted for some (13.3%) of the variation. Prior hospitalization (odds ratio [OR] 1.32, 95% CI, 1.01-1.71), presumed pneumonia (OR 6.77, 95% CI, 3.28-13.99), intensive care unit (ICU) admission (OR 0.38, 95% CI, 0.21-0.66), and renal impairment (OR 0.70, 95% CI, 0.52-0.93) were factors associated with patients’ receipt of CDSS-recommended antibiotic therapies. Conclusions We observed that ICU admission and renal impairment were negative predictors of patients’ receipt of CDSS-recommended antibiotic therapies. Patients admitted to ICU and those with renal impairment might have more complex clinical conditions that

Comparison of Antibiotic Therapy and Appendectomy for Acute Uncomplicated Appendicitis in Children: A Meta-analysis.

PubMed

Huang, Libin; Yin, Yuan; Yang, Lie; Wang, Cun; Li, Yuan; Zhou, Zongguang

2017-05-01

Antibiotic therapy for acute uncomplicated appendicitis is effective in adult patients, but its application in pediatric patients remains controversial. To compare the safety and efficacy of antibiotic treatment vs appendectomy as the primary therapy for acute uncomplicated appendicitis in pediatric patients. The PubMed, MEDLINE, EMBASE, and Cochrane Library databases and the Cochrane Controlled Trials Register for randomized clinical trials were searched through April 17, 2016. The search was limited to studies published in English. Search terms included appendicitis, antibiotics, appendectomy, randomized controlled trial, controlled clinical trial, randomized, placebo, drug therapy, randomly, and trial. Randomized clinical trials and prospective clinical controlled trials comparing antibiotic therapy with appendectomy for acute uncomplicated appendicitis in pediatric patients (aged 5-18 years) were included in the meta-analysis. The outcomes included at least 2 of the following terms: success rate of antibiotic treatment and appendectomy, complications, readmissions, length of stay, total cost, and disability days. Data were independently extracted by 2 reviewers. The quality of the included studies was examined in accordance with the Cochrane guidelines and the Newcastle-Ottawa criteria. Data were pooled using a logistic fixed-effects model, and the subgroup pooled risk ratio with or without appendicolith was estimated. The primary outcome was the success rate of treatment. The hypothesis was formulated before data collection. A total of 527 articles were screened. In 5 unique studies, 404 unique patients with uncomplicated appendicitis (aged 5-15 years) were enrolled. Nonoperative treatment was successful in 152 of 168 patients (90.5%), with a Mantel-Haenszel fixed-effects risk ratio of 8.92 (95% CI, 2.67-29.79; heterogeneity, P = .99; I2 = 0%). Subgroup analysis showed that the risk for treatment failure in patients with appendicolith increased, with a

Antibiotic Resistance and the Biology of History.

PubMed

Landecker, Hannah

2016-12-01

Beginning in the 1940s, mass production of antibiotics involved the industrial-scale growth of microorganisms to harvest their metabolic products. Unfortunately, the use of antibiotics selects for resistance at answering scale. The turn to the study of antibiotic resistance in microbiology and medicine is examined, focusing on the realization that individual therapies targeted at single pathogens in individual bodies are environmental events affecting bacterial evolution far beyond bodies. In turning to biological manifestations of antibiotic use, sciences fathom material outcomes of their own previous concepts. Archival work with stored soil and clinical samples produces a record described here as 'the biology of history': the physical registration of human history in bacterial life. This account thus foregrounds the importance of understanding both the materiality of history and the historicity of matter in theories and concepts of life today.

Antibiotic Resistance and the Biology of History

PubMed Central

2015-01-01

Beginning in the 1940s, mass production of antibiotics involved the industrial-scale growth of microorganisms to harvest their metabolic products. Unfortunately, the use of antibiotics selects for resistance at answering scale. The turn to the study of antibiotic resistance in microbiology and medicine is examined, focusing on the realization that individual therapies targeted at single pathogens in individual bodies are environmental events affecting bacterial evolution far beyond bodies. In turning to biological manifestations of antibiotic use, sciences fathom material outcomes of their own previous concepts. Archival work with stored soil and clinical samples produces a record described here as ‘the biology of history’: the physical registration of human history in bacterial life. This account thus foregrounds the importance of understanding both the materiality of history and the historicity of matter in theories and concepts of life today. PMID:28458609

Importance of nondrug costs of intravenous antibiotic therapy.

PubMed

van Zanten, Arthur R H; Engelfriet, Peter M; van Dillen, Karin; van Veen, Miriam; Nuijten, Mark J C; Polderman, Kees H

2003-12-01

costs) were calculated this resulted in average costs of 5.65, 7.28, 5.36 and 3.83, respectively, for administration of each dose of antibiotics. These costs represent between 11% and 53% of the total daily costs of antibiotic therapy. Compared with the acquisition costs, these indirect costs ranged from 13% to 113%. Not included in this comparison is the time required for insertion of an IV catheter, which was found to be 10:15 +/- 6:31 min with an average calculated cost of 9.17. Total costs of IV antibiotic administration are formed not only by the costs of the drugs themselves, but also, to a substantial degree, by the time expended by medical and nursing staff, costs of disposable materials and overhead costs. Physicians making decisions regarding the use of specific medications in intensive care unit patients should take these factors into account. Use of IV antibiotics is associated with considerable workload and additional costs that can exceed the acquisition costs of the medications themselves.

Targeted therapies for cancer

MedlinePlus

Targeted therapies are promising new treatments, but they have limitations. Cancer cells can become resistant to these drugs. The target sometimes changes, so the treatment no longer works. The cancer may find a different way to grow and survive that ...

Immunomodulatory activity of pidotimod administered with standard antibiotic therapy in children hospitalized for community-acquired pneumonia.

PubMed

Esposito, Susanna; Garziano, Micaela; Rainone, Veronica; Trabattoni, Daria; Biasin, Mara; Senatore, Laura; Marchisio, Paola; Rossi, Marta; Principi, Nicola; Clerici, Mario

2015-09-03

Several attempts to improve immune function in young children have been made and encouraging results have been collected with pidotimod (PDT), a synthetic dipeptide molecule that seems to have immunomodulatory activity on both innate and adaptive responses. Until now, the effects of PDT on the immune system have only been studied in vivo after long-term administration to evaluate whether its immunomodulatory activity might prevent the development of infections. This study was planned to evaluate the immunomodulatory activity of PDT administered together with standard antibiotic therapy in children hospitalized for community-acquired pneumonia (CAP). A total of 20 children hospitalized for community-acquired pneumonia (CAP) were randomized at a 1:1 ratio to receive either standard antibiotics plus pidotimod (PDT) or standard antibiotics alone to evaluate the immunomodulatory activity of PDT. Blood samples for the evaluation of immunological parameters were drawn at the time of recruitment (T0) (i.e., before therapy administration), at T3 and T5 (i.e., 3 and 5 days after the initiation of therapy) as well as at T21 (i.e., 7 days after the therapy ended). Following pneumococcal polysaccharide stimulation, the percentage of dendritic cells (DCs) expressing activation and costimulatory molecules was significantly higher in children receiving PDT plus antibiotics than in the controls. A significant increase in tumor necrosis factor-α and/or interleukin-12 secretion and expression of toll like receptor 2 was observed in PDT-treated children compared with controls; this was followed by an increased release of proinflammatory cytokines by monocytes. In the PDT-treated group, mRNA expression of antimicrobial peptides and genes involved in the inflammatory response were also augmented in comparison with the controls. These results demonstrate, for the first time, that PDT administered together with standard antibiotics is associated with a favorable persistent

Synergistic antimicrobial therapy using nanoparticles and antibiotics for the treatment of multidrug-resistant bacterial infection

NASA Astrophysics Data System (ADS)

Gupta, Akash; Saleh, Neveen M.; Das, Riddha; Landis, Ryan F.; Bigdeli, Arafeh; Motamedchaboki, Khatereh; Rosa Campos, Alexandre; Pomeroy, Kenneth; Mahmoudi, Morteza; Rotello, Vincent M.

2017-06-01

Infections caused by multidrug-resistant (MDR) bacteria pose a serious global burden of mortality, causing thousands of deaths each year. Antibiotic treatment of resistant infections further contributes to the rapidly increasing number of antibiotic-resistant species and strains. Synthetic macromolecules such as nanoparticles (NPs) exhibit broad-spectrum activity against MDR species, however lack of specificity towards bacteria relative to their mammalian hosts limits their widespread therapeutic application. Here, we demonstrate synergistic antimicrobial therapy using hydrophobically functionalized NPs and fluoroquinolone antibiotics for treatment of MDR bacterial strains. An 8-16-fold decrease in antibiotic dosage is achieved in presence of engineered NPs to combat MDR strains. This strategy demonstrates the potential of using NPs to ‘revive’ antibiotics that have been rendered ineffective due to the development of resistance by pathogenic bacteria.

Variability in Antibiotic Use Across PICUs.

PubMed

Brogan, Thomas V; Thurm, Cary; Hersh, Adam L; Gerber, Jeffrey S; Smith, Michael J; Shah, Samir S; Courter, Joshua D; Patel, Sameer J; Parker, Sarah K; Kronman, Matthew P; Lee, Brian R; Newland, Jason G

2018-06-01

To characterize and compare antibiotic prescribing across PICUs to evaluate the degree of variability. Retrospective analysis from 2010 through 2014 of the Pediatric Health Information System. Forty-one freestanding children's hospital. Children aged 30 days to 18 years admitted to a PICU in children's hospitals contributing data to Pediatric Health Information System. To normalize for potential differences in disease severity and case mix across centers, a subanalysis was performed of children admitted with one of the 20 All Patient Refined-Diagnosis Related Groups and the seven All Patient Refined-Diagnosis Related Groups shared by all PICUs with the highest antibiotic use. The study included 3,101,201 hospital discharges from 41 institutions with 386,914 PICU patients. All antibiotic use declined during the study period. The median-adjusted antibiotic use among PICU patients was 1,043 days of therapy/1,000 patient-days (interquartile range, 977-1,147 days of therapy/1,000 patient-days) compared with 893 among non-ICU children (interquartile range, 805-968 days of therapy/1,000 patient-days). For PICU patients, the median adjusted use of broad-spectrum antibiotics was 176 days of therapy/1,000 patient-days (interquartile range, 152-217 days of therapy/1,000 patient-days) and was 302 days of therapy/1,000 patient-days (interquartile range, 220-351 days of therapy/1,000 patient-days) for antimethicillin-resistant Staphylococcus aureus agents, compared with 153 days of therapy/1,000 patient-days (interquartile range, 130-182 days of therapy/1,000 patient-days) and 244 days of therapy/1,000 patient-days (interquartile range, 203-270 days of therapy/1,000 patient-days) for non-ICU children. After adjusting for potential confounders, significant institutional variability existed in antibiotic use in PICU patients, in the 20 All Patient Refined-Diagnosis Related Groups with the highest antibiotic usage and in the seven All Patient Refined-Diagnosis Related Groups shared

Emerging therapies for Clostridium difficile infection – focus on fidaxomicin

PubMed Central

Chaparro-Rojas, Fredy; Mullane, Kathleen M

2013-01-01

The epidemiology of Clostridium difficile infections (CDI) has evolved during the last decades, with an increase in the reported incidence, severity of cases, and rate of mortality and relapses. These increases have primarily affected some special populations including the elderly, patients requiring concomitant antibiotic therapy, patients with renal failure, and patients with cancer. Until recently, the treatment of CDI was limited to either metronidazole or vancomycin. New therapeutic options have emerged to address the shortcomings of current antibiotic therapy. Fidaxomicin stands out as the first-in-class oral macrocyclic antibiotic with targeted activity against C. difficile and minimal collateral damage on the normal colonic flora. Fidaxomicin has demonstrated performance not inferior to what is considered the “gold standard” available therapy for CDI, vancomycin, in two separate Phase III clinical trials, but with significant advantages, including fewer recurrences and higher rates of sustained clinical cures. Fidaxomicin constitutes an important development in targeted antibiotic therapy for CDI and must be considered as a first-line agent for patients with risk factors known to portend relapse and severe infection. PMID:23843696

New targeted therapies in pancreatic cancer.

PubMed

Seicean, Andrada; Petrusel, Livia; Seicean, Radu

2015-05-28

Patients with pancreatic cancer have a poor prognosis with a median survival of 4-6 mo and a 5-year survival of less than 5%. Despite therapy with gemcitabine, patient survival does not exceed 6 mo, likely due to natural resistance to gemcitabine. Therefore, it is hoped that more favorable results can be obtained by using guided immunotherapy against molecular targets. This review summarizes the new leading targeted therapies in pancreatic cancers, focusing on passive and specific immunotherapies. Passive immunotherapy may have a role for treatment in combination with radiochemotherapy, which otherwise destroys the immune system along with tumor cells. It includes mainly therapies targeting against kinases, including epidermal growth factor receptor, Ras/Raf/mitogen-activated protein kinase cascade, human epidermal growth factor receptor 2, insulin growth factor-1 receptor, phosphoinositide 3-kinase/Akt/mTOR and hepatocyte growth factor receptor. Therapies against DNA repair genes, histone deacetylases, microRNA, and pancreatic tumor tissue stromal elements (stromal extracellular matric and stromal pathways) are also discussed. Specific immunotherapies, such as vaccines (whole cell recombinant, peptide, and dendritic cell vaccines), adoptive cell therapy and immunotherapy targeting tumor stem cells, have the role of activating antitumor immune responses. In the future, treatments will likely include personalized medicine, tailored for numerous molecular therapeutic targets of multiple pathogenetic pathways.

RecA Inhibitors Potentiate Antibiotic Activity and Block Evolution of Antibiotic Resistance.

PubMed

Alam, Md Kausar; Alhhazmi, Areej; DeCoteau, John F; Luo, Yu; Geyer, C Ronald

2016-03-17

Antibiotic resistance arises from the maintenance of resistance mutations or genes acquired from the acquisition of adaptive de novo mutations or the transfer of resistance genes. Antibiotic resistance is acquired in response to antibiotic therapy by activating SOS-mediated DNA repair and mutagenesis and horizontal gene transfer pathways. Initiation of the SOS pathway promotes activation of RecA, inactivation of LexA repressor, and induction of SOS genes. Here, we have identified and characterized phthalocyanine tetrasulfonic acid RecA inhibitors that block antibiotic-induced activation of the SOS response. These inhibitors potentiate the activity of bactericidal antibiotics, including members of the quinolone, β-lactam, and aminoglycoside families in both Gram-negative and Gram-positive bacteria. They reduce the ability of bacteria to acquire antibiotic resistance mutations and to transfer mobile genetic elements conferring resistance. This study highlights the advantage of including RecA inhibitors in bactericidal antibiotic therapies and provides a new strategy for prolonging antibiotic shelf life. Copyright © 2016 Elsevier Ltd. All rights reserved.

Protocol for extended antibiotic therapy after laparoscopic cholecystectomy for acute calculous cholecystitis (Cholecystectomy Antibiotic Randomised Trial, CHART).

PubMed

Pellegrini, Pablo; Campana, Juan Pablo; Dietrich, Agustín; Goransky, Jeremías; Glinka, Juan; Giunta, Diego; Barcan, Laura; Alvarez, Fernando; Mazza, Oscar; Sánchez Claria, Rodrigo; Palavecino, Martin; Arbues, Guillermo; Ardiles, Victoria; de Santibañes, Eduardo; Pekolj, Juan; de Santibañes, Martin

2015-11-18

Acute calculous cholecystitis represents one of the most common complications of cholelithiasis. While laparoscopic cholecystectomy is the standard treatment in mild and moderate forms, the need for antibiotic therapy after surgery remains undefined. The aim of the randomised controlled Cholecystectomy Antibiotic Randomised Trial (CHART) is therefore to assess if there are benefits in the use of postoperative antibiotics in patients with mild or moderate acute cholecystitis in whom a laparoscopic cholecystectomy is performed. A single-centre, double-blind, randomised trial. After screening for eligibility and informed consent, 300 patients admitted for acute calculus cholecystitis will be randomised into two groups of treatment, either receiving amoxicillin/clavulanic acid or placebo for 5 consecutive days. Postoperative evaluation will take place during the first 30 days. Postoperative infectious complications are the primary end point. Secondary end points are length of hospital stay, readmissions, need of reintervention (percutaneous or surgical reinterventions) and overall mortality. The results of this trial will provide strong evidence to either support or abandon the use of antibiotics after surgery, impacting directly in the incidence of adverse events associated with the use of antibiotics, the emergence of bacterial resistance and treatment costs. This study and informed consent sheets have been approved by the Research Projects Evaluating Committee (CEPI) of Hospital Italiano de Buenos Aires (protocol N° 2111). The results of the trial will be reported in a peer-reviewed publication. NCT02057679. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Target-aptamer binding triggered quadratic recycling amplification for highly specific and ultrasensitive detection of antibiotics at the attomole level.

PubMed

Wang, Hongzhi; Wang, Yu; Liu, Su; Yu, Jinghua; Xu, Wei; Guo, Yuna; Huang, Jiadong

2015-05-14

A novel electrochemical aptasensor for ultrasensitive detection of antibiotics by combining polymerase-assisted target recycling amplification with strand displacement amplification with the help of polymerase and nicking endonuclease has been reported. This work is the first time that target-aptamer binding triggered quadratic recycling amplification has been utilized for electrochemical detection of antibiotics.

Antibiotic prescription patterns in the empiric therapy of severe sepsis: combination of antimicrobials with different mechanisms of action reduces mortality.

PubMed

Díaz-Martín, Ana; Martínez-González, María Luisa; Ferrer, Ricard; Ortiz-Leyba, Carlos; Piacentini, Enrique; Lopez-Pueyo, Maria Jesus; Martín-Loeches, Ignacio; Levy, Mitchell M; Artigas, Antoni; Garnacho-Montero, José

2012-11-18

Although early institution of adequate antimicrobial therapy is lifesaving in sepsis patients, optimal antimicrobial strategy has not been established. Moreover, the benefit of combination therapy over monotherapy remains to be determined. Our aims are to describe patterns of empiric antimicrobial therapy in severe sepsis, assessing the impact of combination therapy, including antimicrobials with different mechanisms of action, on mortality. This is a Spanish national multicenter study, analyzing all patients admitted to ICUs who received antibiotics within the first 6 hours of diagnosis of severe sepsis or septic shock. Antibiotic-prescription patterns in community-acquired infections and nosocomial infections were analyzed separately and compared. We compared the impact on mortality of empiric antibiotic treatment, including antibiotics with different mechanisms of action, termed different-class combination therapy (DCCT), with that of monotherapy and any other combination therapy possibilities (non-DCCT). We included 1,372 patients, 1,022 (74.5%) of whom had community-acquired sepsis and 350 (25.5%) of whom had nosocomial sepsis. The most frequently prescribed antibiotic agents were β-lactams (902, 65.7%) and carbapenems (345, 25.1%). DCCT was administered to 388 patients (28.3%), whereas non-DCCT was administered to 984 (71.7%). The mortality rate was significantly lower in patients administered DCCTs than in those who were administered non-DCCTs (34% versus 40%; P = 0.042). The variables independently associated with mortality were age, male sex, APACHE II score, and community origin of the infection. DCCT was a protective factor against in-hospital mortality (odds ratio (OR), 0.699; 95% confidence interval (CI), 0.522 to 0.936; P = 0.016), as was urologic focus of infection (OR, 0.241; 95% CI, 0.102 to 0.569; P = 0.001). β-Lactams, including carbapenems, are the most frequently prescribed antibiotics in empiric therapy in patients with severe sepsis and

Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD).

PubMed

Herath, Samantha C; Poole, Phillippa

2013-11-28

.The development of antibiotic resistance in the community is of major concern. One study found newly colonised patients to have higher rates of antibiotic resistance. Patients colonised with moxifloxacin-sensitive pseudomonas at initiation of therapy rapidly became resistant with the quinolone treatment. Use of continuous prophylactic antibiotics results in a clinically significant benefit in reducing exacerbations in COPD patients. All trials of continuous antibiotics used macrolides hence the noted benefit applies only to the use of continuous macrolide antibiotics. The impact of pulsed antibiotics remains uncertain and requires further research.The trials in this review included patients who were frequent exacerbators and needed treatment with antibiotics or systemic steroids, or who were on supplemental oxygen. There were also older individuals with a mean age of 66 years. The results of these trials apply only to the group of patients who were studied in these trials and may not be generalisable to other groups.Because of concerns about antibiotic resistance and specific adverse effects, consideration of prophylactic antibiotic use should be mindful of the balance between benefits to individual patients and the potential harms to society created by antibiotic overuse.

A fluorescent glycosyl-imprinted polymer for pH and temperature regulated sensing of target glycopeptide antibiotic.

PubMed

Chen, Kuncai; He, Rong; Luo, Xiaoyan; Qin, Pengzhe; Tan, Lei; Tang, Youwen; Yang, Zhicong

2017-08-15

This paper demonstrates a new strategy for developing a fluorescent glycosyl-imprinted polymer for pH and temperature regulated sensing of target glycopeptide antibiotic. The technique provides amino modified Mn-doped ZnS QDs as fluorescent supports, 4-vinylphenylbronic acid as a covalent monomer, N-isopropyl acrylamide as a thermo-responsive monomer in combination with acrylamide as a non-covalent monomer, and glycosyl moiety of a glycopeptide antibiotic as a template to produce fluorescent molecularly imprinted polymer (FMIP) in aqueous solution. The FMIP can alter its functional moieties and structure with pH and temperature stimulation. This allows recognition of target molecules through control of pH and temperature. The fluorescence intensity of the FMIP was enhanced gradually as the concentration of telavancin increased, and showed selective recognition toward the target glycopeptide antibiotic preferentially among other antibiotics. Using the FMIP as a sensing material, good linear correlations were obtained over the concentration range of 3.0-300.0μg/L and with a low limit of detection of 1.0μg/L. The analysis results of telavancin in real samples were consistent with that obtained by liquid chromatography tandem mass spectrometry. Copyright © 2017 Elsevier B.V. All rights reserved.

Antibiotic Therapy of Staphylococcal Infections

PubMed Central

Hawks, Gordon H.

1965-01-01

The antibiotic treatment of staphylococcal infections remains a problem. Isolation of the organism and sensitivity testing are necessary in the choice of antibiotic. Penicillin G is the most effective penicillin against non-penicillinase-producing staphy-lococci; for the penicillinase producers there is very little to choose between the semisynthetic penicillins, methicillin, cloxacillin, nafcillin and oxacillin. For patients who are hypersensitive to penicillin, the bacteriostatic drugs (erythromycin, novobiocin, tetracycline, chloramphenicol, oleandomycin) are useful for mild infections, while for more severe illness the bactericidal drugs (vancomycin, ristocetin, kanamycin, bacitracin, neomycin) have been used successfully. Acute staphylococcal enterocolitis is probably best treated by a semisynthetic penicillin. Other antibiotics which have been found useful, with clinical trials, for staphylococcal infections are cephalosporin, fucidin, cephaloridine and lincomycin. The latter drug has been reported of value in the treatment of osteomyelitis. There is little justification for the prophylactic use of antibiotics to prevent staphylococcal infection. Surgical drainage is still an important adjunct in the treatment of many staphylococcal infections. PMID:5318575

[Antibiotics in the critically ill].

PubMed

Kolak, Radmila R

2010-01-01

Antibiotics are one the most common therapies administered in the intensive care unit setting. This review outlines the strategy for optimal use of antimicrobial agents in the critically ill. In severely ill patients, empirical antimicrobial therapy should be used when a suspected infection may impair the outcome. It is necessary to collect microbiological documentation before initiating empirical antimicrobial therapy. In addition to antimicrobial therapy, it is recommended to control a focus of infection and to modify factors that promote microbial growth or impair the host's antimicrobial defence. A judicious choice of antimicrobial therapy should be based on the host characteristics, the site of injection, the local ecology, and the pharmacokinetics/pharmacodynamics of antibiotics. This means treating empirically with broad-spectrum antimicrobials as soon as possible and narrowing the spectrum once the organism is identified (de-escalation), and limiting duration of therapy to the minimum effective period. Despite theoretical advantages, a combined antibiotic therapy is nor more effective than a mono-therapy in curing infections in most clinical trials involving intensive care patients. Nevertheless, textbooks and guidelines recommend a combination for specific pathogens and for infections commonly caused by these pathogens. Avoiding unnecessary antibiotic use and optimizing the administration of antimicrobial agents will improve patient outcomes while minimizing risks for the development of bacterial resistance. It is important to note that each intensive care unit should have a program in place which monitors antibiotic utilisation and its effectiveness. Only in this way can the impact of interventions aimed at improving antibiotic use be evaluated at the local level.

Antibiotic Susceptibilities of Bacteria Isolated within the Oral Flora of Florida Blacktip Sharks: Guidance for Empiric Antibiotic Therapy

PubMed Central

Unger, Nathan R.; Ritter, Erich; Borrego, Robert; Goodman, Jay; Osiyemi, Olayemi O.

2014-01-01

Sharks possess a variety of pathogenic bacteria in their oral cavity that may potentially be transferred into humans during a bite. The aim of the presented study focused on the identification of the bacteria present in the mouths of live blacktip sharks, Carcharhinus limbatus, and the extent that these bacteria possess multi-drug resistance. Swabs were taken from the oral cavity of nineteen live blacktip sharks, which were subsequently released. The average fork length was 146 cm (±11), suggesting the blacktip sharks were mature adults at least 8 years old. All swabs underwent standard microbiological work-up with identification of organisms and reporting of antibiotic susceptibilities using an automated microbiology system. The oral samples revealed an average of 2.72 (±1.4) bacterial isolates per shark. Gram-negative bacteria, making up 61% of all bacterial isolates, were significantly (p<0.001) more common than gram-positive bacteria (39%). The most common organisms were Vibrio spp. (28%), various coagulase-negative Staphylococcus spp. (16%), and Pasteurella spp. (12%). The overall resistance rate was 12% for all antibiotics tested with nearly 43% of bacteria resistant to at least one antibiotic. Multi-drug resistance was seen in 4% of bacteria. No association between shark gender or fork length with bacterial density or antibiotic resistance was observed. Antibiotics with the highest overall susceptibility rates included fluoroquinolones, 3rd generation cephalosporins and sulfamethoxazole/trimethoprim. Recommended empiric antimicrobial therapy for adult blacktip shark bites should encompass either a fluoroquinolone or combination of a 3rd generation cephalosporin plus doxycycline. PMID:25110948

[Special characteristics of antibiotic therapy in the elderly].

PubMed

Stock, Ingo

2012-03-01

The ever-increasing proportion of elderly people in the general population represents physicians and pharmacists with new challenges. Older people suffer more frequently than younger persons from bacterial diseases, and they have a higher tendency to develop more severe or progressive forms of these illnesses. Bacterial diseases of the urinary tract, respiratory tract, skin and soft tissues are especially common in old age. In general, most antibacterial agents are also promising agents for the therapy of bacterial diseases in the elderly. Prior to initiating therapy, however, the modified organ functions of the elderly have to be considered carefully. Depending on the individual and the antibacterial agent, a dose adjustment may be necessary. To reduce the high mortality rate characteristic for many infectious diseases in the elderly, antibacterial therapy ought to be carefully calculated and initiated as quickly as possible. It has to be born in mind that some side effects of antibiotics are more common and more severe in old age. Since older people often take several drugs simultaneously, the probability for the occurrence of side effects and drug interactions in this population is greatly increased. Significant compliance problems may also arise.

Improvement of antibiotic therapy and ICU survival in severe non-pneumococcal community-acquired pneumonia: a matched case-control study.

PubMed

Gattarello, Simone; Lagunes, Leonel; Vidaur, Loreto; Solé-Violán, Jordi; Zaragoza, Rafael; Vallés, Jordi; Torres, Antoni; Sierra, Rafael; Sebastian, Rosa; Rello, Jordi

2015-09-10

We aimed to compare intensive care unit mortality due to non-pneumococcal severe community-acquired pneumonia between the periods 2000-2002 and 2008-2014, and the impact of the improvement in antibiotic strategies on outcomes. This was a matched case-control study enrolling 144 patients with non-pneumococcal severe pneumonia: 72 patients from the 2000-2002 database (CAPUCI I group) were paired with 72 from the 2008-2014 period (CAPUCI II group), matched by the following variables: microorganism, shock at admission, invasive mechanical ventilation, immunocompromise, chronic obstructive pulmonary disease, and age over 65 years. The most frequent microorganism was methicillin-susceptible Staphylococcus aureus (22.1%) followed by Legionella pneumophila and Haemophilus influenzae (each 20.7%); prevalence of shock was 59.7%, while 73.6% of patients needed invasive mechanical ventilation. Intensive care unit mortality was significantly lower in the CAPUCI II group (34.7% versus 16.7%; odds ratio (OR) 0.78, 95% confidence interval (CI) 0.64-0.95; p = 0.02). Appropriate therapy according to microorganism was 91.5% in CAPUCI I and 92.7% in CAPUCI II, while combined therapy and early antibiotic treatment were significantly higher in CAPUCI II (76.4 versus 90.3% and 37.5 versus 63.9%; p < 0.05). In the multivariate analysis, combined antibiotic therapy (OR 0.23, 95% CI 0.07-0.74) and early antibiotic treatment (OR 0.07, 95% CI 0.02-0.22) were independently associated with decreased intensive care unit mortality. In non-pneumococcal severe community-acquired pneumonia , early antibiotic administration and use of combined antibiotic therapy were both associated with increased intensive care unit survival during the study period.

Duration of intravenous antibiotic therapy for children with acute osteomyelitis or septic arthritis: a feasibility study.

PubMed

de Graaf, Hans; Sukhtankar, Priya; Arch, Barbara; Ahmad, Nusreen; Lees, Amanda; Bennett, Abigail; Spowart, Catherine; Hickey, Helen; Jeanes, Annmarie; Armon, Kate; Riordan, Andrew; Herberg, Jethro; Hackett, Scott; Gamble, Carrol; Shingadia, Delane; Pallett, Ann; Clarke, Stuart C; Henman, Philip; Emonts, Marieke; Sharland, Mike; Finn, Adam; Pollard, Andrew J; Powell, Colin; Marsh, Peter; Ballinger, Claire; Williamson, Paula R; Clarke, Nicholas Mp; Faust, Saul N

2017-09-01

There is little current consensus regarding the route or duration of antibiotic treatment for acute osteomyelitis (OM) and septic arthritis (SA) in children. To assess the overall feasibility and inform the design of a future randomised controlled trial (RCT) to reduce the duration of intravenous (i.v.) antibiotic use in paediatric OM and SA. (1) A prospective service evaluation (cohort study) to determine the current disease spectrum and UK clinical practice in paediatric OM/SA; (2) a prospective cohort substudy to assess the use of targeted polymerase chain reaction (PCR) in diagnosing paediatric OM/SA; (3) a qualitative study to explore families' views and experiences of OM/SA; and (4) the development of a core outcome set via a systematic review of literature, Delphi clinician survey and stakeholder consensus meeting. Forty-four UK secondary and tertiary UK centres (service evaluation). Children with OM/SA. PCR diagnostics were compared with culture as standard of care. Semistructured interviews were used in the qualitative study. Data were obtained on 313 cases of OM/SA, of which 218 (61.2%) were defined as simple disease and 95 (26.7%) were defined as complex disease. The epidemiology of paediatric OM/SA in this study was consistent with existing European data. Children who met oral switch criteria less than 7 days from starting i.v. antibiotics were less likely to experience treatment failure (9.6%) than children who met oral switch criteria after 7 days of i.v. therapy (16.1% when switch was between 1 and 2 weeks; 18.2% when switch was > 2 weeks). In 24 out of 32 simple cases (75%) and 8 out of 12 complex cases (67%) in which the targeted PCR was used, a pathogen was detected. The qualitative study demonstrated the importance to parents and children of consideration of short- and long-term outcomes meaningful to families themselves. The consensus meeting agreed on the following outcomes: rehospitalisation or recurrence of symptoms while on oral

Prospective open-label randomized comparative, non-inferiority study of two initial antibiotic strategies for patients with nursing- and healthcare-associated pneumonia: Guideline-concordant therapy versus empiric therapy.

PubMed

Matsuda, Shuichi; Ogasawara, Takashi; Sugimoto, Shunsuke; Kato, Shinpei; Umezawa, Hiroki; Yano, Toshiaki; Kasamatsu, Norio

2016-06-01

The nursing- and healthcare-associated pneumonia guideline, proposed by the Japan Respiratory Society, recommends that patients at risk of exposure to drug-resistant pathogens, classified as treatment category C, be treated with antipseudomonal antibiotics. This study aimed to prove the non-inferiority of empirical therapy in our hospital compared with guideline-concordant therapy. This was a randomized controlled trial conducted from December 2011 to December 2012. Patients were randomized to the Guideline group receiving guideline-concordant therapy, and the Empiric group treated with sulbactam/ampicillin or ceftriaxone. The primary endpoint was in-hospital relapse of pneumonia and mortality within 30 days, with a predefined non-inferiority margin of 10%. The secondary endpoints included duration, adverse effects, and cost of antibiotic therapy. One hundred and eleven patients were assigned to the Guideline group (n = 55) and the Empiric group (n = 56; 3 of which were excluded). The incidence of relapse and death within 30 days was similar in the Guideline and the Empiric groups (31% vs. 26%, risk difference -4.5%, 95% CI -21.5% to 12.5%). While the duration of antibiotic therapy was slightly shorter in the Guideline group than in the Empiric group (7 vs. 8 days), there were no significant differences in adverse effects or cost. The efficacy of empiric therapy was comparable to guideline-concordant therapy, although non-inferiority was not proven. The administration of broad-spectrum antibiotics to patients at risk of exposure to drug-resistant pathogens may not necessarily improve the prognosis. UMIN000006792. Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Infectious olecranon and patellar bursitis: short-course adjuvant antibiotic therapy is not a risk factor for recurrence in adult hospitalized patients.

PubMed

Perez, Cédric; Huttner, Angela; Assal, Mathieu; Bernard, Louis; Lew, Daniel; Hoffmeyer, Pierre; Uçkay, Ilker

2010-05-01

No evidence-based recommendations exist for the management of infectious bursitis. We examined epidemiology and risk factors for recurrence of septic bursitis. Specifically, we compared outcome in patients receiving bursectomy plus short-course adjuvant antibiotic therapy (antibiotic therapy (>7 days). Retrospective study of adult patients with infectious olecranon and patellar bursitis requiring hospitalization at Geneva University Hospital from January 1996 to March 2009. We identified 343 episodes of infectious bursitis (237 olecranon and 106 patellar). Staphylococcus aureus predominated among the 256 cases with an identifiable pathogen (85%). Three hundred and twelve cases (91%) were treated surgically; 142 (41%) with one-stage bursectomy and closure and 146 with two-stage bursectomy. All received antibiotics for a median duration of 13 days with a median intravenous component of 3 days. Cure was achieved in 293 (85%) episodes. Total duration of antibiotic therapy [odds ratio (OR) 0.9; 95% confidence interval (95% CI) 0.8-1.1] showed no association with cure. In multivariate analysis, only immunosuppression was linked to recurrence (OR 5.6; 95% CI 1.9-18.4). Compared with antibiotic treatment (OR 0.6; 95% CI 0.1-2.9) or >14 days of antibiotic treatment (OR 0.9; 95% CI 0.1-10.7) was equivalent, as was the intravenous component (OR 1.1; 95% CI 1.0-1.3). In severe infectious bursitis requiring hospitalization, adjuvant antibiotic therapy might be limited to 7 days in non-immunosuppressed patients.

Newly approved antibiotics and antibiotics reserved for resistant infections: Implications for emergency medicine.

PubMed

Mazer-Amirshahi, Maryann; Pourmand, Ali; May, Larissa

2017-01-01

Millions of patients are evaluated every year in the emergency department (ED) for bacterial infections. Emergency physicians often diagnose and prescribe initial antibiotic therapy for a variety of bacterial infections, ranging from simple urinary tract infections to severe sepsis. In life-threatening infections, inappropriate choice of initial antibiotic has been shown to increase morbidity and mortality. As such, initiation of appropriate antibiotic therapy on the part of the emergency physician is critical. Increasing rates of antibiotic resistance, drug allergies, and antibiotic shortages further complicates the choice of antibiotics. Patients may have a history of prior resistant infections or culture data indicating that common first-line antibiotics used in the ED may be ineffective. In recent years, there have been several new antibiotic approvals as well as renewed interest in second and third line antibiotics because of the aforementioned concerns. In addition, several newly approved antibiotics have the advantage of being administered once weekly or even as a single infusion, which has the potential to decrease hospitalizations and healthcare costs. This article reviews newly approved antibiotics and antibiotics used to treat resistant infections with a focus on implications for emergency medicine. Copyright © 2016 Elsevier Inc. All rights reserved.

Targeting Enterococcus faecalis Biofilms with Phage Therapy

PubMed Central

Khalifa, Leron; Brosh, Yair; Gelman, Daniel; Coppenhagen-Glazer, Shunit; Beyth, Shaul; Poradosu-Cohen, Ronit; Que, Yok-Ai; Beyth, Nurit

2015-01-01

Phage therapy has been proven to be more effective, in some cases, than conventional antibiotics, especially regarding multidrug-resistant biofilm infections. The objective here was to isolate an anti-Enterococcus faecalis bacteriophage and to evaluate its efficacy against planktonic and biofilm cultures. E. faecalis is an important pathogen found in many infections, including endocarditis and persistent infections associated with root canal treatment failure. The difficulty in E. faecalis treatment has been attributed to the lack of anti-infective strategies to eradicate its biofilm and to the frequent emergence of multidrug-resistant strains. To this end, an anti-E. faecalis and E. faecium phage, termed EFDG1, was isolated from sewage effluents. The phage was visualized by electron microscopy. EFDG1 coding sequences and phylogeny were determined by whole genome sequencing (GenBank accession number KP339049), revealing it belongs to the Spounavirinae subfamily of the Myoviridae phages, which includes promising candidates for therapy against Gram-positive pathogens. This analysis also showed that the EFDG1 genome does not contain apparent harmful genes. EFDG1 antibacterial efficacy was evaluated in vitro against planktonic and biofilm cultures, showing effective lytic activity against various E. faecalis and E. faecium isolates, regardless of their antibiotic resistance profile. In addition, EFDG1 efficiently prevented ex vivo E. faecalis root canal infection. These findings suggest that phage therapy using EFDG1 might be efficacious to prevent E. faecalis infection after root canal treatment. PMID:25662974

Clinical efficacy of cycling empirical antibiotic therapy for febrile neutropenia in pediatric cancer patients.

PubMed

Teranishi, Hideto; Koga, Yuhki; Nishio, Hisanori; Kato, Wakako; Ono, Hiroaki; Kanno, Shunsuke; Nakashima, Kentaro; Takada, Hidetoshi

2017-07-01

Febrile neutropenia (FN) is the main treatment-related cause of mortality among children with cancer, as the prolonged use of broad-spectrum antibiotics can lead to antibiotic resistance in these patients. Antibiotic cycling has been reported to limit the emergence of antibiotic-resistant bacteria among adult patients. However, no studies have evaluated pediatric patients with FN. Between September 2011 and February 2014, 126 pediatric cancer patients were admitted to our center for chemotherapy and/or hematopoietic stem cell transplantation and were included in this study. Retrospective and prospective data collection were performed before and after antibiotic cycling, respectively. Between September 2011 and November 2012 (before antibiotic cycling was implemented), intravenous cefpirome was used as the empirical therapy for FN. Between December 2012 and February 2014 (after antibiotic cycling was implemented), the monthly antibiotic cycling involved intravenous piperacillin-tazobactam (PIPC/TAZ), intravenous meropenem or ciprofloxacin (CPFX), and intravenous cefepime in that order. For children aged ≥13 years, the monthly cycling involved intravenous PIPC/TAZ, and CPFX was administered. The detection rates for extended-spectrum β-lactamase producers in blood and stool culture samples decreased significantly after the implementation of antibiotic cycling (0.33/1000 patient-days vs 0/1000 patient-days, p = 0.03; 1.00/1000 patient-days vs 0/1000 patient-days, p < 0.01; respectively). Antibiotic cycling was associated with a decreased emergence of multidrug-resistant microbes. Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Metabolic engineering of an industrial polyoxin producer for the targeted overproduction of designer nucleoside antibiotics.

PubMed

Qi, Jianzhao; Liu, Jin; Wan, Dan; Cai, You-Sheng; Wang, Yinghu; Li, Shunying; Wu, Pan; Feng, Xuan; Qiu, Guofu; Yang, Sheng-Ping; Chen, Wenqing; Deng, Zixin

2015-09-01

Polyoxin and nikkomycin are naturally occurring peptidyl nucleoside antibiotics with potent antifungal bioactivity. Both exhibit similar structural features, having a nucleoside skeleton and one or two peptidyl moieties. Combining the refactoring of the polyoxin producer Streptomyces aureochromogenes with import of the hydroxypyridylhomothreonine pathway of nikkomycin allows the targeted production of three designer nucleoside antibiotics designated as nikkoxin E, F, and G. These structures were determined by NMR and/or high resolution mass spectrometry. Remarkably, the introduction of an extra copy of the nikS gene encoding an ATP-dependent ligase significantly enhanced the production of the designer antibiotics. Moreover, all three nikkoxins displayed improved bioactivity against several pathogenic fungi as compared with the naturally-occurring antibiotics. These data provide a feasible model for high efficiency generation of nucleoside antibiotics related to polyoxins and nikkomycins in a polyoxin cell factory via synthetic biology strategy. © 2015 Wiley Periodicals, Inc.

