A Salmonella nanoparticle mimic overcomes multidrug resistance in tumours.

PubMed

Mercado-Lubo, Regino; Zhang, Yuanwei; Zhao, Liang; Rossi, Kyle; Wu, Xiang; Zou, Yekui; Castillo, Antonio; Leonard, Jack; Bortell, Rita; Greiner, Dale L; Shultz, Leonard D; Han, Gang; McCormick, Beth A

2016-07-25

Salmonella enterica serotype Typhimurium is a food-borne pathogen that also selectively grows in tumours and functionally decreases P-glycoprotein (P-gp), a multidrug resistance transporter. Here we report that the Salmonella type III secretion effector, SipA, is responsible for P-gp modulation through a pathway involving caspase-3. Mimicking the ability of Salmonella to reverse multidrug resistance, we constructed a gold nanoparticle system packaged with a SipA corona, and found this bacterial mimic not only accumulates in tumours but also reduces P-gp at a SipA dose significantly lower than free SipA. Moreover, the Salmonella nanoparticle mimic suppresses tumour growth with a concomitant reduction in P-gp when used with an existing chemotherapeutic drug (that is, doxorubicin). On the basis of our finding that the SipA Salmonella effector is fundamental for functionally decreasing P-gp, we engineered a nanoparticle mimic that both overcomes multidrug resistance in cancer cells and increases tumour sensitivity to conventional chemotherapeutics.

Detection of Multi-drug Resistant Acinetobacter Lwoffii Isolated from Soil of Mink Farm.

PubMed

Sun, Na; Wen, Yong Jun; Zhang, Shu Qin; Zhu, Hong Wei; Guo, Li; Wang, Feng Xue; Chen, Qiang; Ma, Hong Xia; Cheng, Shi Peng

2016-07-01

There were 4 Acinetobacter lwoffii obtained from soil samples. The antimicrobial susceptibility of the strains to 16 antimicrobial agents was investigated using K-B method. Three isolates showed the multi-drug resistance. The presence of resistance genes and integrons was determined using PCR. The aadA1, aac(3')-IIc, aph(3')-VII, aac(6')-Ib, sul2, cat2, floR, and tet(K) genes were detected, respectively. Three class 1 integrons were obtained. The arr-3-aacA4 and blaPSE-1 gene cassette, which cause resistance to aminoglycoside and beta-lactamase antibiotics. Our results reported the detection of multi-drug resistant and carried resistant genes Acinetobacter lwoffii from soil. The findings suggested that we should pay close attention to the prevalence of multi-drug resistant bacterial species of environment. Copyright © 2016 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

Tackling Threats and Future Problems of Multidrug-Resistant Bacteria.

PubMed

Medina, Eva; Pieper, Dietmar Helmut

With the advent of the antibiotic era, the overuse and inappropriate consumption and application of antibiotics have driven the rapid emergence of multidrug-resistant pathogens. Antimicrobial resistance increases the morbidity, mortality, length of hospitalization and healthcare costs. Among Gram-positive bacteria, Staphylococcus aureus (MRSA) and multidrug-resistant (MDR) Mycobacterium tuberculosis, and among the Gram-negative bacteria, extended-spectrum beta-lactamase (ESBLs)-producing bacteria have become a major global healthcare problem in the 21st century. The pressure to use antibiotics guarantees that the spread and prevalence of these as well as of future emerging multidrug-resistant pathogens will be a persistent phenomenon. The unfeasibility of reversing antimicrobial resistance back towards susceptibility and the critical need to treat bacterial infection in modern medicine have burdened researchers and pharmaceutical companies to develop new antimicrobials effective against these difficult-to-treat multidrug-resistant pathogens. However, it can be anticipated that antibiotic resistance will continue to develop more rapidly than new agents to treat these infections become available and a better understanding of the molecular, evolutionary and ecological mechanisms governing the spread of antibiotic resistance is needed. The only way to curb the current crisis of antimicrobial resistance will be to develop entirely novel strategies to fight these pathogens such as combining antimicrobial drugs with other agents that counteract and obstruct the antibiotic resistant mechanisms expressed by the pathogen. Furthermore, as many antibiotics are often inappropriately prescribed, a more personalized approach based on precise diagnosis tools will ensure that proper treatments can be promptly applied leading to more targeted and effective therapies. However, in more general terms, also the overall use and release of antibiotics in the environment needs to be

The Culturable Soil Antibiotic Resistome: A Community of Multi-Drug Resistant Bacteria

PubMed Central

Walsh, Fiona; Duffy, Brion

2013-01-01

Understanding the soil bacterial resistome is essential to understanding the evolution and development of antibiotic resistance, and its spread between species and biomes. We have identified and characterized multi-drug resistance (MDR) mechanisms in the culturable soil antibiotic resistome and linked the resistance profiles to bacterial species. We isolated 412 antibiotic resistant bacteria from agricultural, urban and pristine soils. All isolates were multi-drug resistant, of which greater than 80% were resistant to 16–23 antibiotics, comprising almost all classes of antibiotic. The mobile resistance genes investigated, (ESBL, bla NDM-1, and plasmid mediated quinolone resistance (PMQR) resistance genes) were not responsible for the respective resistance phenotypes nor were they present in the extracted soil DNA. Efflux was demonstrated to play an important role in MDR and many resistance phenotypes. Clinically relevant Burkholderia species are intrinsically resistant to ciprofloxacin but the soil Burkholderia species were not intrinsically resistant to ciprofloxacin. Using a phenotypic enzyme assay we identified the antibiotic specific inactivation of trimethoprim in 21 bacteria from different soils. The results of this study identified the importance of the efflux mechanism in the soil resistome and variations between the intrinsic resistance profiles of clinical and soil bacteria of the same family. PMID:23776501

The culturable soil antibiotic resistome: a community of multi-drug resistant bacteria.

PubMed

Walsh, Fiona; Duffy, Brion

2013-01-01

Understanding the soil bacterial resistome is essential to understanding the evolution and development of antibiotic resistance, and its spread between species and biomes. We have identified and characterized multi-drug resistance (MDR) mechanisms in the culturable soil antibiotic resistome and linked the resistance profiles to bacterial species. We isolated 412 antibiotic resistant bacteria from agricultural, urban and pristine soils. All isolates were multi-drug resistant, of which greater than 80% were resistant to 16-23 antibiotics, comprising almost all classes of antibiotic. The mobile resistance genes investigated, (ESBL, bla NDM-1, and plasmid mediated quinolone resistance (PMQR) resistance genes) were not responsible for the respective resistance phenotypes nor were they present in the extracted soil DNA. Efflux was demonstrated to play an important role in MDR and many resistance phenotypes. Clinically relevant Burkholderia species are intrinsically resistant to ciprofloxacin but the soil Burkholderia species were not intrinsically resistant to ciprofloxacin. Using a phenotypic enzyme assay we identified the antibiotic specific inactivation of trimethoprim in 21 bacteria from different soils. The results of this study identified the importance of the efflux mechanism in the soil resistome and variations between the intrinsic resistance profiles of clinical and soil bacteria of the same family.

Management of multidrug resistant bacterial endemic.

PubMed

Zahar, J-R; Lesprit, P

2014-09-01

The fight against multi-drug resistant Gram-negative bacilli (MDRGNB), especially extended-spectrum β-lactamase producing Enterobacteriaceae, is about to be lost in our country. The emergence of new resistance mechanisms to carbapenems in these Enterobacteriaceae exposes patients to a risk of treatment failure without any other therapeutic options. This dramatic situation is paradoxical because we are well aware of the 2 major factors responsible for this situation: 1) MDRO cross-transmission, associated with a low compliance to standard precautions, especially hand hygiene, and 2) overexposure of patients to antibiotics. The implementation of a "search and isolate" policy, which was justified to control the spread of some MDRO that remained rare in the country, was not associated with a better adherence to standard precautions. The antibiotic policy and the measures implemented to control antibiotic consumptions have rarely been enforced and have shown inconsistent results. Notably, no significant decrease of antibiotic consumption has been observed. There is no excuse for these poor results, because some authors evaluating the effectiveness of programs for the control of MDRO have reported their positive effects on antimicrobial resistance without any detrimental effects. It is now urgent to deal with the 2 major factors by establishing an educational and persuasive program with quantified and opposable objectives. Firstly, we have to improve the observance of hand hygiene above 70%. Secondly, we have to define and reach a target for the reduction of antibiotic consumption both in community and in hospital settings. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Antibacterial activity of local herbs collected from Murree (Pakistan) against multi-drug resistant Klebsiella pneumonae, E. coli and methyciline resistant Staphylococcus aureus.

PubMed

Mansoor, Qaisar; Shaheen, Saira; Javed, Uzma; Shaheen, Uzma; Iqrar, Irum; Ismail, Muhammad

2013-07-01

Exploring healing power in plants emerged in prehistory of human civilization. Sustaining good health has been achieved over the millions of years by use of plant products in various traditional sockets. A major contribution of medicinal plants to health care systems is their limitless possession of bioactive components that stimulate explicit physiological actions. Luckily Pakistan is blessed with huge reservoir of plants with medicinal potential and some of them; we focused in this study for their medicinal importance.In this study we checked the antibacterial activity inherent in Ricinus communis, Solanum nigrum, Dodonaea viscose and Berberis lyceum extracts for multidrug resistance bacterial strains Klebsiella pneumonae, E. coli and methyciline resistant Staphylococcus aureus. MRSA showed sensitivity for Ricinus communis. Multidrug resistant Klebsiella pneumonae was sensitive with Pine roxburgii and Ricinus communis but weakly susceptible for Solanum nigrum. Multidrug resistant E. coli was resistant to all plant extracts. Treatment of severe infections caused by the bacterial strains used in this study with Ricinus communis, Pine roxburgii and Solanum nigrum can lower the undesired side effects of synthetic medicine and also reduce the economic burden.

Molecular epidemiological survey of bacteremia by multidrug resistant Pseudomonas aeruginosa: the relevance of intrinsic resistance mechanisms

PubMed Central

Dantas, Raquel Cristina Cavalcanti; Silva, Rebecca Tavares e; Ferreira, Melina Lorraine; Gonçalves, Iara Rossi; Araújo, Bruna Fuga; de Campos, Paola Amaral; Royer, Sabrina; Batistão, Deivid William da Fonseca; Gontijo-Filho, Paulo Pinto; Ribas, Rosineide Marques

2017-01-01

The bacterial factors associated with bacteremia by multidrug-resistant and extensively drug-resistant P. aeruginosa, including overexpression of efflux pumps, AmpC overproduction, and loss/alteration of the OprD porin in isolates that are non-Metallo-β-Lactamase producing were analyzed in a retrospective study. Molecular analyses included strain typing by Pulsed Field Gel Electrophoresis and identification of key genes via qualitative and quantitative PCR-based assays. Previous use of carbapenems and tracheostomy was independently associated with the development of bacteremia by extensively drug-resistant and multidrug-resistant strains of P. aeruginosa. A high consumption of antimicrobials was observed, and 75.0% of the isolates contained amplicons with the blaSPM-1 and blaVIM genes. Of the 47 non-Metallo-β-Lactamase isolates, none had another type of carbapenemase. However, the isolates exhibited high rates of hyperproduction of AmpC, loss of the OprD porin (71.4%) and the presence of MexABOprM (57.1%) and MexXY (64.3%). This study suggests that in non-Metallo-β-Lactamase isolates, the association of intrinsic resistance mechanisms could contributes to the expression of multidrug-resistant/extensively drug-resistant phenotypes. PMID:28481953

Diverse and abundant multi-drug resistant E. coli in Matang mangrove estuaries, Malaysia

PubMed Central

Ghaderpour, Aziz; Ho, Wing Sze; Chew, Li-Lee; Bong, Chui Wei; Chong, Ving Ching; Thong, Kwai-Lin; Chai, Lay Ching

2015-01-01

E.coli, an important vector distributing antimicrobial resistance in the environment, was found to be multi-drug resistant, abundant, and genetically diverse in the Matang mangrove estuaries, Malaysia. One-third (34%) of the estuarine E. coli was multi-drug resistant. The highest antibiotic resistance prevalence was observed for aminoglycosides (83%) and beta-lactams (37%). Phylogenetic groups A and B1, being the most predominant E. coli, demonstrated the highest antibiotic resistant level and prevalence of integrons (integron I, 21%; integron II, 3%). Detection of phylogenetic group B23 downstream of fishing villages indicates human fecal contamination as a source of E. coli pollution. Enteroaggregative E. coli (1%) were also detected immediately downstream of the fishing village. The results indicated multi-drug resistance among E. coli circulating in Matang estuaries, which could be reflective of anthropogenic activities and aggravated by bacterial and antibiotic discharges from village lack of a sewerage system, aquaculture farms and upstream animal husbandry. PMID:26483759

Airborne Multidrug-Resistant Bacteria Isolated from a Concentrated Swine Feeding Operation

PubMed Central

Chapin, Amy; Rule, Ana; Gibson, Kristen; Buckley, Timothy; Schwab, Kellogg

2005-01-01

The use of nontherapeutic levels of antibiotics in swine production can select for antibiotic resistance in commensal and pathogenic bacteria in swine. As a result, retail pork products, as well as surface and groundwaters contaminated with swine waste, have been shown to be sources of human exposure to antibiotic-resistant bacteria. However, it is unclear whether the air within swine operations also serves as a source of exposure to antibiotic-resistant bacterial pathogens. To investigate this issue, we sampled the air within a concentrated swine feeding operation with an all-glass impinger. Samples were analyzed using a method for the isolation of Enterococcus. A total of 137 presumptive Enterococcus isolates were identified to species level using standard biochemical tests and analyzed for resistance to erythromycin, clindamycin, virginiamycin, tetracycline, and vancomycin using the agar dilution method. Thirty-four percent of the isolates were confirmed as Enterococcus, 32% were identified as coagulase-negative staphylococci, and 33% were identified as viridans group streptococci. Regardless of bacterial species, 98% of the isolates expressed high-level resistance to at least two antibiotics commonly used in swine production. None of the isolates were resistant to vancomycin, an antibiotic that has never been approved for use in livestock in the United States. In conclusion, high-level multidrug-resistant Enterococcus, coagulase-negative staphylococci, and viridans group streptococci were detected in the air of a concentrated swine feeding operation. These findings suggest that the inhalation of air from these facilities may serve as an exposure pathway for the transfer of multidrug-resistant bacterial pathogens from swine to humans. PMID:15687049

Epidemiologic analysis: Prophylaxis and multidrug-resistance in surgery.