Antibiotic resistance in Burkholderia species.

PubMed

Rhodes, Katherine A; Schweizer, Herbert P

2016-09-01

The genus Burkholderia comprises metabolically diverse and adaptable Gram-negative bacteria, which thrive in often adversarial environments. A few members of the genus are prominent opportunistic pathogens. These include Burkholderia mallei and Burkholderia pseudomallei of the B. pseudomallei complex, which cause glanders and melioidosis, respectively. Burkholderia cenocepacia, Burkholderia multivorans, and Burkholderia vietnamiensis belong to the Burkholderia cepacia complex and affect mostly cystic fibrosis patients. Infections caused by these bacteria are difficult to treat because of significant antibiotic resistance. The first line of defense against antimicrobials in Burkholderia species is the outer membrane penetration barrier. Most Burkholderia contain a modified lipopolysaccharide that causes intrinsic polymyxin resistance. Contributing to reduced drug penetration are restrictive porin proteins. Efflux pumps of the resistance nodulation cell division family are major players in Burkholderia multidrug resistance. Third and fourth generation β-lactam antibiotics are seminal for treatment of Burkholderia infections, but therapeutic efficacy is compromised by expression of several β-lactamases and ceftazidime target mutations. Altered DNA gyrase and dihydrofolate reductase targets cause fluoroquinolone and trimethoprim resistance, respectively. Although antibiotic resistance hampers therapy of Burkholderia infections, the characterization of resistance mechanisms lags behind other non-enteric Gram-negative pathogens, especially ESKAPE bacteria such as Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa. Copyright © 2016 Elsevier Ltd. All rights reserved.

Antibiotic Resistance in Burkholderia Species

PubMed Central

Rhodes, Katherine A.; Schweizer, Herbert P.

2016-01-01

The genus Burkholderia comprises metabolically diverse and adaptable Gram-negative bacteria, which thrive in often adversarial environments. A few members of the genus are prominent opportunistic pathogens. These include B. mallei and B. pseudomallei of the B. pseudomallei complex, which cause glanders and melioidosis, respectively. B. cenocepacia, B. multivorans, and B. vietnamiensis belong to the B. cepacia complex and affect mostly cystic fibrosis patients. Infections caused by these bacteria are difficult to treat because of significant antibiotic resistance. The first line of defense against antimicrobials in Burkholderia species is the outer membrane penetration barrier. Most Burkholderia contain a modified lipopolysaccharide that causes intrinsic polymyxin resistance. Contributing to reduced drug penetration are restrictive porin proteins. Efflux pumps of the resistance nodulation cell division family are major players in Burkholderia multidrug resistance. Third and fourth generation β-lactam antibiotics are seminal for treatment of Burkholderia infections, but therapeutic efficacy is compromised by expression of several β-lactamases and ceftazidime target mutations. Altered DNA gyrase and dihydrofolate reductase targets cause fluoroquinolone and trimethoprim resistance, respectively. Although antibiotic resistance hampers therapy of Burkholderia infections, the characterization of resistance mechanisms lags behind other non-enteric Gram-negative pathogens, especially ESKAPE bacteria such as Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa. PMID:27620956

PIRATE project: point-of-care, informatics-based randomised controlled trial for decreasing overuse of antibiotic therapy in Gram-negative bacteraemia.

PubMed

Huttner, Angela; Albrich, Werner C; Bochud, Pierre-Yves; Gayet-Ageron, Angèle; Rossel, Anne; Dach, Elodie von; Harbarth, Stephan; Kaiser, Laurent

2017-07-13

Antibiotic overuse drives antibiotic resistance. The optimal duration of antibiotic therapy for Gram-negative bacteraemia (GNB), a common community and hospital-associated infection, remains unknown and unstudied via randomised controlled trials (RCTs). This investigator-initiated, multicentre, non-inferiority, informatics-based point-of-care RCT will randomly assign adult hospitalised patients receiving microbiologically efficacious antibiotic(s) for GNB to (1) 14 days of antibiotic therapy, (2) 7 days of therapy or (3) an individualised duration determined by clinical response and 75% reduction in peak C reactive protein (CRP) values. The randomisation will occur in equal proportions (1:1:1) on day 5 (±1) of efficacious antibiotic therapy as determined by antibiogram; patients, their physicians and study investigators will be blind to treatment duration allocation until the day of antibiotic discontinuation. Immunosuppressed patients and those with GNB due to complicated infections (endocarditis, osteomyelitis, etc) and/or non-fermenting bacilli ( Acinetobacter spp, Burkholderia spp, Pseudomonas spp) Brucella spp, Fusobacterium spp or polymicrobial growth with Gram-positive organisms will be ineligible. The primary outcome is incidence of clinical failure at day 30; secondary outcomes include clinical failure, all-cause mortality and incidence of Clostridiumdifficile infection in the 90-day study period. An interim safety analysis will be performed after the first 150 patients have been followed for ≤30 days. Given a chosen margin of 10%, the required sample size to determine non-inferiority is roughly 500 patients. Analyses will be performed on both intention-to-treat and per-protocol populations. Ethics approval was obtained from the cantonal ethics committees of all three participating sites. Results of the main trial and each of the secondary endpoints will be submitted for publication in a peer-reviewed journal. This trial is registered at www

Genome-wide dynamics of a bacterial response to antibiotics that target the cell envelope

PubMed Central

2011-01-01

Background A decline in the discovery of new antibacterial drugs, coupled with a persistent rise in the occurrence of drug-resistant bacteria, has highlighted antibiotics as a diminishing resource. The future development of new drugs with novel antibacterial activities requires a detailed understanding of adaptive responses to existing compounds. This study uses Streptomyces coelicolor A3(2) as a model system to determine the genome-wide transcriptional response following exposure to three antibiotics (vancomycin, moenomycin A and bacitracin) that target distinct stages of cell wall biosynthesis. Results A generalised response to all three antibiotics was identified which involves activation of transcription of the cell envelope stress sigma factor σE, together with elements of the stringent response, and of the heat, osmotic and oxidative stress regulons. Attenuation of this system by deletion of genes encoding the osmotic stress sigma factor σB or the ppGpp synthetase RelA reduced resistance to both vancomycin and bacitracin. Many antibiotic-specific transcriptional changes were identified, representing cellular processes potentially important for tolerance to each antibiotic. Sensitivity studies using mutants constructed on the basis of the transcriptome profiling confirmed a role for several such genes in antibiotic resistance, validating the usefulness of the approach. Conclusions Antibiotic inhibition of bacterial cell wall biosynthesis induces both common and compound-specific transcriptional responses. Both can be exploited to increase antibiotic susceptibility. Regulatory networks known to govern responses to environmental and nutritional stresses are also at the core of the common antibiotic response, and likely help cells survive until any specific resistance mechanisms are fully functional. PMID:21569315

Targeted therapy in lung cancer: IPASS and beyond, keeping abreast of the explosion of targeted therapies for lung cancer

PubMed Central

Savas, Peter; Hughes, Brett

2013-01-01

Advances in the treatment of non-small cell lung cancer (NSCLC) over the last decade have predominantly involved the development of therapies directed at molecular targets such as mutations in the epidermal growth factor receptor (EGFR) or rearrangements in the anaplastic lymphoma kinase (ALK) gene. Other targets have been discovered at low frequency, with multiple agents approved or in development for treatment of these rare molecular subtypes. The tumour microenvironment has also provided opportunities for therapies targeting angiogenesis and the host immune response. This review will provide an overview of current targeted therapies in NSCLC and promising treatment approaches on the horizon. PMID:24163750

Recent advances in the understanding of antibiotic resistance in Clostridium difficile infection

PubMed Central

2016-01-01

Clostridium difficile epidemiology has changed in recent years, with the emergence of highly virulent types associated with severe infections, high rates of recurrences and mortality. Antibiotic resistance plays an important role in driving these epidemiological changes and the emergence of new types. While clindamycin resistance was driving historical endemic types, new types are associated with resistance to fluoroquinolones. Furthermore, resistance to multiple antibiotics is a common feature of the newly emergent strains and, in general, of many epidemic isolates. A reduced susceptibility to antibiotics used for C. difficile infection (CDI) treatment, in particular to metronidazole, has recently been described in several studies. Furthermore, an increased number of strains show resistance to rifamycins, used for the treatment of relapsing CDI. Several mechanisms of resistance have been identified in C. difficile, including acquisition of genetic elements and alterations of the antibiotic target sites. The C. difficile genome contains a plethora of mobile genetic elements, many of them involved in antibiotic resistance. Transfer of genetic elements among C. difficile strains or between C. difficile and other bacterial species can occur through different mechanisms that facilitate their spread. Investigations of the fitness cost in C. difficile indicate that both genetic elements and mutations in the molecular targets of antibiotics can be maintained regardless of the burden imposed on fitness, suggesting that resistances may persist in the C. difficile population also in absence of antibiotic selective pressure. The rapid evolution of antibiotic resistance and its composite nature complicate strategies in the treatment and prevention of CDI. The rapid identification of new phenotypic and genotypic traits, the implementation of effective antimicrobial stewardship and infection control programs, and the development of alternative therapies are needed to prevent and

The human microbiota: novel targets for hospital-acquired infections and antibiotic resistance.

PubMed

Pettigrew, Melinda M; Johnson, J Kristie; Harris, Anthony D

2016-05-01

Hospital-acquired infections are increasing in frequency due to multidrug resistant organisms (MDROs), and the spread of MDROs has eroded our ability to treat infections. Health care professionals cannot rely solely on traditional infection control measures and antimicrobial stewardship to prevent MDRO transmission. We review research on the microbiota as a target for infection control interventions. We performed a literature review of key research findings related to the microbiota as a target for infection control interventions. These data are summarized and used to outline challenges, opportunities, and unanswered questions in the field. The healthy microbiota provides protective functions including colonization resistance, which refers to the microbiota's ability to prevent colonization and/or expansion of pathogens. Antibiotic use and other exposures in hospitalized patients are associated with disruptions of the microbiota that may reduce colonization resistance and select for antibiotic resistance. Novel methods to exploit protective mechanisms provided by an intact microbiota may provide the key to preventing the spread of MDROs in the health care setting. Research on the microbiota as a target for infection control has been limited. Epidemiologic studies will facilitate progress toward the goal of manipulating the microbiota for control of MDROs in the health care setting. Copyright © 2016 Elsevier Inc. All rights reserved.

Antibiotic therapy of community respiratory tract infections: strategies for optimal outcomes and minimized resistance emergence.

PubMed

Ball, P; Baquero, F; Cars, O; File, T; Garau, J; Klugman, K; Low, D E; Rubinstein, E; Wise, R

2002-01-01

Widespread, increasing antibiotic resistance amongst the major respiratory pathogens has compromised traditional therapy of the major infective respiratory syndromes, including bacterial pneumonia and acute exacerbations of chronic bronchitis. Guidelines for antibiotic prescribing dating from the 1980s to 1990s, which attempted to address such problems, were commonly too prescriptive and difficult to apply, and took little account of end-user practice or locally prevalent resistance levels. Further confusion was caused by conflicting recommendations emanating from differing specialty groups. The evidence that such guidelines benefited either clinical outcomes or treatment costs has been disputed. They have probably had little effect on resistance emergence. We report the recommendations of an independent, multi-national, inter-disciplinary group, which met to identify principles underlying prescribing and guideline formulation in an age of increasing bacterial resistance. Unnecessary prescribing was recognized as the major factor in influencing resistance and costs. Antibiotic therapy must be limited to syndromes in which bacterial infection is the predominant cause and should attempt maximal reduction in bacterial load, with the ultimate aim of bacterial eradication. It should be appropriate in type and context of local resistance prevalence, and optimal in dosage for the pathogen(s) involved. Prescribing should be based on pharmacodynamic principles that predict efficacy, bacterial eradication and prevention of resistance emergence. Pharmacoeconomic analyses confirm that bacteriologically more effective antibiotics can reduce overall management costs, particularly with respect to consequential morbidity and hospital admission. Application of these principles should positively benefit therapeutic outcomes, resistance avoidance and management costs and will more accurately guide antibiotic choices by both individuals and formulary/guideline committees.

Targeted Nanoparticles for Kidney Cancer Therapy

DTIC Science & Technology

2013-10-01

AD_________________ Award Number: W81XWH-10-1-0434 TITLE: Targeted Nanoparticles for Kidney Cancer Therapy PRINCIPAL...Targeted Nanoparticles for Kidney Cancer Therapy 5b. GRANT NUMBER W81XWH-10-1-0434 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT...lines following treatment with D5 nanotubes. Tthermoablation will be studied initially. Human kidney cancer cells will be injected into the kidney

Salinomycin, a polyether ionophoric antibiotic, inhibits adipogenesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Szkudlarek-Mikho, Maria; Saunders, Rudel A.; Yap, Sook Fan

2012-11-30

Highlights: Black-Right-Pointing-Pointer Salinomycin inhibits preadipocyte differentiation into adipocytes. Black-Right-Pointing-Pointer Salinomycin inhibits transcriptional regulation of adipogenesis. Black-Right-Pointing-Pointer Pharmacological effects of salinomycin suggest toxicity in cancer therapy. -- Abstract: The polyether ionophoric antibiotics including monensin, salinomycin, and narasin, are widely used in veterinary medicine and as food additives and growth promoters in animal husbandry including poultry farming. Their effects on human health, however, are not fully understood. Recent studies showed that salinomycin is a cancer stem cell inhibitor. Since poultry consumption has risen sharply in the last three decades, we asked whether the consumption of meat tainted with growth promoting antibiotics mightmore » have effects on adipose cells. We showed in this report that the ionophoric antibiotics inhibit the differentiation of preadipocytes into adipocytes. The block of differentiation is not due to the induction of apoptosis nor the inhibition of cell proliferation. In addition, salinomycin also suppresses the transcriptional activity of the CCAAT/enhancer binding proteins and the peroxisome proliferator-activated receptor {gamma}. These results suggest that the ionophoric antibiotics can be exploited as novel anti-obesity therapeutics and as pharmacological probes for the study of adipose biology. Further, the pharmacological effects of salinomycin could be a harbinger of its toxicity on the adipose tissue and other susceptible target cells in cancer therapy.« less

International experts' practice in the antibiotic therapy of infective endocarditis is not following the guidelines.

PubMed

Tissot-Dupont, H; Casalta, J P; Gouriet, F; Hubert, S; Salaun, E; Habib, G; Fernandez-Gerlinger, M P; Mainardi, J L; Tattevin, P; Revest, M; Lucht, F; Botelho-Nevers, E; Gagneux-Brunon, A; Snygg-Martin, U; Chan, K L; Bishara, J; Vilacosta, I; Olmos, C; San Román, J A; López, J; Tornos, P; Fernández-Hidalgo, N; Durante-Mangoni, E; Utili, R; Paul, M; Baddour, L M; DeSimone, D C; Sohail, M R; Steckelberg, J M; Wilson, W R; Raoult, D

2017-10-01

The management of infective endocarditis (IE) may differ from international guidelines, even in reference centres. This is probably because most recommendations are not based on hard evidence, so the consensus obtained for the guidelines does not represent actual practices. For this reason, we aimed to evaluate this question in the particular field of antibiotic therapy. Thirteen international centres specialized in the management of IE were selected, according to their reputation, clinical results, original research publications and quotations. They were asked to detail their actual practice in terms of IE antibiotic treatment in various bacteriological and clinical situations. They were also asked to declare their IE-related in-hospital mortality for the year 2015. The global compliance with guidelines concerning antibiotic therapy was 58%, revealing the differences between theoretical 'consensus', local recommendations and actual practice. Some conflicts of interest were also probably expressed. The adherence to guidelines was 100% when the protocol was simple, and decreased with the seriousness of the situation (Staphylococus spp. 54%-62%) or in blood-culture-negative endocarditis (0%-15%) that requires adaptation to clinical and epidemiological data. Worldwide experts in IE management, although the majority of them were involved and co-signed the guidelines, do not follow international consensus guidelines on the particular point of the use of antibiotics. Copyright © 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Targeted nanosystems: Advances in targeted dendrimers for cancer therapy.

PubMed

Yang, Hu

2016-02-01

Dendrimers possess discrete highly compact nanostructures constituted of successive branched layers. Soon after the inception of dendrimers, recognition of their tunable structures and biologically favorable properties provoked a great enthusiasm in delving deeply into the utility of dendrimers for biomedical and pharmaceutical applications. One of the most important nanotechnology applications is the development of nanomedicines for targeted cancer therapies. Tremendous success in targeted therapies has been achieved with the use of dendrimer-based nanomedicines. This article provides a concise review on latest advances in the utility of dendrimers in immunotherapies and hormone therapies. Much basic and clinical research has been done since the invention of dendrimers, which are highly branched nano-sized molecules with the ability to act as carriers in nanomedicine. In this concise review article, the authors highlighted the current use of dendrimers in immunotherapies and hormone therapies in the fight against cancers. Copyright © 2015 Elsevier Inc. All rights reserved.

Insights into early stage of antibiotic development in small- and medium-sized enterprises: a survey of targets, costs, and durations.

PubMed

Årdal, Christine; Baraldi, Enrico; Theuretzbacher, Ursula; Outterson, Kevin; Plahte, Jens; Ciabuschi, Francesco; Røttingen, John-Arne

2018-01-01

Antibiotic innovation has dwindled to dangerously low levels in the past 30 years. Since resistance continues to evolve, this innovation deficit can have perilous consequences on patients. A number of new incentives have been suggested to stimulate greater antibacterial drug innovation. To design effective solutions, a greater understanding is needed of actual antibiotic discovery and development costs and timelines. Small and medium-sized enterprises (SMEs) undertake most discovery and early phase development for antibiotics and other drugs. This paper attempts to gather a better understanding of SMEs' targets, costs, and durations related to discovery and early phase development of antibacterial therapies. DRIVE-AB, a project focused on developing new economic incentives to stimulate antibacterial innovation, held a European stakeholder meeting in February 2015. All SMEs invited to this meeting ( n  = 44) were subsequently sent a survey to gather more data regarding their areas of activity, completed and expected development costs and timelines, and business models. Twenty-five companies responded to the survey. Respondents were primarily small companies each focusing on developing 1 to 3 new antibiotics, focused on pathogens of public health importance. Most have not yet completed any clinical trials. They have reported ranges of discovery and development out-of-pocket costs that appear to be less expensive than other studies of general pharmaceutical research and development (R&D) costs. The duration ranges reported for completing each phase of R&D are highly variable when compared to previously published general pharmaceutical innovation average durations. However, our sample population is small and may not be fully representative of all relevant antibiotic SMEs. The data collected by this study provide important insights and estimates about R&D in European SMEs focusing on antibiotics, which can be combined with other data to design incentives to

Duration of oral tetracycline-class antibiotic therapy and use of topical retinoids for the treatment of acne among general practitioners (GP): A retrospective cohort study.

PubMed

Barbieri, John S; Hoffstad, Ole; Margolis, David J

2016-12-01

Guidelines recommend limiting the duration of oral antibiotic therapy in acne to 3 to 6 months and prescribing concomitant topical retinoids for all patients. We sought to evaluate the duration of therapy with oral tetracyclines and the use of topical retinoids among patients with acne treated primarily by general practitioners in the United Kingdom. We conducted a retrospective cohort study using the Health Improvement Network database. The mean duration of therapy was 175.1 days. Of antibiotic courses, 62% were not associated with a topical retinoid; 29% exceeded 6 months in duration. If all regions were to achieve uses similar to the region with the shortest mean duration of therapy, approximately 3.3 million antibiotic days per year could be avoided in the United Kingdom. The Health Improvement Network does not include information on acne severity and clinical outcomes. Prescribing behavior for oral antibiotics in the treatment of acne among general practitioners is not aligned with current guideline recommendations. Increasing the use of topical retinoids and considering alternative agents to oral antibiotics when appropriate represent opportunities to reduce antibiotic exposure and associated complications such as antibiotic resistance and to improve outcomes in patients treated for acne. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Novel targets for HIV therapy.

PubMed

Greene, Warner C; Debyser, Zeger; Ikeda, Yasuhiro; Freed, Eric O; Stephens, Edward; Yonemoto, Wes; Buckheit, Robert W; Esté, José A; Cihlar, Tomas

2008-12-01

There are currently 25 drugs belonging to 6 different inhibitor classes approved for the treatment of human immunodeficiency virus (HIV) infection. However, new anti-HIV agents are still needed to confront the emergence of drug resistance and various adverse effects associated with long-term use of antiretroviral therapy. The 21st International Conference on Antiviral Research, held in April 2008 in Montreal, Canada, therefore featured a special session focused on novel targets for HIV therapy. The session included presentations by world-renowned experts in HIV virology and covered a diverse array of potential targets for the development of new classes of HIV therapies. This review contains concise summaries of discussed topics that included Vif-APOBEC3G, LEDGF/p75, TRIM 5alpha, virus assembly and maturation, and Vpu. The described viral and host factors represent some of the most noted examples of recent scientific breakthroughs that are opening unexplored avenues to novel anti-HIV target discovery and validation, and should feed the antiretroviral drug development pipeline in the near future.

Antibiotic Therapy vs Appendectomy for Treatment of Uncomplicated Acute Appendicitis: The APPAC Randomized Clinical Trial.

PubMed

Salminen, Paulina; Paajanen, Hannu; Rautio, Tero; Nordström, Pia; Aarnio, Markku; Rantanen, Tuomo; Tuominen, Risto; Hurme, Saija; Virtanen, Johanna; Mecklin, Jukka-Pekka; Sand, Juhani; Jartti, Airi; Rinta-Kiikka, Irina; Grönroos, Juha M

2015-06-16

An increasing amount of evidence supports the use of antibiotics instead of surgery for treating patients with uncomplicated acute appendicitis. To compare antibiotic therapy with appendectomy in the treatment of uncomplicated acute appendicitis confirmed by computed tomography (CT). The Appendicitis Acuta (APPAC) multicenter, open-label, noninferiority randomized clinical trial was conducted from November 2009 until June 2012 in Finland. The trial enrolled 530 patients aged 18 to 60 years with uncomplicated acute appendicitis confirmed by a CT scan. Patients were randomly assigned to early appendectomy or antibiotic treatment with a 1-year follow-up period. Patients randomized to antibiotic therapy received intravenous ertapenem (1 g/d) for 3 days followed by 7 days of oral levofloxacin (500 mg once daily) and metronidazole (500 mg 3 times per day). Patients randomized to the surgical treatment group were assigned to undergo standard open appendectomy. The primary end point for the surgical intervention was the successful completion of an appendectomy. The primary end point for antibiotic-treated patients was discharge from the hospital without the need for surgery and no recurrent appendicitis during a 1-year follow-up period. There were 273 patients in the surgical group and 257 in the antibiotic group. Of 273 patients in the surgical group, all but 1 underwent successful appendectomy, resulting in a success rate of 99.6% (95% CI, 98.0% to 100.0%). In the antibiotic group, 70 patients (27.3%; 95% CI, 22.0% to 33.2%) underwent appendectomy within 1 year of initial presentation for appendicitis. Of the 256 patients available for follow-up in the antibiotic group, 186 (72.7%; 95% CI, 66.8% to 78.0%) did not require surgery. The intention-to-treat analysis yielded a difference in treatment efficacy between groups of -27.0% (95% CI, -31.6% to ∞) (P = .89). Given the prespecified noninferiority margin of 24%, we were unable to demonstrate noninferiority of

Prophylactic Antibiotic Use in COPD and the Potential Anti-Inflammatory Activities of Antibiotics.

PubMed

Huckle, Anthony W; Fairclough, Lucy C; Todd, Ian

2018-05-01

Antibiotics have previously demonstrated anti-inflammatory properties, and they have been linked to therapeutic benefit in several pulmonary conditions that feature inflammation. Previous research suggests that these anti-inflammatory properties may be beneficial in the treatment of COPD. This review assesses the potential benefit of prophylactic, long-term, and low-dose antibiotic therapy in COPD, and whether any effects seen are anti-inflammatory in nature. Randomized, controlled trials comparing antibiotic therapy with placebo in subjects with stable COPD were evaluated. Twelve trials involving 3,784 participants and a range of antibiotics were included: azithromycin (6 studies, 1,972 participants), clarithromycin (1 study, 67 participants), erythromycin (3 studies, 254 participants), roxithromycin (1 study, 191 participants), and moxifloxacin (2 studies, 1,198 participants). In vitro, in vivo, and ex vivo experimental study designs exploring the mechanisms via which antibiotics may act in subjects with stable COPD were evaluated. Azithromycin and erythromycin showed the greatest effect in subjects with COPD, with evidence suggesting improvement in exacerbation-related outcomes and health status, as measured by the St George Respiratory Questionnaire. An increase in antibiotic resistance was reported in 2 studies. The macrolide class of antibiotics exhibited convincing anti-inflammatory properties with relevance to COPD, implicating several pathways as potential mechanisms of action. In conclusion, the therapeutic benefit of macrolide antibiotics in subjects with stable COPD is consistent with anti-inflammatory properties, and macrolides should be considered as a potential therapy in COPD. Safety concerns regarding antibiotic resistance need to be addressed before widespread use in clinical practice. Copyright © 2018 by Daedalus Enterprises.

Combination antibiotic therapy for the treatment of infective endocarditis due to enterococci.

PubMed

Leone, Sebastiano; Noviello, Silvana; Esposito, Silvano

2016-06-01

Enterococci are common causes of infective endocarditis (IE) in both health care and community-based setting. Enterococcal IE requires bactericidal therapy for an optimal outcome. For decades, cell-wall-active antimicrobial agents (penicillins or vancomycin) in combination with aminoglycosides were the cornerstone of the treatment; however, the emergence of antibiotic resistance has significantly reduced the efficacy of these regimens. Data for this review were identified by searches of MEDLINE and references from relevant articles on antibiotic combination regimens for the treatment of enterococcal IE. Abstracts presented in scientific conferences were not searched for. New effective and safe combination treatments, including double-β-lactam and daptomycin/β-lactam combination, are proving useful for the management of IE due to enterococci.

Gene Therapy and Targeted Toxins for Glioma

PubMed Central

Castro, Maria G.; Candolfi, Marianela; Kroeger, Kurt; King, Gwendalyn D.; Curtin, James F.; Yagiz, Kader; Mineharu, Yohei; Assi, Hikmat; Wibowo, Mia; Muhammad, AKM Ghulam; Foulad, David; Puntel, Mariana; Lowenstein, Pedro R.

2011-01-01

The most common primary brain tumor in adults is glioblastoma. These tumors are highly invasive and aggressive with a mean survival time of nine to twelve months from diagnosis to death. Current treatment modalities are unable to significantly prolong survival in patients diagnosed with glioblastoma. As such, glioma is an attractive target for developing novel therapeutic approaches utilizing gene therapy. This review will examine the available preclinical models for glioma including xenographs, syngeneic and genetic models. Several promising therapeutic targets are currently being pursued in pre-clinical investigations. These targets will be reviewed by mechanism of action, i.e., conditional cytotoxic, targeted toxins, oncolytic viruses, tumor suppressors/oncogenes, and immune stimulatory approaches. Preclinical gene therapy paradigms aim to determine which strategies will provide rapid tumor regression and long-term protection from recurrence. While a wide range of potential targets are being investigated preclinically, only the most efficacious are further transitioned into clinical trial paradigms. Clinical trials reported to date are summarized including results from conditionally cytotoxic, targeted toxins, oncolytic viruses and oncogene targeting approaches. Clinical trial results have not been as robust as preclinical models predicted; this could be due to the limitations of the GBM models employed. Once this is addressed, and we develop effective gene therapies in models that better replicate the clinical scenario, gene therapy will provide a powerful approach to treat and manage brain tumors. PMID:21453286

Targeted polymeric nanoparticles for cancer gene therapy

PubMed Central

Kim, Jayoung; Wilson, David R.; Zamboni, Camila G.; Green, Jordan J.

2015-01-01

In this article, advances in designing polymeric nanoparticles for targeted cancer gene therapy are reviewed. Characterization and evaluation of biomaterials, targeting ligands, and transcriptional elements are each discussed. Advances in biomaterials have driven improvements to nanoparticle stability and tissue targeting, conjugation of ligands to the surface of polymeric nanoparticles enable binding to specific cancer cells, and the design of transcriptional elements has enabled selective DNA expression specific to the cancer cells. Together, these features have improved the performance of polymeric nanoparticles as targeted non-viral gene delivery vectors to treat cancer. As polymeric nanoparticles can be designed to be biodegradable, non-toxic, and to have reduced immunogenicity and tumorigenicity compared to viral platforms, they have significant potential for clinical use. Results of polymeric gene therapy in clinical trials and future directions for the engineering of nanoparticle systems for targeted cancer gene therapy are also presented. PMID:26061296

Heart failure—potential new targets for therapy

PubMed Central

Nabeebaccus, Adam; Zheng, Sean; Shah, Ajay M.

2016-01-01

Abstract Introduction/background Heart failure is a major cause of cardiovascular morbidity and mortality. This review covers current heart failure treatment guidelines, emerging therapies that are undergoing clinical trial, and potential new therapeutic targets arising from basic science advances. Sources of data A non-systematic search of MEDLINE was carried out. International guidelines and relevant reviews were searched for additional articles. Areas of agreement Angiotensin-converting enzyme inhibitors and beta-blockers are first line treatments for chronic heart failure with reduced left ventricular function. Areas of controversy Treatment strategies to improve mortality in heart failure with preserved left ventricular function are unclear. Growing points Many novel therapies are being tested for clinical efficacy in heart failure, including those that target natriuretic peptides and myosin activators. A large number of completely novel targets are also emerging from laboratory-based research. Better understanding of pathophysiological mechanisms driving heart failure in different settings (e.g. hypertension, post-myocardial infarction, metabolic dysfunction) may allow for targeted therapies. Areas timely for developing research Therapeutic targets directed towards modifying the extracellular environment, angiogenesis, cell viability, contractile function and microRNA-based therapies. PMID:27365454

Bacteriocins from lactic acid bacteria as an alternative to antibiotics.

PubMed

Ołdak, Aleksandra; Zielińska, Dorota

2017-05-05

Bacteriocins are ribosomally synthesized, proteinaceous substances that inhibit the growth of closely related species through numerous mechanisms. The classification system used in this review divided bacteriocins into four sub-groups based on their size. Currently, there is extensive research focused on bacteriocins and their usage as a food preservative. The increasing incidence of multidrug resistant bacterial pathogens is one of the most pressing medical problems in recent years. Recently, the potential clinical application of LAB (Lactic Acid Bacteria) bacteriocin has been the subject of investigations by many scientists. Bacteriocins can be considered in a sense as antibiotic, although they differ from conventional antibiotics in numerous aspects. The gene-encoded nature of bacteriocins makes them easily amenable through bioengineering to either increase their activity or specify target microorganism. Owing to this feature of bacteriocins, antibiotic therapy would become less damaging to the natural gut microflora, which is a common drawback of conventional antibiotic use. Bacteriocins from lactic acid bacteria represent one of the most studied microbial defense systems and the idea of subjecting them to bioengineering to either increase antimicrobial activity or further specify their target microorganism is now a rapidly expanding field. This review aimed to present bacteriocins as a possible alternative to conventional antibiotics basic on latest scientific data.

Full and Broad-Spectrum In Vivo Eradication of Catheter-Associated Biofilms Using Gentamicin-EDTA Antibiotic Lock Therapy

PubMed Central

Chauhan, Ashwini; Lebeaux, David; Ghigo, Jean-Marc

2012-01-01

Biofilms that develop on indwelling devices are a major concern in clinical settings. While removal of colonized devices remains the most frequent strategy for avoiding device-related complications, antibiotic lock therapy constitutes an adjunct therapy for catheter-related infection. However, currently used antibiotic lock solutions are not fully effective against biofilms, thus warranting a search for new antibiotic locks. Metal-binding chelators have emerged as potential adjuvants due to their dual anticoagulant/antibiofilm activities, but studies investigating their efficiency were mainly in vitro or else focused on their effects in prevention of infection. To assess the ability of such chelators to eradicate mature biofilms, we used an in vivo model of a totally implantable venous access port inserted in rats and colonized by either Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, or Pseudomonas aeruginosa. We demonstrate that use of tetrasodium EDTA (30 mg/ml) as a supplement to the gentamicin (5 mg/ml) antibiotic lock solution associated with systemic antibiotics completely eradicated Gram-positive and Gram-negative bacterial biofilms developed in totally implantable venous access ports. Gentamicin-EDTA lock was able to eliminate biofilms with a single instillation, thus reducing length of treatment. Moreover, we show that this combination was effective for immunosuppressed rats. Lastly, we demonstrate that a gentamicin-EDTA lock is able to eradicate the biofilm formed by a gentamicin-resistant strain of methicillin-resistant S. aureus. This in vivo study demonstrates the potential of EDTA as an efficient antibiotic adjuvant to eradicate catheter-associated biofilms of major bacterial pathogens and thus provides a promising new lock solution. PMID:23027191

Targeted Therapy for Melanoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Quinn, Thomas; Moore, Herbert

The research project, entitled ”Targeted Therapy for Melanoma,” was focused on investigating the use of kidney protection measures to lower the non-specific kidney uptake of the radiolabeled Pb-DOTA-ReCCMSH peptide. Previous published work demonstrated that the kidney exhibited the highest non-target tissue uptake of the 212Pb/203Pb radiolabeled melanoma targeting peptide DOTA-ReCCMSH. The radiolabeled alpha-melanocyte stimulating hormone (α-MSH) peptide analog DOTA-Re(Arg 11)CCMSH, which binds the melanocortin-1 receptor over-expressed on melanoma tumor cells, has shown promise as a PRRT agent in pre-clinical studies. High tumor uptake of 212Pb labeled DOTA-Re(Arg 11)CCMSH resulted in tumor reduction or eradication in melanoma therapy studies. Of particularmore » note was the 20-50% cure rate observed when melanoma mice were treated with alpha particle emitter 212Pb. However, as with most PRRT agents, high radiation doses to the kidneys where observed. To optimize tumor treatment efficacy and reduce nephrotoxicity, the tumor to kidney uptake ratio must be improved. Strategies to reduce kidney retention of the radiolabeled peptide, while not effecting tumor uptake and retention, can be broken into several categories including modification of the targeting peptide sequence and reducing proximal tubule reabsorption.« less

INTRAVENOUS REGIONAL ANTIBIOTIC PERFUSION THERAPY AS AN ADJUNCTIVE TREATMENT FOR DIGITAL LESIONS IN SEABIRDS.

PubMed

Fiorello, Christine V

2017-03-01

Foot infections are a common problem among seabirds in wildlife rehabilitation. Pododermatitis and digital infections are often challenging to treat because of the presence of suboptimal substrates, abnormal weight-bearing due to injuries, and suboptimal nutritional or health status. Seabirds represent the majority of animals requiring rehabilitation after oil spills, and foot problems are a common reason for euthanasia among these birds. Antibiotic intravenous regional perfusion therapy is frequently used in humans and other species to treat infections of the distal extremities, but it has not been evaluated in seabirds. During the 2015 Refugio oil spill response, four birds with foot lesions (pododermatitis, osteomyelitis, or both) were treated with ampicillin/sulbactam administered intravenously to the affected limb(s) in addition to systemic antibiotics and anti-inflammatories. Three of the birds, all brown pelicans ( Pelecanus occidentalis ) recovered rapidly and were released. Two of these birds had acute pododermatitis and were treated once with intravenous regional perfusion. They were released approximately 3 wk after the perfusion therapy. The third pelican had osteomyelitis of a digit. It was treated twice with intravenous regional perfusion and was released about 1 mo after the initial perfusion therapy. The fourth bird, a Pacific loon ( Gavia pacifica ), was treated once with perfusion therapy but did not respond to treatment and was euthanatized. No serious adverse effects were observed. This technique should be explored further in avian species.

Signal-on electrochemical detection of antibiotics at zeptomole level based on target-aptamer binding triggered multiple recycling amplification.

PubMed

Wang, Hongzhi; Wang, Yu; Liu, Su; Yu, Jinghua; Guo, Yuna; Xu, Ying; Huang, Jiadong

2016-06-15

In the work, a signal-on electrochemical DNA sensor based on multiple amplification for ultrasensitive detection of antibiotics has been reported. In the presence of target, the ingeniously designed hairpin probe (HP1) is opened and the polymerase-assisted target recycling amplification is triggered, resulting in autonomous generation of secondary target. It is worth noting that the produced secondary target could not only hybridize with other HP1, but also displace the Helper from the electrode. Consequently, methylene blue labeled HP2 forms a "close" probe structure, and the increase of signal is monitored. The increasing current provides an ultrasensitive electrochemical detection for antibiotics down to 1.3 fM. To our best knowledge, such work is the first report about multiple recycling amplification combing with signal-on sensing strategy, which has been utilized for quantitative determination of antibiotics. It would be further used as a general strategy associated with more analytical techniques toward the detection of a wide spectrum of analytes. Thus, it holds great potential for the development of ultrasensitive biosensing platform for the applications in bioanalysis, disease diagnostics, and clinical biomedicine. Copyright © 2016 Elsevier B.V. All rights reserved.

Biomarker-guided antibiotic therapy—strengths and limitations

PubMed Central

Salluh, Jorge; Martin-Loeches, Ignacio; Póvoa, Pedro

2017-01-01

Biomarkers as C-reactive protein (CRP) and procalcitonin (PCT) emerged as tools to help clinicians to diagnose infection and to properly initiate and define the duration of antibiotic therapy. Several randomized controlled trials, including adult critically ill patients, showed that PCT-guided antibiotic stewardship was repeatedly associated with a decrease in the duration of antibiotic therapy with no apparent harm. There are however some relevant limitations in these trials namely the low rate of compliance of PCT-guided algorithms, the high rate of exclusion (without including common clinical situations and pathogens) and the long duration of antibiotic therapy in control groups. Such limitations weakened the real impact of such algorithms in the clinical decision-making process and strengthened the concept that the initiation and the duration of antibiotic therapy cannot depend solely on a biomarker. Future efforts should address these limitations in order to better clarify the role of biomarkers on the complex and multifactorial issue of antibiotic management and to deeply understand its potential effect on mortality. PMID:28603723

Targeted Drug-Carrying Bacteriophages as Antibacterial Nanomedicines▿

PubMed Central

Yacoby, Iftach; Bar, Hagit; Benhar, Itai

2007-01-01

While the resistance of bacteria to traditional antibiotics is a major public health concern, the use of extremely potent antibacterial agents is limited by their lack of selectivity. As in cancer therapy, antibacterial targeted therapy could provide an opportunity to reintroduce toxic substances to the antibacterial arsenal. A desirable targeted antibacterial agent should combine binding specificity, a large drug payload per binding event, and a programmed drug release mechanism. Recently, we presented a novel application of filamentous bacteriophages as targeted drug carriers that could partially inhibit the growth of Staphylococcus aureus bacteria. This partial success was due to limitations of drug-loading capacity that resulted from the hydrophobicity of the drug. Here we present a novel drug conjugation chemistry which is based on connecting hydrophobic drugs to the phage via aminoglycoside antibiotics that serve as solubility-enhancing branched linkers. This new formulation allowed a significantly larger drug-carrying capacity of the phages, resulting in a drastic improvement in their performance as targeted drug-carrying nanoparticles. As an example for a potential systemic use for potent agents that are limited for topical use, we present antibody-targeted phage nanoparticles that carry a large payload of the hemolytic antibiotic chloramphenicol connected through the aminoglycoside neomycin. We demonstrate complete growth inhibition toward the pathogens Staphylococcus aureus, Streptococcus pyogenes, and Escherichia coli with an improvement in potency by a factor of ∼20,000 compared to the free drug. PMID:17404004

Targeted therapies in gastric cancer and future perspectives.

PubMed

Yazici, Ozan; Sendur, M Ali Nahit; Ozdemir, Nuriye; Aksoy, Sercan

2016-01-14

Advanced gastric cancer (AGC) is associated with a high mortality rate and, despite multiple new chemotherapy options, the survival rates of patients with AGC remains poor. After the discovery of targeted therapies, research has focused on the new treatment options for AGC. In the last two decades, many targeted molecules were developed against AGC. Currently, two targeted therapy molecules have been approved for patients with AGC. In 2010, trastuzumab was the first molecule shown to improve survival in patients with HER2-positive AGC as part of a first-line combination regimen. In 2014, ramucirumab was the second targeted molecule to improve survival rates and was suggested as treatment for patients with AGC who had progressed after first-line platinum plus fluoropyrimidine with or without anthracycline chemotherapy. Ramucirumab was the first targeted therapy acting as a single agent in patients with advanced gastroesophageal cancers. Although these two molecules were introduced into clinical use, many other promising molecules have been tested in phase I-II trials. It is obvious that in the near future many different targeted therapies will be in use for treatment of AGC. In this review, the current status of targeted therapies in the treatment of AGC and gastroesophageal junction tumors, including HER (2-3) inhibitors, epidermal growth factor receptor inhibitors, tyrosine kinase inhibitors, antiangiogenic agents, c-MET inhibitors, mammalian target of rapamycin inhibitors, agents against other molecular pathways fibroblast growth factor, Claudins, insulin-like growth factor, heat shock proteins, and immunotherapy, will be discussed.

A Peptidomimetic Antibiotic Targets Outer Membrane Proteins and Disrupts Selectively the Outer Membrane in Escherichia coli*

PubMed Central

Urfer, Matthias; Bogdanovic, Jasmina; Lo Monte, Fabio; Moehle, Kerstin; Zerbe, Katja; Omasits, Ulrich; Ahrens, Christian H.; Pessi, Gabriella; Eberl, Leo; Robinson, John A.

2016-01-01

Increasing antibacterial resistance presents a major challenge in antibiotic discovery. One attractive target in Gram-negative bacteria is the unique asymmetric outer membrane (OM), which acts as a permeability barrier that protects the cell from external stresses, such as the presence of antibiotics. We describe a novel β-hairpin macrocyclic peptide JB-95 with potent antimicrobial activity against Escherichia coli. This peptide exhibits no cellular lytic activity, but electron microscopy and fluorescence studies reveal an ability to selectively disrupt the OM but not the inner membrane of E. coli. The selective targeting of the OM probably occurs through interactions of JB-95 with selected β-barrel OM proteins, including BamA and LptD as shown by photolabeling experiments. Membrane proteomic studies reveal rapid depletion of many β-barrel OM proteins from JB-95-treated E. coli, consistent with induction of a membrane stress response and/or direct inhibition of the Bam folding machine. The results suggest that lethal disruption of the OM by JB-95 occurs through a novel mechanism of action at key interaction sites within clusters of β-barrel proteins in the OM. These findings open new avenues for developing antibiotics that specifically target β-barrel proteins and the integrity of the Gram-negative OM. PMID:26627837

Duration of oral antibiotic therapy for the treatment of adult acne: a retrospective analysis investigating adherence to guideline recommendations and opportunities for cost-savings.

PubMed

Straight, Chelsey E; Lee, Young H; Liu, Guodong; Kirby, Joslyn S

2015-05-01

The duration of oral antibiotic acne therapy for adolescents compared with guidelines was recently investigated; however it was uncertain if duration of antibiotics for adult acne therapy differed. This study aimed to evaluate duration of oral antibiotics for adult acne compared with guidelines and determine possible cost-savings. This was a retrospective cohort study of MarketScan Commercial Claims and Encounters database that incorporated claims data to determine duration and costs of antibiotic treatment among adults ages 21 years and older. Of 17,448 courses, 84.5% (14,737) aligned with duration guidelines, although 12,040 (69.0%) courses did not include concomitant topical retinoid therapy. Mean savings of $592.26 per person could result if prolonged courses met guidelines. Mean (median) costs of generic and branded formulations for the most frequent course duration (90-179 days) were $103.77 ($54.27) and $1421.61 ($1462.25), respectively. Actual patient prescription adherence is uncertain and database lacks information regarding acne severity, patient physical characteristics, and clinical outcomes. The majority of oral antibiotic course durations follow guidelines, although topical retinoids are underused. Costs of antibiotic therapy were lower for shorter courses and those using generic medications; the cost-effectiveness of these modifications has not been investigated. Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

The bacterial envelope as a target for novel anti-MRSA antibiotics.

PubMed

Van Bambeke, Françoise; Mingeot-Leclercq, Marie-Paule; Struelens, Marc J; Tulkens, Paul M

2008-03-01

Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-intermediate S. aureus (VISA) are spreading worldwide, making the search for antibiotics directed against new targets a high priority. Drugs that anchor in the bacterial membrane (e.g. ceragenins and lipopeptides) or that target the bacterial membrane and proteic (lipoglycopeptides) or lipidic (glycodepsipeptides) cell wall precursors seem to have the most potential because they show a fast and extensive bactericidal effect and are probably less prone to select for resistance owing to the difficulty in modifying their targets in a way that is compatible with bacterial survival. The efficacy of lipopeptides and lipoglycopeptides has been demonstrated in the treatment of skin and skin structure infections, and bacteremia caused by resistant S. aureus. Ceragenins and glycodepsipeptides are restricted to topical applications because of their unsatisfactory safety profile. The mode of action, pharmacological and microbiological properties and target indications of these anti-MRSA agents, which function by disturbing membrane integrity, are reviewed in this article.

Prostate Cancer Clinical Consortium Clinical Research Site:Targeted Therapies

DTIC Science & Technology

2015-10-01

AWARD NUMBER: W81XWH-14-2-0159 TITLE: Prostate Cancer Clinical Consortium Clinical Research Site: Targeted Therapies PRINCIPAL INVESTIGATOR...Sep 2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Prostate Cancer Clinical Consortium Clinical Research Site: Targeted Therapies 5b. GRANT NUMBER... therapy resistance/sensitivity, identification of new therapeutic targets through high quality genomic analyses, providing access to the highest quality

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

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

Gram-negative bacteraemia; a multi-centre prospective evaluation of empiric antibiotic therapy and outcome in English acute hospitals.

PubMed

Fitzpatrick, J M; Biswas, J S; Edgeworth, J D; Islam, J; Jenkins, N; Judge, R; Lavery, A J; Melzer, M; Morris-Jones, S; Nsutebu, E F; Peters, J; Pillay, D G; Pink, F; Price, J R; Scarborough, M; Thwaites, G E; Tilley, R; Walker, A S; Llewelyn, M J

2016-03-01

Increasing antibiotic resistance makes choosing antibiotics for suspected Gram-negative infection challenging. This study set out to identify key determinants of mortality among patients with Gram-negative bacteraemia, focusing particularly on the importance of appropriate empiric antibiotic treatment. We conducted a prospective observational study of 679 unselected adults with Gram-negative bacteraemia at ten acute english hospitals between October 2013 and March 2014. Appropriate empiric antibiotic treatment was defined as intravenous treatment on the day of blood culture collection with an antibiotic to which the cultured organism was sensitive in vitro. Mortality analyses were adjusted for patient demographics, co-morbidities and illness severity. The majority of bacteraemias were community-onset (70%); most were caused by Escherichia coli (65%), Klebsiella spp. (15%) or Pseudomonas spp. (7%). Main foci of infection were urinary tract (51%), abdomen/biliary tract (20%) and lower respiratory tract (14%). The main antibiotics used were co-amoxiclav (32%) and piperacillin-tazobactam (30%) with 34% receiving combination therapy (predominantly aminoglycosides). Empiric treatment was inappropriate in 34%. All-cause mortality was 8% at 7 days and 15% at 30 days. Independent predictors of mortality (p <0.05) included older age, greater burden of co-morbid disease, severity of illness at presentation and inflammatory response. Inappropriate empiric antibiotic therapy was not associated with mortality at either time-point (adjusted OR 0.82; 95% CI 0.35-1.94 and adjusted OR 0.92; 95% CI 0.50-1.66, respectively). Although our study does not exclude an impact of empiric antibiotic choice on survival in Gram-negative bacteraemia, outcome is determined primarily by patient and disease factors. Copyright © 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Surface Ligand Density of Antibiotic-Nanoparticle Conjugates Enhances Target Avidity and Membrane Permeabilization of Vancomycin-Resistant Bacteria.

PubMed

Hassan, Marwa M; Ranzoni, Andrea; Phetsang, Wanida; Blaskovich, Mark A T; Cooper, Matthew A

2017-02-15

Many bacterial pathogens have now acquired resistance toward commonly used antibiotics, such as the glycopeptide antibiotic vancomycin. In this study, we show that immobilization of vancomycin onto a nanometer-scale solid surface with controlled local density can potentiate antibiotic action and increase target affinity of the drug. Magnetic nanoparticles were conjugated with vancomycin and used as a model system to investigate the relationship between surface density and drug potency. We showed remarkable improvement in minimum inhibitory concentration against vancomycin-resistant strains with values of 13-28 μg/mL for conjugated vancomycin compared to 250-4000 μg/mL for unconjugated vancomycin. Higher surface densities resulted in enhanced affinity toward the bacterial target compared to that of unconjugated vancomycin, as measured by a competition experiment using a surrogate ligand for bacterial Lipid II, N-Acetyl-l-Lys-d-Ala-d-Ala. High density vancomycin nanoparticles required >64 times molar excess of ligand (relative to the vancomycin surface density) to abrogate antibacterial activity compared to only 2 molar excess for unconjugated vancomycin. Further, the drug-nanoparticle conjugates caused rapid permeabilization of the bacterial cell wall within 2 h, whereas no effect was seen with unconjugated vancomycin, suggesting additional modes of action for the nanoparticle-conjugated drug. Hence, immobilization of readily available antibiotics on nanocarriers may present a general strategy for repotentiating drugs that act on bacterial membranes or membrane-bound targets but have lost effectiveness against resistant bacterial strains.

Will nanotechnology influence targeted cancer therapy?

PubMed Central

Grimm, Jan; Scheinberg, David A.

2011-01-01

The rapid development of techniques that enable synthesis (and manipulation) of matter on the nanometer scale, as well as the development of new nano-materials, will play a large role in disease diagnosis and treatment, specifically in targeted cancer therapy. Targeted nanocarriers are an intriguing means to selectively deliver high concentrations of cytotoxic agents or imaging labels directly to the cancer site. Often solubility issues and an unfavorable biodistribution can result in a suboptimal response of novel agents even though they are very potent. New nanoparticulate formulations allow simultaneous imaging and therapy (“theranostics”), which can provide a realistic means for the clinical implementation of such otherwise suboptimal formulations. In this review we will not attempt to provide a complete overview of the rapidly enlarging field of nanotechnology in cancer; rather, we will present properties specific to nanoparticles, and examples of their uses, which demonstrate their importance for targeted cancer therapy. PMID:21356476

Prophylactic antibiotics in dermatological surgery.

PubMed

Lee, Michael R; Paver, Robert

2016-05-01

This is a review of the common pathogens of surgical site infections, antibiotic coverage for particular anatomical sites, mechanisms by which surgical site infections occur and the latest data and recommendations for prophylactic antibiotics in the prevention of surgical site infections, infective endocarditis and haematogenous joint infections. Recent evidence-based guidelines on surgical prophylaxis is for restricted indications and a shorter duration of antibiotic prophylaxis in situations where no clinical benefit of prolonged therapy has been proven, in order to minimise the potential adverse ecological and clinical effects associated with antibiotic therapy. This review recommends the cautious use of prophylactic antibiotics in dermatological surgery to help prevent the growing problem of bacterial resistance as well as other morbidity and health-care costs. © 2015 The Australasian College of Dermatologists.

Systematically Altering Bacterial SOS Activity under Stress Reveals Therapeutic Strategies for Potentiating Antibiotics.

PubMed

Mo, Charlie Y; Manning, Sara A; Roggiani, Manuela; Culyba, Matthew J; Samuels, Amanda N; Sniegowski, Paul D; Goulian, Mark; Kohli, Rahul M

2016-01-01

The bacterial SOS response is a DNA damage repair network that is strongly implicated in both survival and acquired drug resistance under antimicrobial stress. The two SOS regulators, LexA and RecA, have therefore emerged as potential targets for adjuvant therapies aimed at combating resistance, although many open questions remain. For example, it is not well understood whether SOS hyperactivation is a viable therapeutic approach or whether LexA or RecA is a better target. Furthermore, it is important to determine which antimicrobials could serve as the best treatment partners with SOS-targeting adjuvants. Here we derived Escherichia coli strains that have mutations in either lexA or recA genes in order to cover the full spectrum of possible SOS activity levels. We then systematically analyzed a wide range of antimicrobials by comparing the mean inhibitory concentrations (MICs) and induced mutation rates for each drug-strain combination. We first show that significant changes in MICs are largely confined to DNA-damaging antibiotics, with strains containing a constitutively repressed SOS response impacted to a greater extent than hyperactivated strains. Second, antibiotic-induced mutation rates were suppressed when SOS activity was reduced, and this trend was observed across a wider spectrum of antibiotics. Finally, perturbing either LexA or RecA proved to be equally viable strategies for targeting the SOS response. Our work provides support for multiple adjuvant strategies, while also suggesting that the combination of an SOS inhibitor with a DNA-damaging antibiotic could offer the best potential for lowering MICs and decreasing acquired drug resistance. IMPORTANCE Our antibiotic arsenal is becoming depleted, in part, because bacteria have the ability to rapidly adapt and acquire resistance to our best agents. The SOS pathway, a widely conserved DNA damage stress response in bacteria, is activated by many antibiotics and has been shown to play central role in

Systematically Altering Bacterial SOS Activity under Stress Reveals Therapeutic Strategies for Potentiating Antibiotics

PubMed Central

Mo, Charlie Y.; Manning, Sara A.; Roggiani, Manuela; Culyba, Matthew J.; Samuels, Amanda N.; Sniegowski, Paul D.; Goulian, Mark

2016-01-01

ABSTRACT The bacterial SOS response is a DNA damage repair network that is strongly implicated in both survival and acquired drug resistance under antimicrobial stress. The two SOS regulators, LexA and RecA, have therefore emerged as potential targets for adjuvant therapies aimed at combating resistance, although many open questions remain. For example, it is not well understood whether SOS hyperactivation is a viable therapeutic approach or whether LexA or RecA is a better target. Furthermore, it is important to determine which antimicrobials could serve as the best treatment partners with SOS-targeting adjuvants. Here we derived Escherichia coli strains that have mutations in either lexA or recA genes in order to cover the full spectrum of possible SOS activity levels. We then systematically analyzed a wide range of antimicrobials by comparing the mean inhibitory concentrations (MICs) and induced mutation rates for each drug-strain combination. We first show that significant changes in MICs are largely confined to DNA-damaging antibiotics, with strains containing a constitutively repressed SOS response impacted to a greater extent than hyperactivated strains. Second, antibiotic-induced mutation rates were suppressed when SOS activity was reduced, and this trend was observed across a wider spectrum of antibiotics. Finally, perturbing either LexA or RecA proved to be equally viable strategies for targeting the SOS response. Our work provides support for multiple adjuvant strategies, while also suggesting that the combination of an SOS inhibitor with a DNA-damaging antibiotic could offer the best potential for lowering MICs and decreasing acquired drug resistance. IMPORTANCE Our antibiotic arsenal is becoming depleted, in part, because bacteria have the ability to rapidly adapt and acquire resistance to our best agents. The SOS pathway, a widely conserved DNA damage stress response in bacteria, is activated by many antibiotics and has been shown to play central role

Does vaginal irrigation with saline solution in women with infectious vaginitis contribute to the clinical and microbiological results of antibiotic therapy?

PubMed

Derbent, Aysel Uysal; Ulukanlıgil, Mustafa; Keskin, Esra Aktepe; Soylu, Gül; Kafalı, Hasan

2012-01-01

To compare the clinical and microbiological results between patients with infectious vaginitis receiving vaginal irrigation with saline or no irrigation before standard antibiotic therapy. Women with vaginitis (n = 109) were randomized to receive vaginal irrigation with saline or no irrigation before standard antibiotic therapy. The vaginal symptoms perceived by subjects and clinical findings were assessed with a standardized scale during four follow-up visits, and Gram stain Nugent scores and vaginal fluid cultures were analyzed at each visit. Vaginal discharge (z = 7.159; p < 0.001), pruritus (z = 5.169; p < 0.001), itching (z = 2.969; p < 0.003) and odor scores (z = 2.303; p < 0.021) were significantly reduced in the study group compared to the control group between the first visit and 3-5 days after irrigation, before the start of antibiotic therapy. The second and third visits (15 and 30-45 days after antibiotic therapy) showed that the patients' symptoms and amounts of visible vaginal discharge did not differ between the two groups. Moreover, the microbiological cures of patients in each group did not differ at these visits (z = 0.447; p = 0.655). Vaginal irrigation with saline significantly reduces self-reported symptoms in the short term but has no effect on long-term clinical and laboratory results in women with infectious vaginitis. Copyright © 2012 S. Karger AG, Basel.

The efficacy of combined therapy with metronidazole and broad-spectrum antibiotics on postoperative outcomes for pediatric patients with perforated appendicitis.

PubMed

Shang, Qingjuan; Geng, Qiankun; Zhang, Xuebing; Guo, Chunbao

2017-11-01

The aim of this study was to evaluate the efficacy of combined therapy with metronidazole and broad-spectrum antibiotics for patients with perforated appendicitis who underwent surgical intervention.Broad-spectrum antibiotic therapy is warranted in the treatment of perforated appendicitis. Metronidazole has been used as anaerobic antimicrobial therapy. However, few studies about the use of metronidazole in perforated appendicitis have been reported.The medical records of 249 patients treated with metronidazole combined with broad-spectrum antibiotics following perforated appendicitis surgery were reviewed retrospectively and compared with the medical records of 149 patients treated only with broad-spectrum antibiotics. Propensity score matching was performed to adjust for selected baseline variables. Clinical outcomes, including postoperative complications and length of hospital stay, were compared between the 2 groups.No differences were found between the use of combined therapy with metronidazole and the use of solely broad-spectrum antibiotic agents with regard to postoperative duration of intravenous antibiotic treatment (6.8 ± 1.3 vs 7.9 ± 2.1 days, respectively, P = .18), inflammation variables at POD 5 (white blood cell [WBC] [risk ratio [RR], 1.06; 95% confidence interval [CI], 0.67-1.93, P = .15] and C-reactive protein [CRP] [RR, 1.18; 95% CI, 0.73-2.25, P = .36]) (Table 2), and the mean postoperative length of hospital stay (LOS) (RR, 0.68, 95% CI, 0.41-0.94, P = .41). There were also no differences in the incidence of postoperative complications, including the intra-abdominal or pelvic abscess rate (7[7.1%] vs 9[9.2%], respectively, P = .40), the incidence of wound infection (14[14.3%] vs 15[15.3%], respectively, P = .50), and the 30-day readmission rate (9[9.2%] vs 12[12.2%], respectively, P = .32).Regarding overall postoperative outcomes and complications, our study demonstrated no beneficial clinical effects of

The efficacy of combined therapy with metronidazole and broad-spectrum antibiotics on postoperative outcomes for pediatric patients with perforated appendicitis

PubMed Central

Shang, Qingjuan; Geng, Qiankun; Zhang, Xuebing; Guo, Chunbao

2017-01-01

Abstract The aim of this study was to evaluate the efficacy of combined therapy with metronidazole and broad-spectrum antibiotics for patients with perforated appendicitis who underwent surgical intervention. Broad-spectrum antibiotic therapy is warranted in the treatment of perforated appendicitis. Metronidazole has been used as anaerobic antimicrobial therapy. However, few studies about the use of metronidazole in perforated appendicitis have been reported. The medical records of 249 patients treated with metronidazole combined with broad-spectrum antibiotics following perforated appendicitis surgery were reviewed retrospectively and compared with the medical records of 149 patients treated only with broad-spectrum antibiotics. Propensity score matching was performed to adjust for selected baseline variables. Clinical outcomes, including postoperative complications and length of hospital stay, were compared between the 2 groups. No differences were found between the use of combined therapy with metronidazole and the use of solely broad-spectrum antibiotic agents with regard to postoperative duration of intravenous antibiotic treatment (6.8 ± 1.3 vs 7.9 ± 2.1 days, respectively, P = .18), inflammation variables at POD 5 (white blood cell [WBC] [risk ratio [RR], 1.06; 95% confidence interval [CI], 0.67–1.93, P = .15] and C-reactive protein [CRP] [RR, 1.18; 95% CI, 0.73–2.25, P = .36]) (Table 2), and the mean postoperative length of hospital stay (LOS) (RR, 0.68, 95% CI, 0.41–0.94, P = .41). There were also no differences in the incidence of postoperative complications, including the intra-abdominal or pelvic abscess rate (7[7.1%] vs 9[9.2%], respectively, P = .40), the incidence of wound infection (14[14.3%] vs 15[15.3%], respectively, P = .50), and the 30-day readmission rate (9[9.2%] vs 12[12.2%], respectively, P = .32). Regarding overall postoperative outcomes and complications, our study demonstrated no beneficial

Boron neutron capture therapy: Moving toward targeted cancer therapy.

PubMed

Mirzaei, Hamid Reza; Sahebkar, Amirhossein; Salehi, Rasoul; Nahand, Javid Sadri; Karimi, Ehsan; Jaafari, Mahmoud Reza; Mirzaei, Hamed

2016-01-01

Boron neutron capture therapy (BNCT) occurs when a stable isotope, boton-10, is irradiated with low-energy thermal neutrons to yield stripped down helium-4 nuclei and lithium-7 nuclei. It is a binary therapy in the treatment of cancer in which a cytotoxic event is triggered when an atom placed in a cancer cell. Here, we provide an overview on the application of BNCT in cancer therapy as well as current preclinical and clinical evidence on the efficacy of BNCT in the treatment of melanoma, brain tumors, head and neck cancer, and thyroid cancer. Several studies have shown that BNCT is effective in patients who had been treated with a full dose of conventional radiotherapy, because of its selectivity. In addition, BNCT is dependent on the normal/tumor tissue ratio of boron distribution. Increasing evidence has shown that BNCT can be combined with different drug delivery systems to enhance the delivery of boron to cancer cells. The flexibility of BNCT to be used in combination with different tumor-targeting approaches has made this strategy a promising option for cancer therapy. This review aims to provide a state-of-the-art overview of the recent advances in the use of BNCT for targeted therapy of cancer.

DD-ligases as a potential target for antibiotics: past, present and future.

PubMed

Tytgat, I; Colacino, E; Tulkens, P M; Poupaert, J H; Prévost, M; Van Bambeke, F

2009-01-01

DD-ligases catalyze the synthesis of the D-Ala-D-Ala and D-Ala-D-Ser dipeptides or the D Ala-D-Lac depsipeptide in an early step of peptidoglycan synthesis. Their function is essential for bacterial growth and specific to bacteria, making them attractive targets for the development of novel antibiotics. This review examines the biochemical and structural features of these enzymes and presents the main families of inhibitors described so far. Over the last 20 years, 7 structures of DD-ligases have been solved by X-ray crystallography, giving a detailed view of the general topology of the active site and of the residues in the catalytic pocket that play a central role in substrate recognition. This has paved the way to the rational design of inhibitors, which can be classified as (i) analogues of substrates, (ii) analogues of the product of the reaction, (iii) analogues of the transition state, and (iv) original scaffolds discovered by screening or by rational computer-aided design. The three first strategies have led to molecules that are polar by nature and have therefore poor access to their cytosolic target. The fourth one is potentially most promising as it yields more diverse structures. The most active molecules show affinity constants in the microM range, but microbiological evaluation remains scarce (typical MIC 1-8 mg/L for the tested compounds). These data strongly suggest targeting DD-ligases is a promising approach for discovery of new antibiotics. Future research should, however, aim at finding more potent inhibitors endowed with the appropriate pharmacokinetic properties that ensure access to their intracellular target.

Subinhibitory Antibiotic Therapy Alters Recurrent Urinary Tract Infection Pathogenesis through Modulation of Bacterial Virulence and Host Immunity

PubMed Central

Hannan, Thomas J.; MacPhee, Roderick A.; Schwartz, Drew J.; Macklaim, Jean M.; Gloor, Gregory B.; Razvi, Hassan; Reid, Gregor; Hultgren, Scott J.; Burton, Jeremy P.

2015-01-01

ABSTRACT The capacity of subinhibitory levels of antibiotics to modulate bacterial virulence in vitro has recently been brought to light, raising concerns over the appropriateness of low-dose therapies, including antibiotic prophylaxis for recurrent urinary tract infection management. However, the mechanisms involved and their relevance in influencing pathogenesis have not been investigated. We characterized the ability of antibiotics to modulate virulence in the uropathogens Staphylococcus saprophyticus and Escherichia coli. Several antibiotics were able to induce the expression of adhesins critical to urothelial colonization, resulting in increased biofilm formation, colonization of murine bladders and kidneys, and promotion of intracellular niche formation. Mice receiving subinhibitory ciprofloxacin treatment were also more susceptible to severe infections and frequent recurrences. A ciprofloxacin prophylaxis model revealed this strategy to be ineffective in reducing recurrences and worsened infection by creating larger intracellular reservoirs at higher frequencies. Our study indicates that certain agents used for antibiotic prophylaxis have the potential to complicate infections. PMID:25827417

Immunomodulatory effects of pidotimod in adults with community-acquired pneumonia undergoing standard antibiotic therapy.

PubMed

Trabattoni, D; Clerici, M; Centanni, S; Mantero, M; Garziano, M; Blasi, F

2017-06-01

The morbidity and mortality of community-acquired pneumonia (CAP) are still elevated and two aspects seem to contribute to a worse outcome: an uncontrolled inflammatory reaction and an inadequate immune response. Adjuvants, including corticosteroids and intravenous immunoglobulins, have been proposed to counterbalance these effects but their efficacy is only partial. We examined the immunomodulatory activity of Pidotimod (PDT), a synthetic dipeptide molecule in adult patients hospitalized for CAP. Sixteen patients with a diagnosis of CAP and a PSI score III or IV and/or a CURB-65 0-2 were randomized to receive either levofloxacin 500 mg b.i.d. alone or levofloxacin plus PDT (800mg, 2 daily doses). Blood samples were drawn at baseline (T0), before initiation of therapy, as well as 3 (T3), and 5 (T5) days after initiation of therapy. Immunologic and clinical parameters were analyzed at each time point. Supplementation of antibiotic therapy with PDT resulted in an upregulation of antimicrobial and of immunomodulatory proteins as well as in an increased percentage of Toll like receptor (TLR)2- and TLR4, and of CD80- and CD86-expressing immune cells. Notably, Pidotimod supplementation was also associated with a robust reduction of TNFα-producing immune cells. No significant differences were observed in clinical parameters. These results confirm that supplementation of antibiotic therapy with Pidotimod in patients with CAP results in a potentially beneficial modulation of innate immunity. Copyright © 2017 Elsevier Ltd. All rights reserved.

A Randomized Control Trial of Preoperative Oral Antibiotics as Adjunct Therapy to Systemic Antibiotics for Preventing Surgical Site Infection in Clean Contaminated, Contaminated, and Dirty Type of Colorectal Surgeries.

PubMed

Anjum, Nadeem; Ren, Jianan; Wang, Gefei; Li, Guanwei; Wu, Xiuwen; Dong, Hu; Wu, Qin; Li, Jieshou

2017-12-01

Preoperative bowel preparation with or without oral antibiotics is controversial in terms of postoperative surgical site infections. This study aimed to evaluate the efficacy of oral antibiotics as adjunct therapy to systemic antibiotics with mechanical bowel preparation for preventing surgical site infections in clean contaminated, contaminated, and dirty colorectal procedures. This was a single-center, prospective randomized study. This study was conducted at the General Surgery Department at Jinling Hospital, Nanjing University, China, from July 15, 2014 to January 20, 2016. Patients aged ≥18 years scheduled for abdominal surgery with clean-contaminated, contaminated, and dirty wounds were selected. Patients were randomly assigned to receive preoperative mechanical bowel preparation or mechanical bowel preparation with oral antibiotics. The primary outcome was the rate of surgical site infections. The secondary outcomes were extra-abdominal complications, duration of postoperative ileus, and readmission rate. Ninety-five patients were allocated to each group. Eight and 26 surgical site infections (8.42% vs 27.3 %, p = 0.004) occurred in the mechanical bowel preparation with oral antibiotics and mechanical bowel preparation groups. Thirteen extra-abdominal complications were reported: 6 in the mechanical bowel preparation with oral antibiotics group and 7 in the mechanical bowel preparation group (6.3% vs 7.3%, p = 0.77). Postoperative ileus duration did not differ between groups (p = 0.23). There were 4 readmissions in the mechanical bowel preparation group and none in the mechanical bowel preparation with oral antibiotics group (p = 0.04). On multivariable analysis, blood loss ≥500 mL (OR, 5.1; 95% CI, 1.27-20.4; p = 0.02), ASA score ≥3 (OR, 3.9; 95% CI, 1.2-12.5; p = 0.01), contaminated types (OR, 3.6; 95% CI, 1.5-8.6; p = 0.01), and administration of preoperative oral antibiotics (OR, 0.20; 95% CI, 0.06-0.60; p = 0.005) independently affected the

[A study of non-antibiotic versus antibiotic prophylaxis for recurrent urinary-tract infections in women (the NAPRUTI study)].

PubMed

Beerepoot, M A J; Stobberingh, E E; Geerlings, S E

2006-03-11

Patient enrolment in the 'Non-antibiotic versus antibiotic prophylaxis for recurrent urinary-tract infections' (NAPRUTI) study was started in September 2005. In this study of women with recurrent urinary-tract infections we aim to investigate the effect of 12 months of non-antibiotic prophylaxis in comparison with antibiotic prophylaxis on the rate of recurrence of urinary-tract infections and the development of antibiotic resistance. The study consists of two interlinked, randomised, clinical non-inferiority trials. In one trial, 280 premenopausal women will receive either cranberry capsules (twice daily 500 mg) or standardised antibiotic therapy (once daily 480 mg trimethoprim-sulfamethoxazole). In the other trial, 280 postmenopausal women will receive either oral lactobacilli (twice daily a capsule with > 10(9) colony-forming units of Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14) or standardised antibiotic therapy. Non-inferiority of non-antibiotic prophylaxis would be attractive given its potential to reduce the prevalence of microbial resistance to antibiotics significantly.

Prophylactic antibiotic therapy prior to dental treatment for patients with end-stage renal disease.

PubMed

Werner, C W; Saad, T F

1999-01-01

In the United States, there is a large and growing population of patients undergoing dialysis because of end-stage renal disease (ESRD). These patients present special management considerations for dentists, including antibiotic prophylaxis for the prevention of bacterial endocarditis (BE). ESRD patients, particularly those with an arteriovenous shunt for hemodialysis access, are predisposed to valvular endocarditis. Thus, BE prevention is the primary goal of antibiotic prophylaxis prior to dental or other invasive procedures in these patients. Bacteremia may predispose to infection of synthetic vascular access grafts, although this form of endovascular infection in ESRD patients has not been as well-characterized as BE. Antibiotic prophylaxis may be of some benefit for prevention of synthetic graft infections as well as BE. Poor dentist and physician compliance with BE prophylaxis regimens, as well as errors in dosing, timing, or duration of prophylaxis, have been reported. These problems are of particular concern in the treatment of chronically ill patients. In this article, we review the rationale for prophylactic antibiotic therapy prior to dental procedures in ESRD patients with vascular access. We also elaborate on the current American Heart Association guidelines for BE prophylaxis, and address special considerations for ESRD patients.

Impact of prospective verification of intravenous antibiotics in an ED.

PubMed

Hunt, Allyson; Nakajima, Steven; Hall Zimmerman, Lisa; Patel, Manav

2016-12-01

Delay in appropriate antibiotic therapy is associated with an increase in mortality and prolonged length of stay. Automatic dispensing machines decrease the delivery time of intravenous (IV) antibiotics to patients in the emergency department (ED). However, when IV antibiotics are not reviewed by pharmacists before being administered, patients are at risk for receiving inappropriate antibiotic therapy. The objective of this study was to determine if a difference exists in the time to administration of appropriate antibiotic therapy before and after implementation of prospective verification of antibiotics in the ED. This retrospective, institutional review board-approved preimplementation vs postimplementation study evaluated patients 18years or older who were started on IV antibiotics in the ED. Patients were excluded if pregnant, if the patient is a prisoner, if no cultures were drawn, or if the patient was transferred from an outside facility. Appropriate antibiotic therapy was based on empiric source-specific evidence-based guidelines, appropriate pharmacokinetic and pharmacodynamic properties, and microbiologic data. The primary end point was the time from ED arrival to administration of appropriate antibiotic therapy. Of the 1628 evaluated, 128 patients met the inclusion criteria (64 pre vs 64 post). Patients were aged 65.2±17.0years, with most of infections being pneumonia (44%) and urinary tract infections (18%) and most patients being noncritically ill. Time to appropriate antibiotic therapy was reduced in the postgroup vs pregroup (8.1±8.6 vs 15.2±22.8hours, respectively, P=.03). In addition, appropriate empiric antibiotics were initiated more frequently after the implementation (92% post vs 66% pre; P=.0001). There was no difference in mortality or length of stay between the 2 groups. Prompt administration of the appropriate antibiotics is imperative in patients with infections presenting to the ED. The impact of prospective verification of

A call for antibiotic alternatives research

USDA-ARS?s Scientific Manuscript database

The persistence and spread of antibiotic resistance and decreased profitability of new antibiotics have created the dangerous prospect of ineffective therapies against bacterial diseases. The discovery, development, and application of effective antibiotic alternatives, especially in agriculture, sho...

Decision and cost analysis of empirical antibiotic therapy of acute sinusitis in the era of increasing antimicrobial resistance: do we have an additional tool for antibiotic policy decisions?

PubMed

Babela, Robert; Jarcuska, Pavol; Uraz, Vladimir; Krčméry, Vladimír; Jadud, Branislav; Stevlik, Jan; Gould, Ian M

2017-11-01

No previous analyses have attempted to determine optimal therapy for upper respiratory tract infections on the basis of cost-minimization models and the prevalence of antimicrobial resistance among respiratory pathogens in Slovakia. This investigation compares macrolides and cephalosporines for empirical therapy and look at this new tool from the aspect of potential antibiotic policy decision-making process. We employed a decision tree model to determine the threshold level of macrolides and cephalosporines resistance among community respiratory pathogens that would make cephalosporines or macrolides cost-minimising. To obtain information on clinical outcomes and cost of URTIs, a systematic review of the literature was performed. The cost-minimization model of upper respiratory tract infections (URTIs) treatment was derived from the review of literature and published models. We found that the mean cost of empirical treatment with macrolides for an URTIs was €93.27 when the percentage of resistant Streptococcus pneumoniae in the community was 0%; at 5%, the mean cost was €96.45; at 10%, €99.63; at 20%, €105.99, and at 30%, €112.36. Our model demonstrated that when the percentage of macrolide resistant Streptococcus pneumoniae exceeds 13.8%, use of empirical cephalosporines rather than macrolides minimizes the treatment cost of URTIs. Empirical macrolide therapy is less expensive than cephalosporines therapy for URTIs unless macrolide resistance exceeds 13.8% in the community. Results have important antibiotic policy implications, since presented model can be use as an additional decision-making tool for new guidelines and reimbursement processes by local authorities in the era of continual increase in antibiotic resistance.

Use of PNA FISH for blood cultures growing Gram-positive cocci in chains without a concomitant antibiotic stewardship intervention does not improve time to appropriate antibiotic therapy.

PubMed

Cosgrove, Sara E; Li, David X; Tamma, Pranita D; Avdic, Edina; Hadhazy, Eric; Wakefield, Teresa; Gherna, Michael; Carroll, Karen C

2016-09-01

Peptide nucleic acid fluorescence in situ hybridization (PNA FISH) is a rapid diagnostic assay that can identify certain organisms growing in blood cultures 30-90 min from the time of positive Gram-stain. Existing studies have demonstrated a clinical utility with this assay when antibiotic stewardship programs assist clinicians with interpreting the results. However, the benefit of these rapid assays in the absence of concomitant antibiotic stewardship involvement is unclear. In this randomized study of 220 patients with enterococcal or streptococcal bacteremia, we found that PNA FISH, in the absence of concomitant input from an antibiotic stewardship program, had no impact on time to effective or optimal therapy, length of hospital stay, or in-hospital mortality. Our results suggest that in the absence of guidance from an antibiotic stewardship program, the clinical benefits of rapid diagnostic microbiological tools may be reduced. Copyright © 2016 Elsevier Inc. All rights reserved.

Antibiotic prescribing practices for catheter urine culture results.

PubMed

Chiu, Jonathan; Thompson, G William; Austin, Thomas W; Hussain, Zafar; John, Michael; Bombassaro, Anne Marie; Connelly, Sarah E; Elsayed, Sameer

2013-01-01

The literature suggests that positive results of catheter urine cultures frequently lead to unnecessary antimicrobial prescribing, which therefore represents an important target for stewardship. To assess the appropriateness of antibiotic prescribing in response to the results of urine cultures from patients with indwelling urinary catheters. This retrospective study was conducted at a tertiary care centre and involved adults with indwelling urinary catheters from whom urine specimens were obtained for culture. Patients with positive or negative culture results were identified from microbiology laboratory reports. The medical records of consecutive patients were screened to select a sample of 80 inpatients (40 per group). Abstracted patient histories were independently evaluated by an expert panel of 3 infectious diseases consultants blinded to the decisions of prescribers and of fellow panelists. The primary end point was concordance of each patient's treatment decision (with respect to the indication) between the expert panel (based on majority agreement, i.e., at least 2 of the 3 expert panelists) and the prescriber. The secondary end points were unnecessary days of therapy and selected outcomes over a predefined period after urine was obtained for culture. A total of 591 charts were screened to generate the targeted number of patients. Baseline demographic characteristics were comparable for the 2 groups, except antibiotic exposure before urine collection was significantly more frequent for the group with negative culture results. The treatment decision was concordant in 40% (16/40) of the patients with a positive culture result and 85% (34/40) of those with a negative culture result (p < 0.001). The most common reason for discordance was administration of antibiotics when not indicated (23 of 24 patients with a positive result and 5 of 6 patients with a negative result), which accounted for 165 and 32 unnecessary days of therapy per 1000 inpatient

[Acne therapy with topical benzoyl peroxide, antibiotics and azelaic acid].

PubMed

Worret, Wolf-Ingo; Fluhr, Joachim W

2006-04-01

Benzoyl peroxide (BPO) was introduced in the treatment of acne in 1934. Despite the fact that only few randomized trials have been published, BPO is considered the standard in topical acne treatment. Anaerobic bacteria are reduced by oxidative mechanisms and the induction of resistant strains is reduced. Topical formulations are available at concentrations of 2.5, 5, 10 and 20 %. The effect is dose-dependent, but the irritation increases with higher concentrations. Usually 5 % BPO is sufficient to control acne grade I-II. Due to its strong oxidative potential, patients should be advised that BPO may bleach colored and dark clothing, bedding and even hair. BPO is safe for use in pregnant and lactating females because it is degraded to benzoic acid. It is a cost-effective treatment for acne grade I-II. Patients with papulopustular acne grade I-II, particularly with marked inflammation, show satisfactory improvement with topical antibiotic treatment. The following compounds are available and effective: erythromycin, clindamycin and tetracycline (the latter being less frequently used). A review in 1990 suggested that topical tetracycline was ineffective in the treatment of acne. Along with eliminating Propionibacterium acnes, the main mechanism of topical antibiotics is their antiinflammatory effect. All three penetrate the epidermal barrier well and are similarly efficacious. Randomized trials have shown that in concentrations of 2-4 %, their effects are comparable to oral tetracycline and minocycline. Combination therapy with retinoids or benzoyl peroxide (BPO) increases efficacy. Retinoids increase penetration and reduce comedones, while topical antibiotics primarily address inflammation. One side effect of topical antibacterial treatment is an increase in drug-resistant resident skin flora with gram-negative microorganisms prevailing, which can lead to gram-negative folliculitis. All three antibiotics fluoresce under black light which may produce interesting

Antibiotic susceptibility of Gram-negatives isolated from bacteremia in children with cancer. Implications for empirical therapy of febrile neutropenia.

PubMed

Castagnola, Elio; Caviglia, Ilaria; Pescetto, Luisa; Bagnasco, Francesca; Haupt, Riccardo; Bandettini, Roberto

2015-01-01

Monotherapy is recommended as the first choice for initial empirical therapy of febrile neutropenia, but local epidemiological and antibiotic susceptibility data are now considered pivotal to design a correct management strategy. To evaluate the proportion of Gram-negative rods isolated in bloodstream infections in children with cancer resistant to antibiotics recommended for this indication. The in vitro susceptibility to ceftazidime, piperacillin-tazobactam, meropenem and amikacin of Gram-negatives isolated in bacteremic episodes in children with cancer followed at the Istituto "Giannina Gaslini", Genoa, Italy in the period of 2001-2013 was retrospectively analyzed using the definitions recommended by EUCAST in 2014. Data were analyzed for any single drug and to the combination of amikacin with each β-lactam. The combination was considered effective in absence of concomitant resistance to both drugs, and not evaluated by means of in vitro analysis of antibiotic combinations (e.g., checkerboard). A total of 263 strains were evaluated: 27% were resistant to piperacillin-tazobactam, 23% to ceftazidime, 12% to meropenem and 13% to amikacin. Concomitant resistance to β-lactam and amikacin was detected in 6% of strains for piperacillin-tazobactam, 5% for ceftazidime and 5% for meropenem. During the study period there was a nonsignificant increase in the proportions of strains resistant to β-lactams indicated for monotherapy, and also increase in the resistance to combined therapies. in an era of increasing resistance to antibiotics guideline-recommended monotherapy could be not appropriate for initial empirical therapy of febrile neutropenia. Strict local survey on etiology and antibiotic susceptibility is mandatory for a correct management of this complication in cancer patients.