PubMed

Solís-Téllez, H; Mondragón-Pinzón, E E; Ramírez-Marino, M; Espinoza-López, F R; Domínguez-Sosa, F; Rubio-Suarez, J F; Romero-Morelos, R D

Surgical site infection is defined as an infection related to the surgical procedure in the area of manipulation occurring within the first 30 postoperative days. The diagnostic criteria include: purulent drainage, isolation of microorganisms, and signs of infection. To describe the epidemiologic characteristics and differences among the types of prophylactic regimens associated with hospital-acquired infections at the general surgery service of a tertiary care hospital. The electronic case records of patients that underwent general surgery at a tertiary care hospital within the time frame of January 1, 2013 and December 31, 2014 were reviewed. A convenience sample of 728 patients was established and divided into the following groups: Group 1: n=728 for the epidemiologic study; Group 2: n=638 for the evaluation of antimicrobial prophylaxis; and Group 3: n=50 for the evaluation of multidrug-resistant bacterial strains in the intensive care unit. The statistical analysis was carried out with the SPSS 19 program, using the Mann-Whitney U test and the chi-square test. A total of 728 procedures were performed (65.9% were elective surgeries). Three hundred twelve of the patients were males and 416 were females. Only 3.98% of the patients complied with the recommended antimicrobial prophylaxis, and multidrug-resistant bacterial strains were found in the intensive care unit. A single prophylactic dose is effective, but adherence to this recommendation was not adequate. The prophylactic guidelines are not strictly adhered to in our environment. There was a significant association between the development of nosocomial infections from multidrug-resistant germs and admission to the intensive care unit. Copyright © 2016 Asociación Mexicana de Gastroenterología. Publicado por Masson Doyma México S.A. All rights reserved.

Quantitative Assessment of Combination Antimicrobial Therapy against Multidrug-Resistant Acinetobacter baumannii▿

PubMed Central

Lim, Tze-Peng; Ledesma, Kimberly R.; Chang, Kai-Tai; Hou, Jing-Guo; Kwa, Andrea L.; Nikolaou, Michael; Quinn, John P.; Prince, Randall A.; Tam, Vincent H.

2008-01-01

Treatment of multidrug-resistant bacterial infections poses a therapeutic challenge to clinicians; combination therapy is often the only viable option for multidrug-resistant infections. A quantitative method was developed to assess the combined killing abilities of antimicrobial agents. Time-kill studies (TKS) were performed using a multidrug-resistant clinical isolate of Acinetobacter baumannii with escalating concentrations of cefepime (0 to 512 mg/liter), amikacin (0 to 256 mg/liter), and levofloxacin (0 to 64 mg/liter). The bacterial burden data in single and combined (two of the three agents with clinically achievable concentrations in serum) TKS at 24 h were mathematically modeled to provide an objective basis for comparing various antimicrobial agent combinations. Synergy and antagonism were defined as interaction indices of <1 and >1, respectively. A hollow-fiber infection model (HFIM) simulating various clinical (fluctuating concentrations over time) dosing exposures was used to selectively validate our quantitative assessment of the combined killing effect. Model fits in all single-agent TKS were satisfactory (r2 > 0.97). An enhanced combined overall killing effect was seen in the cefepime-amikacin combination (interactive index, 0.698; 95% confidence interval [CI], 0.675 to 0.722) and the cefepime-levofloxacin combination (interactive index, 0.929; 95% CI, 0.903 to 0.956), but no significant difference in the combined overall killing effect for the levofloxacin-amikacin combination was observed (interactive index, 0.994; 95% CI, 0.982 to 1.005). These assessments were consistent with observations in HFIM validation studies. Our method could be used to objectively rank the combined killing activities of two antimicrobial agents when used together against a multidrug-resistant A. baumannii isolate. It may offer better insights into the effectiveness of various antimicrobial combinations and warrants further investigations. PMID:18505848

Multiple molecular mechanisms for multidrug resistance transporters.

PubMed

Higgins, Christopher F

2007-04-12

The acquisition of multidrug resistance is a serious impediment to improved healthcare. Multidrug resistance is most frequently due to active transporters that pump a broad spectrum of chemically distinct, cytotoxic molecules out of cells, including antibiotics, antimalarials, herbicides and cancer chemotherapeutics in humans. The paradigm multidrug transporter, mammalian P-glycoprotein, was identified 30 years ago. Nonetheless, success in overcoming or circumventing multidrug resistance in a clinical setting has been modest. Recent structural and biochemical data for several multidrug transporters now provide mechanistic insights into how they work. Organisms have evolved several elegant solutions to ridding the cell of such cytotoxic compounds. Answers are emerging to questions such as how multispecificity for different drugs is achieved, why multidrug resistance arises so readily, and what chance there is of devising a clinical solution.

Synergistic antibacterial effect of silver and ebselen against multidrug-resistant Gram-negative bacterial infections.

PubMed

Zou, Lili; Lu, Jun; Wang, Jun; Ren, Xiaoyuan; Zhang, Lanlan; Gao, Yu; Rottenberg, Martin E; Holmgren, Arne

2017-08-01

Multidrug-resistant (MDR) Gram-negative bacteria account for a majority of fatal infections, and development of new antibiotic principles and drugs is therefore of outstanding importance. Here, we report that five most clinically difficult-to-treat MDR Gram-negative bacteria are highly sensitive to a synergistic combination of silver and ebselen. In contrast, silver has no synergistic toxicity with ebselen on mammalian cells. The silver and ebselen combination causes a rapid depletion of glutathione and inhibition of the thioredoxin system in bacteria. Silver ions were identified as strong inhibitors of Escherichia coli thioredoxin and thioredoxin reductase, which are required for ribonucleotide reductase and DNA synthesis and defense against oxidative stress. The bactericidal efficacy of silver and ebselen was further verified in the treatment of mild and acute MDR E. coli peritonitis in mice. These results demonstrate that thiol-dependent redox systems in bacteria can be targeted in the design of new antibacterial drugs. The silver and ebselen combination offers a proof of concept in targeting essential bacterial systems and might be developed for novel efficient treatments against MDR Gram-negative bacterial infections. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

Inhibition of bacterial multidrug resistance by celecoxib, a cyclooxygenase-2 inhibitor.

PubMed

Kalle, Arunasree M; Rizvi, Arshad

2011-01-01

Multidrug resistance (MDR) is a major problem in the treatment of infectious diseases and cancer. Accumulating evidence suggests that the cyclooxygenase-2 (COX-2)-specific inhibitor celecoxib would not only inhibit COX-2 but also help in the reversal of drug resistance in cancers by inhibiting the MDR1 efflux pump. Here, we demonstrate that celecoxib increases the sensitivity of bacteria to the antibiotics ampicillin, kanamycin, chloramphenicol, and ciprofloxacin by accumulating the drugs inside the cell, thus reversing MDR in bacteria.

Activity of Norspermidine on Bacterial Biofilms of Multidrug-Resistant Clinical Isolates Associated with Persistent Extremity Wound Infections.

PubMed

Cardile, Anthony P; Woodbury, Ronald L; Sanchez, Carlos J; Becerra, Sandra C; Garcia, Rebecca A; Mende, Katrin; Wenke, Joseph C; Akers, Kevin S

2017-01-01

Biofilm formation is a major virulence factor for numerous pathogenic bacteria and is cited as a central event in the pathogenesis of chronic human infections, which is in large part due to excessive extracellular matrix secretion and metabolic changes that occur within the biofilm rendering them highly tolerant to antimicrobial treatments. Polyamines, including norspermidine, play central roles in bacterial biofilm development, but have also recently been shown to inhibit biofilm formation in select strains of various pathogenic bacteria. The aim of this study was to evaluate in vitro the biofilm dispersive and inhibitory activities of norspermidine against multidrug-resistant clinical isolates of Acinetobacter baumannii(n = 4), Klebsiella pneumoniae (n = 3), Pseudomonas aeruginosa (n = 5) and Staphylococcus aureus (n = 4) associated with chronic extremity wound infections using the semi-quantitative 96-well plate method and confocal laser microscopy. In addition to the antibiofilm activity, biocompatibility of norspermidine was also evaluated by measuring toxicity in vitro to human cell lines and whole porcine tissue explants using MTT viability assay and histological analysis. Norspermidine (5-20 mM) had variable dispersive and inhibitory activity on biofilms which was dependent on both the strain and species. Of the clinical bacterial species evaluated herein, A. baumannii isolates were the most sensitive to the effect of norspermidine, which was in part due to the inhibitory effects of norspermidine on bacterial motility and expression of genes involved in the production of homoserine lactones and quorum sensing molecules both essential for biofilm formation. Importantly, exposure of cell lines and whole tissues to norspermidine for prolonged periods of time (≥24 h) was observed to reduce viability and alter tissue histology in a time and concentration dependent manner, with 20 mM exposure having the greatest negative effects on both tissues and individual

Bacterial resistance modifying tetrasaccharide agents from Ipomoea murucoides.

PubMed

Chérigo, Lilia; Pereda-Miranda, Rogelio; Gibbons, Simon

2009-01-01

As part of an ongoing project to identify oligosaccharides which modulate bacterial multidrug resistance, the CHCl(3)-soluble extract from flowers of a Mexican arborescent morning glory, Ipomoea murucoides, through preparative-scale recycling HPLC, yielded five lipophilic tetrasaccharide inhibitors of Staphylococcusaureus multidrug efflux pumps, murucoidins XII-XVI (1-5). The macrocyclic lactone-type structures for these linear hetero-tetraglycoside derivatives of jalapinolic acid were established by spectroscopic methods. These compounds were tested for in vitro antibacterial and resistance modifying activity against strains of Staphylococcus aureus possessing multidrug resistance efflux mechanisms. Only murucoidin XIV (3) displayed antimicrobial activity against SA-1199B (MIC 32microg/ml), a norfloxacin-resistant strain that over-expresses the NorA MDR efflux pump. The four microbiologically inactive (MIC>512microg/ml) tetrasaccharides increased norfloxacin susceptibility of this strain by 4-fold (8microg/ml from 32microg/ml) at concentrations of 25microg/ml, while murucoidin XIV (3) exerted the same potentiation effect at a concentration of 5microg/ml.

Isolation and characterization of antimicrobial compounds in plant extracts against multidrug-resistant Acinetobacter baumannii.

PubMed

Miyasaki, Yoko; Rabenstein, John D; Rhea, Joshua; Crouch, Marie-Laure; Mocek, Ulla M; Kittell, Patricia Emmett; Morgan, Margie A; Nichols, Wesley Stephen; Van Benschoten, M M; Hardy, William David; Liu, George Y

2013-01-01

The number of fully active antibiotic options that treat nosocomial infections due to multidrug-resistant Acinetobacter baumannii (A. baumannii) is extremely limited. Magnolia officinalis, Mahonia bealei, Rabdosia rubescens, Rosa rugosa, Rubus chingii, Scutellaria baicalensis, and Terminalia chebula plant extracts were previously shown to have growth inhibitory activity against a multidrug-resistant clinical strain of A. baumannii. In this study, the compounds responsible for their antimicrobial activity were identified by fractionating each plant extract using high performance liquid chromatography, and determining the antimicrobial activity of each fraction against A. baumannii. The chemical structures of the fractions inhibiting >40% of the bacterial growth were elucidated by liquid chromatography/mass spectrometry analysis and nuclear magnetic resonance spectroscopy. The six most active compounds were identified as: ellagic acid in Rosa rugosa; norwogonin in Scutellaria baicalensis; and chebulagic acid, chebulinic acid, corilagin, and terchebulin in Terminalia chebula. The most potent compound was identified as norwogonin with a minimum inhibitory concentration of 128 µg/mL, and minimum bactericidal concentration of 256 µg/mL against clinically relevant strains of A. baumannii. Combination studies of norwogonin with ten anti-Gram negative bacterial agents demonstrated that norwogonin did not enhance the antimicrobial activity of the synthetic antibiotics chosen for this study. In conclusion, of all identified antimicrobial compounds, norwogonin was the most potent against multidrug-resistant A. baumannii strains. Further studies are warranted to ascertain the prophylactic and therapeutic potential of norwogonin for infections due to multidrug-resistant A. baumannii.

Prevalence and multidrug resistance of Escherichia coli from community acquired infections in Lagos, Nigeria

USDA-ARS?s Scientific Manuscript database

Escherichia coli is one of the most frequent causes of bacterial infections among humans. The emergence of multi-drug resistance (MDR; resistance to >2 more antimicrobials) in E. coli is of great concern due to the complications encountered in its treatment in a resource constrained economy. In th...