Oligonucleotide Aptamers: New Tools for Targeted Cancer Therapy

PubMed Central

Sun, Hongguang; Zhu, Xun; Lu, Patrick Y; Rosato, Roberto R; Tan, Wen; Zu, Youli

2014-01-01

Aptamers are a class of small nucleic acid ligands that are composed of RNA or single-stranded DNA oligonucleotides and have high specificity and affinity for their targets. Similar to antibodies, aptamers interact with their targets by recognizing a specific three-dimensional structure and are thus termed “chemical antibodies.” In contrast to protein antibodies, aptamers offer unique chemical and biological characteristics based on their oligonucleotide properties. Hence, they are more suitable for the development of novel clinical applications. Aptamer technology has been widely investigated in various biomedical fields for biomarker discovery, in vitro diagnosis, in vivo imaging, and targeted therapy. This review will discuss the potential applications of aptamer technology as a new tool for targeted cancer therapy with emphasis on the development of aptamers that are able to specifically target cell surface biomarkers. Additionally, we will describe several approaches for the use of aptamers in targeted therapeutics, including aptamer-drug conjugation, aptamer-nanoparticle conjugation, aptamer-mediated targeted gene therapy, aptamer-mediated immunotherapy, and aptamer-mediated biotherapy. PMID:25093706

Apatinib as targeted therapy for sarcoma

PubMed Central

Li, Feng; Liao, Zhichao; Zhang, Chao; Zhao, Jun; Xing, Ruwei; Teng, Sheng; Zhang, Jin; Yang, Yun; Yang, Jilong

2018-01-01

Sarcomas are a group of malignant tumors originating from mesenchymal tissue with a variety of cell subtypes. Despite several major treatment breakthroughs, standard treatment using surgery, radiation, and chemotherapy has failed to improve overall survival. Therefore, there is an urgent need to explore new strategies and innovative therapies to further improve the survival rates of patients with sarcomas. Pathological angiogenesis has an important role in the growth and metastasis of tumors. Vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptors (VEGFRs) play a central role in tumor angiogenesis and represent potential targets for anticancer therapy. As a novel targeted therapy, especially with regard to angiogenesis, apatinib is a new type of small molecule tyrosine kinase inhibitor that selectively targets VEGFR-2 and has shown encouraging anticancer activity in a wide range of malignancies, including gastric cancer, non-small cell lung cancer, breast cancer, hepatocellular carcinoma, and sarcomas. In this review, we summarize the preclinical and clinical data for apatinib, focusing primarily on its use in the treatment of sarcomas. PMID:29849960

The use of inhaled antibiotic therapy in the treatment of ventilator-associated pneumonia and tracheobronchitis: a systematic review.

PubMed

Russell, Christopher J; Shiroishi, Mark S; Siantz, Elizabeth; Wu, Brian W; Patino, Cecilia M

2016-03-08

Ventilator-associated respiratory infections (tracheobronchitis, pneumonia) contribute significant morbidity and mortality to adults receiving care in intensive care units (ICU). Administration of broad-spectrum intravenous antibiotics, the current standard of care, may have systemic adverse effects. The efficacy of aerosolized antibiotics for treatment of ventilator-associated respiratory infections remains unclear. Our objective was to conduct a systematic review of the efficacy of aerosolized antibiotics in the treatment of ventilator-associated pneumonia (VAP) and tracheobronchitis (VAT), using the Cochrane Collaboration guidelines. We conducted a search of three databases (PubMed, Web of Knowledge and the Cochrane Collaboration) for randomized, controlled trials studying the use of nebulized antibiotics in VAP and VAT that measured clinical cure (e.g., change in Clinical Pulmonary Infection Score) as an outcome measurement. We augmented the electronic searches with hand searches of the references for any narrative review articles as well as any article included in the systematic review. Included studies were examined for risk of bias using the Cochrane Handbook's "Risk of Bias" assessment tool. Six studies met full inclusion criteria. For the systemic review's primary outcome (clinical cure), two studies found clinically and statistically significant improvements in measures of VAP cure while four found no statistically significant difference in measurements of cure. No studies found inferiority of aerosolized antibiotics. The included studies had various degrees of biases, particularly in the performance and detection bias domains. Given that outcome measures of clinical cure were not uniform, we were unable to conduct a meta-analysis. There is insufficient evidence for the use of inhaled antibiotic therapy as primary or adjuvant treatment of VAP or VAT. Additional, better-powered randomized-controlled trials are needed to assess the efficacy of inhaled

Novel approaches are needed to develop tomorrow's antibacterial therapies.

PubMed

Spellberg, Brad; Bartlett, John; Wunderink, Rich; Gilbert, David N

2015-01-15

Society faces a crisis of rising antibiotic resistance even as the pipeline of new antibiotics has been drying up. Antibiotics are a public trust; every individual's use of antibiotics affects their efficacy for everyone else. As such, responses to the antibiotic crisis must take a societal perspective. The market failure of antibiotics is due to a combination of scientific challenges to discovering and developing new antibiotics, unfavorable economics, and a hostile regulatory environment. Scientific solutions include changing the way we screen for new antibiotics. More transformationally, developing new treatments that seek to disarm pathogens without killing them, or that modulate the host inflammatory response to infection, will reduce selective pressure and hence minimize resistance emergence. Economic transformation will require new business models to support antibiotic development. Finally, regulatory reform is needed so that clinical development programs are feasible, rigorous, and clinically relevant. Pulmonary and critical care specialists can have tremendous impact on the continued availability of effective antibiotics. Encouraging use of molecular diagnostic tests to allow pathogen-targeted, narrow-spectrum antibiotic therapy, using short rather than unnecessarily long course therapy, reducing inappropriate antibiotic use for probable viral infections, and reducing infection rates will help preserve the antibiotics we have for future generations.

Chemoresistance and targeted therapies in ovarian and endometrial cancers

PubMed Central

Brasseur, Kevin; Gévry, Nicolas; Asselin, Eric

2017-01-01

Gynecological cancers are known for being very aggressive at their advanced stages. Indeed, the survival rate of both ovarian and endometrial cancers is very low when diagnosed lately and the success rate of current chemotherapy regimens is not very efficient. One of the main reasons for this low success rate is the acquired chemoresistance of these cancers during their progression. The mechanisms responsible for this acquired chemoresistance are numerous, including efflux pumps, repair mechanisms, survival pathways (PI3K/AKT, MAPK, EGFR, mTOR, estrogen signaling) and tumor suppressors (P53 and Par-4). To overcome these resistances, a new type of therapy has emerged named targeted therapy. The principle of targeted therapy is simple, taking advantage of changes acquired in malignant cancer cells (receptors, proteins, mechanisms) by using compounds specifically targeting these, thus limiting their action on healthy cells. Targeted therapies are emerging and many clinical trials targeting these pathways, frequently involved in chemoresistance, have been tested on gynecological cancers. Despite some targets being less efficient than expected as mono-therapies, the combination of compounds seems to be the promising avenue. For instance, we demonstrate using ChIP-seq analysis that estrogen downregulate tumor suppressor Par-4 in hormone-dependent cells by directly binding to its DNA regulatory elements and inhibiting estrogen signaling could reinstate Par-4 apoptosis-inducing abilities. This review will focus on the chemoresistance mechanisms and the clinical trials of targeted therapies associated with these, specifically for endometrial and ovarian cancers. PMID:28008141

Salinomycin, A Polyether Ionophoric Antibiotic, Inhibits Adipogenesis

PubMed Central

Szkudlarek-Mikho, Maria; Saunders, Rudel A.; Yap, Sook Fan; Ngeow, Yun Fong; Chin, Khew-Voon

2012-01-01

The polyether ionophoric antibiotics including monensin, salinomycin, and narasin, are widely used in veterinary medicine and as food additives and growth promoters in animal husbandry including poultry farming. Their effects on human health, however, are not fully understood. Recent studies showed that salinomycin is a cancer stem cell inhibitor. Since poultry consumption has risen sharply in the last three decades, we asked whether the consumption of meat tainted with growth promoting antibiotics might have effects on adipose cells. We showed in this report that the ionophoric antibiotics inhibit the differentiation of preadipocytes into adipocytes. The block of differentiation is not due to the induction of apoptosis nor the inhibition of cell proliferation. In addition, salinomycin also suppresses the transcriptional activity of the CCAAT/enhancer binding proteins and the peroxisome proliferator-activated receptor γ. These results suggest that the ionophoric antibiotics can be exploited as novel anti-obesity therapeutics and as pharmacological probes for the study of adipose biology. Further, the pharmacological effects of salinomycin could be a harbinger of its toxicity on the adipose tissue and other susceptible target cells in cancer therapy. PMID:23123626

EGFR-targeted therapies in the post-genomic era.

PubMed

Xu, Mary Jue; Johnson, Daniel E; Grandis, Jennifer R

2017-09-01

Over 90% of head and neck cancers overexpress the epidermal growth factor receptor (EGFR). In diverse tumor types, EGFR overexpression has been associated with poorer prognosis and outcomes. Therapies targeting EGFR include monoclonal antibodies, tyrosine kinase inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, and antisense gene therapy. Few EGFR-targeted therapeutics are approved for clinical use. The monoclonal antibody cetuximab is a Food and Drug Administration (FDA)-approved EGFR-targeted therapy, yet has exhibited modest benefit in clinical trials. The humanized monoclonal antibody nimotuzumab is also approved for head and neck cancers in Cuba, Argentina, Colombia, Peru, India, Ukraine, Ivory Coast, and Gabon in addition to nasopharyngeal cancers in China. Few other EGFR-targeted therapeutics for head and neck cancers have led to as significant responses as seen in lung carcinomas, for instance. Recent genome sequencing of head and neck tumors has helped identify patient subgroups with improved response to EGFR inhibitors, for example, cetuximab in patients with the KRAS-variant and the tyrosine kinase inhibitor erlotinib for tumors harboring MAPK1 E322K mutations. Genome sequencing has furthermore broadened our understanding of dysregulated pathways, holding the potential to enhance the benefit derived from therapies targeting EGFR.

Demographics and microbiology of otorrhea through patent tubes failing ototopical and/or oral antibiotic therapy.

PubMed

Fishman, Inessa; Sykes, Kevin J; Horvat, Rebecca; Selvarangan, Rangaraj; Newland, Jason; Wei, Julie L

2011-12-01

Posttympanostomy tube otorrhea (PTTO) results in significant health care cost and decreased satisfaction with care. The authors reviewed PTTO failing initial ototopical and/or oral antibiotic therapy and microbiology/susceptibility data from cultures. Case series with chart review. A community university satellite ambulatory clinic and the outpatient clinic of a children's hospital. Review of 202 patients with 228 discrete episodes of culture-positive otorrhea from January 2004 to January 2009. PTTO occurred an average of 13 months after tube placement. Median otorrhea duration was 21 days (mean, 42 days). A mean of 1.6 visits (range, 1-6) to the pediatric otolaryngology office was required for PTTO resolution. Ototopical therapy was reported used in 198 of 228 (87%) episodes of otorrhea prior to pediatric otolaryngology visit. Nearly 50% of patients were prescribed at least 1 or more courses of systemic antibiotics. Staphylococcus aureus accounted for 52% of the organisms cultured, with 57% methicillin-resistant S aureus (MRSA). S aureus resistance to clindamycin was high (49%) and resistance to levofloxacin was low (1.8%). MRSA was 68% clindamycin resistant, much higher than both ours and the children's hospital's clindamycin resistance rate of MRSA cultured from all other body sites. PTTO that presents as having failed ototopical and/or oral antibiotics most commonly consists of S aureus, Streptococcus pneumoniae, and Pseudomonas aeruginosa. MRSA is highly prevalent in this population. It is not necessary to culture PTTO that presents to an otolaryngology office, as resistance to levofloxacin was only 1.8%. It is unclear why the same fluoroquinolone ototopical therapy that failed initially is often successful in treating PTTO after otolaryngologist visit.

Novel Targeted Therapies for Inflammatory Breast Cancer

DTIC Science & Technology

2017-10-01

AWARD NUMBER: W81XWH-16-1-0461 TITLE: Novel Targeted Therapies for Inflammatory Breast Cancer PRINCIPAL INVESTIGATOR: Jose Silva CONTRACTING...CONTRACT NUMBER Novel Targeted Therapies for Inflammatory Breast Cancer 5b. GRANT NUMBER W81XWH-16-1-0461 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) l 5d...NOTES 14. ABSTRACT Inflammatory breast cancer (IBC, ~5% of all breast cancers ) is the most lethal form of breast cancer , presenting a 5- year

Antibiotics for acute pyelonephritis in children.

PubMed

Strohmeier, Yvonne; Hodson, Elisabeth M; Willis, Narelle S; Webster, Angela C; Craig, Jonathan C

2014-07-28

Urinary tract infection (UTI) is one of the most common bacterial infections in infants. The most severe form of UTI is acute pyelonephritis, which results in significant acute morbidity and may cause permanent kidney damage. There remains uncertainty regarding the optimum antibiotic regimen, route of administration and duration of treatment. This is an update of a review that was first published in 2003 and updated in 2005 and 2007. To evaluate the benefits and harms of antibiotics used to treat children with acute pyelonephritis. The aspects of therapy considered were 1) different antibiotics, 2) different dosing regimens of the same antibiotic, 3) different duration of treatment, and 4) different routes of administration. We searched the Cochrane Renal Group's Specialised Register, CENTRAL, MEDLINE, EMBASE, reference lists of articles and conference proceedings without language restriction to 10 April 2014. Randomised and quasi-randomised controlled trials comparing different antibiotic agents, routes, frequencies or durations of therapy in children aged 0 to 18 years with proven UTI and acute pyelonephritis were selected. Four authors independently assessed study quality and extracted data. Statistical analyses were performed using the random-effects model and the results expressed as risk ratio (RR) for dichotomous outcomes or mean difference (MD) for continuous data with 95% confidence intervals (CI). This updated review included 27 studies (4452 children). This update included evidence from three new studies, and following re-evaluation, a previously excluded study was included because it now met our inclusion criteria.Risk of bias was assessed as low for sequence generation (12 studies), allocation concealment (six studies), blinding of outcome assessors (17 studies), incomplete outcome reporting (19 studies) and selective outcome reporting (13 studies). No study was blinded for participants or investigators. The 27 included studies evaluated 12 different

Impact of acute antibiotic therapy on the pulmonary exacerbation endpoint in cystic fibrosis clinical trials.

PubMed

Mayer-Hamblett, Nicole; Saiman, Lisa; Lands, Larry C; Anstead, Michael; Rosenfeld, Margaret; Kloster, Margaret; Fisher, Leigh; Ratjen, Felix

2013-09-01

In a chronic disease setting such as cystic fibrosis (CF), antibiotics are often prescribed for emergent symptoms and it is unclear whether this affects endpoints in a clinical trial. Pulmonary exacerbations (PEs) are defined episodes of acute worsening and a key clinical efficacy measure in CF. Our hypothesis was that acute antibiotics given for illnesses not meeting the PE definition may alter estimates of treatment effect that do not account for this antibiotic use. A randomized, placebo-controlled trial of azithromycin (AZ) including 260 participants with CF was utilized for this study. PEs were defined using a priori criteria. Physician initiated antibiotic therapy (PIT) not meeting the PE endpoint was characterized and its impact on treatment effect assessed. 40% (104/260) of participants were prescribed 188 courses of PIT in the absence of a PE; 19% (25/129) of placebo and 10% (13/131) of AZ participants received ≥2 courses of PIT and never fulfilled the PE definition (9% difference, 95% confidence interval: 1%, 18%, p = 0.04). Accounting for PIT through use of a composite endpoint including time to PE or need for repeated PIT altered treatment effect estimates (a 56% reduction in the event rate comparing AZ to placebo [p < 0.0001] as compared to a 50% reduction not accounting for PIT [p = 0.003]). PIT is common in CF and may impact treatment effect estimates. Optimization of the PE endpoint to include meaningful events necessitating treatment may improve our ability to conduct efficient trials by reducing the sample size 30-50%, ultimately enabling rapid evaluation of new therapies. Copyright © 2013 Elsevier Inc. All rights reserved.

Adjunctive steroid therapy versus antibiotics alone for acute endophthalmitis after intraocular procedure.

PubMed

Kim, Carole H; Chen, Monica F; Coleman, Anne L

2017-02-22

search results, assessed risk of bias, and extracted data using methods expected by Cochrane. We contacted study authors to try to obtain missing information or information to clarify risk of bias. We conducted a meta-analysis for any outcomes that were reported by at least two studies. Outcomes reported from single studies were summarized in the text. We assessed the certainty of the evidence using GRADE. We included three trials with a total of 95 randomized participants in this review and identified one ongoing trial. The studies were conducted in South Africa, India, and the Netherlands. Out of the 92 analyzed participants, 91 participants were diagnosed with endophthalmitis following cataract surgery. In the remaining participant, endophthalmitis was attributable to penetrating keratoplasty. All studies used intravitreous dexamethasone for adjunctive steroid therapy and a combination of two intravitreous antibiotics that provided gram-positive and gram-negative coverage for the antibiotic therapy. We judged one trial to be at overall low risk of bias and two studies to be at overall unclear risk of bias due to lack of reporting of study methods. None of the three trials had been registered in a clinical trial register.While none of the included studies reported the primary outcome of complete resolution of endophthalmitis as defined in our protocol, one study reported combined anatomical and functional success (i.e. proportion of participants with intraocular pressure of at least 5 mmHg and visual acuity of at least 6/120). Very low-certainty evidence suggested no difference in combined success when comparing adjunctive steroid antibiotics alone (risk ratio (RR) 1.08, 95% confidence interval (CI) 0.80 to 1.45; 32 participants). Low-certainty evidence from two studies showed that a higher proportion of participants who received adjunctive dexamethasone had a good visual outcome (Snellen visual acuity 6/6 to 6/18) at three months compared with those in the antibiotics

Adjunctive steroid therapy versus antibiotics alone for acute endophthalmitis after intraocular procedure

PubMed Central

Kim, Carole H; Chen, Monica F; Coleman, Anne L

2017-01-01

steroids. Data collection and analysis Two review authors independently screened the search results, assessed risk of bias, and extracted data using methods expected by Cochrane. We contacted study authors to try to obtain missing information or information to clarify risk of bias. We conducted a meta-analysis for any outcomes that were reported by at least two studies. Outcomes reported from single studies were summarized in the text. We assessed the certainty of the evidence using GRADE. Main results We included three trials with a total of 95 randomized participants in this review and identified one ongoing trial. The studies were conducted in South Africa, India, and the Netherlands. Out of the 92 analyzed participants, 91 participants were diagnosed with endophthalmitis following cataract surgery. In the remaining participant, endophthalmitis was attributable to penetrating keratoplasty. All studies used intravitreous dexamethasone for adjunctive steroid therapy and a combination of two intravitreous antibiotics that provided gram-positive and gram-negative coverage for the antibiotic therapy. We judged one trial to be at overall low risk of bias and two studies to be at overall unclear risk of bias due to lack of reporting of study methods. None of the three trials had been registered in a clinical trial register. While none of the included studies reported the primary outcome of complete resolution of endophthalmitis as defined in our protocol, one study reported combined anatomical and functional success (i.e. proportion of participants with intraocular pressure of at least 5 mmHg and visual acuity of at least 6/120). Very low-certainty evidence suggested no difference in combined success when comparing adjunctive steroid antibiotics alone (risk ratio (RR) 1.08, 95% confidence interval (CI) 0.80 to 1.45; 32 participants). Low-certainty evidence from two studies showed that a higher proportion of participants who received adjunctive dexamethasone had a good visual

Targeted therapies for the treatment of leukemia.

PubMed

Stull, Dawn Marie

2003-05-01

To review novel targeted therapies for the treatment of leukemia. Professional journals, books, and government publications. Nonspecific cytotoxic chemotherapeutic agents provide marginal therapeutic benefit and significant toxicity when used in the treatment of leukemia. There is a tremendous need for new therapies with increased efficacy and decreased adverse effects. Advances in molecular science, genetics, and immunology, along with improved laboratory technology, have led to the discovery of unique targets integral to the growth and proliferation of malignant cells which are providing the foundation for the development of a new generation of antitumor agents. Nurses must be prepared to educate patients, administer novel therapies, and manage side effects.

Changing strategies for target therapy in gastric cancer.

PubMed

Lee, Suk-Young; Oh, Sang Cheul

2016-01-21

In spite of a worldwide decrease in the incidence of gastric cancer, this malignancy still remains one of the leading causes of cancer mortality. Great efforts have been made to improve treatment outcomes in patients with metastatic gastric cancer, and the introduction of trastuzumab has greatly improved the overall survival. The trastuzumab treatment took its first step in opening the era of molecular targeted therapy, however several issues still need to be resolved to increase the efficacy of targeted therapy. Firstly, many patients with metastatic gastric cancer who receive trastuzumab in combination with chemotherapeutic agents develop resistance to the targeted therapy. Secondly, many clinical trials testing novel molecular targeted agents with demonstrated efficacy in other malignancies have failed to show benefit in patients with metastatic gastric cancer, suggesting the importance of the selection of appropriate indications according to molecular characteristics in application of targeted agents. Herein, we review the molecular targeted agents currently approved and in use, and clinical trials in patients with metastatic gastric cancer, and demonstrate the limitations and future direction in treatment of advanced gastric cancer.

Procalcitonin guided antibiotic therapy and hospitalization in patients with lower respiratory tract infections: a prospective, multicenter, randomized controlled trial.

PubMed

Schuetz, Philipp; Christ-Crain, Mirjam; Wolbers, Marcel; Schild, Ursula; Thomann, Robert; Falconnier, Claudine; Widmer, Isabelle; Neidert, Stefanie; Blum, Claudine A; Schönenberger, Ronald; Henzen, Christoph; Bregenzer, Thomas; Hoess, Claus; Krause, Martin; Bucher, Heiner C; Zimmerli, Werner; Müller, Beat

2007-07-05

Lower respiratory tract infections like acute bronchitis, exacerbated chronic obstructive pulmonary disease and community-acquired pneumonia are often unnecessarily treated with antibiotics, mainly because of physicians' difficulties to distinguish viral from bacterial cause and to estimate disease-severity. The goal of this trial is to compare medical outcomes, use of antibiotics and hospital resources in a strategy based on enforced evidence-based guidelines versus procalcitonin guided antibiotic therapy in patients with lower respiratory tract infections. We describe a prospective randomized controlled non-inferiority trial with an open intervention. We aim to randomize over a fixed recruitment period of 18 months a minimal number of 1002 patients from 6 hospitals in Switzerland. Patients must be >18 years of age with a lower respiratory tract infections <28 days of duration. Patients with no informed consent, not fluent in German, a previous hospital stay within 14 days, severe immunosuppression or chronic infection, intravenous drug use or a terminal condition are excluded. Randomization to either guidelines-enforced management or procalcitonin-guided antibiotic therapy is stratified by centre and type of lower respiratory tract infections. During hospitalization, all patients are reassessed at days 3, 5, 7 and at the day of discharge. After 30 and 180 days, structured phone interviews by blinded medical students are conducted. Depending on the randomization allocation, initiation and discontinuation of antibiotics is encouraged or discouraged based on evidence-based guidelines or procalcitonin cut off ranges, respectively. The primary endpoint is the risk of combined disease-specific failure after 30 days. Secondary outcomes are antibiotic exposure, side effects from antibiotics, rate and duration of hospitalization, time to clinical stability, disease activity scores and cost effectiveness. The study hypothesis is that procalcitonin-guidance is non

Epidemiology of Antibiotic Use and Antimicrobial Resistance in Selected Communities in Thailand.

PubMed

Khamsarn, Sompong; Nampoonsak, Yupin; Busamaro, Supunnee; Tangkoskul, Teerawit; Seenama, Chakkraphong; Rattanaumpawan, Pinyo; Boonyasiri, Adhiratha; Thamlikitkul, Visanu

2016-03-01

To generate epidemiological information regarding antibiotic use and antimicrobial resistance (AMR) in targeted communities for use by the Thailand AMR Containment and Prevention Program. A survey of antibiotics sold by 215 grocery stores and retail shops located in the target communities was done by the local people who were instructed to purchase specified antibiotics and to present to such stores and shops with symptoms of sore throat, backache, common cold, acute diarrhea, inflamed uterus, and dysuria. The purchased drugs were then identified and recorded. Contamination of extended-spectrum β-lactamase (ESBL)-producing E. coli was identified in 174 samples of foods and open water sources collected from the target communities. Carriage of ESBL-producing E. coli in gastrointestinal tracts of 534 adults living in the target communities was performed by stool sample culture. One thousand three hundred one patients with upper respiratory infection (URI) and 235 patients with acute diarrhea who attended the tambon health promoting hospitals located in the target communities were monitored for their clinical outcomes of treatments. The patients with URI and acute diarrhea with no indication of antibiotic received symptomatic treatments as appropriate and they were followed via telephone contact every few days until all symptoms related to URI and acute diarrhea disappeared. The data were analyzed by descriptive statistics. Antibiotics were sold to the local people who were presenting with common ailments at many grocery stores and retail shops in their respective communities. In almost all cases, antibiotics were inappropriately given. Overall prevalence of ESBL-producing E. coli contamination in foods and open water sources was 26.4%. ESBL-producing E. coli was isolated from fresh meat and open water sources in many samples. Overall prevalence of ESBL-producing E. coli carriage in gastrointestinal tracts of the adults cultured was 66.5%. All patients with URI and

Synthesis and evaluation of hetero- and homo-dimers of ribosome-targeting antibiotics: Antimicrobial activity, in vitro inhibition of translation, and drug resistance

PubMed Central

Berkov-Zrihen, Yifat; Green, Keith D.; Labby, Kristin J.; Feldman, Mark; Garneau-Tsodikova, Sylvie; Fridman, Micha

2013-01-01

In this study, we describe the synthesis of a full set of homo- and hetero-dimers of three intact structures of different ribosome-targeting antibiotics: tobramycin, clindamycin, and chloramphenicol. Several aspects of the biological activity of the dimeric structures were evaluated including antimicrobial activity, inhibition of in vitro bacterial protein translation, and the effect of dimerization on the action of several bacterial resistance mechanisms that deactivate tobramycin and chloramphenicol. This study demonstrates that covalently linking two identical or different ribosome-targeting antibiotics may lead to (i) a broader spectrum of antimicrobial activity, (ii) improved inhibition of bacterial translation properties compared to that of the parent antibiotics, and (iii) reduction in the efficacy of some drug-modifying enzymes that confer high levels of resistance to the parent antibiotics from which the dimers were derived. PMID:23786357

Use of bacteriophage to target bacterial surface structures required for virulence: a systematic search for antibiotic alternatives.

PubMed

Orndorff, Paul E

2016-11-01

Bacteriophages (phage) that infect pathogenic bacteria often attach to surface receptors that are coincidentally required for virulence. Receptor loss or modification through mutation renders mutants both attenuated and phage resistant. Such attenuated mutants frequently have no apparent laboratory growth defects, but in the host, they fail to exhibit properties needed to produce disease such as mucosal colonization or survival within professional phagocytic cells. The connection between attenuation and phage resistance has been exploited in experimental demonstrations of phage therapy. In such experiments, phage resistant mutants that arise naturally during therapy are inconsequential because of their attenuated status. A more contemporary approach to exploiting this connection involves identifying small effector molecules, identified in high-throughput screens, that inhibit one or more of the steps needed to produce a functioning phage receptor. Since such biosynthetic steps are unique to bacteria, inhibitors can be utilized therapeutically, in lieu of antibiotics. Also, since the inhibitor is specific to a particular bacterium or group of bacteria, no off-target resistance is generated in the host's commensal bacterial population. This brief review covers examples of how mutations that confer phage resistance produce attenuation, and how this coincidental relationship can be exploited in the search for the next generation of therapeutic agents for bacterial diseases.

Validation approach for a fast and simple targeted screening method for 75 antibiotics in meat and aquaculture products using LC-MS/MS.

PubMed

Dubreil, Estelle; Gautier, Sophie; Fourmond, Marie-Pierre; Bessiral, Mélaine; Gaugain, Murielle; Verdon, Eric; Pessel, Dominique

2017-04-01

An approach is described to validate a fast and simple targeted screening method for antibiotic analysis in meat and aquaculture products by LC-MS/MS. The strategy of validation was applied for a panel of 75 antibiotics belonging to different families, i.e., penicillins, cephalosporins, sulfonamides, macrolides, quinolones and phenicols. The samples were extracted once with acetonitrile, concentrated by evaporation and injected into the LC-MS/MS system. The approach chosen for the validation was based on the Community Reference Laboratory (CRL) guidelines for the validation of screening qualitative methods. The aim of the validation was to prove sufficient sensitivity of the method to detect all the targeted antibiotics at the level of interest, generally the maximum residue limit (MRL). A robustness study was also performed to test the influence of different factors. The validation showed that the method is valid to detect and identify 73 antibiotics of the 75 antibiotics studied in meat and aquaculture products at the validation levels.

Combination therapy including serratiopeptidase improves outcomes of mechanical-antibiotic treatment of periimplantitis.

PubMed

Sannino, G; Gigola, P; Puttini, M; Pera, F; Passariello, C

2013-01-01

This study was designed as a retrospective analysis of clinical outcomes of cases of periimplantitis treated by mechanical debridement and the administration of antibiotics combined or not with the administration of either the proteolytic enzyme serratiopeptidase (SPEP) or non-steroidal anti-inflammatory drugs (NSAIDs). Clinical charts of 544 partially edentulous patients treated for periimplantitis between June 1996 and December 2010 were analyzed to obtain clinical data of the affected implants just before the beginning of treatment and 12 months later to evaluate the outcomes of combined mechanical antibiotic treatment alone or in combination with the co-administration of the anti-inflammatory SPEP or NSAIDs. The comparative analysis revealed that therapeutic outcomes were significantly different in the three groups. Failure rate in the group that received SPEP (6 percent) was significantly lower compared to the group that received NSAIDS (16.9 percent; P less than 0.01) and to the group that received no anti-inflammatory therapy (18.9 percent; P less than 0.01). Treatment including SPEP was associated with significantly better healing also when successful treatments alone were considered. The data reported in this paper strongly support the hypothesis that SPEP is a valid addition to protocols for the combined therapy of peri-implantitis. In fact, it allows to enhance success rates significantly and also favors better tissue repair around successfully treated implants as compared to other regimens.

DNA-aptamers binding aminoglycoside antibiotics.

PubMed

Nikolaus, Nadia; Strehlitz, Beate

2014-02-21

Aptamers are short, single stranded DNA or RNA oligonucleotides that are able to bind specifically and with high affinity to their non-nucleic acid target molecules. This binding reaction enables their application as biorecognition elements in biosensors and assays. As antibiotic residues pose a problem contributing to the emergence of antibiotic-resistant pathogens and thereby reducing the effectiveness of the drug to fight human infections, we selected aptamers targeted against the aminoglycoside antibiotic kanamycin A with the aim of constructing a robust and functional assay that can be used for water analysis. With this work we show that aptamers that were derived from a Capture-SELEX procedure targeting against kanamycin A also display binding to related aminoglycoside antibiotics. The binding patterns differ among all tested aptamers so that there are highly substance specific aptamers and more group specific aptamers binding to a different variety of aminoglycoside antibiotics. Also the region of the aminoglycoside antibiotics responsible for aptamer binding can be estimated. Affinities of the different aptamers for their target substance, kanamycin A, are measured with different approaches and are in the micromolar range. Finally, the proof of principle of an assay for detection of kanamycin A in a real water sample is given.

A retrospective analysis of the duration of oral antibiotic therapy for the treatment of acne among adolescents: investigating practice gaps and potential cost-savings.

PubMed

Lee, Young H; Liu, Guodong; Thiboutot, Diane M; Leslie, Douglas L; Kirby, Joslyn S

2014-07-01

Duration of oral antibiotic therapy in acne has not been widely studied. Recent guidelines suggest it should be limited to 3 to 6 months. We sought to compare the duration of oral antibiotic use with recent guidelines and determine the potential cost-savings related to shortened durations. This is a retrospective cohort study from the MarketScan Commercial Claims and Encounters database. Claims data were used to determine duration and costs of antibiotic therapy. The mean course duration was 129 days. The majority (93%) of courses were less than 9 months. Among the 31,634 courses, 18,280 (57.8%) did not include concomitant topical retinoid therapy. The mean (95% confidence interval) duration with and without topical retinoid use was 133 (131.5-134.7) days and 127 (125.4-127.9) days, respectively. The mean excess direct cost of antibiotic treatment for longer than 6 months was $580.99/person. Claims cannot be attributed to a specific diagnosis or provider. The database does not provide information on acne severity. Duration of antibiotic use is decreasing when compared with previous data. However, 5547 (17.53%) courses exceeded 6 months, highlighting an opportunity for reduced antibiotic use. If courses greater than 6 months were shortened to 6 months, savings would be $580.99/person. Copyright © 2014 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

Correlation of antigenic expression with progress in antibiotic therapy of acute human brucellosis.

PubMed

Kwaasi, A A A; Al-Mohanna, F A; Nakeeb, S M; Roberts, G T; Al-Thawadi, S; Hassan, A Y; Al-Hokail, A; Elfaki, M G

2005-06-01

Human brucellosis is a zoonotic disease which is endemic in Saudi Arabia. The aim of this study was to investigate the humoral immune responses and identify the target antigens that persist at different stages in human brucellosis during antibiotic therapy. To do this, an acute case of accidental nosocomial infection was studied experimentally. Blood was collected from the patient at the time of diagnosis, and at weekly intervals during therapy until remission. IgG and IgM immunoblotting was used to characterize specific antigenic determinants, and ELISA antibody titration was performed to quantify the circulating antibodies. Results indicated that protein bands of 12-13.5 kDa bound IgG in the patient's sera but did not bind IgM on immunoblots and are probably not specific for, or important in, early stage infections. However, an 18 kDa band persisted during infection through remission. The pivotal and most important findings were that the number of protein bands seen on immunoblots, the magnitude of ELISA antibody titres and the concomitant changes in the intensity of the polypeptide bands of 42-43 kDa were positively correlated with the stage of infection. High numbers of anti-IgG and -IgM immunoblot bands coupled with high ELISA antibody titres and a concomitant increase in intensity of the 42-43 kDa bands were positively correlated with acute and severe infection. Conversely, a reduction in the number of polypeptide bands as well as a decrease in the intensity, until the complete disappearance of the 42-43 kDa bands, coupled with low (baseline) ELISA antibody titration values indicated successful treatment and remission. The routine use of the methods described here to ascertain the stage of the disease, assess the progress of antimicrobial therapy and monitor cases of relapse in human brucellosis is suggested.

Anthrax prevention and treatment: utility of therapy combining antibiotic plus vaccine.

PubMed

Klinman, Dennis M; Yamamoto, Masaki; Tross, Debra; Tomaru, Koji

2009-12-01

The intentional release of anthrax spores in 2001 confirmed this pathogen's ability to cause widespread panic, morbidity and mortality. While individuals exposed to anthrax can be successfully treated with antibiotics, pre-exposure vaccination can reduce susceptibility to infection-induced illness. Concern over the safety and immunogenicity of the licensed US vaccine (Anthrax Vaccine Adsorbed (AVA)) has fueled research into alternatives. Second-generation anthrax vaccines based on purified recombinant protective antigen (rPA) have entered clinical trials. These rPA vaccines induce neutralizing antibodies that prevent illness, but the magnitude and duration of the resultant protective response is modest. Efforts are underway to bolster the immunogenicity of rPA by combining it with adjuvants and other immunostimulatory agents. Third generation vaccines are under development that utilize a wide variety of immunization platforms, antigens, adjuvants, delivery methods and routes of delivery to optimize the induction of a protective immunity. For the foreseeable future, vaccination will rely on first and second generation vaccines co-administered with immune adjuvants. Optimal post-exposure treatment of immunologically naive individuals should include a combination of vaccine plus antibiotic therapy.

Supplementation of standard antibiotic therapy with oral probiotics for bacterial vaginosis and aerobic vaginitis: a randomised, double-blind, placebo-controlled trial.

PubMed

Heczko, Piotr B; Tomusiak, Anna; Adamski, Paweł; Jakimiuk, Artur J; Stefański, Grzegorz; Mikołajczyk-Cichońska, Aleksandra; Suda-Szczurek, Magdalena; Strus, Magdalena

2015-12-03

This multicentre, randomised, double-blind, placebo-controlled trial was performed to determine whether the use of oral probiotic preparation (prOVag®) containing three Lactobacillus strains together with standard metronidazole treatment and also targeted antibiotic treatment (following the failure of metronidazole therapy) could reduce the recurrence rates of bacterial vaginosis (BV) and aerobic vaginitis (AV). Patients at private gynaecological clinics in Poland with histories of recurrent BV/AV and current symptoms were randomly allocated to receive metronidazole and probiotic or placebo, and assessed monthly on visits II and III-V. The total number of study visits was 5-6 (I, II, II bis - if applicable, III, IV, V). One probiotic or placebo capsule was administered with metronidazole/targeted antibiotic twice daily for 10 days; during follow up, patients took one capsule daily for 10 days perimenstrually. Clinical examination and vaginal swabbing were performed at each visit. Primary outcomes were clinical or microbiological BV/AV recurrence and probiotic safety. Secondary outcomes were vaginal pH, Nugent score, and Lactobacillus counts in the vaginal microbiota. Safety analysis was performed in 578 (probiotic, n = 285; placebo, n = 293) 18-50-year-old women who were randomised. BV/AV was confirmed microbiologically in 241 (probiotic, n = 118; placebo, n = 123) participants, who continued the trial. Data from 154 (probiotic, n = 73; placebo, n = 81) participants who completed the study were analysed to determine the efficacy of prOVag. Additional analyses included 37 (probiotic, n = 22; placebo, n = 15) participants who received targeted antibiotics and probiotics or placebo. prOVag lengthened the time to clinical relapse of BV/AV symptoms up to 51 % (p < 0.05) compared with placebo; AV relapse was delayed by up to 76 % (p < 0.05). Probiotic use also reduced and maintained low vaginal pH and Nugent score, and increased

Targeted cancer therapy--are the days of systemic chemotherapy numbered?

PubMed

Joo, Won Duk; Visintin, Irene; Mor, Gil

2013-12-01

Targeted therapy or molecular targeted therapy has been defined as a type of treatment that blocks the growth of cancer cells by interfering with specific cell molecules required for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells as with traditional chemotherapy. There is a growing number of FDA approved monoclonal antibodies and small molecules targeting specific types of cancer suggestive of the growing relevance of this therapeutic approach. Targeted cancer therapies, also referred to as "Personalized Medicine", are being studied for use alone, in combination with other targeted therapies, and in combination with chemotherapy. The objective of personalized medicine is the identification of patients that would benefit from a specific treatment based on the expression of molecular markers. Examples of this approach include bevacizumab and olaparib, which have been designated as promising targeted therapies for ovarian cancer. Combinations of trastuzumab with pertuzumab, or T-DM1 and mTOR inhibitors added to an aromatase inhibitor are new therapeutic strategies for breast cancer. Although this approach has been seen as a major step in the expansion of personalized medicine, it has substantial limitations including its high cost and the presence of serious adverse effects. The Cancer Genome Atlas is a useful resource to identify novel and more effective targets, which may help to overcome the present limitations. In this review we will discuss the clinical outcome of some of these new therapies with a focus on ovarian and breast cancer. We will also discuss novel concepts in targeted therapy, the target of cancer stem cells. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Nano-antibiotics in chronic lung infection therapy against Pseudomonas aeruginosa.

PubMed

Hadinoto, Kunn; Cheow, Wean Sin

2014-04-01

Antibiotic encapsulation into nanoparticle carriers has emerged as a promising inhaled antibiotic formulation for treatment of chronic Pseudomonas aeruginosa lung infection prevalent in chronic obstructive pulmonary diseases. Attributed to their prolonged lung retention, sustained antibiotic release, and mucus penetrating ability, antibiotic nanoparticles, or nano-antibiotics in short, can address the principal weakness of inhaled antibiotic solution, i.e. low antibiotic exposure in the vicinity of P. aeruginosa biofilm colonies resulting in diminished anti-pseudomonal efficacy after repeated uses. This review details the current state of development and limitations of the two most widely studied forms of nano-antibiotics, i.e. liposomes and polymer nanoparticles. Factors in their formulation that influence the anti-pseudomonal efficacy in vitro and in vivo, such as liposome's membrane rigidity, surface charge, size, and polymer hydrophobicity, are discussed. This review reveals that the superior anti-pseudomonal efficacy of liposomal antibiotics to free antibiotics has been clearly established when they are correctly formulated, with several liposomal antibiotic formulations are currently undergoing clinical trials. Liposomal antibiotics, nevertheless, are not without limitation due to their weak physicochemical stability. In contrast, only mucus penetrating ability of the more stable polymeric nano-antibiotics has been established, while their anti-pseudomonal efficacy has only been examined in vitro from which their superiority to free antibiotics has not been ascertained. Lastly, future research needs to bring liposome and polymer-based nano-antibiotics closer to their clinical realization are identified. Copyright © 2014 Elsevier B.V. All rights reserved.