Design, synthesis and biological evaluation of novel aryldiketo acids with enhanced antibacterial activity against multidrug resistant bacterial strains.

PubMed

Cvijetić, Ilija N; Verbić, Tatjana Ž; Ernesto de Resende, Pedro; Stapleton, Paul; Gibbons, Simon; Juranić, Ivan O; Drakulić, Branko J; Zloh, Mire

2018-01-01

Antimicrobial resistance (AMR) is a major health problem worldwide, because of ability of bacteria, fungi and viruses to evade known therapeutic agents used in treatment of infections. Aryldiketo acids (ADK) have shown antimicrobial activity against several resistant strains including Gram-positive Staphylococcus aureus bacteria. Our previous studies revealed that ADK analogues having bulky alkyl group in ortho position on a phenyl ring have up to ten times better activity than norfloxacin against the same strains. Rational modifications of analogues by introduction of hydrophobic substituents on the aromatic ring has led to more than tenfold increase in antibacterial activity against multidrug resistant Gram positive strains. To elucidate a potential mechanism of action for this potentially novel class of antimicrobials, several bacterial enzymes were identified as putative targets according to literature data and pharmacophoric similarity searches for potent ADK analogues. Among the seven bacterial targets chosen, the strongest favorable binding interactions were observed between most active analogue and S. aureus dehydrosqualene synthase and DNA gyrase. Furthermore, the docking results in combination with literature data suggest that these novel molecules could also target several other bacterial enzymes, including prenyl-transferases and methionine aminopeptidase. These results and our statistically significant 3D QSAR model could be used to guide the further design of more potent derivatives as well as in virtual screening for novel antibacterial agents. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Development of hydroxyapatite-chitosan gel sunscreen combating clinical multidrug-resistant bacteria

NASA Astrophysics Data System (ADS)

Morsy, Reda; Ali, Sameh S.; El-Shetehy, Mohamed

2017-09-01

The several harmful effects on infected human skin resulting from exposure to the sun's UV radiation generate an interest in the development of a multifunctional hydroxyapatite-chitosan (HAp-chitosan) gel that works as an antibacterial sunscreen agent for skin care. In this work, HAp-chitosan gel was synthesized via coprecipitation method by dissolving chitosan in phosphoric acid and adding HAp. The characteristics of HAp-chitosan composite were investigated by conventional techniques, such as XRD, FTIR, and SEM techniques, while its sunscreen property was investigated by UV-spectroscopy. In addition to the influence of the gel on bacterial cell morphology, the antibacterial activity of HAp-chitosan gel against clinical multidrug resistant skin pathogens, such as Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa has been studied. The results revealed the formation of HAp-chitosan gel having nanosized particles, which confers protection against UV-radiation. The antibacterial activity records showed that chitosan-HAp gel exhibits a significant effect on the growth and ultrastructure of multi-drug resistant bacterial activities. Therefore, the chitosan-HAp gel is promising for skin health care as an antibacterial sunscreen.

Novel antimicrobial peptide CPF-C1 analogs with superior stabilities and activities against multidrug-resistant bacteria.

PubMed

Xie, Junqiu; Zhao, Qian; Li, Sisi; Yan, Zhibin; Li, Jing; Li, Yao; Mou, Lingyun; Zhang, Bangzhi; Yang, Wenle; Miao, Xiaokang; Jiang, Xianxing; Wang, Rui

2017-11-01

As numerous clinical isolates are resistant to most conventional antibiotics, infections caused by multidrug-resistant bacteria are associated with a higher death rate. Antimicrobial peptides show great potential as new antibiotics. However, a major obstacle to the development of these peptides as useful drugs is their low stability. To overcome the problem of the natural antimicrobial peptide CPF-C1, we designed and synthesized a series of analogs. Our results indicated that by introducing lysine, which could increase the number of positive charges, and by introducing tryptophan, which could increase the hydrophobicity, we could improve the antimicrobial activity of the peptides against multidrug-resistant strains. The introduction of d-amino acids significantly improved stability. Certain analogs demonstrated antibiofilm activities. In mechanistic studies, the analogs eradicated bacteria not just by interrupting the bacterial membranes, but also by linking to DNA, which was not impacted by known mechanisms of resistance. In a mouse model, certain analogs were able to significantly reduce the bacterial load. Among the analogs, CPF-9 was notable due to its greater antimicrobial potency in vitro and in vivo and its superior stability, lower hemolytic activity, and higher antibiofilm activity. This analog is a potential antibiotic candidate for treating infections induced by multidrug-resistant bacteria. © 2017 John Wiley & Sons A/S.

Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance.

PubMed

Magiorakos, A-P; Srinivasan, A; Carey, R B; Carmeli, Y; Falagas, M E; Giske, C G; Harbarth, S; Hindler, J F; Kahlmeter, G; Olsson-Liljequist, B; Paterson, D L; Rice, L B; Stelling, J; Struelens, M J; Vatopoulos, A; Weber, J T; Monnet, D L

2012-03-01

Many different definitions for multidrug-resistant (MDR), extensively drug-resistant (XDR) and pandrug-resistant (PDR) bacteria are being used in the medical literature to characterize the different patterns of resistance found in healthcare-associated, antimicrobial-resistant bacteria. A group of international experts came together through a joint initiative by the European Centre for Disease Prevention and Control (ECDC) and the Centers for Disease Control and Prevention (CDC), to create a standardized international terminology with which to describe acquired resistance profiles in Staphylococcus aureus, Enterococcus spp., Enterobacteriaceae (other than Salmonella and Shigella), Pseudomonas aeruginosa and Acinetobacter spp., all bacteria often responsible for healthcare-associated infections and prone to multidrug resistance. Epidemiologically significant antimicrobial categories were constructed for each bacterium. Lists of antimicrobial categories proposed for antimicrobial susceptibility testing were created using documents and breakpoints from the Clinical Laboratory Standards Institute (CLSI), the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the United States Food and Drug Administration (FDA). MDR was defined as acquired non-susceptibility to at least one agent in three or more antimicrobial categories, XDR was defined as non-susceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e. bacterial isolates remain susceptible to only one or two categories) and PDR was defined as non-susceptibility to all agents in all antimicrobial categories. To ensure correct application of these definitions, bacterial isolates should be tested against all or nearly all of the antimicrobial agents within the antimicrobial categories and selective reporting and suppression of results should be avoided. © 2011 European Society of Clinical Microbiology and Infectious Diseases. No claim to original US government works.

Exogenous l-Valine Promotes Phagocytosis to Kill Multidrug-Resistant Bacterial Pathogens

PubMed Central

Chen, Xin-hai; Liu, Shi-rao; Peng, Bo; Li, Dan; Cheng, Zhi-xue; Zhu, Jia-xin; Zhang, Song; Peng, Yu-ming; Li, Hui; Zhang, Tian-tuo; Peng, Xuan-xian

2017-01-01

The emergence of multidrug-resistant bacteria presents a severe threat to public health and causes extensive losses in livestock husbandry and aquaculture. Effective strategies to control such infections are in high demand. Enhancing host immunity is an ideal strategy with fewer side effects than antibiotics. To explore metabolite candidates, we applied a metabolomics approach to investigate the metabolic profiles of mice after Klebsiella pneumoniae infection. Compared with the mice that died from K. pneumoniae infection, mice that survived the infection displayed elevated levels of l-valine. Our analysis showed that l-valine increased macrophage phagocytosis, thereby reducing the load of pathogens; this effect was not only limited to K. pneumoniae but also included Escherichia coli clinical isolates in infected tissues. Two mechanisms are involved in this process: l-valine activating the PI3K/Akt1 pathway and promoting NO production through the inhibition of arginase activity. The NO precursor l-arginine is necessary for l-valine-stimulated macrophage phagocytosis. The valine-arginine combination therapy effectively killed K. pneumoniae and exerted similar effects in other Gram-negative (E. coli and Pseudomonas aeruginosa) and Gram-positive (Staphylococcus aureus) bacteria. Our study extends the role of metabolism in innate immunity and develops the possibility of employing the metabolic modulator-mediated innate immunity as a therapy for bacterial infections. PMID:28321214

Current Advances in Developing Inhibitors of Bacterial Multidrug 
Efflux Pumps

PubMed Central

Mahmood, Hannah Y.; Jamshidi, Shirin; Sutton, J. Mark; Rahman, Khondaker M.

2016-01-01

Antimicrobial resistance represents a significant challenge to future healthcare provision. An acronym ESKAPEE has been derived from the names of the organisms recognised as the major threats although there are a number of other organisms, notably Neisseria gonorrhoeae, that have become equally challenging to treat in the clinic. These pathogens are characterised by the ability to rapidly develop and/or acquire resistance mechanisms in response to exposure to different antimicrobial agents. A key part of the armoury of these pathogens is a series of efflux pumps, which effectively exclude or reduce the intracellular concentration of a large number of antibiotics, making the pathogens significantly more resistant. These efflux pumps are the topic of considerable interest, both from the perspective of basic understanding of efflux pump function, and its role in drug resistance but also as targets for the development of novel adjunct therapies. The necessity to overcome antimicrobial resistance has encouraged investigations into the characterisation of resistance-modifying efflux pump inhibitors to block the mechanisms of drug extrusion, thereby restoring antibacterial susceptibility and returning existing antibiotics into the clinic. A greater understanding of drug recognition and transport by multidrug efflux pumps is needed to develop clinically useful inhibitors, given the breadth of molecules that can be effluxed by these systems. This review discusses different bacterial EPIs originating from both natural source and chemical synthesis and examines the challenges to designing successful EPIs that can be useful against multidrug resistant bacteria. PMID:26947776

Antimicrobial peptides as potential anti-biofilm agents against multidrug-resistant bacteria.

PubMed

Chung, Pooi Yin; Khanum, Ramona

2017-08-01

Bacterial resistance to commonly used drugs has become a global health problem, causing increased infection cases and mortality rate. One of the main virulence determinants in many bacterial infections is biofilm formation, which significantly increases bacterial resistance to antibiotics and innate host defence. In the search to address the chronic infections caused by biofilms, antimicrobial peptides (AMP) have been considered as potential alternative agents to conventional antibiotics. Although AMPs are commonly considered as the primitive mechanism of immunity and has been extensively studied in insects and non-vertebrate organisms, there is now increasing evidence that AMPs also play a crucial role in human immunity. AMPs have exhibited broad-spectrum activity against many strains of Gram-positive and Gram-negative bacteria, including drug-resistant strains, and fungi. In addition, AMPs also showed synergy with classical antibiotics, neutralize toxins and are active in animal models. In this review, the important mechanisms of action and potential of AMPs in the eradication of biofilm formation in multidrug-resistant pathogen, with the goal of designing novel antimicrobial therapeutics, are discussed. Copyright © 2017. Published by Elsevier B.V.

Tetracycline improved the efficiency of other antimicrobials against Gram-negative multidrug-resistant bacteria.

PubMed

Mawabo, Isabelle K; Noumedem, Jaurès A K; Kuiate, Jules R; Kuete, Victor

2015-01-01

Treatment of infectious diseases with antimicrobials constituted a great achievement in the history of medicine. Unfortunately, the emergence of resistant strains of bacteria to all classes of antimicrobials limited their efficacy. The present study was aimed at evaluating the effect of combinations of antibiotics on multi-drug resistant Gram-negative (MDRGN) bacteria. A liquid micro-broth dilution method was used to evaluate the antibacterial activity of 10 different classes of antimicrobials on 20 bacterial strains belonging to six different species. The antimicrobials were associated with phenylalanine β-naphthylamide (PAβN), an efflux pump inhibitor, and with other antimicrobials at their sub-inhibitory concentrations. The effectiveness of each combination was monitored using the minimal inhibitory concentration (MIC) and the fractional inhibitory concentration (FIC). Most of the antimicrobials tested showed low antibacterial activity with a MIC value of 128 mg/L on a majority of the bacterial strains, justifying their multidrug-resistant (MDR) profile. Synergistic effects were mostly observed (FIC≤0.5) when ampicillin (AMP), cloxacillin (CLX), erythromycin (ERY), chloramphenicol (CHL), kanamycin (KAN) and streptomycin (STR) were combined with tetracycline (TET) at the sub-inhibitory concentration of MIC/5 or MIC/10. The results of the present work suggest that the association of several antimicrobials with TET could improve the fight against MDRGN bacterial species. Copyright © 2014 King Saud Bin Abdulaziz University for Health Sciences. Published by Elsevier Ltd. All rights reserved.

Multidrug resistance in parasites: ABC transporters, P-glycoproteins and molecular modelling.

PubMed

Jones, P M; George, A M

2005-04-30

Parasitic diseases, caused by protozoa, helminths and arthropods, rank among the most important problems in human and veterinary medicine, and in agriculture, leading to debilitating sicknesses and loss of life. In the absence of vaccines and with the general failure of vector eradication programs, drugs are the main line of defence, but the newest drugs are being tracked by the emergence of resistance in parasites, sharing ominous parallels with multidrug resistance in bacterial pathogens. Any of a number of mechanisms will elicit a drug resistance phenotype in parasites, including: active efflux, reduced uptake, target modification, drug modification, drug sequestration, by-pass shunting, or substrate competition. The role of ABC transporters in parasitic multidrug resistance mechanisms is being subjected to more scrutiny, due in part to the established roles of certain ABC transporters in human diseases, and also to an increasing portfolio of ABC transporters from parasite genome sequencing projects. For example, over 100 ABC transporters have been identified in the Escherichia coli genome, but to date only about 65 in all parasitic genomes. Long established laboratory investigations are now being assisted by molecular biology, bioinformatics, and computational modelling, and it is in these areas that the role of ABC transporters in parasitic multidrug resistance mechanisms may be defined and put in perspective with that of other proteins. We discuss ABC transporters in parasites, and conclude with an example of molecular modelling that identifies a new interaction between the structural domains of a parasite P-glycoprotein.

Biofilm is a Major Virulence Determinant in Bacterial Colonization of Chronic Skin Ulcers Independently from the Multidrug Resistant Phenotype

PubMed Central

Di Domenico, Enea Gino; Farulla, Ilaria; Prignano, Grazia; Gallo, Maria Teresa; Vespaziani, Matteo; Cavallo, Ilaria; Sperduti, Isabella; Pontone, Martina; Bordignon, Valentina; Cilli, Laura; De Santis, Alessandra; Di Salvo, Fabiola; Pimpinelli, Fulvia; Lesnoni La Parola, Ilaria; Toma, Luigi; Ensoli, Fabrizio

2017-01-01

Bacterial biofilm is a major factor in delayed wound healing and high levels of biofilm production have been repeatedly described in multidrug resistant organisms (MDROs). Nevertheless, a quantitative correlation between biofilm production and the profile of antimicrobial drug resistance in delayed wound healing remains to be determined. Microbial identification, antibiotic susceptibility and biofilm production were assessed in 135 clinical isolates from 87 patients. Gram-negative bacteria were the most represented microorganisms (60.8%) with MDROs accounting for 31.8% of the total isolates. Assessment of biofilm production revealed that 80% of the strains were able to form biofilm. A comparable level of biofilm production was found with both MDRO and not-MDRO with no significant differences between groups. All the methicillin-resistant Staphylococcus aureus (MRSA) and 80% of Pseudomonas aeruginosa MDR strains were found as moderate/high biofilm producers. Conversely, less than 17% of Klebsiella pneumoniae extended-spectrum beta-lactamase (ESBL), Escherichia coli-ESBL and Acinetobacter baumannii were moderate/high biofilm producers. Notably, those strains classified as non-biofilm producers, were always associated with biofilm producer bacteria in polymicrobial colonization. This study shows that biofilm producers were present in all chronic skin ulcers, suggesting that biofilm represents a key virulence determinant in promoting bacterial persistence and chronicity of ulcerative lesions independently from the MDRO phenotype. PMID:28513576

Infective endocarditis caused by multidrug-resistant Streptococcus mitis in a combined immunocompromised patient: an autopsy case report.

PubMed

Matsui, Natsuko; Ito, Makoto; Kuramae, Hitoshi; Inukai, Tomomi; Sakai, Akiyoshi; Okugawa, Masaru

2013-04-01

An autopsy case of infective endocarditis caused by multidrug-resistant Streptococcus mitis was described in a patient with a combination of factors that compromised immune status, including autoimmune hemolytic anemia, post-splenectomy state, prolonged steroid treatment, and IgA deficiency. The isolated S. mitis strain from blood culture was broadly resistant to penicillin, cephalosporins, carbapenem, macrolides, and fluoroquinolone. Recurrent episodes of bacterial infections and therapeutic use of several antibiotics may underlie the development of multidrug resistance for S. mitis. Because clinically isolated S. mitis strains from chronically immunocompromised patients have become resistant to a wide spectrum of antibiotics, appropriate antibiotic regimens should be selected when treating invasive S. mitis infections in these compromised patients.

Expression of multidrug resistance proteins in retinoblastoma

PubMed Central

Shukla, Swati; Srivastava, Arpna; Kumar, Sunil; Singh, Usha; Goswami, Sandeep; Chawla, Bhavna; Bajaj, Mandeep Singh; Kashyap, Seema; Kaur, Jasbir

2017-01-01

AIM To elucidate the mechanism of multidrug resistance in retinoblastoma, and to acquire more insights into in vivo drug resistance. METHODS Three anticancer drug resistant Y79 human RB cells were generated against vincristine, etoposide or carboplatin, which are used for conventional chemotherapy in RB. Primary cultures from enucleated eyes after chemotherapy (PCNC) were also prepared. Their chemosensitivity to chemotherapeutic agents (vincristine, etoposide and carboplatin) were measured using MTT assay. Western blot analysis was performed to evaluate the expression of p53, Bcl-2 and various multidrug resistant proteins in retinoblastoma cells. RESULTS Following exposure to chemotherapeutic drugs, PCNC showed less sensitivity to drugs. No significant changes observed in the p53 expression, whereas Bcl-2 expression was found to be increased in the drug resistant cells as well as in PCNC. Increased expression of P-glycoprotein (P-gp) was observed in drug resistant Y79 cells; however there was no significant change in the expression of P-gp found between primary cultures of primarily enucleated eyes and PCNC. Multidrug resistance protein 1 (Mrp-1) expression was found to be elevated in the drug resistant Y79 cells as well as in PCNC. No significant change in the expression of lung resistance associated protein (Lrp) was observed in the drug resistant Y79 cells as well as in PCNC. CONCLUSION Our results suggest that multidrug resistant proteins are intrinsically present in retinoblastoma which causes treatment failure in managing retinoblastoma with chemotherapy. PMID:29181307

Inhibition of multidrug resistant Listeria monocytogenes by peptides isolated from combinatorial phage display libraries.

PubMed

Flachbartova, Z; Pulzova, L; Bencurova, E; Potocnakova, L; Comor, L; Bednarikova, Z; Bhide, M

2016-01-01

The aim of the study was to isolate and characterize novel antimicrobial peptides from peptide phage library with antimicrobial activity against multidrug resistant Listeria monocytogenes. Combinatorial phage-display library was used to affinity select peptides binding to the cell surface of multidrug resistant L. monocytogenes. After several rounds of affinity selection followed by sequencing, three peptides were revealed as the most promising candidates. Peptide L2 exhibited features common to antimicrobial peptides (AMPs), and was rich in Asp, His and Lys residues. Peptide L3 (NSWIQAPDTKSI), like peptide L2, inhibited bacterial growth in vitro, without any hemolytic or cytotoxic effects on eukaryotic cells. L1 peptide showed no inhibitory effect on Listeria. Structurally, peptides L2 and L3 formed random coils composed of α-helix and β-sheet units. Peptides L2 and L3 exhibited antimicrobial activity against multidrug resistant isolates of L. monocytogenes with no haemolytic or toxic effects. Both peptides identified in this study have the potential to be beneficial in human and veterinary medicine. Copyright © 2016 Elsevier GmbH. All rights reserved.

Repurposing ebselen for treatment of multidrug-resistant staphylococcal infections.

PubMed

Thangamani, Shankar; Younis, Waleed; Seleem, Mohamed N

2015-06-26

Novel antimicrobials and new approaches to developing them are urgently needed. Repurposing already-approved drugs with well-characterized toxicology and pharmacology is a novel way to reduce the time, cost, and risk associated with antibiotic innovation. Ebselen, an organoselenium compound, is known to be clinically safe and has a well-known pharmacology profile. It has shown potent bactericidal activity against multidrug-resistant clinical isolates of staphylococcus aureus, including methicillin- and vancomycin-resistant S. aureus (MRSA and VRSA). We demonstrated that ebselen acts through inhibition of protein synthesis and subsequently inhibited toxin production in MRSA. Additionally, ebselen was remarkably active and significantly reduced established staphylococcal biofilms. The therapeutic efficacy of ebselen was evaluated in a mouse model of staphylococcal skin infections. Ebselen 1% and 2% significantly reduced the bacterial load and the levels of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and monocyte chemo attractant protein-1 (MCP-1) in MRSA USA300 skin lesions. Furthermore, it acts synergistically with traditional antimicrobials. This study provides evidence that ebselen has great potential for topical treatment of MRSA skin infections and lays the foundation for further analysis and development of ebselen as a potential treatment for multidrug-resistant staphylococcal infections.

Complete Genome Sequence of Streptococcus pneumoniae Strain A026, a Clinical Multidrug-Resistant Isolate Carrying Tn2010

PubMed Central

Sui, Zhihai; Zhou, Wenqing; Yao, Kaihu; Liu, Li; Zhang, Gang; Yang, Yonghong

2013-01-01

Streptococcus pneumoniae is a primary cause of bacterial infection in humans. Here, we present the complete genome sequence of S. pneumoniae strain A026, which is a multidrug-resistant strain isolated from cerebrospinal fluid. PMID:24336372

A retrospective analysis of antimicrobial resistance in bacterial pathogens in an equine hospital (2012-2015).

PubMed

van Spijk, J N; Schmitt, S; Fürst, A E; Schoster, A

2016-06-01

Antimicrobial resistance has become an important concern in veterinary medicine. The aim of this study was to describe the rate of antimicrobial resistance in common equine pathogens and to determine the occurrence of multidrug-resistant isolates. A retrospective analysis of all susceptibility testing results from bacterial pathogens cultured from horses at the University of Zurich Equine Hospital (2012-2015) was performed. Strains exhibiting resistance to 3 or more antimicrobial categories were defined as multidrug-resistant. Susceptibility results from 303 bacterial pathogens were analyzed, most commonly Escherichia coli (60/303, 20%) and Staphylococcus aureus (40/303, 13%). High rates of acquired resistance against commonly used antimicrobials were found in most of the frequently isolated equine pathogens. The highest rate of multidrug resistance was found in isolates of Acinetobacter baumannii (23/24, 96%), followed by Enterobacter cloacae complex (24/28, 86%) and Escherichia coli (48/60, 80%). Overall, 60% of Escherichia coli isolates were phenotypically ESBL-producing and 68% of Staphylococcus spp. were phenotypically methicillin-resistant. High rates of acquired antimicrobial resistance towards commonly used antibiotics are concerning and underline the importance of individual bacteriological and antimicrobial susceptibility testing to guide antimicrobial therapy. Minimizing and optimizing antimicrobial therapy in horses is needed.

Production of putrescine-capped stable silver nanoparticle: its characterization and antibacterial activity against multidrug-resistant bacterial strains

NASA Astrophysics Data System (ADS)

Saha, Saswati; Gupta, Bhaskar; Gupta, Kamala; Chaudhuri, Mahua Ghosh

2016-11-01

Integration of biology with nanotechnology is now becoming attention-grabbing area of research. The antimicrobial potency of silver has been eminent from antiquity. Due to the recent desire for the enhancement of antibacterial efficacy of silver, various synthesis methods of silver in their nano dimensions are being practiced using a range of capping material. The present work highlights a facile biomimetic approach for production of silver nanoparticle being capped and stabilized by putrescine, possessing a diameter of 10-25 ± 1.5 nm. The synthesized nanoparticles have been analyzed spectrally and analytically. Morphological studies are carried out by high-resolution transmission electron microscopy and crystallinity by selected area electron diffraction patterns. Moreover, the elemental composition of the capped nanoparticles was confirmed by energy-dispersive X-ray spectroscopy analysis. A comparative study (zone of inhibition and minimum inhibitory concentration) regarding the interactions and antibacterial potentiality of the capped silver nanoparticles with respect to the bare ones reveal the efficiency of the capped one over the bare one. The bacterial kinetic study was executed to monitor the interference of nanoparticles with bacterial growth rate. The results also highlight the efficacy of putrescine-capped silver nanoparticles as effective growth inhibitors against multi-drug resistant human pathogenic bacterial strains, which may, thus, potentially be applicable as an effective antibacterial control system to fight diseases.

Multidrug resistance in enteric and other gram-negative bacteria.

PubMed

George, A M

1996-05-15

In Gram-negative bacteria, multidrug resistance is a term that is used to describe mechanisms of resistance by chromosomal genes that are activated by induction or mutation caused by the stress of exposure to antibiotics in natural and clinical environments. Unlike plasmid-borne resistance genes, there is no alteration or degradation of drugs or need for genetic transfer. Exposure to a single drug leads to cross-resistance to many other structurally and functionally unrelated drugs. The only mechanism identified for multidrug resistance in bacteria is drug efflux by membrane transporters, even though many of these transporters remain to be identified. The enteric bacteria exhibit mostly complex multidrug resistance systems which are often regulated by operons or regulons. The purpose of this review is to survey molecular mechanisms of multidrug resistance in enteric and other Gram-negative bacteria, and to speculate on the origins and natural physiological functions of the genes involved.

Multidrug-resistant organisms, wounds and topical antimicrobial protection.

PubMed

Bowler, Philip G; Welsby, Sarah; Towers, Victoria; Booth, Rebecca; Hogarth, Andrea; Rowlands, Victoria; Joseph, Alexis; Jones, Samantha A

2012-08-01

Multidrug-resistant organisms (MDROs) are increasingly implicated in both acute and chronic wound infections. The limited therapeutic options are further compromised by the fact that wound bacteria often co-exist within a biofilm community which enhances bacterial tolerance to antibiotics. As a consequence, topical antiseptics may be an important consideration for minimising the opportunity for wound infections involving MDROs. The objective of this research was to investigate the antimicrobial activity of a silver-containing gelling fibre dressing against a variety of MDROs in free-living and biofilm states, using stringent in vitro models designed to simulate a variety of wound conditions. MDROs included Acinetobacter baumannii, community-associated methicillin-resistant Staphylococcus aureus, and extended-spectrum beta-lactamase-producing bacteria. Clostridium difficile was also included in the study because it carries many of the characteristics seen in MDROs and evidence of multidrug resistance is emerging. Sustained in vitro antimicrobial activity of the silver-containing dressing was shown against 10 MDROs in a simulated wound fluid over 7 days, and inhibitory and bactericidal effects against both free-living and biofilm phenotypes were also consistently shown in simulated colonised wound surface models. The in vitro data support consideration of the silver-containing gelling fibre dressing as part of a protocol of care in the management of wounds colonised or infected with MDROs. © 2012 The Authors. International Wound Journal © 2012 Blackwell Publishing Ltd and Medicalhelplines.com Inc.