Controversies in targeted therapy of adult T cell leukemia/lymphoma: ON target or OFF target effects?

PubMed

Nasr, Rihab; El Hajj, Hiba; Kfoury, Youmna; de Thé, Hugues; Hermine, Olivier; Bazarbachi, Ali

2011-06-01

Adult T cell leukemia/lymphoma (ATL) represents an ideal model for targeted therapy because of intrinsic chemo-resistance of ATL cells and the presence of two well identified targets: the HTLV-I retrovirus and the viral oncoprotein Tax. The combination of zidovudine (AZT) and interferon-alpha (IFN) has a dramatic impact on survival of ATL patients. Although the mechanism of action remains unclear, arguments in favor or against a direct antiviral effect will be discussed. Yet, most patients relapse and alternative therapies are mandatory. IFN and arsenic trioxide induce Tax proteolysis, synergize to induce apoptosis in ATL cells and cure Tax-driven ATL in mice through specific targeting of leukemia initiating cell activity. These results provide a biological basis for the clinical success of arsenic/IFN/AZT therapy in ATL patients and suggest that both extinction of viral replication (AZT) and Tax degradation (arsenic/IFN) are needed to cure ATL.

WAAR (World Alliance against Antibiotic Resistance): Safeguarding antibiotics.

PubMed

Carlet, Jean; Rambaud, Claude; Pulcini, Céline

2012-07-09

Resistance to antibiotics has increased recently to a dramatic extend, and the pipeline of new antibiotics is almost dry for the five next years. Failures happen already for trivial community acquired infections, like pyelonephritis, or peritonitis, and this is likely to increase. Difficult surgical procedures, transplants, and other immunosuppressive therapies will become far more risky. Resistance is mainly due to an excessive usage of antibiotics, in all sectors, including the animal one. Action is urgently needed. Therefore, an alliance against MDRO has been recently created, which includes health care professionals, consumers, health managers, and politicians. The document highlights the different proposed measures, and represents a strong consensus between the different professionals, including general practicionners, and veterinarians.

Recent Advances in Targeted Therapy for Glioma.

PubMed

Lin, Lin; Cai, Jinquan; Jiang, Chuanlu

2017-01-01

Gliomas are the most common primary malignant brain tumors, which have a universally fatal outcome. Current standard treatment for glioma patients is surgical removal followed by radiotherapy and adjuvant chemotherapy. Due to therapeutic resistance and tumor recurrence, efforts are ongoing to identify the molecules that are fundamental to regulate the tumor progression and provide additional methods for individual treatment of glioma patients. By studying the initiation and maintenance of glioma, studies focused on the targets of tyrosine kinase receptors including EGFR, PDGFR and other crucial signal pathways such as PI3K/AKT and RAS/RAF/MAPK pathway. Furthermore, recent advances in targeting immunotherapy and stem cell therapy also brought numerous strategies to glioma treatment. This article reviewed the researches focused on the advanced strategies of various target therapies for improving the glioma treatment efficacy, and discussed the challenges and future directions for glioma therapy. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A prospective randomized controlled multicenter trial comparing antibiotic therapy with appendectomy in the treatment of uncomplicated acute appendicitis (APPAC trial).

PubMed

Paajanen, Hannu; Grönroos, Juha M; Rautio, Tero; Nordström, Pia; Aarnio, Markku; Rantanen, Tuomo; Hurme, Saija; Dean, Kirsti; Jartti, Airi; Mecklin, Jukka-Pekka; Sand, Juhani; Salminen, Paulina

2013-02-08

Although the standard treatment of acute appendicitis (AA) consists of an early appendectomy, there has recently been both an interest and an increase in the use of antibiotic therapy as the primary treatment for uncomplicated AA. However, the use of antibiotic therapy in the treatment of uncomplicated AA is still controversial. The APPAC trial is a randomized prospective controlled, open label, non-inferiority multicenter trial designed to compare antibiotic therapy (ertapenem) with emergency appendectomy in the treatment of uncomplicated AA. The primary endpoint of the study is the success of the randomized treatment. In the antibiotic treatment arm successful treatment is defined as being discharged from the hospital without the need for surgical intervention and no recurrent appendicitis during a minimum follow-up of one-year (treatment efficacy). Treatment efficacy in the operative treatment arm is defined as successful appendectomy evaluated to be 100%. Secondary endpoints are post-intervention complications, overall morbidity and mortality, the length of hospital stay and sick leave, treatment costs and pain scores (VAS, visual analoque scale). A maximum of 610 adult patients (aged 18-60 years) with a CT scan confirmed uncomplicated AA will be enrolled from six hospitals and randomized by a closed envelope method in a 1:1 ratio either to undergo emergency appendectomy or to receive ertapenem (1 g per day) for three days continued by oral levofloxacin (500 mg per day) plus metronidazole (1.5 g per day) for seven days. Follow-up by a telephone interview will be at 1 week, 2 months and 1, 3, 5 and 10 years; the primary and secondary endpoints of the trial will be evaluated at each time point. The APPAC trial aims to provide level I evidence to support the hypothesis that approximately 75-85% of patients with uncomplicated AA can be treated with effective antibiotic therapy avoiding unnecessary appendectomies and the related operative morbidity, also resulting

Impact of procalcitonin-guided therapy for hospitalized community-acquired pneumonia on reducing antibiotic consumption and costs in Japan.

PubMed

Ito, Akihiro; Ishida, Tadashi; Tokumasu, Hironobu; Washio, Yasuyoshi; Yamazaki, Akio; Ito, Yuhei; Tachibana, Hiromasa

2017-03-01

This study aimed to investigate the usefulness of procalcitonin-guided therapy in hospitalized community-acquired pneumonia patients to reduce antibiotic duration and costs without worsening prognosis. 352 hospitalized community-acquired pneumonia patients in an observational cohort study in which procalcitonin was measured three times serially, on admission (Day 1) and 2-3 days (Day 3) and 6-8 days (Day 7) after admission, between October 2010 and February 2016 were reviewed retrospectively. Antibiotics could be stopped if Day 7 procalcitonin was <0.25 ng mL -1 or ≤10% of the higher value of procalcitonin on Day 1 or 3. Antibiotic duration and costs and recurrence and mortality rates were evaluated in mild to moderate or severe pneumonia by theoretical procalcitonin guidance for community-acquired pneumonia treatment. Using theoretical procalcitonin guidance, antibiotic duration could be reduced from 12.6 to 8.6 days (P < 0.001), while costs could be reduced from 45,833 to 38,952 yen (P = 0.005). Among the patients in whom theoretical procalcitonin guidance could be adopted, recurrence rates (5.6% vs. 8.1%, P = 0.15) and mortality rates (0% vs. 5.1%, P = 0.07) did not worsen between the group having the same antibiotic durations as with theoretical procalcitonin guidance in actual practice (N = 71) and the group having durations more than 2 days longer in actual practice than in theoretical procalcitonin guidance (N = 198). There was no significant difference in pneumonia severity using A-DROP, CURB-65, and PSI between two groups. Procalcitonin-guided therapy may be useful in hospitalized community-acquired pneumonia patients to reduce antibiotic duration and costs without worsening the prognosis. Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Advances of Molecular Targeted Therapy in Gastric Cancer.

PubMed

Cetin, Bulent; Gumusay, Ozge; Cengiz, Mustafa; Ozet, Ahmet

2016-06-01

Gastric cancer is the second most common cause of cancer-related death in the world, and its prognosis remains poor with a median overall survival of 12 months for advanced disease. Advances in the understanding of molecular genetics have led to the development of directed molecular targeted therapy in gastric cancer, leading to improve patient outcomes and quality of life. In the treatment of human epidermal growth factor receptor 2 (HER2)-positive gastric cancer, the addition of trastuzumab significantly improves survival in the first-line setting of therapy. Ramucirumab, an antibody directed against vascular endothelial growth factor receptor 2, significantly improved progression-free and overall survival and has been approved for second-line treatment of gastric cancer. Anti-mesenchymal-epithelial transition (c-MET), mammalian target of rapamycin inhibitors, and polo-like kinase 1 inhibitors are under investigation as a novel therapeutic option for the treatment of gastric cancer. The novel therapies target the key immune checkpoint interaction between a T cell co-inhibitory receptor called programmed death 1 (PD-1) and one of its immunosuppressive ligands, PD-L1. This article reviews molecular targeted therapies in gastric cancer, in light of recent advances.

Identification of Thiotetronic Acid Antibiotic Biosynthetic Pathways by Target-directed Genome Mining.

PubMed

Tang, Xiaoyu; Li, Jie; Millán-Aguiñaga, Natalie; Zhang, Jia Jia; O'Neill, Ellis C; Ugalde, Juan A; Jensen, Paul R; Mantovani, Simone M; Moore, Bradley S

2015-12-18

Recent genome sequencing efforts have led to the rapid accumulation of uncharacterized or "orphaned" secondary metabolic biosynthesis gene clusters (BGCs) in public databases. This increase in DNA-sequenced big data has given rise to significant challenges in the applied field of natural product genome mining, including (i) how to prioritize the characterization of orphan BGCs and (ii) how to rapidly connect genes to biosynthesized small molecules. Here, we show that by correlating putative antibiotic resistance genes that encode target-modified proteins with orphan BGCs, we predict the biological function of pathway specific small molecules before they have been revealed in a process we call target-directed genome mining. By querying the pan-genome of 86 Salinispora bacterial genomes for duplicated house-keeping genes colocalized with natural product BGCs, we prioritized an orphan polyketide synthase-nonribosomal peptide synthetase hybrid BGC (tlm) with a putative fatty acid synthase resistance gene. We employed a new synthetic double-stranded DNA-mediated cloning strategy based on transformation-associated recombination to efficiently capture tlm and the related ttm BGCs directly from genomic DNA and to heterologously express them in Streptomyces hosts. We show the production of a group of unusual thiotetronic acid natural products, including the well-known fatty acid synthase inhibitor thiolactomycin that was first described over 30 years ago, yet never at the genetic level in regards to biosynthesis and autoresistance. This finding not only validates the target-directed genome mining strategy for the discovery of antibiotic producing gene clusters without a priori knowledge of the molecule synthesized but also paves the way for the investigation of novel enzymology involved in thiotetronic acid natural product biosynthesis.

Antibiotic prescribing for endodontic therapies: a comparative survey between general dental practitioners and final year Bachelor of Dental Surgery students in Cardiff, UK.

PubMed

Al Masan, A A; Dummer, P M H; Farnell, D J J; Vianna, M E

2018-07-01

To evaluate the views of final year dental surgery students (BDS; G1) at Cardiff University and general dental practitioners (GDPs; G2) within the geographic area of Cardiff, Wales, on antibiotic prescribing for endodontic conditions, and investigate the potential differences between the two groups. A cross-sectional online questionnaire-based survey of 12 qualitative and quantitative questions was distributed to 76 final year BDS Cardiff University students and 55 dental practices within Cardiff, UK. Six questions recorded general information, and the remaining questions included a series of hypothetical clinical scenarios, where the participants were asked to state whether they would or would not prescribe antibiotics. The data were analysed using spss version 23 to produce descriptive statistics, contingency tables and to run chi-square (χ²) tests, Fisher's exact tests and relative risk calculations. The response rate was 60% (n = 79). All G1 participants were aware of the consequences of antibiotic overuse. Approximately 60% of responders were aware of guidelines for antibiotic use in endodontic therapies, and 83% would only use antibiotics for a limited selection of patients (e.g. patients with systemic complications). G1 responses to clinical scenarios indicated overall that they were comparable to the ideal answers except for acute apical abscess (64% believed that antibiotics were indicated). The majority of G2 were aware of the consequences of antibiotic overuse. Only 28% of G2 were aware of guidelines for antibiotic use in endodontic therapies. Overall responses revealed that antibiotics would be prescribed for: systemic complications (78%), acute apical abscess (72%) and symptomatic apical periodontitis (28%). The clinical scenarios revealed G1 were more likely to prescribe antibiotics compared to G2 for cases of necrotic pulp with symptomatic apical periodontitis without systemic complications (incorrect answer) and less likely to other clinical

Antibiotic prescribing at the transition from hospitalization to discharge: a target for antibiotic stewardship

PubMed Central

Yogo, Norihiro; Haas, Michelle K; Knepper, Bryan C; Burman, William J; Mehler, Philip S; Jenkins, Timothy C

2016-01-01

Of 300 patients prescribed oral antibiotics at the time of hospital discharge, urinary tract infection, community-acquired pneumonia , and skin infections accounted for 181 (60%) of the treatment indications. Half of the prescriptions were antibiotics with broad gram-negative activity. Discharge prescriptions were inappropriate in 79 (53%) of 150 cases reviewed. PMID:25782905

Antibiotic treatment for Helicobacter pylori: Is the end coming?

PubMed Central

Kim, Su Young; Choi, Duck Joo; Chung, Jun-Won

2015-01-01

Infection with the Gram-negative pathogen Helicobacter pylori (H. pylori) has been associated with gastro-duodenal disease and the importance of H. pylori eradication is underscored by its designation as a group I carcinogen. The standard triple therapy consists of a proton pump inhibitor, amoxicillin and clarithromycin, although many other regimens are used, including quadruple, sequential and concomitant therapy regimens supplemented with metronidazole, clarithromycin and levofloxacin. Despite these efforts, current therapeutic regimens lack efficacy in eradication due to antibiotic resistance, drug compliance and antibiotic degradation by the acidic stomach environment. Antibiotic resistance to clarithromycin and metronidazole is particularly problematic and several approaches have been proposed to overcome this issue, such as complementary probiotic therapy with Lactobacillus. Other studies have identified novel molecules with an anti-H. pylori effect, as well as tailored therapy and nanotechnology as viable alternative eradication strategies. This review discusses current antibiotic therapy for H. pylori infections, limitations of this type of therapy and predicts the availability of newly developed therapies for H. pylori eradication. PMID:26558152

Bacteriophage-Derived Vectors for Targeted Cancer Gene Therapy

PubMed Central

Pranjol, Md Zahidul Islam; Hajitou, Amin

2015-01-01

Cancer gene therapy expanded and reached its pinnacle in research in the last decade. Both viral and non-viral vectors have entered clinical trials, and significant successes have been achieved. However, a systemic administration of a vector, illustrating safe, efficient, and targeted gene delivery to solid tumors has proven to be a major challenge. In this review, we summarize the current progress and challenges in the targeted gene therapy of cancer. Moreover, we highlight the recent developments of bacteriophage-derived vectors and their contributions in targeting cancer with therapeutic genes following systemic administration. PMID:25606974

Bacteriophage-derived vectors for targeted cancer gene therapy.

PubMed

Pranjol, Md Zahidul Islam; Hajitou, Amin

2015-01-19

Cancer gene therapy expanded and reached its pinnacle in research in the last decade. Both viral and non-viral vectors have entered clinical trials, and significant successes have been achieved. However, a systemic administration of a vector, illustrating safe, efficient, and targeted gene delivery to solid tumors has proven to be a major challenge. In this review, we summarize the current progress and challenges in the targeted gene therapy of cancer. Moreover, we highlight the recent developments of bacteriophage-derived vectors and their contributions in targeting cancer with therapeutic genes following systemic administration.

Do we treat our patients or rather periodontal microbes with adjunctive antibiotics in periodontal therapy? A 16S rDNA microbial community analysis.

PubMed

Hagenfeld, Daniel; Koch, Raphael; Jünemann, Sebastian; Prior, Karola; Harks, Inga; Eickholz, Peter; Hoffmann, Thomas; Kim, Ti-Sun; Kocher, Thomas; Meyle, Jörg; Kaner, Doğan; Schlagenhauf, Ulrich; Ehmke, Benjamin; Harmsen, Dag

2018-01-01

Empiric antibiotics are often used in combination with mechanical debridement to treat patients suffering from periodontitis and to eliminate disease-associated pathogens. Until now, only a few next generation sequencing 16S rDNA amplicon based publications with rather small sample sizes studied the effect of those interventions on the subgingival microbiome. Therefore, we studied subgingival samples of 89 patients with chronic periodontitis (solely non-smokers) before and two months after therapy. Forty-seven patients received mechanical periodontal therapy only, whereas 42 patients additionally received oral administered amoxicillin plus metronidazole (500 and 400 mg, respectively; 3x/day for 7 days). Samples were sequenced with Illumina MiSeq 300 base pairs paired end technology (V3 and V4 hypervariable regions of the 16S rDNA). Inter-group differences before and after therapy of clinical variables (percentage of sites with pocket depth ≥ 5mm, percentage of sites with bleeding on probing) and microbiome variables (diversity, richness, evenness, and dissimilarity) were calculated, a principal coordinate analysis (PCoA) was conducted, and differential abundance of agglomerated ribosomal sequence variants (aRSVs) classified on genus level was calculated using a negative binomial regression model. We found statistically noticeable decreased richness, and increased dissimilarity in the antibiotic, but not in the placebo group after therapy. The PCoA revealed a clear compositional separation of microbiomes after therapy in the antibiotic group, which could not be seen in the group receiving mechanical therapy only. This difference was even more pronounced on aRSV level. Here, adjunctive antibiotics were able to induce a microbiome shift by statistically noticeably reducing aRSVs belonging to genera containing disease-associated species, e.g., Porphyromonas, Tannerella, Treponema, and Aggregatibacter, and by noticeably increasing genera containing health

Continuous versus intermittent antibiotics for bronchiectasis.

PubMed

Donovan, Tim; Felix, Lambert M; Chalmers, James D; Milan, Stephen J; Mathioudakis, Alexander G; Spencer, Sally

2018-06-03

Bronchiectasis is a chronic airway disease characterised by a destructive cycle of recurrent airway infection, inflammation and tissue damage. Antibiotics are a main treatment for bronchiectasis. The aim of continuous therapy with prophylactic antibiotics is to suppress bacterial load, but bacteria may become resistant to the antibiotic, leading to a loss of effectiveness. On the other hand, intermittent prophylactic antibiotics, given over a predefined duration and interval, may reduce antibiotic selection pressure and reduce or prevent the development of resistance. This systematic review aimed to evaluate the current evidence for studies comparing continuous versus intermittent administration of antibiotic treatment in bronchiectasis in terms of clinical efficacy, the emergence of resistance and serious adverse events. To evaluate the effectiveness of continuous versus intermittent antibiotics in the treatment of adults and children with bronchiectasis, using the primary outcomes of exacerbations, antibiotic resistance and serious adverse events. On 1 August 2017 and 4 May 2018 we searched the Cochrane Airways Review Group Specialised Register (CAGR), CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and AMED. On 25 September 2017 and 4 May 2018 we also searched www.clinicaltrials.gov, the World Health Organization (WHO) trials portal, conference proceedings and the reference lists of existing systematic reviews. We planned to include randomised controlled trials (RCTs) of adults or children with bronchiectasis that compared continuous versus intermittent administration of long-term prophylactic antibiotics of at least three months' duration. We considered eligible studies reported as full-text articles, as abstracts only and unpublished data. Two review authors independently screened the search results and full-text reports. We identified 268 unique records. Of these we retrieved and examined 126 full-text reports, representing 114 studies, but none of these studies

Antibiotic alternatives: the substitution of antibiotics in animal husbandry?

PubMed Central

Cheng, Guyue; Hao, Haihong; Xie, Shuyu; Wang, Xu; Dai, Menghong; Huang, Lingli; Yuan, Zonghui

2014-01-01

It is a common practice for decades to use of sub-therapeutic dose of antibiotics in food-animal feeds to prevent animals from diseases and to improve production performance in modern animal husbandry. In the meantime, concerns over the increasing emergence of antibiotic-resistant bacteria due to the unreasonable use of antibiotics and an appearance of less novelty antibiotics have prompted efforts to develop so-called alternatives to antibiotics. Whether or not the alternatives could really replace antibiotics remains a controversial issue. This review summarizes recent development and perspectives of alternatives to antibiotics. The mechanism of actions, applications, and prospectives of the alternatives such as immunity modulating agents, bacteriophages and their lysins, antimicrobial peptides, pro-, pre-, and synbiotics, plant extracts, inhibitors targeting pathogenicity (bacterial quorum sensing, biofilm, and virulence), and feeding enzymes are thoroughly discussed. Lastly, the feasibility of alternatives to antibiotics is deeply analyzed. It is hard to conclude that the alternatives might substitute antibiotics in veterinary medicine in the foreseeable future. At the present time, prudent use of antibiotics and the establishment of scientific monitoring systems are the best and fastest way to limit the adverse effects of the abuse of antibiotics and to ensure the safety of animal-derived food and environment. PMID:24860564

Controversies in Targeted Therapy of Adult T Cell Leukemia/Lymphoma: ON Target or OFF Target Effects?

PubMed Central

Nasr, Rihab; Hajj, Hiba El; Kfoury, Youmna; de Thé, Hugues; Hermine, Olivier; Bazarbachi, Ali

2011-01-01

Adult T cell leukemia/lymphoma (ATL) represents an ideal model for targeted therapy because of intrinsic chemo-resistance of ATL cells and the presence of two well identified targets: the HTLV-I retrovirus and the viral oncoprotein Tax. The combination of zidovudine (AZT) and interferon-alpha (IFN) has a dramatic impact on survival of ATL patients. Although the mechanism of action remains unclear, arguments in favor or against a direct antiviral effect will be discussed. Yet, most patients relapse and alternative therapies are mandatory. IFN and arsenic trioxide induce Tax proteolysis, synergize to induce apoptosis in ATL cells and cure Tax-driven ATL in mice through specific targeting of leukemia initiating cell activity. These results provide a biological basis for the clinical success of arsenic/IFN/AZT therapy in ATL patients and suggest that both extinction of viral replication (AZT) and Tax degradation (arsenic/IFN) are needed to cure ATL. PMID:21994752

Targeting the Nonmevalonate Pathway in Burkholderia cenocepacia Increases Susceptibility to Certain β-Lactam Antibiotics.

PubMed

Sass, Andrea; Everaert, Annelien; Van Acker, Heleen; Van den Driessche, Freija; Coenye, Tom

2018-05-01

The nonmevalonate pathway is the sole pathway for isoprenoid biosynthesis in Burkholderia cenocepacia and is possibly a novel target for the development of antibacterial chemotherapy. The goals of the present study were to evaluate the essentiality of dxr , the second gene of the nonmevalonate pathway, in B. cenocepacia and to determine whether interfering with the nonmevalonate pathway increases susceptibility toward antibiotics. To this end, a rhamnose-inducible conditional dxr knockdown mutant of B. cenocepacia strain K56-2 ( B. cenocepacia K56-2 dxr ) was constructed, using a plasmid which enables the delivery of a rhamnose-inducible promoter in the chromosome. Expression of dxr is essential for bacterial growth; the growth defect observed in the dxr mutant could be complemented by expressing dxr in trans under the control of a constitutive promoter, but not by providing 2- C -methyl-d-erythritol-4-phosphate, the reaction product of DXR (1-deoxy-d-xylulose 5-phosphate reductoisomerase). B. cenocepacia K56-2 dxr showed markedly increased susceptibility to the β-lactam antibiotics aztreonam, ceftazidime, and cefotaxime, while susceptibility to other antibiotics was not (or was much less) affected; this increased susceptibility could also be complemented by in trans expression of dxr A similarly increased susceptibility was observed when antibiotics were combined with FR900098, a known DXR inhibitor. Our data confirm that the nonmevalonate pathway is essential in B. cenocepacia and suggest that combining potent DXR inhibitors with selected β-lactam antibiotics is a useful strategy to combat B. cenocepacia infections. Copyright © 2018 American Society for Microbiology.

Antibiotic pharmacoeconomics: an attempt to find the real cost of hospital antibiotic prescribing.

PubMed Central

Kerr, J. R.; Barr, J. G.; Smyth, E. T.; O'Hare, J.; Bell, P. M.; Callender, M. E.

1993-01-01

Antibiotics account for a large part of all hospital pharmacy budgets, but the actual cost of their prescription is unknown. These costs include intravenous administration, labour, serum antibiotic assay, monitoring of haematological and biochemical indices, disposal of sharps and adverse effects. An in-house method of costing antibiotic therapy is presented, to quantify these hidden expenses. Since not only an awareness, but an accurate quantification, of hidden costs is required, a study of various hospital procedures relating directly to antibiotic therapy was undertaken in an acute medical ward; this involved the identification of particular staff members performing various procedures, consumables used and time taken. The cost of five-day courses of gentamicin, penicillin G, ampicillin, flucloxacillin, cefuroxime, ceftotaxime and erythromycin has been calculated; drug and hidden costs for each are presented graphically for comparison. The breakdown cost for gentamicin is presented to illustrate the method. The costing of adverse effects has not been attempted. We suggest that costings of this sort are used in cost-benefit analysis of antibiotic use. These calculations have been incorporated into a computer spreadsheet and this costing service will be offered to clinical areas of our hospital. PMID:8516976

Mucin-based targeted pancreatic cancer therapy.

PubMed

Torres, Maria P; Chakraborty, Subhankar; Souchek, Joshua; Batra, Surinder K

2012-01-01

The prognosis of pancreatic cancer (PC) patients is very poor with a five-year survival of less than 5%. One of the major challenges in developing new therapies for PC is the lack of expression of specific markers by pancreatic tumor cells. Mucins are heavily Oglycosylated proteins characterized by the presence of short stretches of amino acid sequences repeated several times in tandem. The expression of several mucins including MUC1, MUC4, MUC5AC, and MUC16 is strongly upregulated in PC. Recent studies have also demonstrated a link between the aberrant expression and differential overexpression of mucin glycoproteins to the initiation, progression, and poor prognosis of the disease. These studies have led to increasing recognition of mucins as potential diagnostic markers and therapeutic targets in PC. In this focused review we present an overview of the therapies targeting mucins in PC, including immunotherapy (i.e. vaccines, antibodies, and radioimmunoconjugates), gene therapy, and other novel therapeutic strategies.

Negative Pressure Wound Therapy Reduces the Effectiveness of Traditional Local Antibiotic Depot in a Large Complex Musculoskeletal Wound Animal Model

DTIC Science & Technology

2012-09-01

in particular, local antibiotic delivery via polymethylmethacrylate (PMMA) bone cement and negative pressure wound therapy (NPWT). In cases with gross...release of gentamicin from polymethylmethacrylate beads. An experimental and pharmacoki- netic study. J Bone Joint Surg Br. 1978;60-B:270 275. 7...diffusion from antibiotic-impregnated polymethylmethacrylate beads. Clin Orthop Relat Res. 1992;278:244 252. Stinner et al J Orthop Trauma Volume

Imatinib: A Breakthrough of Targeted Therapy in Cancer

PubMed Central

Iqbal, Naveed

2014-01-01

Deregulated protein tyrosine kinase activity is central to the pathogenesis of human cancers. Targeted therapy in the form of selective tyrosine kinase inhibitors (TKIs) has transformed the approach to management of various cancers and represents a therapeutic breakthrough. Imatinib was one of the first cancer therapies to show the potential for such targeted action. Imatinib, an oral targeted therapy, inhibits tyrosine kinases specifically BCR-ABL, c-KIT, and PDGFRA. Apart from its remarkable success in CML and GIST, Imatinib benefits various other tumors caused by Imatinib-specific abnormalities of PDGFR and c-KIT. Imatinib has also been proven to be effective in steroid-refractory chronic graft-versus-host disease because of its anti-PDGFR action. This paper is a comprehensive review of the role of Imatinib in oncology. PMID:24963404

Improving patient outcomes to targeted therapies in melanoma.

PubMed

Eroglu, Zeynep; Smalley, Keiran S M; Sondak, Vernon K

2016-06-01

The arrival of targeted therapies has led to significant improvements in clinical outcomes for patients with BRAFV600 mutated advanced melanoma over the past five years. In several clinical trials, BRAF and MEK inhibitors have shown improvement in progression free and overall survival, along with much higher tumor response rates in comparison to chemotherapy, with the combination of these drugs superior to monotherapy. These agents are also being tested in earlier-stage patients, in addition to alternative dosing regimens and in combinations with other therapeutics. Efforts are also ongoing to expand the success found with targeted therapies to other subtypes of melanoma, including NRAS and c-kit mutated melanomas, uveal melanomas, and BRAF/NRAS wild type melanomas. Expert Commentary: We aim to provide an overview of clinical outcomes with targeted therapies in melanoma patients.

The Rationale and Evidence for Use of Inhaled Antibiotics to Control Pseudomonas aeruginosa Infection in Non-cystic Fibrosis Bronchiectasis

PubMed Central

2018-01-01

Abstract Non-cystic fibrosis bronchiectasis (NCFBE) is a chronic inflammatory lung disease characterized by irreversible dilation of the bronchi, symptoms of persistent cough and expectoration, and recurrent infective exacerbations. The prevalence of NCFBE is on the increase in the United States and Europe, but no licensed therapies are currently available for its treatment. Although there are many similarities between NCFBE and cystic fibrosis (CF) in terms of respiratory symptoms, airway microbiology, and disease progression, there are key differences, for example, in response to treatment, suggesting differences in pathogenesis. This review discusses possible reasons underlying differences in response to inhaled antibiotics in people with CF and NCFBE. Pseudomonas aeruginosa infections are associated with the most severe forms of bronchiectasis. Suboptimal levels of antibiotics in the lung increase the mutation frequency of P. aeruginosa and lead to the development of mucoid strains characterized by formation of a protective polysaccharide biofilm. Mucoid strains of P. aeruginosa are associated with a chronic infection stage, requiring long-term antibiotic therapy. Inhaled antibiotics provide targeted delivery to the lung with minimal systemic toxicity and adverse events compared with oral/intravenous routes of administration, and they could be alternative treatment options to help address some of the treatment challenges in the management of severe cases of NCFBE. This review provides an overview of completed and ongoing trials that evaluated inhaled antibiotic therapy for NCFBE. Recently, several investigators conducted phase 3 randomized controlled trials with inhaled aztreonam and ciprofloxacin in patients with NCFBE. While the aztreonam trial results were not associated with significant clinical benefit in NCFBE, initial results reported from the inhaled ciprofloxacin (dry powder for inhalation and liposome-encapsulated/dual-release formulations) trials

Target marketing strategies for occupational therapy entrepreneurs.

PubMed

Kautzmann, L N; Kautzmann, F N; Navarro, F H

1989-01-01

Understanding marketing techniques is one of the skills needed by successful entre renews. Target marketing is an effective method for occupational therapy entrepreneurs to use in determining when and where to enter the marketplace. The two components of target marketing, market segmentation and the development of marketing mix strategies for each identified market segment, are described. The Profife of Attitudes Toward Health Care (PATH) method of psychographic market segmentation of health care consumers is presented. Occupational therapy marketing mix strategies for each PATH consumer group are delineated and compatible groupings of market segments are suggested.

Bacterial fatty acid metabolism in modern antibiotic discovery.

PubMed

Yao, Jiangwei; Rock, Charles O

2017-11-01

Bacterial fatty acid synthesis is essential for many pathogens and different from the mammalian counterpart. These features make bacterial fatty acid synthesis a desirable target for antibiotic discovery. The structural divergence of the conserved enzymes and the presence of different isozymes catalyzing the same reactions in the pathway make bacterial fatty acid synthesis a narrow spectrum target rather than the traditional broad spectrum target. Furthermore, bacterial fatty acid synthesis inhibitors are single-targeting, rather than multi-targeting like traditional monotherapeutic, broad-spectrum antibiotics. The single-targeting nature of bacterial fatty acid synthesis inhibitors makes overcoming fast-developing, target-based resistance a necessary consideration for antibiotic development. Target-based resistance can be overcome through multi-targeting inhibitors, a cocktail of single-targeting inhibitors, or by making the single targeting inhibitor sufficiently high affinity through a pathogen selective approach such that target-based mutants are still susceptible to therapeutic concentrations of drug. Many of the pathogens requiring new antibiotic treatment options encode for essential bacterial fatty acid synthesis enzymes. This review will evaluate the most promising targets in bacterial fatty acid metabolism for antibiotic therapeutics development and review the potential and challenges in advancing each of these targets to the clinic and circumventing target-based resistance. This article is part of a Special Issue entitled: Bacterial Lipids edited by Russell E. Bishop. Copyright © 2016 Elsevier B.V. All rights reserved.

Grievances in cases using antibiotics due to orodental problems and assessment of the need for antibiotics.

PubMed

Kandemir, S; Ergül, N

2000-04-01

To assess the complaints of patients who were prescribed antibiotics following orodental problems and the need for antibiotics prescribed for this purpose. Examinations were carried out in the Department of Oral Diagnosis and Radiology, Ege University, Turkey. A total of 203 patients (129 females and 74 males) between 8-70 years of age (mean age 37.7 +/- 13.9). Examination and report. Frequency of unnecessary antibiotic use. Antibiotic therapy was not necessary for 151 (74.4 per cent) cases. Antibiotics were unnecessarily prescribed in 45 cases of acute irreversible pulpitis, 10 chronic apical abscess, 6 acute apical paradontitis, 7 gingivitis, 10 periodontitis, 4 epulis, 2 TMJ (temporomandibular junction) dysfunction, 2 sharp ridge of alveolar bone, 1 burning mouth syndrome and 1 recurrent aphthous stomatitis. In 108 (53.2 per cent) of the cases, the prescribed antibiotics were found to be penicillins, 102 of which were broad-spectrum. It was also determined that only 6 (7.7 per cent) of the 78 cases diagnosed as acute apical abscess were given drainage as local therapy. Principles for treating dental infections suggest that an antibiotic should only be used to supplement and not substitute for conventional surgical methods. Therefore, in cases with acute apical abscess, mechanical treatment (drainage) should be the first step. Inappropriate antibiotic use is quite widespread in dentistry. Dentists should avoid inappropriate use of antibiotics. To prevent inappropriate administration, necessary precautions need to be taken against dispensing antibiotics without prescription.

Empirical mono- versus combination antibiotic therapy in adult intensive care patients with severe sepsis - A systematic review with meta-analysis and trial sequential analysis.

PubMed

Sjövall, Fredrik; Perner, Anders; Hylander Møller, Morten

2017-04-01

To assess benefits and harms of empirical mono- vs. combination antibiotic therapy in adult patients with severe sepsis in the intensive care unit (ICU). We performed a systematic review according to the Cochrane Collaboration methodology, including meta-analysis, risk of bias assessment and trial sequential analysis (TSA). We included randomised clinical trials (RCT) assessing empirical mono-antibiotic therapy versus a combination of two or more antibiotics in adult ICU patients with severe sepsis. We exclusively assessed patient-important outcomes, including mortality. Two reviewers independently evaluated studies for inclusion, extracted data, and assessed risk of bias. Risk ratios (RRs) with 95% confidence intervals (CIs) were estimated and the risk of random errors was assessed by TSA. Thirteen RCTs (n = 2633) were included; all were judged as having high risk of bias. Carbapenems were the most frequently used mono-antibiotic (8 of 13 trials). There was no difference in mortality (RR 1.11, 95% CI 0.95-1.29; p = 0.19) or in any other patient-important outcomes between mono- vs. combination therapy. In TSA of mortality, the Z-curve reached the futility area, indicating that a 20% relative risk difference in mortality may be excluded between the two groups. For the other outcomes, TSA indicated lack of data and high risk of random errors. This systematic review of RCTs with meta-analysis and TSA demonstrated no differences in mortality or other patient-important outcomes between empirical mono- vs. combination antibiotic therapy in adult ICU patients with severe sepsis. The quantity and quality of data was low without firm evidence for benefit or harm of combination therapy. Copyright © 2016 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Comparing short to standard duration of antibiotic therapy for patients hospitalized with cellulitis (DANCE): study protocol for a randomized controlled trial.

PubMed

Cranendonk, Duncan R; Opmeer, Brent C; Prins, Jan M; Wiersinga, W Joost

2014-05-05

Recommended therapy duration for patients hospitalized with cellulitis is 10-14 days. Unnecessary use of antibiotics is one of the key factors driving resistance. Recent studies have shown that antibiotic therapy for cellulitis in outpatients can safely be shortened, despite residual inflammation. This study will compare in hospitalized patients the safety and effectiveness of shortening antibiotic therapy for cellulitis from 12 to 6 days. In a multicenter, randomized, double-blind, non-inferiority trial, adult patients admitted with cellulitis will be included. Cellulitis is defined as warmth, erythema, and induration of the skin and/or subcutaneous tissue, with or without pain (including erysipelas). All patients will initially be treated with intravenous flucloxacillin, and will be evaluated after 5-6 days. Those who have improved substantially (defined as being afebrile, and having a lower cellulitis severity score) will be randomized at day 6 between additional 6 days of oral flucloxacillin (n = 198) or placebo (n = 198). Treatment success is defined as resolution of cellulitis on day 14 (disappearance of warmth and tenderness, improvement of erythema and edema), without the need of additional antibiotics for cellulitis by day 28. Secondary endpoints are relapse rate (up to day 90), speed of recovery (using a cellulitis severity score until day 28, and VAS scores on pain and swelling until day 90), quality of life (using the SF-36 and EQ-5D questionnaires) and costs (associated with total antibiotic use and health-care resource utilization up to day 90). Inclusion is planned to start in Q2 2014. ClinicalTrials.gov (NCT02032654) and the Netherlands Trial Register (NTR4360).

Osmotic therapies added to antibiotics for acute bacterial meningitis

PubMed Central

Wall, Emma Cb; Ajdukiewicz, Katherine Mb; Bergman, Hanna; Heyderman, Robert S; Garner, Paul

2018-01-01

Background Every day children and adults die from acute community-acquired bacterial meningitis, particularly in low-income countries, and survivors risk deafness, epilepsy and neurological disabilities. Osmotic therapies may attract extra-vascular fluid and reduce cerebral oedema, and thus reduce death and improve neurological outcomes. This is an update of a Cochrane Review first published in 2013. Objectives To evaluate the effects of osmotic therapies added to antibiotics for acute bacterial meningitis in children and adults on mortality, deafness and neurological disability. Search methods We searched CENTRAL (2017, Issue 1), MEDLINE (1950 to 17 February 2017), Embase (1974 to 17 February 2017), CINAHL (1981 to 17 February 2017), LILACS (1982 to 17 February 2017) and registers of ongoing clinical trials (ClinicalTrials.com, WHO ICTRP) (21 February 2017). We also searched conference abstracts and contacted researchers in the field (up to 12 December 2015). Selection criteria Randomised controlled trials testing any osmotic therapy in adults or children with acute bacterial meningitis. Data collection and analysis Two review authors independently screened the search results and selected trials for inclusion. Results are presented using risk ratios (RR) and 95% confidence intervals (CI) and grouped according to whether the participants received steroids or not. We used the GRADE approach to assess the certainty of the evidence. Main results We included five trials with 1451 participants. Four trials evaluated glycerol against placebo, and one evaluated glycerol against 50% dextrose; in addition three trials evaluated dexamethasone and one trial evaluated acetaminophen (paracetamol) in a factorial design. Stratified analysis shows no effect modification with steroids; we present aggregate effect estimates. Compared to placebo, glycerol probably has little or no effect on death in people with bacterial meningitis (RR 1.08, 95% CI 0.90 to 1.30; 5 studies, 1272

Antibiotic-non-antibiotic combinations for combating extremely drug-resistant Gram-negative 'superbugs'.

PubMed

Schneider, Elena K; Reyes-Ortega, Felisa; Velkov, Tony; Li, Jian

2017-02-28

The emergence of antimicrobial resistance of Gram-negative pathogens has become a worldwide crisis. The status quo for combating resistance is to employ synergistic combinations of antibiotics. Faced with this fast-approaching post-antibiotic era, it is critical that we devise strategies to prolong and maximize the clinical efficacy of existing antibiotics. Unfortunately, reports of extremely drug-resistant (XDR) Gram-negative pathogens have become more common. Combining antibiotics such as polymyxin B or the broad-spectrum tetracycline and minocycline with various FDA-approved non-antibiotic drugs have emerged as a novel combination strategy against otherwise untreatable XDR pathogens. This review surveys the available literature on the potential benefits of employing antibiotic-non-antibiotic drug combination therapy. The apex of this review highlights the clinical utility of this novel therapeutic strategy for combating infections caused by 'superbugs'. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Antibiotic Resistance in Sepsis Patients: Evaluation and Recommendation of Antibiotic Use

PubMed Central

Pradipta, Ivan Surya; Sodik, Dian Chairunnisa; Lestari, Keri; Parwati, Ida; Halimah, Eli; Diantini, Ajeng; Abdulah, Rizky

2013-01-01

Background: The appropriate selection of empirical antibiotics based on the pattern of local antibiotic resistance can reduce the mortality rate and increase the rational use of antibiotics. Aims: We analyze the pattern of antibiotic use and the sensitivity patterns of antibiotics to support the rational use of antibiotics in patients with sepsis. Materials and Methods: A retrospective observational study was conducted in adult sepsis patient at one of Indonesian hospital during January-December 2011. Data were collected from the hospital medical record department. Descriptive analysis was used in the processing and interpretation of data. Results: A total of 76 patients were included as research subjects. Lung infection was the highest source of infection. In the 66.3% of clinical specimens that were culture positive for microbes, Klebsiella pneumoniae, Escherichia coli, Staphylococcus hominis were detected with the highest frequency. The six most frequently used antibiotics, levofloxacin, ceftazidime, ciprofloxacin, cefotaxime, ceftriaxone, and erythromycin, showed an average resistance above 50%. Conclusions: The high use of antibiotic with a high level resistance requires a policy to support its rational use. Local microbial pattern based on site infection and pattern of antibiotics sensitivity test can be used as supporting data to optimize appropriateness of empirical antibiotics therapy in sepsis patients. PMID:23923107

Analysis of Acinetobacter baumannii resistance patterns in patients with chronic obstructive pulmonary disease (COPD) in terms of choice of effective empiric antibiotic therapy.