Multidrug resistance in fungi: regulation of transporter-encoding gene expression

PubMed Central

Paul, Sanjoy; Moye-Rowley, W. Scott

2014-01-01

A critical risk to the continued success of antifungal chemotherapy is the acquisition of resistance; a risk exacerbated by the few classes of effective antifungal drugs. Predictably, as the use of these drugs increases in the clinic, more resistant organisms can be isolated from patients. A particularly problematic form of drug resistance that routinely emerges in the major fungal pathogens is known as multidrug resistance. Multidrug resistance refers to the simultaneous acquisition of tolerance to a range of drugs via a limited or even single genetic change. This review will focus on recent progress in understanding pathways of multidrug resistance in fungi including those of most medical relevance. Analyses of multidrug resistance in Saccharomyces cerevisiae have provided the most detailed outline of multidrug resistance in a eukaryotic microorganism. Multidrug resistant isolates of S. cerevisiae typically result from changes in the activity of a pair of related transcription factors that in turn elicit overproduction of several target genes. Chief among these is the ATP-binding cassette (ABC)-encoding gene PDR5. Interestingly, in the medically important Candida species, very similar pathways are involved in acquisition of multidrug resistance. In both C. albicans and C. glabrata, changes in the activity of transcriptional activator proteins elicits overproduction of a protein closely related to S. cerevisiae Pdr5 called Cdr1. The major filamentous fungal pathogen, Aspergillus fumigatus, was previously thought to acquire resistance to azole compounds (the principal antifungal drug class) via alterations in the azole drug target-encoding gene cyp51A. More recent data indicate that pathways in addition to changes in the cyp51A gene are important determinants in A. fumigatus azole resistance. We will discuss findings that suggest azole resistance in A. fumigatus and Candida species may share more mechanistic similarities than previously thought. PMID:24795641

Tris-EDTA significantly enhances antibiotic efficacy against multidrug-resistant Pseudomonas aeruginosa in vitro.

PubMed

Buckley, Laura M; McEwan, Neil A; Nuttall, Tim

2013-10-01

Multidrug-resistant Pseudomonas aeruginosa commonly complicates chronic bacterial otitis in dogs. The aim of this in vitro study was to determine the effect of ethylenediaminetetraacetic acid-tromethamine (Tris-EDTA) on the minimal bactericidal concentrations (MBCs) and minimal inhibitory concentrations (MICs) of marbofloxacin and gentamicin for multidrug-resistant P. aeruginosa isolates from cases of canine otitis. Eleven isolates were identified as multidrug resistant on disc diffusion; 10 were resistant to marbofloxacin and two were resistant to gentamicin. Isolates were incubated for 90 min with each antibiotic alone and in combination with Tris-EDTA at concentrations of 0.075 μg/mL to 5 mg/mL for marbofloxacin, 0.001 μg/mL to 10 mg/mL for gentamicin and 17.8:4.7 to 0.14:0.04 mg/mL for Tris-EDTA. Positive and negative controls were included. Aliquots of each antibiotic and/or Tris-EDTA concentration were subsequently transferred to sheep blood agar to determine the MBCs, and tryptone soy broth was added to the remaining suspensions to determine the MICs. Tris-EDTA alone was bacteriostatic but not bactericidal at any concentration. The addition of Tris-EDTA significantly reduced the median MBC (from 625 to 468.8 μg/mL; P < 0.001) and MIC (from 29.3 to 2.4 μg/mL; P = 0.008) of marbofloxacin, and the median MBC (from 625 to 39.1 μg/mL) and MIC (from 19.5 to 1.2 μg/mL) of gentamicin (both P < 0.001). Tris-EDTA significantly reduced the MBCs and MICs of marbofloxacin and gentamicin for multidrug-resistant P. aeruginosa in vitro. This may be of use to clinicians managing these infections in dogs. © 2013 ESVD and ACVD.

Hospital costs of nosocomial multi-drug resistant Pseudomonas aeruginosa acquisition.

PubMed

Morales, Eva; Cots, Francesc; Sala, Maria; Comas, Mercè; Belvis, Francesc; Riu, Marta; Salvadó, Margarita; Grau, Santiago; Horcajada, Juan P; Montero, Maria Milagro; Castells, Xavier

2012-05-23

We aimed to assess the hospital economic costs of nosocomial multi-drug resistant Pseudomonas aeruginosa acquisition. A retrospective study of all hospital admissions between January 1, 2005, and December 31, 2006 was carried out in a 420-bed, urban, tertiary-care teaching hospital in Barcelona (Spain). All patients with a first positive clinical culture for P. aeruginosa more than 48 h after admission were included. Patient and hospitalization characteristics were collected from hospital and microbiology laboratory computerized records. According to antibiotic susceptibility, isolates were classified as non-resistant, resistant and multi-drug resistant. Cost estimation was based on a full-costing cost accounting system and on the criteria of clinical Activity-Based Costing methods. Multivariate analyses were performed using generalized linear models of log-transformed costs. Cost estimations were available for 402 nosocomial incident P. aeruginosa positive cultures. Their distribution by antibiotic susceptibility pattern was 37.1% non-resistant, 29.6% resistant and 33.3% multi-drug resistant. The total mean economic cost per admission of patients with multi-drug resistant P. aeruginosa strains was higher than that for non-resistant strains (15,265 vs. 4,933 Euros). In multivariate analysis, resistant and multi-drug resistant strains were independently predictive of an increased hospital total cost in compared with non-resistant strains (the incremental increase in total hospital cost was more than 1.37-fold and 1.77-fold that for non-resistant strains, respectively). P. aeruginosa multi-drug resistance independently predicted higher hospital costs with a more than 70% increase per admission compared with non-resistant strains. Prevention of the nosocomial emergence and spread of antimicrobial resistant microorganisms is essential to limit the strong economic impact.

Nosocomial spontaneous bacterial peritonitis antibiotic treatment in the era of multi-drug resistance pathogens: A systematic review.

PubMed

Fiore, Marco; Maraolo, Alberto Enrico; Gentile, Ivan; Borgia, Guglielmo; Leone, Sebastiano; Sansone, Pasquale; Passavanti, Maria Beatrice; Aurilio, Caterina; Pace, Maria Caterina

2017-07-07

To systematically review literature upon aetiology of nosocomial spontaneous bacterial peritonitis (N-SBP) given the rising importance of multidrug-resistant (MDR) bacteria. A literature search was performed on MEDLINE and Google Scholar databases from 2000 to 15 th of November 2016, using the following search strategy: "spontaneous" AND "peritonitis". The initial search through electronic databases retrieved 2556 records. After removing duplicates, 1958 records remained. One thousand seven hundred and thirty-five of them were excluded on the basis of the screening of titles and abstract, and the ensuing number of remaining articles was 223. Of these records, after careful evaluation, only 9 were included in the qualitative analysis. The overall proportion of MDR bacteria turned out to be from 22% to 73% of cases across the studies. N-SBP is caused, in a remarkable proportion, by MDR pathogens. This should prompt a careful re-assessment of guidelines addressing the treatment of this clinical entity.

Hospital costs of nosocomial multi-drug resistant Pseudomonas aeruginosa acquisition

PubMed Central

2012-01-01

Background We aimed to assess the hospital economic costs of nosocomial multi-drug resistant Pseudomonas aeruginosa acquisition. Methods A retrospective study of all hospital admissions between January 1, 2005, and December 31, 2006 was carried out in a 420-bed, urban, tertiary-care teaching hospital in Barcelona (Spain). All patients with a first positive clinical culture for P. aeruginosa more than 48 h after admission were included. Patient and hospitalization characteristics were collected from hospital and microbiology laboratory computerized records. According to antibiotic susceptibility, isolates were classified as non-resistant, resistant and multi-drug resistant. Cost estimation was based on a full-costing cost accounting system and on the criteria of clinical Activity-Based Costing methods. Multivariate analyses were performed using generalized linear models of log-transformed costs. Results Cost estimations were available for 402 nosocomial incident P. aeruginosa positive cultures. Their distribution by antibiotic susceptibility pattern was 37.1% non-resistant, 29.6% resistant and 33.3% multi-drug resistant. The total mean economic cost per admission of patients with multi-drug resistant P. aeruginosa strains was higher than that for non-resistant strains (15,265 vs. 4,933 Euros). In multivariate analysis, resistant and multi-drug resistant strains were independently predictive of an increased hospital total cost in compared with non-resistant strains (the incremental increase in total hospital cost was more than 1.37-fold and 1.77-fold that for non-resistant strains, respectively). Conclusions P. aeruginosa multi-drug resistance independently predicted higher hospital costs with a more than 70% increase per admission compared with non-resistant strains. Prevention of the nosocomial emergence and spread of antimicrobial resistant microorganisms is essential to limit the strong economic impact. PMID:22621745

Prevalence and behavior of multidrug-resistant Salmonella strains on raw whole and cut nopalitos (Opuntia ficus-indica L.) and on nopalitos salads.

PubMed

Gómez-Aldapa, Carlos A; Gutiérrez-Alcántara, Eduardo J; Torres-Vitela, M Refugio; Rangel-Vargas, Esmeralda; Villarruel-López, Angelica; Castro-Rosas, Javier

2017-09-01

The presence of multidrug-resistant Salmonella in vegetables is a significant public health concern. Nopalito is a cactaceous that is commonly consumed either raw or cooked in Mexico and other countries. The presence of antibiotic-resistant Salmonella strains on raw whole nopalitos (RWN, without prickles), raw nopalitos cut into squares (RNCS) and in cooked nopalitos salads (CNS) samples was determined. In addition, the behavior of multidrug-resistant Salmonella isolates on RWN, RNCS and CNS at 25° ± 2 °C and 3° ± 2 °C was investigated. One hundred samples of RWN, 100 of RNCS and 100 more of CNS were collected from public markets. Salmonella strains were isolated and identified in 30, 30 and 10% of the samples, respectively. Seventy multidrug-resistant Salmonella strains were isolated from all the nopalitos samples. Multidrug-resistant Salmonella isolates survived at least 15 days on RWN at 25° ± 2 °C or 3° ± 2 °C. Multidrug-resistant Salmonella isolates grew in the RNCS and CNS samples at 25° ± 2 °C. However, at 3° ± 2 °C the bacterial growth was inhibited. This is the first report about multidrug-resistant Salmonella isolation from raw nopalitos and nopalitos salads. Nopalitos from markets are very likely to be an important factor contributing to the endemicity of multidrug-resistant Salmonella-related gastroenteritis in Mexico. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

Multidrug Resistance: Physiological Principles and Nanomedical Solutions

PubMed Central

Storm, Gert; Kiessling, Fabian; Lammers, Twan

2014-01-01

Multidrug (MDR) resistance is a pathophysiological phenomenon employed by cancer cells which limits the prolonged and effective use of chemotherapeutic agents. MDR is primarily based on the over-expression of drug efflux pumps in the cellular membrane. Prominent examples of such efflux pumps, which belong to the ATP-binding cassette (ABC) superfamily of proteins, are Pgp (P-glycoprotein) and MRP (multidrug resistance-associated protein), nowadays officially known as ABCB1 and ABCC1. Over the years, several strategies have been evaluated to overcome MDR, based not only on the use of low-molecular-weight MDR modulators, but also on the implementation of 1-100(0) nm-sized drug delivery systems. In the present manuscript, after introducing the most important physiological principles of MDR, we summarize prototypic nanomedical strategies to overcome multidrug resistance, including the use of carrier materials with intrinsic anti-MDR properties, the use of nanomedicines to modify the mode of cellular uptake, and the co-formulation of chemotherapeutic drugs together with low- and high-molecular-weight MDR inhibitors within a single drug delivery system. While certain challenges still need to be overcome before such constructs and concepts can be widely applied in the clinic, the insights obtained and the progress made strongly suggest that nanomedicine formulations hold significant potential for improving the treatment of multidrug-resistant malignancies. PMID:24120954

Multidrug-resistant strains of Salmonella enterica Typhimurium, United States, 1997-1998.

PubMed

Rabatsky-Ehr, Therese; Whichard, Jean; Rossiter, Shannon; Holland, Ben; Stamey, Karen; Headrick, Marcia L; Barrett, Timothy J; Angulo, Frederick J

2004-05-01

To evaluate multidrug-resistant strains of Salmonella enterica serotype Typhimurium, including definitive type 104 (DT104) in the United States, we reviewed data from the National Antimicrobial Resistance Monitoring System (NARMS). In 1997 to 1998, 703 (25%) of 2,767 serotyped Salmonella isolates received at NARMS were S. Typhimurium; antimicrobial susceptibility testing and phage typing were completed for 697. Fifty-eight percent (402) were resistant to > or = 1 antimicrobial agent. Three multidrug-resistant (> or = 5 drugs) strains accounted for (74%) 296 of all resistant isolates. Ceftriaxone resistance was present in 8 (3%), and nalidixic acid resistance in 4 (1%), of these multidrug-resistant strains. By phage typing, 259 (37%) of S. Typhimurium isolates were DT104, 209 (30%) were of undefined type and 103 (15%) were untypable. Fifty percent (202) of resistant (> or = 1 drug) isolates were DT104. Multidrug-resistant S. Typhimurium isolates, particularly DT104, account for a substantial proportion of S. Typhimurium isolates; ceftriaxone resistance is exhibited by some of these strains.

Structural basis of RND-type multidrug exporters

PubMed Central

Yamaguchi, Akihito; Nakashima, Ryosuke; Sakurai, Keisuke

2015-01-01

Bacterial multidrug exporters are intrinsic membrane transporters that act as cellular self-defense mechanism. The most notable characteristics of multidrug exporters is that they export a wide range of drugs and toxic compounds. The overexpression of these exporters causes multidrug resistance. Multidrug-resistant pathogens have become a serious problem in modern chemotherapy. Over the past decade, investigations into the structure of bacterial multidrug exporters have revealed the multidrug recognition and export mechanisms. In this review, we primarily discuss RND-type multidrug exporters particularly AcrAB-TolC, major drug exporter in Gram-negative bacteria. RND-type drug exporters are tripartite complexes comprising a cell membrane transporter, an outer membrane channel and an adaptor protein. Cell membrane transporters and outer membrane channels are homo-trimers; however, there is no consensus on the number of adaptor proteins in these tripartite complexes. The three monomers of a cell membrane transporter have varying conformations (access, binding, and extrusion) during transport. Drugs are exported following an ordered conformational change in these three monomers, through a functional rotation mechanism coupled with the proton relay cycle in ion pairs, which is driven by proton translocation. Multidrug recognition is based on a multisite drug-binding mechanism, in which two voluminous multidrug-binding pockets in cell membrane exporters recognize a wide range of substrates as a result of permutations at numerous binding sites that are specific for the partial structures of substrate molecules. The voluminous multidrug-binding pocket may have numerous binding sites even for a single substrate, suggesting that substrates may move between binding sites during transport, an idea named as multisite-drug-oscillation hypothesis. This hypothesis is consistent with the apparently broad substrate specificity of cell membrane exporters and their highly efficient

Structural basis of RND-type multidrug exporters.

PubMed

Yamaguchi, Akihito; Nakashima, Ryosuke; Sakurai, Keisuke

2015-01-01

Bacterial multidrug exporters are intrinsic membrane transporters that act as cellular self-defense mechanism. The most notable characteristics of multidrug exporters is that they export a wide range of drugs and toxic compounds. The overexpression of these exporters causes multidrug resistance. Multidrug-resistant pathogens have become a serious problem in modern chemotherapy. Over the past decade, investigations into the structure of bacterial multidrug exporters have revealed the multidrug recognition and export mechanisms. In this review, we primarily discuss RND-type multidrug exporters particularly AcrAB-TolC, major drug exporter in Gram-negative bacteria. RND-type drug exporters are tripartite complexes comprising a cell membrane transporter, an outer membrane channel and an adaptor protein. Cell membrane transporters and outer membrane channels are homo-trimers; however, there is no consensus on the number of adaptor proteins in these tripartite complexes. The three monomers of a cell membrane transporter have varying conformations (access, binding, and extrusion) during transport. Drugs are exported following an ordered conformational change in these three monomers, through a functional rotation mechanism coupled with the proton relay cycle in ion pairs, which is driven by proton translocation. Multidrug recognition is based on a multisite drug-binding mechanism, in which two voluminous multidrug-binding pockets in cell membrane exporters recognize a wide range of substrates as a result of permutations at numerous binding sites that are specific for the partial structures of substrate molecules. The voluminous multidrug-binding pocket may have numerous binding sites even for a single substrate, suggesting that substrates may move between binding sites during transport, an idea named as multisite-drug-oscillation hypothesis. This hypothesis is consistent with the apparently broad substrate specificity of cell membrane exporters and their highly efficient

Epidemiology of multidrug resistant bacterial organisms and Clostridium difficile in German hospitals in 2014: Results from a nationwide one-day point prevalence of 329 German hospitals.

PubMed

Huebner, Nils-Olaf; Dittmann, Kathleen; Henck, Vivien; Wegner, Christian; Kramer, Axel

2016-09-02

One important aspect in combatting resistance to antibiotics is to increase the awareness and knowledge by epidemiological studies. We therefore conducted a German-wide point-prevalence survey for multidrug resistant bacterial organisms (MDROs) and Clostridium difficile (CD) to assess the epidemiology and structure quality of infection control in German hospitals. 1550 hospitals were asked to participate and to report surveillance data on the prevalence of Methicillin-resistant and Vancomycin resistant Staphylococcus aureus (MRSA, VRSA/GRSA), Vancomycin resistant Enterococcus faecalis/faecium (VRE), multiresistant strains of Escherichia coli (EC), Klebsiella spp. (KS), Enterobacter spp. (ES), Acinetobacter spp. (AB) and Pseudomonas spp. (PS). as well as CD infections. Surveys from 73,983 patients from 329 hospitals were eligible for analysis. MRSA was the most often reported pathogen (prevalence: 1.64 % [CI95: 1.46-1.82]), followed by 3 multidrug resistant EC (3MRGN-EC) (0.75 % [CI95: 0.60-0.89]), CD (0.74 % [CI95: 0.60-0.88]), VRE (0.25 % [CI95: 0.13-0.37]) und 3MRGN-KS (0.22 % [CI95: [0.15-0.29]). The majority of hospitals met the German recommendations for staffing with infection control personnel. The continuing increase in participating hospitals in this third survey in a row indicates a growing awareness to MDROs and our pragmatic approach. Our results confirm that MRSA, 3MRGN-EC, VRE and 3MRGN-KS remain the most prevalent MDROs in German hospitals.

Enhancement of neutrophil autophagy by an IVIG preparation against multidrug-resistant bacteria as well as drug-sensitive strains.

PubMed

Itoh, Hiroshi; Matsuo, Hidemasa; Kitamura, Naoko; Yamamoto, Sho; Higuchi, Takeshi; Takematsu, Hiromu; Kamikubo, Yasuhiko; Kondo, Tadakazu; Yamashita, Kouhei; Sasada, Masataka; Takaori-Kondo, Akifumi; Adachi, Souichi

2015-07-01

Autophagy occurs in human neutrophils after the phagocytosis of multidrug-resistant bacteria and drug-sensitive strains, including Escherichia coli and Pseudomonas aeruginosa. The present study detected autophagy by immunoblot analysis of LC3B conversion, by confocal scanning microscopic examination of LC3B aggregate formation and by transmission electron microscopic examination of bacteria-containing autophagosomes. Patients with severe bacterial infections are often treated with IVIG alongside antimicrobial agents. Here, we showed that IVIG induced neutrophil-mediated phagocytosis of multidrug-resistant strains. Compared with untreated neutrophils, neutrophils exposed to IVIG showed increased levels of bacterial cell killing, phagocytosis, O(2)(-) release, MPO release, and NET formation. IVIG also increased autophagy in these cells. Inhibiting the late phase of autophagy (fusion of lysosomes with autophagosomes) with bafilomycin A1-reduced, neutrophil-mediated bactericidal activity. These findings indicate that autophagy plays a critical role in the bactericidal activity mediated by human neutrophils. Furthermore, the autophagosomes within the neutrophils contained bacteria only and their organelles only, or both bacteria and their organelles, a previously undocumented observation. Taken together, these results suggest that the contents of neutrophil autophagosomes may be derived from specific autophagic systems, which provide the neutrophil with an advantage. Thus, IVIG promotes the neutrophil-mediated killing of multidrug-resistant bacteria as well as drug-sensitive strains. © Society for Leukocyte Biology.

Enhancement of neutrophil autophagy by an IVIG preparation against multidrug-resistant bacteria as well as drug-sensitive strains

PubMed Central

Itoh, Hiroshi; Matsuo, Hidemasa; Kitamura, Naoko; Yamamoto, Sho; Higuchi, Takeshi; Takematsu, Hiromu; Kamikubo, Yasuhiko; Kondo, Tadakazu; Yamashita, Kouhei; Sasada, Masataka; Takaori-Kondo, Akifumi; Adachi, Souichi

2015-01-01

Autophagy occurs in human neutrophils after the phagocytosis of multidrug-resistant bacteria and drug-sensitive strains, including Escherichia coli and Pseudomonas aeruginosa. The present study detected autophagy by immunoblot analysis of LC3B conversion, by confocal scanning microscopic examination of LC3B aggregate formation and by transmission electron microscopic examination of bacteria-containing autophagosomes. Patients with severe bacterial infections are often treated with IVIG alongside antimicrobial agents. Here, we showed that IVIG induced neutrophil-mediated phagocytosis of multidrug-resistant strains. Compared with untreated neutrophils, neutrophils exposed to IVIG showed increased levels of bacterial cell killing, phagocytosis, O2− release, MPO release, and NET formation. IVIG also increased autophagy in these cells. Inhibiting the late phase of autophagy (fusion of lysosomes with autophagosomes) with bafilomycin A1-reduced, neutrophil-mediated bactericidal activity. These findings indicate that autophagy plays a critical role in the bactericidal activity mediated by human neutrophils. Furthermore, the autophagosomes within the neutrophils contained bacteria only and their organelles only, or both bacteria and their organelles, a previously undocumented observation. Taken together, these results suggest that the contents of neutrophil autophagosomes may be derived from specific autophagic systems, which provide the neutrophil with an advantage. Thus, IVIG promotes the neutrophil-mediated killing of multidrug-resistant bacteria as well as drug-sensitive strains. PMID:25908735

Multidrug-Resistant Gram-Negative Bacilli: Infection Control Implications.

PubMed

Adler, Amos; Friedman, N Deborah; Marchaim, Dror

2016-12-01

Antimicrobial resistance is a common iatrogenic complication of both modern life and medical care. Certain multidrug resistant and extensively drug resistant Gram-negative organisms pose the biggest challenges to health care today, predominantly owing to a lack of therapeutic options. Containing the spread of these organisms is challenging, and in reality, the application of multiple control measures during an evolving outbreak makes it difficult to measure the relative impact of each measure. This article reviews the usefulness of various infection control measures in containing the spread of multidrug-resistant Gram-negative bacilli. Copyright © 2016 Elsevier Inc. All rights reserved.

Antimicrobial Blue Light Therapy for Multidrug-Resistant Acinetobacter baumannii Infection in a Mouse Burn Model: Implications for Prophylaxis and Treatment of Combat-related Wound Infections

PubMed Central

Zhang, Yunsong; Zhu, Yingbo; Gupta, Asheesh; Huang, Yingying; Murray, Clinton K.; Vrahas, Mark S.; Sherwood, Margaret E.; Baer, David G.; Hamblin, Michael R.; Dai, Tianhong

2014-01-01

In this study, we investigated the utility of antimicrobial blue light therapy for multidrug-resistant Acinetobacter baumannii infection in a mouse burn model. A bioluminescent clinical isolate of multidrug-resistant A. baumannii was obtained. The susceptibility of A. baumannii to blue light (415 nm)–inactivation was compared in vitro to that of human keratinocytes. Repeated cycles of sublethal inactivation of bacterial by blue light were performed to investigate the potential resistance development of A. baumannii to blue light. A mouse model of third degree burn infected with A. baumannii was developed. A single exposure of blue light was initiated 30 minutes after bacterial inoculation to inactivate A. baumannii in mouse burns. It was found that the multidrug-resistant A. baumannii strain was significantly more susceptible than keratinocytes to blue light inactivation. Transmission electron microscopy revealed blue light–induced ultrastructural damage in A. baumannii cells. Fluorescence spectroscopy suggested that endogenous porphyrins exist in A. baumannii cells. Blue light at an exposure of 55.8 J/cm2 significantly reduced the bacterial burden in mouse burns. No resistance development to blue light inactivation was observed in A. baumannii after 10 cycles of sublethal inactivation of bacteria. No significant DNA damage was detected in mouse skin by means of a skin TUNEL assay after a blue light exposure of 195 J/cm2. PMID:24381206

Monoterpene isolated from the essential oil of Trachyspermum ammi is cytotoxic to multidrug-resistant Pseudomonas aeruginosa and Staphylococcus aureus strains.

PubMed

Hosseinkhani, Faride; Jabalameli, Fereshteh; Banar, Maryam; Abdellahi, Nafiseh; Taherikalani, Morovat; Leeuwen, Willem B van; Emaneini, Mohammad

2016-04-01

The aim of this study was to determine whether an herbal extract containing monoterpene exhibited activity against multidrug-resistant Staphylococcus aureus and Pseudomonas aeruginosa isolated from clinical infection samples. The essential oil of Trachyspermum ammi (L.) Sprague ex Turrill (Apiaceae) fruit was extracted by hydrodistillation. Fruit residues were treated with hydrochloric acid and re-hydrodistilled to obtain volatile compounds. Compounds in the distilled oil were identified using gas-chromatography (GC) and GC-mass spectrometry (MS). The antibiotic susceptibility of all bacterial isolates was analyzed using both the disc diffusion method and determination of the minimum inhibitory concentration (MIC). The sensitivity of antibiotic-resistant isolates to essential oil was also determined by using the disc diffusion method and MIC determination. Of 26 clinical isolates, 92% were multidrug-resistant (MDR). Aromatic monoterpenes (thymol, paracymene, and gamma-terpinene) were the major (90%) components of the oil. Growth of S. aureus strains was successfully inhibited by the oil, with an inhibitory zone diameter (IZD) between 30-60mm and MIC <0.02μL/mL. The oil had no antimicrobial activity against clinical isolates of P. aeruginosa; rather, it prevented pigment production in these isolates. This study revealed that the essential oil of Trachyspermum ammi, which contains monoterpene, has good antibacterial potency. Monoterpenes could thus be incorporated into antimicrobial ointment formulas in order to treat highly drug-resistant S. aureus infections. Our findings also underscore the utility of research on natural products in order to combat bacterial multidrug resistance.