PubMed

Grochowalska, Aneta; Kozioł-Montewka, Maria; Sobieszczańska, Anna

2017-06-12

Introduction. Multi-resistant Acinetobacter baumannii isolated from patients has become one of the most hazardous pathogens in health care settings. The aim of the study was to analyze pneumonia caused by Acinetobacter baumannii in patients hospitalized because of exacerbation of chronic obstructive pulmonary diseases (COPD), who were admitted to the Pulmonology Ward of the Masovian Specialistic Hospital in Radom (MSS). The incidence and drug sensitivity of these non-fermenting rods were evaluated, and compliance with antimicrobial procedure with the algorithm of the guidelines in applicable recommendations, was estimated. This should result in determining the local patterns of resistance and verifying therapeutic procedures in accordance with the assumptions of hospital antibiotic policy. In addition, the study examined the effectiveness of empiric and targeted therapy according to the clinical condition of the patient, and the eradication of A. baumannii, in comparison with the aggravating factors of the patient. Materials and Method. The retrospective study included 90 patients with exacerbation of COPD whose etiological factor of infection was A. baumannii, hospitalized in the Department of Pulmonology (MSS) in 2012-2016. Results. Studies were conducted on 90 patients with COPD exacerbation from which A. baumannii was isolated. Co-infections with other bacterial species among 41 patients were additionally noted. The majority of A. baumannii strains showed a high resistance (90%) to fluoroquinolones, ceftazidime, piperacillin/tazobactam. For strains causing a co-infection, drug resistance was successively 44-56%, 44%, 44%. All of patients received empirical therapy. The most commonly used drug was amoxicillin with a clavulanic acid, often combined with fluoroquinolone. This type of therapy was effective among 10% of patients. The mortality in this group was determined at 29%. Among 79% of patients with COPD, a targeted therapy was performed which proved to be

Curative Treatment of Severe Gram-Negative Bacterial Infections by a New Class of Antibiotics Targeting LpxC

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lemaître, Nadine; Liang, Xiaofei; Najeeb, Javaria

ABSTRACT The infectious diseases caused by multidrug-resistant bacteria pose serious threats to humankind. It has been suggested that an antibiotic targeting LpxC of the lipid A biosynthetic pathway in Gram-negative bacteria is a promising strategy for curing Gram-negative bacterial infections. However, experimental proof of this concept is lacking. Here, we describe our discovery and characterization of a biphenylacetylene-based inhibitor of LpxC, an essential enzyme in the biosynthesis of the lipid A component of the outer membrane of Gram-negative bacteria. The compound LPC-069 has no known adverse effects in mice and is effectivein vitroagainst a broad panel of Gram-negative clinical isolates,more » including several multiresistant and extremely drug-resistant strains involved in nosocomial infections. Furthermore, LPC-069 is curative in a murine model of one of the most severe human diseases, bubonic plague, which is caused by the Gram-negative bacteriumYersinia pestis. Our results demonstrate the safety and efficacy of LpxC inhibitors as a new class of antibiotic against fatal infections caused by extremely virulent pathogens. The present findings also highlight the potential of LpxC inhibitors for clinical development as therapeutics for infections caused by multidrug-resistant bacteria. IMPORTANCEThe rapid spread of antimicrobial resistance among Gram-negative bacilli highlights the urgent need for new antibiotics. Here, we describe a new class of antibiotics lacking cross-resistance with conventional antibiotics. The compounds inhibit LpxC, a key enzyme in the lipid A biosynthetic pathway in Gram-negative bacteria, and are activein vitroagainst a broad panel of clinical isolates of Gram-negative bacilli involved in nosocomial and community infections. The present study also constitutes the first demonstration of the curative treatment of bubonic plague by a novel, broad-spectrum antibiotic targeting LpxC. Hence, the data highlight the therapeutic

Development of a suspect and non-target screening approach to detect veterinary antibiotic residues in a complex biological matrix using liquid chromatography/high-resolution mass spectrometry.

PubMed

Solliec, Morgan; Roy-Lachapelle, Audrey; Sauvé, Sébastien

2015-12-30

Swine manure can contain a wide range of veterinary antibiotics, which could enter the environment via manure spreading on agricultural fields. A suspect and non-target screening method was applied to swine manure samples to attempt to identify veterinary antibiotics and pharmaceutical compounds for a future targeted analysis method. A combination of suspect and non-target screening method was developed to identify various veterinary antibiotic families using liquid chromatography coupled with high-resolution mass spectrometry (LC/HRMS). The sample preparation was based on the physicochemical parameters of antibiotics for the wide scope extraction of polar compounds prior to LC/HRMS analysis. The amount of data produced was processed by applying restrictive thresholds and filters to significantly reduce the number of compounds found and eliminate matrix components. The suspect and non-target screening was applied on swine manure samples and revealed the presence of seven common veterinary antibiotics and some of their relative metabolites, including tetracyclines, β-lactams, sulfonamides and lincosamides. However, one steroid and one analgesic were also identified. The occurrence of the identified compounds was validated by comparing their retention times, isotopic abundance patterns and fragmentation patterns with certified standards. This identification method could be very useful as an initial step to screen for and identify emerging contaminants such as veterinary antibiotics and pharmaceuticals in environmental and biological matrices prior to quantification. Copyright © 2015 John Wiley & Sons, Ltd.

Optimising patient safety when using elastomeric pumps to administer outpatient parenteral antibiotic therapy.

PubMed

Oliver, Gemma

2016-10-27

Outpatient parenteral antibiotic therapy (OPAT) is a growing area of practice that has numerous benefits for both patients and the healthcare system. In order for OPAT services to be successful, strategies need to be in place to maximise efficiency while providing safe, high-quality care. The use of elastomeric pumps to deliver intravenous (IV) antibiotics can have many benefits for OPAT services; they are cost-effective, easy to use and allow the patient to be fully ambulant. However, plans need to be put in place to make sure their use is safe and effective. This article discusses the use of elastomeric pumps by a UK-based OPAT team and the governance processes the team put in place to optimise patient safety when using elastomeric pumps to deliver IV antibiotics. Furthermore, with experience of using elastomeric pumps for more than 4 years the OPAT team was asked to evaluate an elastomeric pump new to the UK market: the Accufuser pump (Vygon (UK) Limited). By collecting data on its use it was found to be safe and easy to use. The team felt that the Accufuser pump ran to time in 96% of completed evaluations and considered it to be clinically acceptable in all responses.

Procalcitonin-guided antibiotic therapy in patients with fever in a general emergency department population: a multicenter noninferiority randomized clinical trial (HiTEMP study).

PubMed

van der Does, Yuri; Limper, Maarten; Jie, Kim E; Schuit, Stephanie C E; Jansen, Henry; Pernot, Niki; van Rosmalen, Joost; Poley, Marten J; Ramakers, Christian; Patka, Peter; van Gorp, Eric C M; Rood, Pleunie P M

2018-06-02

Overuse of broad-spectrum antibiotics in emergency departments(EDs) results in antibiotic resistance. We determined if procalcitonin(PCT)-guided therapy can be used to reduce antibiotic regimens in EDs by investigating efficacy, safety and accuracy. This was a noninferiority multicenter randomized clinical trial, performed in two Dutch hospitals. Adult patients with fever ≥38.2°C(100.8°F) in triage were randomized between standard diagnostic workup(control group) and PCT-guided therapy, defined as standard workup with addition of one single PCT measurement. Treatment algorithm encouraged withholding antibiotic regimens with PCT<0.5μg/L, and starting antibiotic regimens PCT≥0.5μg/L. Exclusion criteria were immunocompromised conditions, pregnancy, moribund patients, patients <72h after surgery or requiring primary surgical intervention. Primary outcomes were efficacy, defined as number of prescribed antibiotic regimens; safety, defined as combined-safety-endpoint(CSE) consisting of 30-days mortality, intensive-care unit admission, ED-return-visit within 2 weeks; accuracy, defined as sensitivity, apecificity and area-under-the-curve(AUC) of PCT for bacterial infections. Noninferiority margin for safety outcome was 7.5%. Between August 2014 and January 2017, 551 patients were included. In the PCT-guided group(n=275) 200(73%)patients were prescribed antibiotic regimens, in the control group(n=276) 212(77%)(p=0.28). There was no significant difference in CSE between the PCT-guided group, 29(11%), and control group, 46(16%)(p=0.16), with a noninferiority margin of 0.46%(n=526). AUC for confirmed bacterial infections for PCT was 0.681(95%CI0.633-0.730), for CRP 0.619(95%CI 0.569-0.669).: CONCLUSIONS.: PCT-guided therapy was noninferior in terms of safety, but did not reduce prescription of antibiotic regimens in an ED population with fever. In this heterogeneous population, the accuracy of PCT in diagnosing bacterial infections was poor. TRIAL REGISTRATION IN

Time to clinical response: an outcome of antibiotic therapy of febrile neutropenia with implications for quality and cost of care.

PubMed

Elting, L S; Rubenstein, E B; Rolston, K; Cantor, S B; Martin, C G; Kurtin, D; Rodriguez, S; Lam, T; Kanesan, K; Bodey, G

2000-11-01

To determine whether antibiotic regimens with similar rates of response differ significantly in the speed of response and to estimate the impact of this difference on the cost of febrile neutropenia. The time point of clinical response was defined by comparing the sensitivity, specificity, and predictive values of alternative objective and subjective definitions. Data from 488 episodes of febrile neutropenia, treated with either of two commonly used antibiotics (coded A or B) during six clinical trials, were pooled to compare the median time to clinical response, days of antibiotic therapy and hospitalization, and estimated costs. Response rates were similar; however, the median time to clinical response was significantly shorter with A-based regimens (5 days) compared with B-based regimens (7 days; P =.003). After 72 hours of therapy, 33% of patients who received A but only 18% of those who received B had responded (P =.01). These differences resulted in fewer days of antibiotic therapy and hospitalization with A-based regimens (7 and 9 days) compared with B-based regimens (9 and 12 days, respectively; P <.04) and in significantly lower estimated median costs ($8,491 v $11,133 per episode; P =.03). Early discharge at the time of clinical response should reduce the median cost from $10,752 to $8,162 (P <.001). Despite virtually identical rates of response, time to clinical response and estimated cost of care varied significantly among regimens. An early discharge strategy based on our definition of the time point of clinical response may further reduce the cost of treating non-low-risk patients with febrile neutropenia.

Targeted and Untargeted Metabolic Profiling of Wild Grassland Plants identifies Antibiotic and Anthelmintic Compounds Targeting Pathogen Physiology, Metabolism and Reproduction.

PubMed

French, Katherine E; Harvey, Joe; McCullagh, James S O

2018-01-26

Plants traditionally used by farmers to manage livestock ailments could reduce reliance on synthetic antibiotics and anthelmintics but in many cases their chemical composition is unknown. As a case study, we analyzed the metabolite profiles of 17 plant species and 45 biomass samples from agricultural grasslands in England using targeted and untargeted metabolite profiling by liquid-chromatography mass spectrometry. We identified a range of plant secondary metabolites, including 32 compounds with known antimicrobial/anthelmintic properties which varied considerably across the different plant samples. These compounds have been shown previously to target multiple aspects of pathogen physiology and metabolism in vitro and in vivo, including inhibition of quorum sensing in bacteria and egg viability in nematodes. The most abundant bioactive compounds were benzoic acid, myricetin, p-coumaric acid, rhamnetin, and rosmarinic acid. Four wild plants (Filipendula ulmaria (L.) Maxim., Prunella vulgaris L., Centuarea nigra L., and Rhinanthus minor L.) and two forage legumes (Medicago sativa L., Trifolium hybridium L.) contained high levels of these compounds. Forage samples from native high-diversity grasslands had a greater abundance of medicinal compounds than samples from agriculturally improved grasslands. Incorporating plants with antibiotic/anthelmintic compounds into livestock feeds may reduce global drug-resistance and preserve the efficacy of last-resort drugs.

Optimal Duration of Antibiotic Therapy in Patients With Hematogenous Vertebral Osteomyelitis at Low Risk and High Risk of Recurrence.

PubMed

Park, Ki-Ho; Cho, Oh-Hyun; Lee, Jung Hee; Park, Ji Seon; Ryu, Kyung Nam; Park, Seong Yeon; Lee, Yu-Mi; Chong, Yong Pil; Kim, Sung-Han; Lee, Sang-Oh; Choi, Sang-Ho; Bae, In-Gyu; Kim, Yang Soo; Woo, Jun Hee; Lee, Mi Suk

2016-05-15

The optimal duration of antibiotic treatment for hematogenous vertebral osteomyelitis (HVO) should be based on the patient's risk of recurrence, but it is not well established. A retrospective review was conducted to evaluate the optimal duration of antibiotic treatment in patients with HVO at low and high risk of recurrence. Patients with at least 1 independent baseline risk factor for recurrence, determined by multivariable analysis, were considered as high risk and those with no risk factor as low risk. A total of 314 patients with microbiologically diagnosed HVO were evaluable for recurrence. In multivariable analysis, methicillin-resistant Staphylococcus aureus infection (adjusted odds ratio [aOR], 2.61; 95% confidence interval [CI], 1.16-5.87), undrained paravertebral/psoas abscesses (aOR, 4.09; 95% CI, 1.82-9.19), and end-stage renal disease (aOR, 6.58; 95% CI, 1.63-26.54) were independent baseline risk factors for recurrence. Therefore, 191 (60.8%) patients were classified as low risk and 123 (39.2%) as high risk. Among high-risk patients, there was a significant decreasing trend for recurrence according to total duration of antibiotic therapy: 34.8% (4-6 weeks [28-41 days]), 29.6% (6-8 weeks [42-55 days]), and 9.6% (≥8 weeks [≥56 days]) (P = .002). For low-risk patients, this association was still significant but the recurrence rates were much lower: 12.0% (4-6 weeks), 6.3% (6-8 weeks), and 2.2% (≥8 weeks) (P = .02). Antibiotic therapy of prolonged duration (≥8 weeks) should be given to patients with HVO at high risk of recurrence. For low-risk patients, a shorter duration (6-8 weeks) of pathogen-directed antibiotic therapy may be sufficient. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Topical antibiotics: therapeutic value or ecologic mischief?

PubMed

Del Rosso, James Q; Kim, Grace K

2009-01-01

Based on antibiotic prescribing data from 2003, dermatologists account annually for 8-9 million prescriptions for oral antibiotics, and 3-4 million prescriptions for topical antibiotics. Overall, much of the emphasis on concerns related to emergence of clinically significant antibiotic-resistant bacterial strains focuses on use of systemic antibiotics, however, topical antibiotic use may also have potential implications. The following article discusses the perspectives of the authors related to the potential therapeutic benefits and ecologic implications ("ecologic mischief") of topical antibiotic therapy for specific indications encountered in ambulatory dermatology practice.

Role of (18)F-FDG PET/CT in the evaluation of response to antibiotic therapy in patients affected by infectious spondylodiscitis.

PubMed

Niccoli Asabella, Artor; Iuele, Francesca; Simone, Francesco; Fanelli, Margherita; Lavelli, Valentina; Ferrari, Cristina; Di Palo, Alessandra; Notaristefano, Antonio; Merenda, Nunzio Clemente; Rubini, Giuseppe

2015-01-01

Spondylodiscitis is characterized by infection involving the intervertebral disc and adjacent vertebrae. It can occur anywhere in the vertebral column but more commonly involves lumbar spine. Our aim was to evaluate the usefulness of (18)F-FDG PET/CT to detect the early response to antibiotic therapy in patients affected by infectious spondylodiscitis and to compare the role of (18)F-FDG PET/CT and MRI in post-treatment evaluation. 15 patients (12M, 3F), with mean age 65±13 years old, with typical clinical symptoms of Infectious Spondylodiscitis (pain, fever and increase of inflammatory indexes) and confirmed by blood culture or vertebral biopsy underwent within three day-interval a (18)F-FDG PET/CT and Magnetic Resonance (MR) at "baseline" and after antibiotic therapy. Semiquantitative parameters at (18)F-FDG PET/CT "baseline" SUVmax1, MTV1 and TLG1 and after therapy SUVmax2, MTV2 and TLG2 of involved vertebrae were calculated. Follow-up period of at least three months was available for all patients. T-student test for paired groups was performed to compare baseline and after therapy (18)F-FDG PET/CT semiquantitative parameters. According to (18)F-FDG PET/CT parameters all patients showed a response to antibiotic therapy. All patients were positive at "baseline" MRI of the spine, while at follow-up, 7/15 patients showed MR signs of infection and were considered "positive" and 8/15 showed resolution of infectious condition and, therefore they were considered "negative". A statistical significant difference between (18)F-FDG PET/CT "baseline" and after antibiotic therapy was found for all semiquantitative parameters: SUVmax (t=5.8, P=0.01); MTV (t=5.17, P=0.001); TLG (t=5,26, P=0,001). The comparison between the "baseline" and "after treatment" (18)F-FDG semiquantitative parameters showed a significant reduction of all parameters. This reduction was relevant also in patients with positive post-treatment MRI. This can be probably related to the tissue remodeling in

Dynamics of success and failure in phage and antibiotic therapy in experimental infections.

PubMed

Bull, J J; Levin, Bruce R; DeRouin, Terry; Walker, Nina; Bloch, Craig A

2002-11-26

In 1982 Smith and Huggins showed that bacteriophages could be at least as effective as antibiotics in preventing mortality from experimental infections with a capsulated E. coli (K1) in mice. Phages that required the K1 capsule for infection were more effective than phages that did not require this capsule, but the efficacies of phages and antibiotics in preventing mortality both declined with time between infection and treatment, becoming virtually ineffective within 16 hours. We develop quantitative microbiological procedures that (1) explore the in vivo processes responsible for the efficacy of phage and antibiotic treatment protocols in experimental infections (the Resistance Competition Assay, or RCA), and (2) survey the therapeutic potential of phages in vitro (the Phage Replication Assay or PRA). We illustrate the application and utility of these methods in a repetition of Smith and Huggins' experiments, using the E. coli K1 mouse thigh infection model, and applying treatments of phages or streptomycin. 1) The Smith and Huggins phage and antibiotic therapy results are quantitatively and qualitatively robust. (2) Our RCA values reflect the microbiological efficacies of the different phages and of streptomycin in preventing mortality, and reflect the decline in their efficacy with a delay in treatment. These results show specifically that bacteria become refractory to treatment over the term of infection. (3) The K1-specific and non-specific phages had similar replication rates on bacteria grown in broth (based on the PRA), but the K1-specific phage had markedly greater replication rates in mouse serum.

Effects of inappropriate empirical antibiotic therapy on mortality in patients with healthcare-associated methicillin-resistant Staphylococcus aureus bacteremia: a propensity-matched analysis.

PubMed

Yoon, Young Kyung; Park, Dae Won; Sohn, Jang Wook; Kim, Hyo Youl; Kim, Yeon-Sook; Lee, Chang-Seop; Lee, Mi Suk; Ryu, Seong-Yeol; Jang, Hee-Chang; Choi, Young Ju; Kang, Cheol-In; Choi, Hee Jung; Lee, Seung Soon; Kim, Shin Woo; Kim, Sang Il; Kim, Eu Suk; Kim, Jeong Yeon; Yang, Kyung Sook; Peck, Kyong Ran; Kim, Min Ja

2016-07-15

The purported value of empirical therapy to cover methicillin-resistant Staphylococcus aureus (MRSA) has been debated for decades. The purpose of this study was to evaluate the effects of inappropriate empirical antibiotic therapy on clinical outcomes in patients with healthcare-associated MRSA bacteremia (HA-MRSAB). A prospective, multicenter, observational study was conducted in 15 teaching hospitals in the Republic of Korea from February 2010 to July 2011. The study subjects included adult patients with HA-MRSAB. Covariate adjustment using the propensity score was performed to control for bias in treatment assignment. The predictors of in-hospital mortality were determined by multivariate logistic regression analyses. In total, 345 patients with HA-MRSAB were analyzed. The overall in-hospital mortality rate was 33.0 %. Appropriate empirical antibiotic therapy was given to 154 (44.6 %) patients. The vancomycin minimum inhibitory concentrations of the MRSA isolates ranged from 0.5 to 2 mg/L by E-test. There was no significant difference in mortality between propensity-matched patient pairs receiving inappropriate or appropriate empirical antibiotics (odds ratio [OR] = 1.20; 95 % confidence interval [CI] = 0.71-2.03). Among patients with severe sepsis or septic shock, there was no significant difference in mortality between the treatment groups. In multivariate analyses, severe sepsis or septic shock (OR = 5.45; 95 % CI = 2.14-13.87), Charlson's comorbidity index (per 1-point increment; OR = 1.52; 95 % CI = 1.27-1.83), and prior receipt of glycopeptides (OR = 3.24; 95 % CI = 1.08-9.67) were independent risk factors for mortality. Inappropriate empirical antibiotic therapy was not associated with clinical outcome in patients with HA-MRSAB. Prudent use of empirical glycopeptide therapy should be justified even in hospitals with high MRSA prevalence.

Novel high throughput pooled shRNA screening identifies NQO1 as a potential drug target for host directed therapy for tuberculosis

PubMed Central

Li, Qing; Karim, Ahmad F.; Ding, Xuedong; Das, Biswajit; Dobrowolski, Curtis; Gibson, Richard M.; Quiñones-Mateu, Miguel E.; Karn, Jonathan; Rojas, Roxana E.

2016-01-01

Chemical regulation of macrophage function is one key strategy for developing host-directed adjuvant therapies for tuberculosis (TB). A critical step to develop these therapies is the identification and characterization of specific macrophage molecules and pathways with a high potential to serve as drug targets. Using a barcoded lentivirus-based pooled short-hairpin RNA (shRNA) library combined with next generation sequencing, we identified 205 silenced host genes highly enriched in mycobacteria-resistant macrophages. Twenty-one of these “hits” belonged to the oxidoreductase functional category. NAD(P)H:quinone oxidoreductase 1 (NQO1) was the top oxidoreductase “hit”. NQO1 expression was increased after mycobacterial infection, and NQO1 knockdown increased macrophage differentiation, NF-κB activation, and the secretion of pro-inflammatory cytokines TNF-α and IL-1β in response to infection. This suggests that mycobacteria hijacks NQO1 to down-regulate pro-inflammatory and anti-bacterial functions. The competitive inhibitor of NQO1 dicoumarol synergized with rifampin to promote intracellular killing of mycobacteria. Thus, NQO1 is a new host target in mycobacterial infection that could potentially be exploited to increase antibiotic efficacy in vivo. Our findings also suggest that pooled shRNA libraries could be valuable tools for genome-wide screening in the search for novel druggable host targets for adjunctive TB therapies. PMID:27297123

Antibiotics for PANDAS? Limited Evidence: Review and Putative Mechanisms of Action.

PubMed

Burchi, Elisabetta; Pallanti, Stefano

2018-05-03

Antibiotics have been used extensively by clinicians to treat patients with PANDAS or PANS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections and pediatric acute-onset neuropsychiatric syndrome, respectively). This review examines the best-quality evidence supporting the practice-based use of antibiotics in these psychiatric conditions. PubMed was searched for English-language articles published between January 1994 and July 2017 using the search terms [PANDAS OR PANS OR new-onset pediatric OCD] AND [antibiotics OR macrolides OR beta-lactams]. Randomized clinical trials, observational studies, and case reports concerning antibiotic use in PANDAS/PANS were reviewed. Four publications were included in the quantitative synthesis. The evidence was rated using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) method. Although the single studies conveyed no statistically significant results, there is some evidence for efficacy of antibiotic therapy in reducing neuropsychiatric symptoms in the PANDAS/PANS population. Whereas the use of eradicating antibiotic therapy during active infections in PANDAS/PANS is well established, there is still a need for studies that improve the quality of evidence supporting use of antibiotics in this population independent of ongoing infections. Studies that compare antibiotics with other therapies, as well as studies that assess safety and efficacy of long-term use of antibiotic therapy in PANDAS/PANS, are still lacking. However, the available research supports evidence of a subgroup in the pediatric OCD population that is sensitive to antibiotic treatment and immunomodulatory therapy, independent of ongoing infectious conditions. Thus, more studies are warranted in the overall OCD spectrum. © Copyright 2018 Physicians Postgraduate Press, Inc.

Targeted photodynamic therapy for infected wounds in mice

NASA Astrophysics Data System (ADS)

Hamblin, Michael R.; O'Donnell, David A.; Zahra, Touqir; Contag, Christopher H.; McManus, Albert T.; Hasan, Tayyaba

2002-06-01

Although many workers have used photodynamic therapy to kill bacteria in vitro, the use of this approach has seldom been reported in vivo in animal models of infection. We report on the use of a targeted polycationic photosensitizer conjugate between poly-L-lysine and chlorin(e6) that can penetrate the Gram (-) outer membrane together with red laser light to kill Escherichia coli and Pseudomonas aeruginosa infecting excisional wounds in mice. We used genetically engineered luminescent bacteria that allowed the infection to be imaged in mouse wounds using a sensitive CCD camera. Wounds were infected with 5x106 bacteria, followed by application of the conjugate in solution and illumination. There was a light-dose dependent loss of luminescence as measured by image analysis in the wound treated with conjugate and light, not seen in control wounds. This strain of E coli is non-invasive and the infection in untreated wounds spontaneously resolved in a few days and all wounds healed equally well showing the photodynamic treatment did not damage the host tissue. P aeruginosa is highly invasive and mice with untreated or control wounds all died while 90% of PDT treated mice survived. PDT may have a role to play in the rapid treatment of infected wounds in view of the worldwide rise in antibiotic resistance.

Economic evaluation of antibiotic therapy versus appendicectomy for the treatment of uncomplicated acute appendicitis from the APPAC randomized clinical trial.

PubMed

Sippola, S; Grönroos, J; Tuominen, R; Paajanen, H; Rautio, T; Nordström, P; Aarnio, M; Rantanen, T; Hurme, S; Salminen, P

2017-09-01

An increasing amount of evidence supports antibiotic therapy for treating uncomplicated acute appendicitis. The objective of this study was to compare the costs of antibiotics alone versus appendicectomy in treating uncomplicated acute appendicitis within the randomized controlled APPAC (APPendicitis ACuta) trial. The APPAC multicentre, non-inferiority RCT was conducted on patients with CT-confirmed uncomplicated acute appendicitis. Patients were assigned randomly to appendicectomy or antibiotic treatment. All costs were recorded, whether generated by the initial visit and subsequent treatment or possible recurrent appendicitis during the 1-year follow-up. The cost estimates were based on cost levels for the year 2012. Some 273 patients were assigned to the appendicectomy group and 257 to antibiotic treatment. Most patients randomized to antibiotic treatment did not require appendicectomy during the 1-year follow-up. In the operative group, overall societal costs (€5989·2, 95 per cent c.i. 5787·3 to 6191·1) were 1·6 times higher (€2244·8, 1940·5 to 2549·1) than those in the antibiotic group (€3744·4, 3514·6 to 3974·2). In both groups, productivity losses represented a slightly higher proportion of overall societal costs than all treatment costs together, with diagnostics and medicines having a minor role. Those in the operative group were prescribed significantly more sick leave than those in the antibiotic group (mean(s.d.) 17·0(8·3) (95 per cent c.i. 16·0 to 18·0) versus 9·2(6·9) (8·3 to 10·0) days respectively; P < 0·001). When the age and sex of the patient as well as the hospital were controlled for simultaneously, the operative treatment generated significantly more costs in all models. Patients receiving antibiotic therapy for uncomplicated appendicitis incurred lower costs than those who had surgery. © 2017 BJS Society Ltd Published by John Wiley & Sons Ltd.

Antibiotic therapy prior to hospital admission is associated with reduced septic shock and need for mechanical ventilation in patients with community-acquired pneumonia.

PubMed

Amaro, Rosanel; Sellarés, Jacobo; Polverino, Eva; Cillóniz, Catia; Ferrer, Miquel; Fernández-Barat, Laia; Mensa, Josep; Niederman, Michael S; Torres, Antoni

2017-05-01

A subgroup of patients admitted to the hospital with a diagnosis of community-acquired pneumonia (CAP) have received antibiotic therapy prior to admission for the current episode of pneumonia. The objective of this study was to assess the clinical course of patients receiving antibiotics prior to admission, compared to patients not previously treated. An observational cohort of 3364 CAP patients consecutively admitted to our hospital, and prospectively included, were studied. We collected clinical, microbiological and biochemical parameters, focusing on recent antibiotics received prior to admission. 610 (18%) patients received antibiotics prior to hospital admission for the current CAP episode. Patients with previous antibiotic use developed septic shock less frequently (4% vs. 7%, p = 0.007) and required invasive ventilation less often (3% vs. 6%, p = 0.002). After adjustment by different covariate factors and propensity score, antibiotic therapy was still independently associated with a lower incidence of septic shock at admission (OR 0.54 [95% CI 0.31-0.95], p = 0.03) and less need for invasive ventilation (OR 0.38 [95% CI 0.16-0.91], p = 0.03). In this cohort, recent use of antibiotics before hospital admission in CAP seems to be associated with a lower incidence of septic shock on admission and a lower need for invasive ventilation. Copyright © 2017 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

A New Era for Cancer Target Therapies: Applying Systems Biology and Computer-Aided Drug Design to Cancer Therapies.

PubMed

Wong, Yung-Hao; Chiu, Chia-Chiun; Lin, Chih-Lung; Chen, Ting-Shou; Jheng, Bo-Ren; Lee, Yu-Ching; Chen, Jeremy; Chen, Bor-Sen

In recent years, many systems biology approaches have been used with various cancers. The materials described here can be used to build bases to discover novel cancer therapy targets in connection with computer-aided drug design (CADD). A deeper understanding of the mechanisms of cancer will provide more choices and correct strategies in the development of multiple target drug therapies, which is quite different from the traditional cancer single target therapy. Targeted therapy is one of the most powerful strategies against cancer and can also be applied to other diseases. Due to the large amount of progress in computer hardware and the theories of computational chemistry and physics, CADD has been the main strategy for developing novel drugs for cancer therapy. In contrast to traditional single target therapies, in this review we will emphasize the future direction of the field, i.e., multiple target therapies. Structure-based and ligand-based drug designs are the two main topics of CADD. The former needs both 3D protein structures and ligand structures, while the latter only needs ligand structures. Ordinarily it is estimated to take more than 14 years and 800 million dollars to develop a new drug. Many new CADD software programs and techniques have been developed in recent decades. We conclude with an example where we combined and applied systems biology and CADD to the core networks of four cancers and successfully developed a novel cocktail for drug therapy that treats multiple targets.

Choosing a therapy electron accelerator target.

PubMed

Hutcheon, R M; Schriber, S O; Funk, L W; Sherman, N K

1979-01-01

Angular distributions of photon depth dose produced by 25-MeV electrons incident on several fully stopping single-element targets (C, Al, Cu, Mo, Ta, Pb) and two composite layered targets (Ni-Al, W-Al) were studied. Depth-dose curves measured using TLD-700 (thermoluminescent dosimeter) chips embedded in lucite phantoms. Several useful therapy electron accelerator design curves were determined, including relative flattener thickness as a function of target atomic number, "effective" bremsstrahlung endpoint energy or beam "hardness" as a function of target atomic number and photon emission angle, and estimates of shielding thickness as a function of angle required to reduce the radiation outside the treatment cone to required levels.

Non-antibiotic treatments for bacterial diseases in an era of progressive antibiotic resistance.

PubMed

Opal, Steven M

2016-12-16

The emergence of multi-drug resistant (MDR) microbial pathogens threatens the very foundation upon which standard antibacterial chemotherapy is based. We must consider non-antibiotic solutions to manage invasive bacterial infections. Transition from antibiotics to non-traditional treatments poses real clinical challenges that will not be easy to solve. Antibiotics will continue to reliably treat some infections (e.g., group A streptococci and Treponema pallidum) but will likely need adjuvant therapies or will need to be replaced for many bacterial infections in the future.

Nonviral Genome Editing Based on a Polymer-Derivatized CRISPR Nanocomplex for Targeting Bacterial Pathogens and Antibiotic Resistance.

PubMed

Kang, Yoo Kyung; Kwon, Kyu; Ryu, Jea Sung; Lee, Ha Neul; Park, Chankyu; Chung, Hyun Jung

2017-04-19

The overuse of antibiotics plays a major role in the emergence and spread of multidrug-resistant bacteria. A molecularly targeted, specific treatment method for bacterial pathogens can prevent this problem by reducing the selective pressure during microbial growth. Herein, we introduce a nonviral treatment strategy delivering genome editing material for targeting antibacterial resistance. We apply the CRISPR-Cas9 system, which has been recognized as an innovative tool for highly specific and efficient genome engineering in different organisms, as the delivery cargo. We utilize polymer-derivatized Cas9, by direct covalent modification of the protein with cationic polymer, for subsequent complexation with single-guide RNA targeting antibiotic resistance. We show that nanosized CRISPR complexes (= Cr-Nanocomplex) were successfully formed, while maintaining the functional activity of Cas9 endonuclease to induce double-strand DNA cleavage. We also demonstrate that the Cr-Nanocomplex designed to target mecA-the major gene involved in methicillin resistance-can be efficiently delivered into Methicillin-resistant Staphylococcus aureus (MRSA), and allow the editing of the bacterial genome with much higher efficiency compared to using native Cas9 complexes or conventional lipid-based formulations. The present study shows for the first time that a covalently modified CRISPR system allows nonviral, therapeutic genome editing, and can be potentially applied as a target specific antimicrobial.

Plant Growth, Antibiotic Uptake, and Prevalence of Antibiotic Resistance in an Endophytic System of Pakchoi under Antibiotic Exposure

PubMed Central

Zhang, Hao; Li, Xunan; Yang, Qingxiang; Sun, Linlin; Yang, Xinxin; Zhou, Mingming; Deng, Rongzhen; Bi, Linqian

2017-01-01

Antibiotic contamination in agroecosystems may cause serious problems, such as the proliferation of various antibiotic resistant bacteria and the spreading of antibiotic resistance genes (ARGs) in the environment or even to human beings. However, it is unclear whether environmental antibiotics, antibiotic resistant bacteria, and ARGs can directly enter into, or occur in, the endophytic systems of plants exposed to pollutants. In this study, a hydroponic experiment exposing pakchoi (Brassica chinensis L.) to tetracycline, cephalexin, and sulfamethoxazole at 50% minimum inhibitory concentration (MIC) levels and MIC levels, respectively, was conducted to explore plant growth, antibiotic uptake, and the development of antibiotic resistance in endophytic systems. The three antibiotics promoted pakchoi growth at 50% MIC values. Target antibiotics at concentrations ranging from 6.9 to 48.1 µg·kg−1 were detected in the treated vegetables. Additionally, the rates of antibiotic-resistant endophytic bacteria to total cultivable endophytic bacteria significantly increased as the antibiotics accumulated in the plants. The detection and quantification of ARGs indicated that four types, tetX, blaCTX-M, and sul1 and sul2, which correspond to tetracycline, cephalexin, and sulfamethoxazole resistance, respectively, were present in the pakchoi endophytic system and increased with the antibiotic concentrations. The results highlight a potential risk of the development and spread of antibiotic resistance in vegetable endophytic systems. PMID:29099753

Plant Growth, Antibiotic Uptake, and Prevalence of Antibiotic Resistance in an Endophytic System of Pakchoi under Antibiotic Exposure.

PubMed

Zhang, Hao; Li, Xunan; Yang, Qingxiang; Sun, Linlin; Yang, Xinxin; Zhou, Mingming; Deng, Rongzhen; Bi, Linqian

2017-11-03

Antibiotic contamination in agroecosystems may cause serious problems, such as the proliferation of various antibiotic resistant bacteria and the spreading of antibiotic resistance genes (ARGs) in the environment or even to human beings. However, it is unclear whether environmental antibiotics, antibiotic resistant bacteria, and ARGs can directly enter into, or occur in, the endophytic systems of plants exposed to pollutants. In this study, a hydroponic experiment exposing pakchoi ( Brassica chinensis L.) to tetracycline, cephalexin, and sulfamethoxazole at 50% minimum inhibitory concentration (MIC) levels and MIC levels, respectively, was conducted to explore plant growth, antibiotic uptake, and the development of antibiotic resistance in endophytic systems. The three antibiotics promoted pakchoi growth at 50% MIC values. Target antibiotics at concentrations ranging from 6.9 to 48.1 µg·kg -1 were detected in the treated vegetables. Additionally, the rates of antibiotic-resistant endophytic bacteria to total cultivable endophytic bacteria significantly increased as the antibiotics accumulated in the plants. The detection and quantification of ARGs indicated that four types, tet X, bla CTX-M , and sul 1 and sul 2, which correspond to tetracycline, cephalexin, and sulfamethoxazole resistance, respectively, were present in the pakchoi endophytic system and increased with the antibiotic concentrations. The results highlight a potential risk of the development and spread of antibiotic resistance in vegetable endophytic systems.

Enterotoxicity of a nonribosomal peptide causes antibiotic-associated colitis.

PubMed

Schneditz, Georg; Rentner, Jana; Roier, Sandro; Pletz, Jakob; Herzog, Kathrin A T; Bücker, Roland; Troeger, Hanno; Schild, Stefan; Weber, Hansjörg; Breinbauer, Rolf; Gorkiewicz, Gregor; Högenauer, Christoph; Zechner, Ellen L

2014-09-09

Antibiotic therapy disrupts the human intestinal microbiota. In some patients rapid overgrowth of the enteric bacterium Klebsiella oxytoca results in antibiotic-associated hemorrhagic colitis (AAHC). We isolated and identified a toxin produced by K. oxytoca as the pyrrolobenzodiazepine tilivalline and demonstrated its causative action in the pathogenesis of colitis in an animal model. Tilivalline induced apoptosis in cultured human cells in vitro and disrupted epithelial barrier function, consistent with the mucosal damage associated with colitis observed in human AAHC and the corresponding animal model. Our findings reveal the presence of pyrrolobenzodiazepines in the intestinal microbiota and provide a mechanism for colitis caused by a resident pathobiont. The data link pyrrolobenzodiazepines to human disease and identify tilivalline as a target for diagnosis and neutralizing strategies in prevention and treatment of colitis.

Prostate Cancer Clinical Consortium Clinical Research Site: Targeted Therapies

DTIC Science & Technology

2017-10-01

AWARD NUMBER: W81XWH-14-2-0159 TITLE: Prostate Cancer Clinical Consortium Clinical Research Site: Targeted Therapies PRINCIPAL INVESTIGATOR...Annual PREPARED FOR: U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 DISTRIBUTION STATEMENT: Approved for...AND SUBTITLE Prostate Cancer Clinical Consortium Clinical Research Site: Targeted Therapies 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT

Reducing Second Gram-Negative Antibiotic Therapy on Pediatric Oncology and Hematopoietic Stem Cell Transplantation Services.

PubMed

Wattier, Rachel L; Levy, Emily R; Sabnis, Amit J; Dvorak, Christopher C; Auerbach, Andrew D

2017-09-01

OBJECTIVE To evaluate interventions to reduce avoidable antibiotic use on pediatric oncology and hematopoietic stem cell transplantation (HSCT) services. DESIGN Interrupted time series. SETTING Academic pediatric hospital with separate oncology and HSCT services. PARTICIPANTS Children admitted to the services during baseline (October 2011-August 2013) and 2 intervention periods, September 2013-June 2015 and July 2015-June 2016, including 1,525 oncology hospitalizations and 301 HSCT hospitalizations. INTERVENTION In phase 1, we completed an update of the institutional febrile neutropenia (FN) guideline for the pediatric oncology service, recommending first-line β-lactam monotherapy rather than routine use of 2 gram-negative agents. Phase 2 included updating the HSCT service FN guideline and engagement with a new pediatric antimicrobial stewardship program. The use of target antibiotics (tobramycin and ciprofloxacin) was measured in days of therapy per 1,000 patient days collected from administrative data. Intervention effects were evaluated using interrupted time series with segmented regression. RESULTS Phase 1 had mixed effects-long-term reduction in tobramycin use (97% below projected at 18 months) but rebound with increasing slope in ciprofloxacin use (+18% per month). Following phase 2, tobramycin and ciprofloxacin use on the oncology service were both 99% below projected levels at 12 months. On the HSCT service, tobramycin use was 99% below the projected level and ciprofloxacin use was 96% below the projected level at 12 months. CONCLUSIONS Locally adapted guidelines can facilitate practice changes in oncology and HSCT settings. More comprehensive and ongoing interventions, including follow-up education, feedback, and engagement of companion services may be needed to sustain changes. Infect Control Hosp Epidemiol 2017;38:1039-1047.