Feasibility of Neurapheresis™ as a Therapy for Multidrug Resistant Gram-negative Bacterial Meningitis

PubMed Central

Ballard, Christi; Ashraf, Bilal; Ejikeme, Tiffany; Hansen, Brenda; Charalambous, Lefko; Pagadala, Promila; Sharma-Kuinkel, Batu K; Giamberardino, Charles; Hedstrom, Blake; Verbick, Laura Zitella; Mccabe, Aaron; Lad, Shivanand P; Fowler, Vance; Perfect, John R

2017-01-01

Abstract Background The World Health Organization has identified Pseudomonas, Acinetobacter and Klebsiella (PAK) as three multidrug resistant (MDR) gram-negative pathogens that pose a threat to human health. The greatest threat lies in hospitals, nursing homes, and patients with devices such as intravenous catheters and ventilators. Gram-negative bacterial meningitis (GBM) manifests when these bacteria invade the central nervous system. Due to the threat of increasing antibiotic resistance and the high mortality associated with MDR GBM, we have tested a closed-loop, extracorporeal cerebrospinal fluid (CSF) filtration system (NeurapheresisTM) for its applicability in this context. Here we demonstrate feasibility of Neurapheresis for MDR GBM and characterize system parameters for bacterial clearance. Methods PAK cultures were grown and diluted to 1 × 107 cells/mL in artificial CSF or Luria-Miller broth. Both single pass and closed loop filtration were performed with various tangential flow filtration (TFF) and dead-end filter paradigms. Samples were taken either immediately post-filter or after every full CSF volume cycle (150 mL) during a long-term closed loop experiment. Bacterial load, endotoxin and cytokines were quantified. Results In single pass tests, 5kDa and 100kDa TFF filters and 0.2µm and 0.45µm dead-end filters excluded all PAK organisms completely. The 100kDa and 5kDa TFF filters significantly reduced endotoxin concentration by >95% and >99% of baseline, respectively. The 5 kDa TFF filters produced a 2-log (>99%) reduction in cytokines (IL-1ra, IL-6, TNF, CRP, and CXCL10). In closed-loop experiments, both TFF filters demonstrated a 1–2 Log CFU (90–99%) reduction of all PAK organisms over 4 filtration cycles. Conclusion Neurapheresis shows potential to be an efficient multi-modal tool for controlling and treating MDR GBM in this in vitro model. Extending closed loop filtration over time demonstrates capability for rapid sterilization of the CSF

Multidrug-Resistant Candida: Epidemiology, Molecular Mechanisms, and Treatment.

PubMed

Arendrup, Maiken Cavling; Patterson, Thomas F

2017-08-15

Invasive Candida infections remain an important cause of morbidity and mortality, especially in hospitalized and immunocompromised or critically ill patients. A limited number of antifungal agents from only a few drug classes are available to treat patients with these serious infections. Resistance can be either intrinsic or acquired. Resistance mechanisms are not exchanged between Candida; thus, acquired resistance either emerges in response to an antifungal selection pressure in the individual patient or, more rarely, occur due to horizontal transmission of resistant strains between patients. Although multidrug resistance is uncommon, increasing reports of multidrug resistance to the azoles, echinocandins, and polyenes have occurred in several Candida species, most notably Candida glabrata and more recently Candida auris. Drivers are overall antifungal use, subtherapeutic drug levels at sites of infection/colonization, drug sequestration in the biofilm matrix, and, in the setting of outbreaks, suboptimal infection control. Moreover, recent research suggests that DNA mismatch repair gene mutations may facilitate acquisition of resistance mutations in C. glabrata specifically. Diagnosis of antifungal-resistant Candida infections is critical to the successful management of patients with these infections. Reduction of unnecessary use of antifungals via antifungal stewardship is critical to limit multidrug resistance emergence. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Multidrug-resistant Strains of Salmonella enterica Typhimurium, United States, 1997–19981

PubMed Central

Whichard, Jean; Rossiter, Shannon; Holland, Ben; Stamey, Karen; Headrick, Marcia L.; Barrett, Timothy J.; Angulo, Frederick J.

2004-01-01

To evaluate multidrug-resistant strains of Salmonella enterica Typhimurium, including definitive type 104 (DT104) in the United States, we reviewed data from the National Antimicrobial Resistance Monitoring System (NARMS). In 1997–1998, 25% (703) of 2,767 serotyped Salmonella isolates received at NARMS were S. Typhimurium; antimicrobial susceptibility testing and phage typing were completed for 697. Fifty-eight percent (402) were resistant to >1 antimicrobial agent. Three multidrug-resistant (>5 drugs) strains accounted for 74% (296) of all resistant isolates. Ceftriaxone resistance was present in 3% (8), and nalidixic acid resistance in 1% (4), of these multidrug-resistant strains. By phage typing, 37% (259) of S. Typhimurium isolates were DT104, 30% (209) were of undefined type and 15% (103) were untypable. Fifty percent (202) of resistant (>1 drug) isolates were DT104. Multidrug-resistant S. Typhimurium isolates, particularly DT104, account for a substantial proportion of S. Typhimurium isolates; ceftriaxone resistance is exhibited by some of these strains. PMID:15200811

Research Progress in Reversal of Tumor Multi-drug Resistance via Natural Products.

PubMed

Guo, Qi; Cao, Hongyan; Qi, Xianghui; Li, Huikai; Ye, Peizhi; Wang, Zhiguo; Wang, Danqiao; Sun, Mingyu

2017-11-24

Multidrug resistance occurs when a tumor develops resistance to multiple chemotherapeutic drugs, which may include antitumor drugs with different chemical structures and mechanisms. Multidrug resistance limits the treatment effects of antitumor drugs, and is the main cause of chemotherapy failure. Multidrug resistance is caused by numerous factors including changes in ATP-binding cassette transporters, target proteins, detoxification, deoxyribonucleic acid repair, drug metabolic enzymes, and signal pathways of apoptosis. Clinical research indicates that natural products have great potential to treat tumors and reverse multidrug resistance. Natural products, which often have multiple targets, could play an important role in tumor treatment, have beneficial effects on tumor inhibition, improve symptoms, reduce radiotherapy and chemotherapy side effects, enhance immunity, and prolong survival. Because natural products often have few adverse reactions and less drug resistance, the antitumor activities of natural products have attracted extensive research. We aimed to review the basic research and clinical application of natural products in the reversal of multidrug resistance. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Insights into the environmental resistance gene pool from the genome sequence of the multidrug-resistant environmental isolate Escherichia coli SMS-3-5.

PubMed

Fricke, W Florian; Wright, Meredith S; Lindell, Angela H; Harkins, Derek M; Baker-Austin, Craig; Ravel, Jacques; Stepanauskas, Ramunas

2008-10-01

The increasing occurrence of multidrug-resistant pathogens of clinical and agricultural importance is a global public health concern. While antimicrobial use in human and veterinary medicine is known to contribute to the dissemination of antimicrobial resistance, the impact of microbial communities and mobile resistance genes from the environment in this process is not well understood. Isolated from an industrially polluted aquatic environment, Escherichia coli SMS-3-5 is resistant to a record number of antimicrobial compounds from all major classes, including two front-line fluoroquinolones (ciprofloxacin and moxifloxacin), and in many cases at record-high concentrations. To gain insights into antimicrobial resistance in environmental bacterial populations, the genome of E. coli SMS-3-5 was sequenced and compared to the genome sequences of other E. coli strains. In addition, selected genetic loci from E. coli SMS-3-5 predicted to be involved in antimicrobial resistance were phenotypically characterized. Using recombinant vector clones from shotgun sequencing libraries, resistance to tetracycline, streptomycin, and sulfonamide/trimethoprim was assigned to a single mosaic region on a 130-kb plasmid (pSMS35_130). The remaining plasmid backbone showed similarity to virulence plasmids from avian-pathogenic E. coli (APEC) strains. Individual resistance gene cassettes from pSMS35_130 are conserved among resistant bacterial isolates from multiple phylogenetic and geographic sources. Resistance to quinolones was assigned to several chromosomal loci, mostly encoding transport systems that are also present in susceptible E. coli isolates. Antimicrobial resistance in E. coli SMS-3-5 is therefore dependent both on determinants acquired from a mobile gene pool that is likely available to clinical and agricultural pathogens, as well, and on specifically adapted multidrug efflux systems. The association of antimicrobial resistance with APEC virulence genes on pSMS35

Antimicrobial activity of octenidine against multidrug-resistant Gram-negative pathogens.

PubMed

Alvarez-Marin, R; Aires-de-Sousa, M; Nordmann, P; Kieffer, N; Poirel, L

2017-12-01

Multidrug-resistant (MR) Gram-negative (GN) pathogens pose a major and growing threat for healthcare systems, as therapy of infections is often limited due to the lack of available systemic antibiotics. Well-tolerated antiseptics, such as octenidine dihydrochloride (OCT), may be a very useful tool in infection control to reduce the dissemination of MRGN. This study aimed to investigate the bactericidal activity of OCT against international epidemic clones of MRGN. A set of five different species (Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Acinetobacter baumannii, and Pseudomonas aeruginosa) was studied to prove OCT efficacy without organic load, under "clean conditions" (0.3 g/L albumin) and under "dirty conditions" (3 g/L albumin + 3 mL/L defibrinated sheep blood), according to an official test norm (EN13727). We used five clonally unrelated isolates per species, including a susceptible wild-type strain, and four MRGN isolates, corresponding to either the 3MRGN or 4MRGN definition of multidrug resistance. A contact time of 1 min was fully effective for all isolates by using different OCT concentrations (0.01% and 0.05%), with a bacterial reduction factor of >5 log 10 systematically observed. Growth kinetics were determined with two different wild-type strains (A. baumannii and K. pneumoniae), proving a time-dependent efficacy of OCT. These results highlight that OCT may be extremely useful to eradicate emerging highly resistant Gram-negative pathogens associated with nosocomial infections.

Therapeutic options and emerging alternatives for multidrug resistant staphylococcal infections.

PubMed

Magana, Maria; Ioannidis, Anastasios; Magiorkinis, Emmanouil; Ursu, Oleg; Bologa, Cristian G; Chatzipanagiotou, Stylianos; Hamblin, Michael R; Tegos, George P

2015-01-01

Methicillin-resistant Staphylococcus aureus (MRSA) remains the single biggest challenge in infectious disease in the civilized world. Moreover, vancomycin resistance is also spreading, leading to fears of untreatable infections as were common in ancient times. Molecular microbiology and bioinformatics have revealed many of the mechanisms involved in resistance development. Mobile genetic elements, up-regulated virulence factors and multi-drug efflux pumps have been implicated. A range of approved antibiotics from the glycopeptide, lipopeptide, pleuromutilin, macrolide, oxazolidinone, lincosamide, aminoglycoside, tetracycline, steptogramin, and cephalosporin classes has been employed to treat MRSA infections. The upcoming pipeline of drugs for MRSA includes some new compounds from the above classes, together with fluoroquinolones, antibacterial peptide mimetics, aminomethylciclines, porphyrins, peptide deformylase inhibitors, oxadiazoles, and diaminopyrimidines. A range of non-drug alternative approaches has emerged for MRSA treatment. Bacteriophage-therapy including purified lysins has made a comeback after being discovered in the 1930s. Quorum-sensing inhibitors are under investigation. Small molecule inhibitors of multi-drug efflux pumps may potentiate existing antibiotics. The relative failure of staphylococcal vaccines is being revisited by efforts with multi-valent vaccines and improved adjuvants. Photodynamic therapy uses non-toxic photosensitizers and harmless visible light to produce reactive oxygen species that can nonspecifically destroy bacteria while preserving host cells. Preparation of nanoparticles can kill bacteria themselves, as well as improve the delivery of anti-bacterial drugs. Anti-MRSA drug discovery remains an exciting field with great promise for the future.

Pathogenic and multidrug-resistant Escherichia fergusonii from broiler chicken.

PubMed

Forgetta, V; Rempel, H; Malouin, F; Vaillancourt, R; Topp, E; Dewar, K; Diarra, M S

2012-02-01

An Escherichia spp. isolate, ECD-227, was previously identified from the broiler chicken as a phylogenetically divergent and multidrug-resistant Escherichia coli possessing numerous virulence genes. In this study, whole genome sequencing and comparative genome analysis was used to further characterize this isolate. The presence of known and putative antibiotic resistance and virulence open reading frames were determined by comparison to pathogenic (E. coli O157:H7 TW14359, APEC O1:K1:H7, and UPEC UTI89) and nonpathogenic species (E. coli K-12 MG1655 and Escherichia fergusonii ATCC 35469). The assembled genome size of 4.87 Mb was sequenced to 18-fold depth of coverage and predicted to contain 4,376 open reading frames. Phylogenetic analysis of 537 open reading frames present across 110 enteric bacterial species identifies ECD-227 to be E. fergusonii. The genome of ECD-227 contains 5 plasmids showing similarity to known E. coli and Salmonella enterica plasmids. The presence of virulence and antibiotic resistance genes were identified and localized to the chromosome and plasmids. The mutation in gyrA (S83L) involved in fluoroquinolone resistance was identified. The Salmonella-like plasmids harbor antibiotic resistance genes on a class I integron (aadA, qacEΔ-sul1, aac3-VI, and sulI) as well as numerous virulence genes (iucABCD, sitABCD, cib, traT). In addition to the genome analysis, the virulence of ECD-227 was evaluated in a 1-d-old chick model. In the virulence assay, ECD-227 was found to induce 18 to 30% mortality in 1-d-old chicks after 24 h and 48 h of infection, respectively. This study documents an avian multidrug-resistant and virulent E. fergusonii. The existence of several resistance genes to multiple classes of antibiotics indicates that infection caused by ECD-227 would be difficult to treat using antimicrobials currently available for poultry.