Time for a change in how new antibiotics are reimbursed: Development of an insurance framework for funding new antibiotics based on a policy of risk mitigation.

PubMed

Towse, Adrian; Hoyle, Christopher K; Goodall, Jonathan; Hirsch, Mark; Mestre-Ferrandiz, Jorge; Rex, John H

2017-10-01

Healthcare systems depend on the availability of new antibiotics. However, there is a lack of treatments for infections caused by multidrug resistant (MDR) pathogens and a weak development pipeline of new therapies. One core challenge to the development of new antibiotics targeting MDR pathogens is that expected revenues are insufficient to drive long-term investment. In the USA and Europe, financial incentives have focussed on supporting R&D, reducing regulatory burden, and extending market exclusivity. Using resistance data to estimate global revenues, we demonstrate that the combined effects of these incentives are unlikely to rekindle investment in antibiotics. We analyse two supplemental approaches: a commercial incentive (a premium price model) and a new business model (an insurance model). A premium price model is familiar and readily implemented but the required price and local budget impact is highly uncertain and sensitive to cross-sectional and longitudinal variation in prevalence of antibiotic resistance. An insurance model delivering risk mitigation for payers, providers and manufacturers would provide an incentive to drive investment in the development of new antibiotics while also facilitating antibiotic conservation. We suggest significant efforts should be made to test the insurance model as one route to stimulate investment in novel antibiotics. Copyright © 2017 Office of Health Economics. Published by Elsevier B.V. All rights reserved.

Molecular targeting agents in cancer therapy: science and society.

PubMed

Shaikh, Asim Jamal

2012-01-01

The inception of targeted agents has revolutionized the cancer therapy paradigm, both for physicians and patients. A large number of molecular targeted agents for cancer therapy are currently available for clinical use today. Many more are in making, but there are issues that remain to be resolved for the scientific as well as social community before the recommendation of their widespread use in may clinical scenarios can be done, one such issue being cost and cost effectiveness, others being resistance and lack of sustained efficacy. With the current knowledge about available targeted agents, the growing knowledge of intricate molecular pathways and unfolding of wider spectrum of molecular targets that can really matter in the disease control, calls for only the just use of the agents available now, drug companies need to make a serious attempt to reduce the cost of the agents. Research should focus on agents that show sustained responses in preclinical data. More needs to be done in laboratories and by the pharmaceutical industries, before we can truly claim to have entered a new era of targeted therapy in cancer care.

Microbial resistance related to antibiotic-loaded bone cement: a historical review.

PubMed

Walker, Lucy C; Baker, Paul; Holleyman, Richard; Deehan, David

2017-12-01

The use of antibiotic-loaded bone cement (ALBC) has a range of indications for use in orthopaedics. It has the advantage of delivering high loads of antibiotics to a targeted site, thereby avoiding the side effects associated with systemic administration. However, there is concern that the use of ALBC may precipitate the development of antibiotic-resistant bacteria. This review focuses on (1) the published research using both animal and human models examining the association between ALBC and the induction of microbial resistance (2) the mechanisms by which antimicrobial resistance develop (3) the research pertaining to specific classes of antibiotics commonly used in orthopaedic practice (4) the recent developments in calcium sulphate beads, nanoparticles and chitosan, as alternative antimicrobial treatments for periprosthetic joint infections. The literature for and against a link between ALBC and the development of microbiological resistance is reviewed and presented. It is concluded that further research is needed to develop a defined set of indications for the use of ALBC in the management of periprosthetic joint infection. In addition, further research into alternative antimicrobial therapies in this area should be encouraged.

Rationalizing antibiotic use to limit antibiotic resistance in India+

PubMed Central

2011-01-01

Antibiotic resistance, a global concern, is particularly pressing in developing nations, including India, where the burden of infectious disease is high and healthcare spending is low. The Global Antibiotic Resistance Partnership (GARP) was established to develop actionable policy recommendations specifically relevant to low- and middle-income countries where suboptimal access to antibiotics - not a major concern in high-income countries - is possibly as severe a problem as is the spread of resistant organisms. This report summarizes the situation as it is known regarding antibiotic use and growing resistance in India and recommends short and long term actions. Recommendations aim at (i) reducing the need for antibiotics; (ii) lowering resistance-enhancing drug pressure through improved antibiotic targeting, and (iii) eliminating antibiotic use for growth promotion in agriculture. The highest priority needs to be given to (i) national surveillance of antibiotic resistance and antibiotic use - better information to underpin decisions on standard treatment guidelines, education and other actions, as well as to monitor changes over time; (ii) increasing the use of diagnostic tests, which necessitates behavioural changes and improvements in microbiology laboratory capacity; (iii) setting up and/or strengthening infection control committees in hospitals; and (iv) restricting the use of antibiotics for non-therapeutic uses in agriculture. These interventions should help to reduce the spread of antibiotic resistance, improve public health directly, benefit the populace and reduce pressure on the healthcare system. Finally, increasing the types and coverage of childhood vaccines offered by the government would reduce the disease burden enormously and spare antibiotics. PMID:21985810

Procalcitonin Biomarker Algorithm Reduces Antibiotic Prescriptions, Duration of Therapy, and Costs in Chronic Obstructive Pulmonary Disease: A Comparison in the Netherlands, Germany, and the United Kingdom.

PubMed

van der Maas, Marloes E; Mantjes, Gertjan; Steuten, Lotte M G

2017-04-01

Antibiotics are often recommended as treatment for patients with chronic obstructive pulmonary disease (COPD) exacerbations. However, not all COPD exacerbations are caused by bacterial infections and there is consequently considerable misuse and overuse of antibiotics among patients with COPD. This poses a severe burden on healthcare resources such as increased risk of developing antibiotic resistance. The biomarker procalcitonin (PCT) displays specificity to distinguish bacterial inflammations from nonbacterial inflammations and may therefore help to rationalize antibiotic prescriptions. We report in this study, a three-country comparison of the health and economic consequences of a PCT biomarker-guided prescription and clinical decision-making strategy compared to current practice in hospitalized patients with COPD exacerbations. A decision tree was developed, comparing the expected costs and effects of the PCT algorithm to current practice in the Netherlands, Germany, and the United Kingdom. The time horizon of the model captured the length of hospital stay and a societal perspective was also adopted. The primary health outcome was the duration of antibiotic therapy. The incremental cost-effectiveness ratio was defined as the incremental costs per antibiotic day avoided. The incremental cost savings per day on antibiotic therapy avoided were (in Euros) €90 in the Netherlands, €125 in Germany, and €52 in the United Kingdom. Probabilistic sensitivity analyses showed that in the majority of simulations, the PCT biomarker strategy was superior to current practice (the Netherlands: 58%, Germany: 58%, and the United Kingdom: 57%). In conclusion, the PCT biomarker algorithm to optimize antibiotic prescriptions in COPD is likely to be cost-effective compared to current practice. Both the percentage of patients who start with antibiotic treatment as well as the duration of antibiotic therapy are reduced with the PCT decision algorithm, leading to a decrease in

Molecular mechanisms for vascular complications of targeted cancer therapies.

PubMed

Gopal, Srila; Miller, Kenneth B; Jaffe, Iris Z

2016-10-01

Molecularly targeted anti-cancer therapies have revolutionized cancer treatment by improving both quality of life and survival in cancer patients. However, many of these drugs are associated with cardiovascular toxicities that are sometimes dose-limiting. Moreover, the long-term cardiovascular consequences of these drugs, some of which are used chronically, are not yet known. Although the scope and mechanisms of the cardiac toxicities are better defined, the mechanisms for vascular toxicities are only beginning to be elucidated. This review summarizes what is known about the vascular adverse events associated with three classes of novel anti-cancer therapies: vascular endothelial growth factor (VEGF) inhibitors, breakpoint cluster-Abelson (BCR-ABL) kinase inhibitors used to treat chronic myelogenous leukaemia (CML) and immunomodulatory agents (IMiDs) used in myeloma therapeutics. Three of the best described vascular toxicities are reviewed including hypertension, increased risk of acute cardiovascular ischaemic events and arteriovenous thrombosis. The available data regarding the mechanism by which each therapy causes vascular complication are summarized. When data are limited, potential mechanisms are inferred from the known effects of inhibiting each target on vascular cell function and disease. Enhanced understanding of the molecular mechanisms of vascular side effects of targeted cancer therapy is necessary to effectively manage cancer patients and to design safer targeted cancer therapies for the future. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Targeting Glutamine Induces Apoptosis: A Cancer Therapy Approach

PubMed Central

Chen, Lian; Cui, Hengmin

2015-01-01

Glutamine metabolism has been proved to be dysregulated in many cancer cells, and is essential for proliferation of most cancer cells, which makes glutamine an appealing target for cancer therapy. In order to be well used by cells, glutamine must be transported to cells by specific transporters and converted to glutamate by glutaminase. There are currently several drugs that target glutaminase under development or clinical trials. Also, glutamine metabolism restriction has been proved to be effective in inhibiting tumor growth both in vivo and vitro through inducing apoptosis, growth arrest and/or autophagy. Here, we review recent researches about glutamine metabolism in cancer, and cell death induced by targeting glutamine, and their potential roles in cancer therapy. PMID:26402672

Cycling Empirical Antibiotic Therapy in Hospitals: Meta-Analysis and Models

PubMed Central

Abel, Sören; Viechtbauer, Wolfgang; Bonhoeffer, Sebastian

2014-01-01

The rise of resistance together with the shortage of new broad-spectrum antibiotics underlines the urgency of optimizing the use of available drugs to minimize disease burden. Theoretical studies suggest that coordinating empirical usage of antibiotics in a hospital ward can contain the spread of resistance. However, theoretical and clinical studies came to different conclusions regarding the usefulness of rotating first-line therapy (cycling). Here, we performed a quantitative pathogen-specific meta-analysis of clinical studies comparing cycling to standard practice. We searched PubMed and Google Scholar and identified 46 clinical studies addressing the effect of cycling on nosocomial infections, of which 11 met our selection criteria. We employed a method for multivariate meta-analysis using incidence rates as endpoints and find that cycling reduced the incidence rate/1000 patient days of both total infections by 4.95 [9.43–0.48] and resistant infections by 7.2 [14.00–0.44]. This positive effect was observed in most pathogens despite a large variance between individual species. Our findings remain robust in uni- and multivariate metaregressions. We used theoretical models that reflect various infections and hospital settings to compare cycling to random assignment to different drugs (mixing). We make the realistic assumption that therapy is changed when first line treatment is ineffective, which we call “adjustable cycling/mixing”. In concordance with earlier theoretical studies, we find that in strict regimens, cycling is detrimental. However, in adjustable regimens single resistance is suppressed and cycling is successful in most settings. Both a meta-regression and our theoretical model indicate that “adjustable cycling” is especially useful to suppress emergence of multiple resistance. While our model predicts that cycling periods of one month perform well, we expect that too long cycling periods are detrimental. Our results suggest that �

Dual antibiotics for bronchiectasis.

PubMed

Felix, Lambert M; Grundy, Seamus; Milan, Stephen J; Armstrong, Ross; Harrison, Haley; Lynes, Dave; Spencer, Sally

2018-06-11

Bronchiectasis is a chronic respiratory disease characterised by abnormal and irreversible dilatation of the smaller airways and associated with a mortality rate greater than twice that of the general population. Antibiotics serve as front-line therapy for managing bacterial load, but their use is weighed against the development of antibiotic resistance. Dual antibiotic therapy has the potential to suppress infection from multiple strains of bacteria, leading to more successful treatment of exacerbations, reduced symptoms, and improved quality of life. Further evidence is required on the efficacy of dual antibiotics in terms of management of exacerbations and extent of antibiotic resistance. To evaluate the effects of dual antibiotics in the treatment of adults and children with bronchiectasis. We identified studies from the Cochrane Airways Group Specialised Register (CAGR), which includes the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Allied and Complementary Medicine (AMED), and PsycINFO, as well as studies obtained by handsearching of journals/abstracts. We also searched the following trial registries: US National Institutes of Health Ongoing Trials Register, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform. We imposed no restriction on language of publication. We conducted our search in October 2017. We searched for randomised controlled trials comparing dual antibiotics versus a single antibiotic for short-term (< 4 weeks) or long-term management of bronchiectasis diagnosed in adults and/or children by bronchography, plain film chest radiography, or high-resolution computed tomography. Primary outcomes included exacerbations, length of hospitalisation, and serious adverse events. Secondary outcomes were response rates, emergence of resistance to antibiotics, systemic markers of infection, sputum

Arylthiazole antibiotics targeting intracellular methicillin-resistant Staphylococcus aureus (MRSA) that interfere with bacterial cell wall synthesis.

PubMed

Eid, Islam; Elsebaei, Mohamed M; Mohammad, Haroon; Hagras, Mohamed; Peters, Christine E; Hegazy, Youssef A; Cooper, Bruce; Pogliano, Joe; Pogliano, Kit; Abulkhair, Hamada S; Seleem, Mohamed N; Mayhoub, Abdelrahman S

2017-10-20

The promising antibacterial potency of arylthiazole antibiotics is offset by their limited activity against intracellular bacteria (namely methicillin-resistant Staphylococcus aureus (MRSA)), similar to many clinically-approved antibiotics. The failure to target these hidden pathogens is due to the compounds' lack of proper characteristics to accumulate intracellularly. Fine tuning of the size and polar-surface-area of the linking heteroaromatic ring provided a new series of 5-thiazolylarylthiazoles with balanced properties that allow them to sufficiently cross and accumulate inside macrophages infected with MRSA. The most promising compound 4i exhibited rapid bactericidal activity, good metabolic stability and produced over 80% reduction of intracellular MRSA in infected macrophages. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Turning Defense into Offense: Defensin Mimetics as Novel Antibiotics Targeting Lipid II

PubMed Central

Ateh, Eugene; Oashi, Taiji; Lu, Wuyuan; Huang, Jing; Diepeveen-de Buin, Marlies; Bryant, Joseph; Breukink, Eefjan; MacKerell, Alexander D.; de Leeuw, Erik P. H.

2013-01-01

We have previously reported on the functional interaction of Lipid II with human alpha-defensins, a class of antimicrobial peptides. Lipid II is an essential precursor for bacterial cell wall biosynthesis and an ideal and validated target for natural antibiotic compounds. Using a combination of structural, functional and in silico analyses, we present here the molecular basis for defensin-Lipid II binding. Based on the complex of Lipid II with Human Neutrophil peptide-1, we could identify and characterize chemically diverse low-molecular weight compounds that mimic the interactions between HNP-1 and Lipid II. Lead compound BAS00127538 was further characterized structurally and functionally; it specifically interacts with the N-acetyl muramic acid moiety and isoprenyl tail of Lipid II, targets cell wall synthesis and was protective in an in vivo model for sepsis. For the first time, we have identified and characterized low molecular weight synthetic compounds that target Lipid II with high specificity and affinity. Optimization of these compounds may allow for their development as novel, next generation therapeutic agents for the treatment of Gram-positive pathogenic infections. PMID:24244161

Principles of Antibiotic Management of Community-Acquired Pneumonia.

PubMed

Bender, Michael T; Niederman, Michael S

2016-12-01

Community-acquired pneumonia (CAP) encompasses a broad spectrum of disease severity and may require outpatient, inpatient, or intensive care management. Successful treatment hinges on expedient delivery of appropriate antibiotic therapy tailored to both the likely offending pathogens and the severity of disease. This review summarizes key principles in starting treatment and provides recommended empiric therapy regimens for each site of care. In addition, we discuss the antimicrobial and anti-inflammatory role macrolides play in CAP, as well as specific information for managing individual CAP pathogens such as community-acquired methicillin-resistant Staphylococcus aureus and drug-resistant Streptococcus pneumoniae . We also examine several novel antibiotics being developed for CAP and review the evidence guiding duration of therapy and current best practices for the transition of hospitalized patients from intravenous antibiotics to oral therapy. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Surveillance of life-long antibiotics: a review of antibiotic prescribing practices in an Australian Healthcare Network.

PubMed

Lau, Jillian S Y; Kiss, Christopher; Roberts, Erika; Horne, Kylie; Korman, Tony M; Woolley, Ian

2017-01-18

The rise of antimicrobial use in the twentieth century has significantly reduced morbidity due to infection, however it has also brought with it the rise of increasing resistance. Some patients are on prolonged, if not "life-long" course of antibiotics. The reasons for this are varied, and include non-infectious indications. We aimed to study the characteristics of this potential source of antibiotic resistance, by exploring the antibiotic dispensing practices and describing the population of patients on long-term antibiotic therapy. A retrospective cross-sectional study of antibiotic dispensing records was performed at a large university hospital-based healthcare network in Melbourne, Australia. Outpatient prescriptions were extracted from the hospital pharmacy database over a 6 month period in 2014. Medical records of these patients were reviewed to determine the indication for prescription, including microbiology, the intended duration, and the prescribing unit. A descriptive analysis was performed on this data. 66,127 dispensing episodes were reviewed. 202 patients were found to have been prescribed 1 or more antibiotics with an intended duration of 1 year or longer. 69/202 (34%) of these patients were prescribed prolonged antibiotics for primary prophylaxis in the setting of immunosuppression. 43/202 (21%) patients were prescribed long-term suppressive antibiotics for infections of thought incurable (e.g. vascular graft infections), and 34/43 (79%) were prescribed by Infectious Diseases doctors. 66/202 (33%) patients with cystic fibrosis were prescribed prolonged courses of macrolides or fluoroquinolones, by respiratory physicians. There was great heterogeneity noted in indications for prolonged antibiotic courses, as well as antibiotic agents utilised. Our study found that that continuous antibiotic therapy represented only a small proportion of overall antibiotic prescribing at our health network. Prolonged courses of antibiotics were used mainly to

Curative Treatment of Severe Gram-Negative Bacterial Infections by a New Class of Antibiotics Targeting LpxC.

PubMed

Lemaître, Nadine; Liang, Xiaofei; Najeeb, Javaria; Lee, Chul-Jin; Titecat, Marie; Leteurtre, Emmanuelle; Simonet, Michel; Toone, Eric J; Zhou, Pei; Sebbane, Florent

2017-07-25

The infectious diseases caused by multidrug-resistant bacteria pose serious threats to humankind. It has been suggested that an antibiotic targeting LpxC of the lipid A biosynthetic pathway in Gram-negative bacteria is a promising strategy for curing Gram-negative bacterial infections. However, experimental proof of this concept is lacking. Here, we describe our discovery and characterization of a biphenylacetylene-based inhibitor of LpxC, an essential enzyme in the biosynthesis of the lipid A component of the outer membrane of Gram-negative bacteria. The compound LPC-069 has no known adverse effects in mice and is effective in vitro against a broad panel of Gram-negative clinical isolates, including several multiresistant and extremely drug-resistant strains involved in nosocomial infections. Furthermore, LPC-069 is curative in a murine model of one of the most severe human diseases, bubonic plague, which is caused by the Gram-negative bacterium Yersinia pestis Our results demonstrate the safety and efficacy of LpxC inhibitors as a new class of antibiotic against fatal infections caused by extremely virulent pathogens. The present findings also highlight the potential of LpxC inhibitors for clinical development as therapeutics for infections caused by multidrug-resistant bacteria. IMPORTANCE The rapid spread of antimicrobial resistance among Gram-negative bacilli highlights the urgent need for new antibiotics. Here, we describe a new class of antibiotics lacking cross-resistance with conventional antibiotics. The compounds inhibit LpxC, a key enzyme in the lipid A biosynthetic pathway in Gram-negative bacteria, and are active in vitro against a broad panel of clinical isolates of Gram-negative bacilli involved in nosocomial and community infections. The present study also constitutes the first demonstration of the curative treatment of bubonic plague by a novel, broad-spectrum antibiotic targeting LpxC. Hence, the data highlight the therapeutic potential of Lpx

Targeted therapies in the treatment of urothelial cancers.

PubMed

Aragon-Ching, Jeanny B; Trump, Donald L

2017-07-01

Progress has been slow in systemic management of locally advanced and metastatic bladder cancer over the past 20 years. However, the recent approval of immunotherapy with atezolizumab and nivolumab for second-line salvage therapy may usher in an era of more rapid improvement. Systemic treatment is suboptimal and is an area of substantial unmet medical need. The recent findings from The Cancer Genome Atlas project revealed promising pathways that may be amenable to targeted therapies. Promising results with treatment using vascular endothelial growth factor inhibitors such as ramucirumab, sunitinib or bevacizumab, and human epidermal growth factor receptor 2 targeted therapies, epidermal growth factor receptor inhibitors, and fibroblast growth factor receptor inhibitors, are undergoing clinical trials and are discussed later. Copyright © 2017 Elsevier Inc. All rights reserved.

Comparison of knowledge and attitudes about antibiotics and resistance, and antibiotics self-practicing between Bachelor of Pharmacy and Doctor of Pharmacy students in Southern India

PubMed Central

Ahmad, Akram; Khan, Muhammad U.; Moorthy, Jagadeesan; Jamshed, Shazia Q.; Patel, Isha

2014-01-01

Background: There is limited research on pharmacy specialization based differences with regards to usage of antibiotics. Objective: To compare the knowledge, attitude and practice of Bachelor of Pharmacy (BPharm) and Doctor of Pharmacy (PharmD) students about usage and resistance of antibiotics in Southern India. Methods: This was a cross sectional study involving final year BPharm and PharmD students studying in two private institutions located in Andra Pradesh, India. The study was conducted for the period of 3 months. The questionnaire was divided into 5 components: demographics, knowledge about antibiotic use, attitude towards antibiotic use and resistance, self-antibiotic usage, and possible causes of antibiotic resistance. The study questionnaire was assessed for reliability. Data were analysed by employing Mann Whitney and chi square tests using SPSS version 19. Results: The sample size comprised of 137 students. The response rate was 76.11% for the study. There was a significant difference in the knowledge of antibiotic use in BPharm and PharmD students (Mean score: 5.09 vs 6.18, p<0.001). The overall attitude of PharmD students about antibiotic use and resistance was positive compared to BPharm students (Mean score: 3.05 vs 2.23, p<0.05). The self-antibiotic practices was higher in BPharm students than PharmD students (36.4% vs 20%, p<0.05). A significantly high number of PharmD students believed that empirical antibiotic therapy led to antibiotic resistance (19.5% versus 48%, P<0.05). Conclusion: PharmD students were more knowledgeable about antibiotic usage and resistance compared to BPharm students who did not have accurate and the much needed information about the same. Future interventions should be targeted towards educating the BPharm students so that they can implement the acquired knowledge in their practice. PMID:25883690

Cardiotoxicity of novel HER2-targeted therapies.

PubMed

Sendur, Mehmet A N; Aksoy, Sercan; Altundag, Kadri

2013-08-01

Trastuzumab, an anti-HER2 humanized monoclonal antibody, is the standard treatment for both early and metastatic HER2-positive breast cancer. In addition to other chemotherapeutic agents, trastuzumab significantly improves response rate and survival in HER2-positive early and metastatic breast cancer. Although it is well known that trastuzumab therapy is closely associated with both symptomatic and asymptomatic cardiotoxicity, less is known about novel HER2-targeted therapies. The aim of this review is to discuss the cardiac safety data from recent studies of novel anti-HER2 drugs other than trastuzumab. Novel HER2-targeted therapies showed favorable results in HER2 positive metastatic breast cancer patients. Pubmed database, ASCO and San Antonio Breast Cancer Symposium Meeting abstracts were searched until January 2013 using the following search keywords; 'trastuzumab, trastuzumab cardiotoxicity, HER-2 targeted therapies, lapatinib, pertuzumab, trastuzumab emtansine, afatinib and neratinib'; papers which were considered relevant for the aim of this review were selected by the authors. Lapatinib, pertuzumab, T-DM1, neratinib and afatinib molecules are evaluated in the study. In a comprehensive analysis, 3689 lapatinib treated patients enrolled in 49 trials; asymptomatic cardiac events were reported in 53 patients (1.4%) and symptomatic grade III and IV systolic dysfunction was observed only in 7 patients (0.2%) treated with lapatinib. In phase I-III trials of pertuzumab, cardiac dysfunction was seen in 4.5-14.5% of patients with pertuzumab treatment and cardiac dysfunction was usually grade I and II. Cardiotoxicity of pertuzumab was usually reported with the trastuzumab combination and no additive cardiotoxicity was reported with addition of pertuzumab to trastuzumab. T-DM1 had a better safety profile compared to trastuzumab, no significant cardiotoxicity was observed with T-DM1 in heavily pre-treated patients. In the EMILIA study, only in 1.7% of patients in the T

Individualizing duration of antibiotic therapy in community-acquired pneumonia.

PubMed

Aliberti, Stefano; Ramirez, Julio; Giuliani, Fabio; Wiemken, Timothy; Sotgiu, Giovanni; Tedeschi, Sara; Carugati, Manuela; Valenti, Vincenzo; Marchioni, Marco; Camera, Marco; Piro, Roberto; Del Forno, Manuela; Milani, Giuseppe; Faverio, Paola; Richeldi, Luca; Deotto, Martina; Villani, Massimiliano; Voza, Antonio; Tobaldini, Eleonora; Bernardi, Mauro; Bellone, Andrea; Bassetti, Matteo; Blasi, Francesco

2017-08-01

International experts suggest tailoring antibiotic duration in community-acquired pneumonia (CAP) according to patients' characteristics. We aimed to assess the effectiveness of an individualized approach to antibiotic duration based on time in which CAP patients reach clinical stability during hospitalization. In a multicenter, non-inferiority, randomized, controlled trial hospitalized adult patients with CAP reaching clinical stability within 5 days after hospitalization were randomized to a standard vs. individualized antibiotic duration. In the Individualized group, antibiotics were discontinued 48 h after the patient reached clinical stability, with at least five days of total antibiotic treatment. Early failure within 30 days was the primary composite outcome. 135 patients were randomized to the Standard group and 125 to the Individualized group. The trial was interrupted by the safety committee because of an apparent inferiority of the Individualized group over the Standard treatment: 14 (11.2%) patients in the Individualized group experienced early failure vs. 10 (7.4%) patients in the Standard group, p = 0.200, at the intention-to-treat analysis. 30-day mortality rate was four-time higher in the Individualized group than the Standard group. Shortening antibiotic duration according to patients' characteristics still remains an open question. Copyright © 2017 Elsevier Ltd. All rights reserved.

Association of Adverse Events With Antibiotic Use in Hospitalized Patients.

PubMed

Tamma, Pranita D; Avdic, Edina; Li, David X; Dzintars, Kathryn; Cosgrove, Sara E

2017-09-01

Estimates of the incidence of overall antibiotic-associated adverse drug events (ADEs) in hospitalized patients are generally unavailable. To describe the incidence of antibiotic-associated ADEs for adult inpatients receiving systemic antibiotic therapy. Retrospective cohort of adult inpatients admitted to general medicine wards at an academic medical center. At least 24 hours of any parenteral or oral antibiotic therapy. Medical records of 1488 patients were examined for 30 days after antibiotic initiation for the development of the following antibiotic-associated ADEs: gastrointestinal, dermatologic, musculoskeletal, hematologic, hepatobiliary, renal, cardiac, and neurologic; and 90 days for the development of Clostridium difficile infection or incident multidrug-resistant organism infection, based on adjudication by 2 infectious diseases trained clinicians. In 1488 patients, the median age was 59 years (interquartile range, 49-69 years), and 758 (51%) participants were female. A total of 298 (20%) patients experienced at least 1 antibiotic-associated ADE. Furthermore, 56 (20%) non-clinically indicated antibiotic regimens were associated with an ADE, including 7 cases of C difficile infection. Every additional 10 days of antibiotic therapy conferred a 3% increased risk of an ADE. The most common ADEs were gastrointestinal, renal, and hematologic abnormalities, accounting for 78 (42%), 45 (24%), and 28 (15%) 30-day ADEs, respectively. Notable differences were identified between the incidence of ADEs associated with specific antibiotics. Although antibiotics may play a critical role when used appropriately, our findings underscore the importance of judicious antibiotic prescribing to reduce the harm that can result from antibiotic-associated ADEs.

Bloodstream infections in patients with solid tumors: epidemiology, antibiotic therapy, and outcomes in 528 episodes in a single cancer center.

PubMed

Marín, Mar; Gudiol, Carlota; Garcia-Vidal, Carol; Ardanuy, Carmen; Carratalà, Jordi

2014-05-01

Current information regarding bloodstream infection (BSI) in patients with solid tumors is scarce. We assessed the epidemiology, antibiotic therapy, and outcomes of BSI in these patients. We also compared patients who died with those who survived to identify risk factors associated with mortality. From January 2006 to July 2012 all episodes of BSI in patients with solid tumors at a cancer center were prospectively recorded and analyzed. A total of 528 episodes of BSI were documented in 489 patients. The most frequent neoplasms were hepatobiliary tumors (19%), followed by lung cancer (18%) and lower gastrointestinal malignancies (16%). Many patients had received corticosteroid therapy (41%), and 15% had neutropenia (<500 neutrophils/μL) at the time of BSI. The most common source of BSI was cholangitis (21%), followed by other abdominal (19.5%) and urinary tract infections (17%). Gram-negative BSI occurred in 55% of cases, mainly due to Escherichia coli (55%), Pseudomonas aeruginosa (18%), and Klebsiella pneumoniae (16%). Among gram-positive BSI (35%), viridans group streptococci were the most frequent causative organisms (22%), followed by Staphylococcus aureus (21%) and Enterococcus species (18%). We identified 61 multidrug-resistant (MDR) organisms (13%), mainly extended-spectrum β-lactamase-producing Enterobacteriaceae (n = 20) and AmpC-producing Enterobacteriaceae (n = 13). The majority of patients with BSI caused by MDR organisms had received antibiotics (70%), and they had been previously hospitalized (61.4%) more frequently than patients with BSI caused by susceptible strains. Inadequate empirical antibiotic therapy was given to 23% of patients, with a higher proportion in those with BSI due to a MDR strain (69%). Early (<48 h) and overall (30 d) case-fatality rates were 7% and 32%, respectively. The overall case-fatality rate was higher among cases caused by MDR organisms (39.3%). The only independent risk factors for the early case-fatality rate were the

Differential effects of antibiotic therapy on the structure and function of human gut microbiota.

PubMed

Pérez-Cobas, Ana Elena; Artacho, Alejandro; Knecht, Henrik; Ferrús, María Loreto; Friedrichs, Anette; Ott, Stephan J; Moya, Andrés; Latorre, Amparo; Gosalbes, María José

2013-01-01

The human intestinal microbiota performs many essential functions for the host. Antimicrobial agents, such as antibiotics (AB), are also known to disturb microbial community equilibrium, thereby having an impact on human physiology. While an increasing number of studies investigate the effects of AB usage on changes in human gut microbiota biodiversity, its functional effects are still poorly understood. We performed a follow-up study to explore the effect of ABs with different modes of action on human gut microbiota composition and function. Four individuals were treated with different antibiotics and samples were taken before, during and after the AB course for all of them. Changes in the total and in the active (growing) microbiota as well as the functional changes were addressed by 16S rRNA gene and metagenomic 454-based pyrosequencing approaches. We have found that the class of antibiotic, particularly its antimicrobial effect and mode of action, played an important role in modulating the gut microbiota composition and function. Furthermore, analysis of the resistome suggested that oscillatory dynamics are not only due to antibiotic-target resistance, but also to fluctuations in the surviving bacterial community. Our results indicated that the effect of AB on the human gut microbiota relates to the interaction of several factors, principally the properties of the antimicrobial agent, and the structure, functions and resistance genes of the microbial community.

Structural characterization of Staphylococcus aureus biotin protein ligase and interaction partners: An antibiotic target

PubMed Central

Pendini, Nicole R; Yap, Min Y; Polyak, Steven W; Cowieson, Nathan P; Abell, Andrew; Booker, Grant W; Wallace, John C; Wilce, Jacqueline A; Wilce, Matthew C J

2013-01-01

The essential metabolic enzyme biotin protein ligase (BPL) is a potential target for the development of new antibiotics required to combat drug-resistant pathogens. Staphylococcus aureus BPL (SaBPL) is a bifunctional protein, possessing both biotin ligase and transcription repressor activities. This positions BPL as a key regulator of several important metabolic pathways. Here, we report the structural analysis of both holo- and apo-forms of SaBPL using X-ray crystallography. We also present small-angle X-ray scattering data of SaBPL in complex with its biotin-carboxyl carrier protein substrate as well as the SaBPL:DNA complex that underlies repression. This has revealed the molecular basis of ligand (biotinyl-5′-AMP) binding and conformational changes associated with catalysis and repressor function. These data provide new information to better understand the bifunctional activities of SaBPL and to inform future strategies for antibiotic discovery. PMID:23559560

The multifaceted roles of antibiotics and antibiotic resistance in nature

PubMed Central

Sengupta, Saswati; Chattopadhyay, Madhab K.; Grossart, Hans-Peter

2013-01-01

Antibiotics are chemotherapeutic agents, which have been a very powerful tool in the clinical management of bacterial diseases since the 1940s. However, benefits offered by these magic bullets have been substantially lost in subsequent days following the widespread emergence and dissemination of antibiotic-resistant strains. While it is obvious that excessive and imprudent use of antibiotics significantly contributes to the emergence of resistant strains, antibiotic resistance is also observed in natural bacteria of remote places unlikely to be impacted by human intervention. Both antibiotic biosynthetic genes and resistance-conferring genes have been known to evolve billions of years ago, long before clinical use of antibiotics. Hence it appears that antibiotics and antibiotics resistance determinants have some other roles in nature, which often elude our attention because of overemphasis on the therapeutic importance of antibiotics and the crisis imposed by the antibiotic resistance in pathogens. In the natural milieu, antibiotics are often found to be present in sub-inhibitory concentrations acting as signaling molecules supporting the process of quorum sensing and biofilm formation. They also play an important role in the production of virulence factors and influence host–parasite interactions (e.g., phagocytosis, adherence to the target cell, and so on). The evolutionary and ecological aspects of antibiotics and antibiotic resistance in the naturally occurring microbial community are little understood. Therefore, the actual role of antibiotics in nature warrants in-depth investigations. Studies on such an intriguing behavior of the microorganisms promise insight into the intricacies of the microbial physiology and are likely to provide some lead in controlling the emergence and subsequent dissemination of antibiotic resistance. This article highlights some of the recent findings on the role of antibiotics and the genes that confer resistance to antibiotics

Glycopeptide antibiotic biosynthesis.

PubMed

Yim, Grace; Thaker, Maulik N; Koteva, Kalinka; Wright, Gerard

2014-01-01

Glycopeptides such as vancomycin, teicoplanin and telavancin are essential for treating infections caused by Gram-positive bacteria. Unfortunately, the dwindled pipeline of new antibiotics into the market and the emergence of glycopeptide-resistant enterococci and other resistant bacteria are increasingly making effective antibiotic treatment difficult. We have now learned a great deal about how bacteria produce antibiotics. This information can be exploited to develop the next generation of antimicrobials. The biosynthesis of glycopeptides via nonribosomal peptide assembly and unusual amino acid synthesis, crosslinking and tailoring enzymes gives rise to intricate chemical structures that target the bacterial cell wall. This review seeks to describe recent advances in our understanding of both biosynthesis and resistance of these important antibiotics.

Efficacy of antibiotic therapy for SAPHO syndrome is lost after its discontinuation: an interventional study

PubMed Central

2009-01-01

Introduction The acronym SAPHO was introduced in 1987 to unify the various descriptions of a seronegative arthritis associated with skin manifestations and to show synovitis, acne, pustulosis, hyperostosis, and osteitis with and without sterile multifocal osteomyelitis. The etiology of SAPHO syndrome is unknown, but an association with infection by semipathogenic bacteria like Propionibacterium acnes has been suggested. We conducted an interventional study of SAPHO patients receiving antibiotics. Methods Thirty-seven patients met the clinical criteria of SAPHO syndrome, 21 of them underwent a needle biopsy of the osteitis lesion, and 14 of them showed positive bacteriological cultures for P. acnes. Thirty patients (14 bacteriological positive and 16 without biopsy) were treated with antibiotics for 16 weeks. The activity of skin disease and osteitis were assessed by a physician using a scoring model (from 0 to 6). In addition, patients completed a Health Assessment Score (HAS, from 0 to 6). The erythrocyte sedimentation rate was determined and a MRI (of the osteitis lesion, radiologic activity score from 0 to 2) was performed in week 1 (W1), week 16 (W16), and week 28 (W28, 12 weeks after antibiotics). Results Twenty-seven patients continued the medication (azithromycin, n = 25, 500 mg twice a week; clindamycin, n = 1, 300 mg daily; or doxycycline, n = 1, 100 mg daily) for 16 weeks. After W16 the scores for MRI (1.5 to 1.1, P = 0.01), skin activity (3.2 to 1.2, P = 0.01), osteitis activity (4.0 to 2.1, P = 0.02), and HAS (3.3 to 2.1, P = 0.01) decreased significantly. However, this was followed by increasing values for MRI scores (1.2 to 1.4, P = 0.08), skin activity (1.2 to 1.7, P = 0.11), osteitis activity (1.9 to 2.7, P = 0.01), and HAS (2.2 to 3.3, P = 0.02) from W16 to W28. The comparison of the scores in W1 and W28 in these 12 patients showed no significant differences. Conclusions For the period of application, the antibiotic therapy seems to have controlled

Antibiotics during childhood and inflammatory bowel disease?

PubMed

2014-10-01

Four epidemiological studies, including two large cohort studies in children aged 17 years or under, have studied the link between antibiotic therapy and inflammatory bowel disease. The risk of inflammatory bowel disease appeared to be twice as high in children exposed to an antibiotic as in unexposed children. The risk appeared higher following exposure during the first year of life, with beta-lactam antibiotics, and with repeated antibiotic courses. One postulated mechanism is through destruction of the anaerobic intestinal flora by antibiotics. In practice, these data provide yet another reason to avoid unnecessarily exposing children to antibiotics.

Efficacy of prophylactic probiotics in combination with antibiotics versus antibiotics alone for colorectal surgery: A meta-analysis of randomized controlled trials.

PubMed

Wu, Xiang-Dong; Xu, Wei; Liu, Meng-Meng; Hu, Ke-Jia; Sun, Ya-Ying; Yang, Xue-Fei; Zhu, Gui-Qi; Wang, Zi-Wei; Huang, Wei

2018-03-24

This meta-analysis aimed to determine whether prophylactic probiotics in combination with antibiotics are superior to antibiotics alone in the prevention of surgical site infection (SSI) after colorectal surgery. Fourteen trials involving 1524 participants were included. Compared with antibiotics alone, prophylactic probiotics in combination with antibiotics reduced the risk of SSI as well as other complications, shortened the cumulative duration of antibiotic therapy. Current evidence suggested that probiotics in combination with antibiotics could be recommended. © 2018 Wiley Periodicals, Inc.

Neonatal Procalcitonin Intervention Study (NeoPInS): Effect of Procalcitonin-guided decision making on duration of antibiotic therapy in suspected neonatal early-onset sepsis: A multi-centre randomized superiority and non-inferiority Intervention Study.

PubMed

Stocker, Martin; Hop, Wim C J; van Rossum, Annemarie M C

2010-12-08

Early diagnosis and treatment of the newborn infant with suspected sepsis are essential to prevent severe and life threatening complications. Diagnosis of neonatal sepsis is difficult because of the variable and nonspecific clinical presentation. Therefore, many newborns with nonspecific symptoms are started on antibiotic treatment before the presence of sepsis has been proven. With our recently published single-centre intervention study we were able to show that Procalcitonin determinations allowed to shorten the duration of antibiotic therapy in newborns with suspected early-onset sepsis. The study is designed as randomized controlled international multicenter intervention trial on the efficacy and safety of Procalcitonin guided treatment. Term and near-term infants (gestational age ≥ 34 0/7 weeks) with suspected sepsis in the first 3 days of life requiring empiric antibiotic therapy will be included. The duration of antibiotic therapy in the standard group is based on the attending physician's assessment of the likelihood of infection (infection unlikely, possible, probable or proven). In the Procalcitonin group, if infection is considered to be unlikely or possible, antibiotic therapy is discontinued when two consecutive Procalcitonin values are within the normal range. Co-primary outcome measures are the duration of antibiotic therapy (superiority aspect of the trial) and the proportion of infants with a recurrence of infection requiring additional courses of antibiotic therapy and/or death in the first month of life (safety of study intervention, non-inferiority aspect of the trial). The number of infants to be included equals 800 per arm. With these numbers the power of the study to demonstrate superiority for duration of antibiotic therapy as well as non-inferiority regarding safety, i.e. excluding a disadvantage difference larger than 2% for the experimental arm, will both be greater than 80%. Benefit of the study is a possible limitation of unnecessary

Gene Therapy Targeting Glaucoma: Where Are We?

PubMed Central

Liu, Xuyang; Rasmussen, Carol A.; Gabelt, B’Ann T.; Brandt, Curtis R.; Kaufman, Paul L.

2010-01-01

In a chronic disease such as glaucoma, a therapy that provides a long lasting local effect, with minimal systemic side effects, while circumventing the issue of patient compliance, is very attractive. The field of gene therapy is growing rapidly and ocular applications are expanding. Our understanding of the molecular pathogenesis of glaucoma is leading to greater specificity in ocular tissue targeting. Improvements in gene delivery techniques, refinement of vector construction methods, and development of better animal models combine to bring this potential therapy closer to reality. PMID:19539835

Development of a patient-centred intervention to improve knowledge and understanding of antibiotic therapy in secondary care.

PubMed

Rawson, Timothy M; Moore, Luke S P; Castro-Sanchez, Enrique; Charani, Esmita; Hernandez, Bernard; Alividza, Vivian; Husson, Fran; Toumazou, Christofer; Ahmad, Raheelah; Georgiou, Pantelis; Holmes, Alison H

2018-01-01

We developed a personalised antimicrobial information module co-designed with patients. This study aimed to evaluate the potential impact of this patient-centred intervention on short-term knowledge and understanding of antimicrobial therapy in secondary care. Thirty previous patients who had received antibiotics in hospital within 12 months were recruited to co-design an intervention to promote patient engagement with infection management. Two workshops, containing five focus-groups were held. These were audio-recorded. Data were analysed using a thematic framework developed deductively based on previous work. Line-by-line coding was performed with new themes added to the framework by two researchers. This was used to inform the development of a patient information module, embedded within an electronic decision support tool (CDSS).The intervention was piloted over a four-week period at Imperial College Healthcare NHS Trust on 30 in-patients. Pre- and post-intervention questionnaires were developed and implemented to assess short term changes in patient knowledge and understanding and provide feedback on the intervention. Data were analysed using SPSS and NVIVO software. Within the workshops, there was consistency in identified themes. The participants agreed upon and co-designed a personalised PDF document that could be integrated into an electronic CDSS to be used by healthcare professionals at the point-of-care. Their aim for the tool was to provide individualised practical information, signpost to reputable information sources, and enhance communication between patients and healthcare professionals.Eighteen out of thirty in-patients consented to participant in the pilot evaluation with 15/18(83%) completing the study. Median (range) age was 66(22-85) years. The majority were male (10/15;66%). Pre-intervention, patients reported desiring further information regarding their infections and antibiotic therapy, including side effects of treatment. Deployment of the

Sonographic Differentiation of Complicated From Uncomplicated Appendicitis: Implications for Antibiotics-First Therapy.

PubMed

Xu, Yingding; Jeffrey, R Brooke; Chang, Stephanie T; DiMaio, Michael A; Olcott, Eric W

2017-02-01

To evaluate sonographic findings as indicators of complicated versus uncomplicated appendicitis in the setting of known appendicitis, a necessary distinction in deciding whether to proceed with antibiotic therapy or with appendectomy. With Institutional Review Board approval and Health Insurance Portability and Accountability Act compliance, appendiceal sonograms of 119 patients with histopathologically proven appendicitis were retrospectively blindly reviewed to determine the presence or absence of the normally echogenic submucosal layer, the presence of mural hyperemia, periappendiceal fluid, appendicoliths, and hyperechoic periappendiceal fat and to determine the maximum outside diameter. Results were compared with the presence of complicated versus uncomplicated appendicitis on histopathologic examination and assessed by both univariate and mulitvariate logistic regression; confidence intervals (CIs) of proportions were assessed by the exact binomial test. Thirty-two (26.9%) of the 119 patients had complicated appendicitis, including 11 with gangrenous appendicitis without perforation and 21 with gangrenous appendicitis and perforation. Loss of the submucosal layer was the only independent significant indicator of complicated appendicitis in multivariate regression (P < .001) and provided sensitivity and specificity values of 100.0% (95% CI, 89.1%-100.0%) and 92.0% (95% CI, 84.1%-96.7%), respectively. Loss of the normally echogenic submucosal layer was the most useful sonographic finding for discriminating complicated from uncomplicated appendicitis, being the only finding independently and significantly associated with complicated appendicitis and, additionally, providing both high sensitivity and high specificity. This information may help a physician decide whether to proceed with antibiotic therapy or with appendectomy when treating a patient with appendicitis. © 2016 by the American Institute of Ultrasound in Medicine.

Role of antibiotic therapy for bacterial vaginosis and intermediate flora in pregnancy.

PubMed

Ugwumadu, Austin

2007-06-01

Bacterial vaginosis and intermediate flora are associated with late miscarriage and preterm delivery. The mechanisms involved are not yet fully understood. Clinical trials of antibiotic therapy to reduce these complications have yielded conflicting results. These trials, however, were conducted in mixed populations of pregnant women with variable risk profiles for preterm delivery. Furthermore, investigators used different criteria for diagnosis, treated with different antibiotics at different doses and via different routes, and initiated treatment at different gestational ages. Over 80% of pregnant women with abnormal vaginal flora have a good outcome, and in some populations the presence of bacterial vaginosis is not associated with preterm delivery, suggesting that other host factors may modify the risk. Recent studies have examined the roles of genetic regulation of host immune response, bacterial pathogenic factors, and enzymes in the vagina, and how these factors interact to drive a given outcome. These markers have the potential to better define the women at maximal risk and therefore guide future interventions. This chapter aims to appraise the current state of treatment of abnormal vaginal flora in pregnancy and suggest appropriate management based on the available evidence.

[Pharmaceutical use and antibiotic therapy in intensive care units].

PubMed

Gauzit, R

2000-05-01

The present study has involved a sample of 750 medical or medical/surgical intensive care units. The aim was to identify the variations of antibiotic (AB) use, measured in monetary terms, and to sort out explicative variables accounting for the corresponding expense. Activity and expense data have been recorded for 1997. "Second intention" antibiotics have been defined as follows: imipenem, ceftazidime, cefpirome, cefepime, piperacillin/tazobactam, amikacin, isepamicin, vancomycin and teicoplanin. Only 60 evaluable sheets have been sent back. They include data about 28,000 admissions and 183,960 hospital days. The results are presented as means +/- standard deviation (SD) and the variability has been considered to be important if the ratio SD/mean was > 1. Nosocomial infections (NI) surveillance, antibiotic advisory board and restriction of use for some molecules were present in 95%, 67% and 78% of units, respectively. The units usually had 10 beds (range: 6-24) and the mean activity was 468 +/- 184 admissions/year and 3,066 +/- 1,454 hospital days/year. Mean duration of hospitalisation (MDH) was 6.9 +/- 2.7 days and mean omega score 114 +/- 61. Mean age of patients was 56.5 years, IGS II score 35.7 +/- 7; 29 +/- 16% of patients were mechanically ventilated for more than 48 hours and mortality rate was 17 +/- 7%. The mean number of bacterial isolates per unit was 369 +/- 323: Staphylococcus sp. 30% [including 25% of meticillin-resistant Staphylococcus aureus (MRSA)]; enterobacteria 30% (including 14% of cefotaxime-resistant isolates); Pseudomonas sp. 14% (including 40% of ticarcillin R isolates); other 26%. Pharmaceutical expense was 834 +/- 364 FF per day of hospitalisation, including 536 +/- 273 FF for drugs. Antibiotics accounted for 32% of the expense and second intention molecules for nearly 50% of antibiotic expense. More than 80% of antibiotic expense was accounted for by only 10 molecules. The mean cost/hospital day for the most expensive antibiotic

[Antibiotics: present and future].

PubMed

Bérdy, János

2013-04-14

The author discuss the up to date interpretation of the concept of antibiotics and antibiotic research, as well as the present role of various natural, semisynthetic and synthetic antibiotic compounds in various areas of the human therapy. The origin and the total number of all antibiotics and applied antibiotics in the practice, as well as the bioactive microbial metabolites (antibiotics) in other therapeutical, non-antibiotic fields (including agriculture) are also reviewed. The author discusses main problems, such as increasing (poly)resistance, virulence of pathogens and the non-scientific factors (such as a decline of research efforts and their sociological, economic, financial and regulatory reasons). A short summary of the history of Hungarian antibiotic research is also provided. The author briefly discusses the prospects in the future and the general advantages of the natural products over synthetic compounds. It is concluded that new approaches for the investigation of the unlimited possibilities of the living world are necessary. The discovery of new types or simply neglected (micro)organisms and their biosynthetic capabilities, the introduction of new biotechnological and genetic methods (genomics, metagenom, genome mining) are absolutely required in the future.

Antibiotic therapy in preterm premature rupture of the membranes.

PubMed

Yudin, Mark H; van Schalkwyk, Julie; Eyk, Nancy Van

2009-09-01

To review the evidence and provide recommendations on the use of antibiotics in preterm premature rupture of the membranes (PPROM). Outcomes evaluated include the effect of antibiotic treatment on maternal infection, chorioamnionitis, and neonatal morbidity and mortality. Published literature was retrieved through searches of Medline, EMBASE, CINAHL, and The Cochrane Library, using appropriate controlled vocabulary and key words (PPROM, infection, and antibiotics). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and new material incorporated in the guideline to July 2008. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. The evidence obtained was reviewed and evaluated by the Infectious Diseases Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC) under the leadership of the principal authors, and recommendations were made according to guidelines developed by the Canadian Task Force on Preventive Health Care. Guideline implementation should assist the practitioner in developing an approach to the use of antibiotics in women with PPROM. Patients will benefit from appropriate management of this condition. This guideline has been reviewed and approved by the Infectious Diseases Committee and the Maternal Fetal Medicine Committee of the SOGC, and approved by the Executive and Council of the SOGC. The Society of Obstetricians and Gynaecologists of Canada. 1. Following PPROM at < or = 32 weeks' gestation, antibiotics should be administered to women who are not in labour in order to prolong pregnancy and to decrease maternal and neonatal morbidity. (I

Antibiotic stewardship and empirical antibiotic treatment: How can they get along?

PubMed

Zuccaro, Valentina; Columpsi, Paola; Sacchi, Paolo; Lucà, Maria Grazia; Fagiuoli, Stefano; Bruno, Raffaele

2017-06-01

The aim of this review is to focus on the recent knowledge on antibiotic stewardship and empiric antibiotic treatment in cirrhotic patients. The application of antimicrobial stewardship (AMS) rules appears to be the most appropriate strategy to globally manage cirrhotic patients with infectious complications: indeed they represent a unique way to provide both early diagnosis and appropriate therapy in order to avoid not only antibiotic over-prescription but, more importantly, selection and spread of antimicrobial resistance. Moreover, cirrhotic patients must be considered "frail" and susceptible to healthcare associated infections: applying AMS policies would assure a cost reduction and thus contribute to the improvement of public health strategies. Copyright © 2017. Published by Elsevier Ltd.

[Pharmacokinetic/pharmacodynamic analysis of antibiotic therapy in dentistry and stomatology].

PubMed

Isla, Arantxazu; Canut, Andrés; Rodríguez-Gascón, Alicia; Labora, Alicia; Ardanza-Trevijano, Bruno; Solinís, María Angeles; Pedraz, José Luis

2005-03-01

This study evaluates the efficacy of various antimicrobial treatments for orofacial infections on the basis of pharmacokinetic/pharmacodynamic (PK/PD) criteria. A complete a literature search was undertaken to establish the MIC90 values of the five microorganisms most frequently isolated in odontogenic infections and the pharmacokinetic parameters of 13 antibiotics used in these infections. Pharmacokinetic simulations were then carried out with mean population parameters and efficacy indexes were calculated for the 47 treatment regimens analyzed. For drugs showing time-dependent antibacterial killing, the time above MIC (t > MIC) was calculated. For drugs with concentration-dependent bactericidal activity, the AUC/MIC was calculated. Amoxicillin-clavulanic (500 mg/8 h or 1000 mg/12 h) and clindamycin (300 mg/6 h) in the time-dependent killing group and moxifloxacin (400 mg/24 h) in the concentration-dependent group showed adequate efficacy indexes against the five pathogens considered to be the most commonly implicated in odontogenic infections. The spiramycin plus metronidazole combination, present in the commercial formulation Rhodogyl, did not reach satisfactory PK/PD indexes. PK/PD indexes, which are useful predictors of the potential efficacy of antibacterial therapy, were used with ontogenic infections in the present study. The PK/PD simulations showed that amoxicillin-clavulanic, clindamycin and moxifloxacin were the most suitable antibiotics for this kind of infection. Clinical trials are required to confirm that this methodology is useful in these pathologic processes.

An empirical broad spectrum antibiotic therapy in health-care-associated infections improves survival in patients with cirrhosis: A randomized trial.

PubMed

Merli, Manuela; Lucidi, Cristina; Di Gregorio, Vincenza; Lattanzi, Barbara; Giannelli, Valerio; Giusto, Michela; Farcomeni, Alessio; Ceccarelli, Giancarlo; Falcone, Marco; Riggio, Oliviero; Venditti, Mario

2016-05-01

Early diagnosis and appropriate treatment of infections in cirrhosis are crucial because of their high morbidity and mortality. Multidrug-resistant (MDR) infections are on the increase in health care settings. Health-care-associated (HCA) infections are still frequently treated as community-acquired with a detrimental effect on survival. We aimed to prospectively evaluate in a randomized trial the effectiveness of a broad spectrum antibiotic treatment in patients with cirrhosis with HCA infections. Consecutive patients with cirrhosis hospitalized with HCA infections were enrolled. After culture sampling, patients were promptly randomized to receive a standard or a broad spectrum antibiotic treatment (NCT01820026). The primary endpoint was in-hospital mortality. Efficacy, side effects, and the length of hospitalization were considered. Treatment failure was followed by a change in antibiotic therapy. Ninety-six patients were randomized and 94 were included. The two groups were similar for demographic, clinical, and microbiological characteristics. The prevalence of MDR pathogens was 40% in the standard versus 46% in the broad spectrum group. In-hospital mortality showed a substantial reduction in the broad spectrum versus standard group (6% vs. 25%; P = 0.01). In a post-hoc analysis, reduction of mortality was more evident in patients with sepsis. The broad spectrum showed a lower rate of treatment failure than the standard therapy (18% vs. 51%; P = 0.001). Length of hospitalization was shorter in the broad spectrum (12.3 ± 7 days) versus standard group (18 ± 15 days; P = 0.03). Five patients in each group developed a second infection during hospitalization with a similar prevalence of MDR (50% broad spectrum vs. 60% standard). A broad spectrum antibiotic therapy as empirical treatment in HCA infections improves survival in cirrhosis. This treatment was significantly effective, safe, and cost saving. © 2015 by the American Association for the

Management of pulmonary toxicity associated with targeted anticancer therapies.

PubMed

Teuwen, Laure-Anne; Van den Mooter, Tom; Dirix, Luc

2015-01-01

Targeted anticancer therapies act by interfering with defined molecular entities and/or biologic pathways. Because of their more specific mechanism of action, adverse events (AEs) on healthy tissues are intended to be minimal, resulting in a different toxicity profile from that observed with conventional cytotoxic chemotherapy. Pulmonary AEs are rare but potentially life-threatening and it is, therefore, critical to recognize early on and manage appropriately. In this review, we aim to offer an overview of both more frequent and rare pulmonary AEs caused by targeted anticancer therapies and discuss possible treatment algorithms. Anti-vascular endothelial growth factor, anti-human epidermal growth factor receptor and anti-CD20 therapy will be reviewed, as well as immune checkpoint inhibitors, anaplastic lymphoma kinase inhibitors and mammalian target of rapamycin inhibitors. Novel agents used in the treatment of cancer have specific side-effects, the result of allergic reactions, on-target and off-target effects. Clinical syndromes associated with pulmonary toxicity vary from bronchospasms, hypersensitivity reactions, pneumonitis, acute respiratory distress, lung bleeding, pleural effusion to pneumothorax. Knowledge of risk factors, a high index of suspicion and a complete diagnostic work-up are essential for limiting the risk of these events becoming life threatening. The development of treatment algorithms is extremely helpful in managing these events. It is probable that these toxicities will be even more frequent with the introduction of combination therapies with the obvious challenge of discerning the responsible agent.

Targeted therapy according to next generation sequencing-based panel sequencing.

PubMed

Saito, Motonobu; Momma, Tomoyuki; Kono, Koji

2018-04-17

Targeted therapy against actionable gene mutations shows a significantly higher response rate as well as longer survival compared to conventional chemotherapy, and has become a standard therapy for many cancers. Recent progress in next-generation sequencing (NGS) has enabled to identify huge number of genetic aberrations. Based on sequencing results, patients recommend to undergo targeted therapy or immunotherapy. In cases where there are no available approved drugs for the genetic mutations detected in the patients, it is recommended to be facilitate the registration for the clinical trials. For that purpose, a NGS-based sequencing panel that can simultaneously target multiple genes in a single investigation has been used in daily clinical practice. To date, various types of sequencing panels have been developed to investigate genetic aberrations with tumor somatic genome variants (gain-of-function or loss-of-function mutations, high-level copy number alterations, and gene fusions) through comprehensive bioinformatics. Because sequencing panels are efficient and cost-effective, they are quickly being adopted outside the lab, in hospitals and clinics, in order to identify personal targeted therapy for individual cancer patients.

New PARP targets for cancer therapy

PubMed Central

Vyas, Sejal; Chang, Paul

2015-01-01

Poly(ADP-ribose) polymerases (PARPs) modify target proteins post-translationally with poly(ADP-ribose) (PAR) or mono(ADP-ribose) (MAR) using NAD+ as substrate. The best-studied PARPs generate PAR modifications and include PARP1 and the tankyrase PARP5a, both of which are targets for cancer therapy with inhibitors in either clinical trials or preclinical development. There are 15 additional PARPs, the majority of which modify proteins with MAR, and their biology is less well understood. Recent data identify potentially cancer relevant functions for these PARPs, indicating that we need to understand more about these PARPs in order to target them effectively. PMID:24898058

A cost analysis of a broad-spectrum antibiotic therapy in the empirical treatment of health care-associated infections in cirrhotic patients

PubMed Central

Lucidi, Cristina; Di Gregorio, Vincenza; Ceccarelli, Giancarlo; Venditti, Mario; Riggio, Oliviero; Merli, Manuela

2017-01-01

Background Early diagnosis and appropriate treatment of infections in cirrhosis are crucial. As new guidelines in this context, particularly for health care-associated (HCA) infections, would be needed, we performed a trial documenting whether an empirical broad-spectrum antibiotic therapy is more effective than the standard one for these infections. Because of the higher daily cost of broad-spectrum than standard antibiotics, we performed a cost analysis to compare: 1) total drug costs, 2) profitability of hospital admissions. Methods This retrospective observational analysis was performed on patients enrolled in the trial NCT01820026, in which consecutive cirrhotic patients with HCA infections were randomly assigned to a standard vs a broad-spectrum treatment. Antibiotic daily doses, days of treatment, length of hospital stay, and DRG (diagnosis-related group) were recorded from the clinical trial medical records. The profitability of hospitalizations was calculated considering DRG tariffs divided by length of hospital stay. Results We considered 84 patients (42 for each group). The standard therapy allowed to obtain a first-line treatment cost lower than in the broad-spectrum therapy. Anyway, the latter, being related to a lower failure rate (19% vs 57.1%), resulted in cost saving in terms of cumulative antibiotic costs (first- and second-line treatments). The mean cost saving per patient for the broad-spectrum arm was €44.18 (−37.6%), with a total cost saving of about €2,000. Compared to standard group, we observed a statistically significant reduction in hospital stay from 17.8 to 11.8 days (p<0.002) for patients treated with broad-spectrum antibiotics. The distribution of DRG tariffs was similar in the two groups. According to DRG, the shorter length of hospital stay of the broad-spectrum group involved a higher mean profitable daily cost than standard group (€345.61 vs €252.23; +37%). Conclusion Our study supports the idea that the use of a broad

A cost analysis of a broad-spectrum antibiotic therapy in the empirical treatment of health care-associated infections in cirrhotic patients.

PubMed

Lucidi, Cristina; Di Gregorio, Vincenza; Ceccarelli, Giancarlo; Venditti, Mario; Riggio, Oliviero; Merli, Manuela

2017-01-01

Early diagnosis and appropriate treatment of infections in cirrhosis are crucial. As new guidelines in this context, particularly for health care-associated (HCA) infections, would be needed, we performed a trial documenting whether an empirical broad-spectrum antibiotic therapy is more effective than the standard one for these infections. Because of the higher daily cost of broad-spectrum than standard antibiotics, we performed a cost analysis to compare: 1) total drug costs, 2) profitability of hospital admissions. This retrospective observational analysis was performed on patients enrolled in the trial NCT01820026, in which consecutive cirrhotic patients with HCA infections were randomly assigned to a standard vs a broad-spectrum treatment. Antibiotic daily doses, days of treatment, length of hospital stay, and DRG (diagnosis-related group) were recorded from the clinical trial medical records. The profitability of hospitalizations was calculated considering DRG tariffs divided by length of hospital stay. We considered 84 patients (42 for each group). The standard therapy allowed to obtain a first-line treatment cost lower than in the broad-spectrum therapy. Anyway, the latter, being related to a lower failure rate (19% vs 57.1%), resulted in cost saving in terms of cumulative antibiotic costs (first- and second-line treatments). The mean cost saving per patient for the broad-spectrum arm was €44.18 (-37.6%), with a total cost saving of about €2,000. Compared to standard group, we observed a statistically significant reduction in hospital stay from 17.8 to 11.8 days ( p <0.002) for patients treated with broad-spectrum antibiotics. The distribution of DRG tariffs was similar in the two groups. According to DRG, the shorter length of hospital stay of the broad-spectrum group involved a higher mean profitable daily cost than standard group (€345.61 vs €252.23; +37%). Our study supports the idea that the use of a broad-spectrum empirical treatment for HCA

Enhancing Targeted Therapy for Myeloproliferative Neoplasms

DTIC Science & Technology

2013-10-01

Myeloproliferative Neoplasms PRINCIPAL INVESTIGATOR: Gary W. Reuther CONTRACTING...2. REPORT TYPE Annual 3. DATES COVERED 30 2012-2 2013 4. TITLE AND SUBTITLE Enhancing Targeted Therapy for Myeloproliferative Neoplasms ...AVAILABILITY STATEMENT Approved for Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Myeloproliferative neoplasms

Antimicrobial strategies centered around reactive oxygen species - bactericidal antibiotics, photodynamic therapy and beyond

PubMed Central

Vatansever, Fatma; de Melo, Wanessa C.M.A.; Avci, Pinar; Vecchio, Daniela; Sadasivam, Magesh; Gupta, Asheesh; Chandran, Rakkiyappan; Karimi, Mahdi; Parizotto, Nivaldo A; Yin, Rui; Tegos, George P; Hamblin, Michael R

2013-01-01

Reactive oxygen species (ROS) can attack a diverse range of targets to exert antimicrobial activity, which accounts for their versatility in mediating host defense against a broad range of pathogens. Most ROS are formed by the partial reduction of molecular oxygen. Four major ROS are recognized comprising: superoxide (O2•−), hydrogen peroxide (H2O2), hydroxyl radical (•OH), and singlet oxygen (1O2), but they display very different kinetics and levels of activity. The effects of O2•− and H2O2 are less acute than those of •OH and 1O2, since the former are much less reactive and can be detoxified by endogenous antioxidants (both enzymatic and non-enzymatic) that are induced by oxidative stress. In contrast, no enzyme can detoxify •OH or 1O2, making them extremely toxic and acutely lethal. The present review will highlight the various methods of ROS formation and their mechanism of action. Antioxidant defenses against ROS in microbial cells and the use of ROS by antimicrobial host defense systems are covered. Antimicrobial approaches primarily utilizing ROS comprise both bactericidal antibiotics, and non-pharmacological methods such as photodynamic therapy, titanium dioxide photocatalysis, cold plasma and medicinal honey. A brief final section covers, reactive nitrogen species, and related therapeutics, such as acidified nitrite and nitric oxide releasing nanoparticles. PMID:23802986

A catheter-related bloodstream infection caused by Chryseobacterium indologenes successfully treated with antibiotic-lock rescue therapy.

PubMed

Corbella, Marta; Brandolini, Micaela; Cambieri, Patrizia; Decembrino, Nunzia; Pagani, Michele; Bottazzi, Andrea; Muzzi, Alba; Zecca, Marco; Mariani, Bianca; Marone, Piero

2017-07-01

We report the case of a catheter-related bloodstream infection caused by Chryseobacterium indologenes, an uncommon and multi-resistant pathogen, in a pediatric patient with a long-term vascular access device placed for chemotherapy treatment. The infection was successfully treated with ciprofloxacin antibiotic-lock therapy. This is the first report on successful salvage of a long-term device colonized by multi-resistant Chryseobacterium indologenes.

Familial breast cancer - targeted therapy in secondary and tertiary prevention.

PubMed

Kast, Karin; Rhiem, Kerstin

2015-02-01

The introduction of an increasing number of individualized molecular targeted therapies into clinical routine mirrors their importance in modern cancer prevention and treatment. Well-known examples for targeted agents are the monoclonal antibody trastuzumab and the selective estrogen receptor modulator tamoxifen. The identification of an unaltered gene in tumor tissue in colon cancer (KRAS) is a predictor for the patient's response to targeted therapy with a monoclonal antibody (cetuximab). Targeted therapy for hereditary breast and ovarian cancer has become a reality with the approval of olaparib for platin-sensitive late relapsed BRCA-associated ovarian cancer in December 2014. This manuscript reviews the status quo of poly-ADP-ribose polymerase inhibitors (PARPi) in the therapy of breast and ovarian cancer as well as the struggle for carboplatin as a potential standard of care for triple-negative and, in particular, BRCA-associated breast cancer. Details of the mechanism of action with information on tumor development are provided, and an outlook for further relevant research is given. The efficacy of agents against molecular targets together with the identification of an increasing number of cancer-associated genes will open the floodgates to a new era of treatment decision-making based on molecular tumor profiles. Current clinical trials involving patients with BRCA-associated cancer explore the efficacy of the molecular targeted therapeutics platinum and PARPi.

Targeted and Nontargeted α-Particle Therapies.

PubMed

McDevitt, Michael R; Sgouros, George; Sofou, Stavroula

2018-06-04

α-Particle irradiation of cancerous tissue is increasingly recognized as a potent therapeutic option. We briefly review the physics, radiobiology, and dosimetry of α-particle emitters, as well as the distinguishing features that make them unique for radiopharmaceutical therapy. We also review the emerging clinical role of α-particle therapy in managing cancer and recent studies on in vitro and preclinical α-particle therapy delivered by antibodies, other small molecules, and nanometer-sized particles. In addition to their unique radiopharmaceutical characteristics, the increased availability and improved radiochemistry of α-particle radionuclides have contributed to the growing recent interest in α-particle radiotherapy. Targeted therapy strategies have presented novel possibilities for the use of α-particles in the treatment of cancer. Clinical experience has already demonstrated the safe and effective use of α-particle emitters as potent tumor-selective drugs for the treatment of leukemia and metastatic disease.

Targeted and Nontargeted α-Particle Therapies

PubMed Central

McDevitt, Michael R.; Sgouros, George; Sofou, Stavroula

2018-01-01

α-Particle irradiation of cancerous tissue is increasingly recognized as a potent therapeutic option. We briefly review the physics, radiobiology, and dosimetry of α-particle emitters, as well as the distinguishing features that make them unique for radiopharmaceutical therapy. We also review the emerging clinical role of α-particle therapy in managing cancer and recent studies on in vitro and preclinical α-particle therapy delivered by antibodies, other small molecules, and nanometer-sized particles. In addition to their unique radiopharmaceutical characteristics, the increased availability and improved radiochemistry of α-particle radionuclides have contributed to the growing recent interest in α-particle radiotherapy. Targeted therapy strategies have presented novel possibilities for the use of α-particles in the treatment of cancer. Clinical experience has already demonstrated the safe and effective use of α-particle emitters as potent tumor-selective drugs for the treatment of leukemia and metastatic disease. PMID:29345977

Structural characterization of Staphylococcus aureus biotin protein ligase and interaction partners: an antibiotic target.

PubMed

Pendini, Nicole R; Yap, Min Y; Traore, D A K; Polyak, Steven W; Cowieson, Nathan P; Abell, Andrew; Booker, Grant W; Wallace, John C; Wilce, Jacqueline A; Wilce, Matthew C J

2013-06-01

The essential metabolic enzyme biotin protein ligase (BPL) is a potential target for the development of new antibiotics required to combat drug-resistant pathogens. Staphylococcus aureus BPL (SaBPL) is a bifunctional protein, possessing both biotin ligase and transcription repressor activities. This positions BPL as a key regulator of several important metabolic pathways. Here, we report the structural analysis of both holo- and apo-forms of SaBPL using X-ray crystallography. We also present small-angle X-ray scattering data of SaBPL in complex with its biotin-carboxyl carrier protein substrate as well as the SaBPL:DNA complex that underlies repression. This has revealed the molecular basis of ligand (biotinyl-5'-AMP) binding and conformational changes associated with catalysis and repressor function. These data provide new information to better understand the bifunctional activities of SaBPL and to inform future strategies for antibiotic discovery. © 2013 The Protein Society.

Successes and limitations of targeted therapies in renal cell carcinoma.

PubMed

Pracht, Marc; Berthold, Dominik

2014-01-01

Until recently, the standard treatment for metastatic renal cell carcinoma (RCC) was nonspecific immunotherapy based on interleukin-2 or interferon-α. This was associated with a modest survival benefit and with significant clinical toxicities. The understanding of numerous molecular pathways in RCC, including HIF, VEGF, mTOR, and the consecutive use of targeted therapies since the beginning of 2005 have significantly improved outcomes for patients with metastatic RCC with an overall survival greater than 2 years. At present, at least 7 targeted agents are approved for first and consecutive lines of treatment of clear cell metastatic RCC. Long-term benefit and extended survival may be achieved through the optimal use of targeted therapies: optimal dosing, adverse event management and treatment duration and compliance. Advances in the finding of prognostic factors highlight the potential for personalizing treatment for patients with metastatic RCC. Data regarding the best sequencing of targeted therapies, predictive biomarkers, best timing of surgery, patient risk profiles, understanding of resistance mechanisms and safety of targeted therapies are growing and will provide a further step ahead in the management of advanced RCC. In parallel, a new class of therapeutics is emerging in RCC: immunotherapy; in particular check-point blockade antibodies are showing very promising results. © 2014 S. Karger AG, Basel.

Effectiveness and safety of procalcitonin-guided antibiotic therapy in lower respiratory tract infections in "real life": an international, multicenter poststudy survey (ProREAL).

PubMed

Albrich, Werner C; Dusemund, Frank; Bucher, Birgit; Meyer, Stefan; Thomann, Robert; Kühn, Felix; Bassetti, Stefano; Sprenger, Martin; Bachli, Esther; Sigrist, Thomas; Schwietert, Martin; Amin, Devendra; Hausfater, Pierre; Carre, Eric; Gaillat, Jacques; Schuetz, Philipp; Regez, Katharina; Bossart, Rita; Schild, Ursula; Mueller, Beat

2012-05-14

In controlled studies, procalcitonin (PCT) has safely and effectively reduced antibiotic drug use for lower respiratory tract infections (LRTIs). However, controlled trial data may not reflect real life. We performed an observational quality surveillance in 14 centers in Switzerland, France, and the United States. Consecutive adults with LRTI presenting to emergency departments or outpatient offices were enrolled and registered on a website, which provided a previously published PCT algorithm for antibiotic guidance. The primary end point was duration of antibiotic therapy within 30 days. Of 1759 patients, 86.4% had a final diagnosis of LRTI (community-acquired pneumonia, 53.7%; acute exacerbation of chronic obstructive pulmonary disease, 17.1%; and bronchitis, 14.4%). Algorithm compliance overall was 68.2%, with differences between diagnoses (bronchitis, 81.0%; AECOPD, 70.1%; and community-acquired pneumonia, 63.7%; P < .001), outpatients (86.1%) and inpatients (65.9%) (P < .001), algorithm-experienced (82.5%) and algorithm-naive (60.1%) centers (P < .001), and countries (Switzerland, 75.8%; France, 73.5%; and the United States, 33.5%; P < .001). After multivariate adjustment, antibiotic therapy duration was significantly shorter if the PCT algorithm was followed compared with when it was overruled (5.9 vs 7.4 days; difference, -1.51 days; 95% CI, -2.04 to -0.98; P < .001). No increase was noted in the risk of the combined adverse outcome end point within 30 days of follow-up when the PCT algorithm was followed regarding withholding antibiotics on hospital admission (adjusted odds ratio, 0.83; 95% CI, 0.44 to 1.55; P = .56) and regarding early cessation of antibiotics (adjusted odds ratio, 0.61; 95% CI, 0.36 to 1.04; P = .07). This study validates previous results from controlled trials in real-life conditions and demonstrates that following a PCT algorithm effectively reduces antibiotic use without increasing the risk of complications. Preexisting differences in

Chronic lymphocytic leukemia therapy: new targeted therapies on the way

PubMed Central

Vitale, Candida; Burger, Jan A

2016-01-01

Introduction The critical role of the tissue microenvironment and B cell receptor (BCR) signaling in chronic lymphocytic leukemia (CLL) pathogenesis, and the clinical success of targeted agents that disrupt BCR signaling are currently changing the CLL landscape. Three new drugs were recently approved for CLL therapy, and other agents are in late development. Areas covered In this review, we summarize data on promising new targeted drugs for CLL. The heterogeneous mechanisms of actions of these molecules are described, such as the inhibition of BCR signaling, direct targeting of CD20 molecules on the CLL cell surface, and BCL-2 inhibition. We present preclinical and clinical data from phase I to III studies in order to describe efficacy and side effect profile of these new drugs. Data are derived from peer-reviewed articles indexed in PubMed and from abstracts presented at major international meetings. Expert opinion Ibrutinib and idelalisib are challenging the role of chemo-immunotherapy in CLL therapy in the frontline and relapsed disease settings. High-risk CLL patients particularly benefit from these new agents. Venetoclax and obinutuzumab are other effective agents added to our therapeutic armamentarium. Studies to better define the optimal use of these drugs, alone, or rather in combination or sequenced are underway. PMID:26988407

Palliative chemotherapy and targeted therapies for esophageal and gastroesophageal junction cancer.

PubMed

Janmaat, Vincent T; Steyerberg, Ewout W; van der Gaast, Ate; Mathijssen, Ron Hj; Bruno, Marco J; Peppelenbosch, Maikel P; Kuipers, Ernst J; Spaander, Manon Cw

2017-11-28

Almost half of people with esophageal or gastroesophageal junction cancer have metastatic disease at the time of diagnosis. Chemotherapy and targeted therapies are increasingly used with a palliative intent to control tumor growth, improve quality of life, and prolong survival. To date, and with the exception of ramucirumab, evidence for the efficacy of palliative treatments for esophageal and gastroesophageal cancer is lacking. To assess the effects of cytostatic or targeted therapy for treating esophageal or gastroesophageal junction cancer with palliative intent. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Web of Science, PubMed Publisher, Google Scholar, and trial registries up to 13 May 2015, and we handsearched the reference lists of studies. We did not restrict the search to publications in English. Additional searches were run in September 2017 prior to publication, and they are listed in the 'Studies awaiting assessment' section. We included randomized controlled trials (RCTs) on palliative chemotherapy and/or targeted therapy versus best supportive care or control in people with esophageal or gastroesophageal junction cancer. Two authors independently extracted data. We assessed the quality and risk of bias of eligible studies according to the Cochrane Handbook for Systematic Reviews of Interventions. We calculated pooled estimates of effect using an inverse variance random-effects model for meta-analysis. We identified 41 RCTs with 11,853 participants for inclusion in the review as well as 49 ongoing studies. For the main comparison of adding a cytostatic and/or targeted agent to a control arm, we included 11 studies with 1347 participants. This analysis demonstrated an increase in overall survival in favor of the arm with an additional cytostatic or targeted therapeutic agent with a hazard ratio (HR) of 0.75 (95% confidence interval (CI) 0.68 to 0.84, high-quality evidence). The median increased

Targeting TREM-1 Signaling in the Presence of Antibiotics is Effective Against Streptococcal Toxic-Shock-Like Syndrome (STSLS) Caused by Streptococcus suis.

PubMed

Yang, Chao; Zhao, Jianqing; Lin, Lan; Pan, Shan; Fu, Lei; Han, Li; Jin, Meilin; Zhou, Rui; Zhang, Anding

2015-01-01

Streptococcus suis (S.suis), a major swine pathogen, is also a severe threat to human health. Infection with highly virulent strains of S. suis can cause human Streptococcal toxic-shock-like syndrome (STSLS), which is associated with high serum pro-inflammatory cytokine levels and a high mortality rate. Our previous study indicated that highly virulent S. suis infection could activate the TREM-1 signaling pathway, which promotes host clearance of S. suis during early infection. However, it remained to be elicited whether TREM-1 signaling could be a target against STSLS in the presence of antibiotic. In the present study, mice were infected with a highly virulent S. suis strain and then treated with rTREM-1 (the recombinant extracellular domain of TREM-1) to block TREM-1 signaling, antibiotics, both rTREM-1 and antibiotics, or PBS. The survival rates, clinical signs, serum IL-1β and TNF-α levels, and serum bacterial loads were evaluated. Treatment with rTREM-1 could aggravate the outcome of infection as described previously. Although the conventional treatment with antibiotics contributed to effective S. suis clearance, it did not improve survival significantly. In comparison, due to the reduction of the exaggerated pro-inflammatory response, treatment combined with rTREM-1 and antibiotics not only led to efficient bacterial clearance but also alleviated inflammation. In conclusion, TREM-1 signaling contributed to severe inflammatory response and benefited S. suis clearance. Therefore, blocking TREM-1 signaling could still be a target for the treatment of STSLS in the presence of antibiotics.

Targeting TREM-1 Signaling in the Presence of Antibiotics is Effective Against Streptococcal Toxic-Shock-Like Syndrome (STSLS) Caused by Streptococcus suis

PubMed Central

Yang, Chao; Zhao, Jianqing; Lin, Lan; Pan, Shan; Fu, Lei; Han, Li; Jin, Meilin; Zhou, Rui; Zhang, Anding

2015-01-01

Streptococcus suis (S.suis), a major swine pathogen, is also a severe threat to human health. Infection with highly virulent strains of S. suis can cause human Streptococcal toxic-shock-like syndrome (STSLS), which is associated with high serum pro-inflammatory cytokine levels and a high mortality rate. Our previous study indicated that highly virulent S. suis infection could activate the TREM-1 signaling pathway, which promotes host clearance of S. suis during early infection. However, it remained to be elicited whether TREM-1 signaling could be a target against STSLS in the presence of antibiotic. In the present study, mice were infected with a highly virulent S. suis strain and then treated with rTREM-1 (the recombinant extracellular domain of TREM-1) to block TREM-1 signaling, antibiotics, both rTREM-1 and antibiotics, or PBS. The survival rates, clinical signs, serum IL-1β and TNF-α levels, and serum bacterial loads were evaluated. Treatment with rTREM-1 could aggravate the outcome of infection as described previously. Although the conventional treatment with antibiotics contributed to effective S. suis clearance, it did not improve survival significantly. In comparison, due to the reduction of the exaggerated pro-inflammatory response, treatment combined with rTREM-1 and antibiotics not only led to efficient bacterial clearance but also alleviated inflammation. In conclusion, TREM-1 signaling contributed to severe inflammatory response and benefited S. suis clearance. Therefore, blocking TREM-1 signaling could still be a target for the treatment of STSLS in the presence of antibiotics. PMID:26618144

Systems, not pills: The options market for antibiotics seeks to rejuvenate the antibiotic pipeline.

PubMed

Brogan, David M; Mossialos, Elias

2016-02-01

Over the past decade, there has been a growing recognition of the increasing growth of antibiotic resistant bacteria and a relative decline in the production of novel antibacterial therapies. The combination of these two forces poses a potentially grave threat to global health, in both developed and developing countries. Current market forces do not provide appropriate incentives to stimulate new antibiotic development, thus we propose a new incentive mechanism: the Options Market for Antibiotics. This mechanism, modelled on the principle of financial call options, allows payers to buy the right, in early stages of development, to purchase antibiotics at a discounted price if and when they ever make it to market approval. This paper demonstrates the effect of such a model on the expected Net Present Value of a typical antibacterial project. As part of an integrated strategy to confront the impending antibiotic crisis, the Options Market for Antibiotics may effectively stimulate corporate and public investment into antibiotic research and development. Copyright © 2016. Published by Elsevier Ltd.

Cancer-targeted therapies and radiopharmaceuticals

PubMed Central

Rachner, Tilman D; Jakob, Franz; Hofbauer, Lorenz C

2015-01-01

The treatment of bone metastases remains a clinical challenge. Although a number of well-established agents, namely bisphosphonates and denosumab, are available to reduce the occurrence of skeletal-related events, additional cancer-targeted therapies are required to improve patients' prognosis and quality of life. This review focuses on novel targets and agents that are under clinical evaluation for the treatment of malignant bone diseases such as activin A, src and endothelin-1 inhibition or agents that are clinically approved and may positively influence bone, such as the mTOR inhibitor everolimus. In addition, the potential of alpharadin, a novel radiopharmaceutical approved for the treatment of prostatic bone disease, is discussed. PMID:26131359

Targeting RNA Splicing for Disease Therapy