Bio-Kil, a nano-based disinfectant, reduces environmental bacterial burden and multidrug-resistant organisms in intensive care units.

PubMed

Lee, Wen-Sen; Hsieh, Tai-Chin; Shiau, Justine C; Ou, Tsong-Yih; Chen, Fu-Lun; Liu, Yu-Hsin; Yen, Muh-Yong; Hsueh, Po-Ren

2017-10-01

This prospective before-after study was intended to investigate the effect of Bio-Kil on reducing environmental bacterial burden and healthcare-associated infections (HAIs) in intensive care units (ICUs) at the Municipal Wan-Fang Hospital, Taipei, Taiwan in 2014. Four rooms in the medical and surgical ICUs were investigated and designated as study rooms (n = 2) or control rooms (n = 2). Routine disinfection was performed during the pre-intervention period in both room types. Bio-Kil was applied to the fomites and surroundings of the study rooms during the intervention period. Total bacterial burden and proportion of colonization of fomites and surroundings by multidrug-resistance organisms (MDROs) were determined before and after the intervention. The demographic characteristics, underlying conditions, and clinical outcomes of patients were analyzed. After application of Bio-Kil, the bacterial burden declined in both groups, although the reduction was greater in the study rooms as compared with the control rooms (p = 0.001). During the pre-intervention period, 16 patients were admitted to control rooms and 18 patients to study rooms. After the intervention, 22 patients were admitted to control rooms and 21 patients to study rooms. The number of cases of new-onset sepsis declined in the intervention group (from 33% to 23.8%), but increased in the control group (from 25% to 40.9%); however, there was no significant difference in incidence of new-onset sepsis between the study and control rooms after intervention. Application of Bio-Kil reduced the environmental bacterial burden and MDROs in ICUs. Further studies are needed to evaluate the efficacy of this nanotechnology-based disinfectant in reducing HAIs. Copyright © 2016. Published by Elsevier B.V.

Glycyrrhiza glabra HPLC fractions: identification of Aldehydo Isoophiopogonone and Liquirtigenin having activity against multidrug resistant bacteria.

PubMed

Rahman, Hazir; Khan, Ilyas; Hussain, Anwar; Shahat, Abdelaaty Abdelaziz; Tawab, Abdul; Qasim, Muhammad; Adnan, Muhammad; Al-Said, Mansour S; Ullah, Riaz; Khan, Shahid Niaz

2018-05-02

Medicinal plants have been founded as traditional herbal medicine worldwide. Most of the plant's therapeutic properties are due to the presence of secondary metabolites such as alkaloids, glycosides, tannins and volatile oil. The present investigation analyzed the High-Pressure Liquid Chromatography (HPLC) fractions of Glycyrrhiza glabra (Aqueous, Chloroform, Ethanol and Hexane) against multidrug resistant human bacterial pathogens (Escherichia coli, Acinetobacter baumannii, Staphylococcus aureus and Pseudomonas aeruginosa). All the fractions showed antibacterial activity, were subjected to LC MS/MS analysis for identification of bioactive compounds. Among total HPLC fractions of G. glabra (n = 20), three HPLC fractions showed potential activity against multidrug resistant (MDR) bacterial isolates. Fraction 1 (F1) of aqueous extracts, showed activity against A. baumannii (15 ± 0.5 mm). F4 from hexane extract of G. glabra showed activity against S. aureus (10 ± 0.2 mm). However, F2 from ethanol extract exhibited activity against S. aureus (10 ± 0.3 mm). These active fractions were further processed by LC MS/MS analysis for the identification of compounds. Ellagic acid was identified in the F1 of aqueous extract while 6-aldehydo-isoophiopogonone was present in F4 of hexane extract. Similarly, Liquirtigenin was identified in F2 of ethanol. Glycyrrhiza glabra extracts HPLC fractions showed anti-MDR activity. Three bioactive compounds were identified in the study. 6-aldehydo-isoophiopogonone and Liquirtigenin were for the first time reported in G. glabra. Further characterization of the identified compounds will be helpful for possible therapeutic uses against infectious diseases caused by multidrug resistant bacteria.

Bacterial Community Shift Drives Antibiotic Resistance Promotion during Drinking Water Chlorination.

PubMed

Jia, Shuyu; Shi, Peng; Hu, Qing; Li, Bing; Zhang, Tong; Zhang, Xu-Xiang

2015-10-20

For comprehensive insights into the effects of chlorination, a widely used disinfection technology, on bacterial community and antibiotic resistome in drinking water, this study applied high-throughput sequencing and metagenomic approaches to investigate the changing patterns of antibiotic resistance genes (ARGs) and bacterial community in a drinking water treatment and distribution system. At genus level, chlorination could effectively remove Methylophilus, Methylotenera, Limnobacter, and Polynucleobacter, while increase the relative abundance of Pseudomonas, Acidovorax, Sphingomonas, Pleomonas, and Undibacterium in the drinking water. A total of 151 ARGs within 15 types were detectable in the drinking water, and chlorination evidently increased their total relative abundance while reduced their diversity in the opportunistic bacteria (p < 0.05). Residual chlorine was identified as the key contributing factor driving the bacterial community shift and resistome alteration. As the dominant persistent ARGs in the treatment and distribution system, multidrug resistance genes (mainly encoding resistance-nodulation-cell division transportation system) and bacitracin resistance gene bacA were mainly carried by chlorine-resistant bacteria Pseudomonas and Acidovorax, which mainly contributed to the ARGs abundance increase. The strong correlation between bacterial community shift and antibiotic resistome alteration observed in this study may shed new light on the mechanism behind the chlorination effects on antibiotic resistance.

Multidrug resistance in pediatric urinary tract infections.

PubMed

Gaspari, Romolo J; Dickson, Eric; Karlowsky, James; Doern, Gary

2006-01-01

Urinary tract infections (UTIs) represent a common infection in the pediatric population. Escherichia coli is the most common uropathogen in children, and antimicrobial resistance in this species complicates the treatment of pediatric UTIs. Despite the impact of resistance on empiric antibiotic choice, there is little data on multidrug resistance in pediatric patients. In this paper, we describe characteristics of multidrug-resistant E. coli in pediatric patients using a large national database of uropathogens antimicrobial sensitivities. Antimicrobial susceptibility patterns to commonly prescribed antibiotics were performed on uropathogens isolated from children presenting to participating hospitals between 1999 and 2001. Data were analyzed separately for four pediatric age groups. Single and multidrug resistance to ampicillin, amoxicillin-clavulanate, cefazolin, ciprofloxacin, nitrofurantoin, and trimethoprim-sulfamethoxazole (TMP-SMX) were performed on all specimens. There were a total of 11,341 E. coli urine cultures from 343 infants (0-4 weeks), 1,801 toddlers (5 weeks-24 months), 6,742 preteens (2-12 years), and 2,455 teens (13-17 years). E. coli resistance to ampicillin peaked in toddlers (52.8%) but was high in preteens (52.1%), infants (50.4%), and teens (40.6%). Resistance to two or more antibiotics varied across age groups, with toddlers (27%) leading preteens (23.1%), infants (21%), and teens (15.9%). Resistance to three or more antibiotics was low in all age groups (range 3.1-5.2%). The most common co-resistance in all age groups was ampicillin/TMP-SMZ. In conclusion, less than half of all pediatric UTIs are susceptible to all commonly used antibiotics. In some age groups, there is a significant percentage of co-resistance between the two most commonly used antibiotics (ampicillin and TMP-SMZ).

Multidrug-resistant malaria and the impact of mass drug administration.

PubMed

Zuber, Janie Anne; Takala-Harrison, Shannon

2018-01-01

Based on the emergence and spread throughout the Greater Mekong Subregion (GMS) of multiple artemisinin-resistant lineages, the prevalence of multidrug resistance leading to high rates of artemisinin-based combination treatment failure in parts of the GMS, and the declining malaria burden in the region, the World Health Organization has recommended complete elimination of falciparum malaria from the GMS. Mass drug administration (MDA) is being piloted as one elimination intervention to be employed as part of this effort. However, concerns remain as to whether MDA might exacerbate the already prevalent problem of multidrug resistance in the region. In this review, we briefly discuss challenges of MDA, the use of MDA in the context of multidrug-resistant malaria, and the potential of different drug combinations and drug-based elimination strategies for mitigating the emergence and spread of resistance.

Prevalence of multidrug-resistant, coagulase-positive Staphylococcus aureus in nasal carriage, food, wastewater and paper currency in Jalandhar city (north-western), an Indian state of Punjab.

PubMed

Kumar, Harsh; Palaha, Rajdeep; Kaur, Navreet; Ratnakar, Wankhede Swapnil; Sodi, Aakanksha; Kaur, Manmeet; Katiyar, Richa; Sharma, Mamta; Kaur, Charanpreet; Kumar, Virendra

2015-01-01

Development of multidrug-resistant pattern in the bacterial community is a major threat to the society. Staphylococcus aureus is perhaps the pathogen of the greatest concern because of its inherent virulence, its ability to cause a diverse array of life-threatening situations and capacity to adapt to different environmental conditions. The aims of this study is to investigate the multidrug-resistant pattern of the coagulase-positive S. aureus isolated from nasal carriage, food, paper currency and wastewater samples. We had also studied the multiple antibiotic resistance index and in vitro production of β-lactamase. The study had found out 130 coagulase-positive S. aureus strains isolated from total of 595 samples such as anterior nares of preschool children (195), hospital nurses (100), drivers (76), food (86), wastewater (3) and paper currency (135) (Indian rupee). The biotypes pattern were as follows; A > D > B > C> UT. Multiple antibiotic resistance (MAR) value clearly defines the multidrug-resistant pattern of the S. aureus among different sources. Statistical analysis (one-way ANOVA) of results obtained indicated that the difference in the antibiotic resistance observed in the 130 bacterial isolates against the 23 different antibiotics used in this study was statically significant (p < 0.01).

Multidrug-resistant tuberculosis, Somalia, 2010-2011.

PubMed

Sindani, Ireneaus; Fitzpatrick, Christopher; Falzon, Dennis; Suleiman, Bashir; Arube, Peter; Adam, Ismail; Baghdadi, Samiha; Bassili, Amal; Zignol, Matteo

2013-03-01

In a nationwide survey in 2011, multidrug-resistant tuberculosis (MDR TB) was found in 5.2% and 40.8% of patients with new and previously treated TB, respectively. These levels of drug resistance are among the highest ever documented in Africa and the Middle East. This finding presents a serious challenge for TB control in Somalia.

Multidrug-Resistant Shigella Infections in Patients with Diarrhea, Cambodia, 2014-2015.

PubMed

Poramathikul, Kamonporn; Bodhidatta, Ladaporn; Chiek, Sivhour; Oransathid, Wilawan; Ruekit, Sirigade; Nobthai, Panida; Lurchachaiwong, Woradee; Serichantalergs, Oralak; Lon, Chanthap; Swierczewski, Brett

2016-09-01

We observed multidrug resistance in 10 (91%) of 11 Shigella isolates from a diarrheal surveillance study in Cambodia. One isolate was resistant to fluoroquinolones and cephalosporins and showed decreased susceptibility to azithromycin. We found mutations in gyrA, parC, β-lactamase, and mphA genes. Multidrug resistance increases concern about shigellosis treatment options.

Variability of cutaneous and nasal population levels between patients colonized and infected by multidrug-resistant bacteria in two Brazilian intensive care units.

PubMed

Damaceno, Quésia; Nicoli, Jacques R; Oliveira, Adriana

2015-01-01

To compare cutaneous and nasal population levels between patients colonized and infected by multidrug-resistant organisms in two intensive care units. A prospective cohort study was performed in adult intensive care units of two hospitals in Belo Horizonte, Brazil (April 2012 to February 2013). Clinical and demographic data were first collected by reviewing patients' charts. Then, samples collected with nasal, groin, and perineum swabs were cultivated in selective media for 48 h at 37°C. After isolation, determination of antimicrobial susceptibility and biochemical identification were performed. A total of 53 cases of colonization were observed by the following bacteria in decreasing frequencies: imipenem-resistant Acinetobacter baumannii (50.9%), vancomycin-resistant Enterococcus faecalis (43.4%), extended-spectrum beta-lactamase-producing Klebsiella pneumoniae (37.7%), imipenem-resistant Pseudomonas aeruginosa (32.1%), oxacillin-resistant Staphylococcus aureus (7.5%), and imipenem-resistant Klebsiella pneumoniae (5.7%). Among these colonization cases, 26 (49.0%) were followed by infection with bacteria phenotypically similar to those of the colonization. A relation between high population levels of colonization by most of the multidrug-resistant organisms at anatomical sites and a subsequent infection was observed. After colonization/infection, bacterial population levels decreased progressively and spontaneously until disappearance by day 45 in all the anatomical sites and for all the multidrug-resistant organisms. There was a correlation between high population levels of colonization by multidrug-resistant organisms at anatomical sites and a subsequent infection. Reduction in multidrug-resistant organism populations after colonization at anatomical sites could be a preventive measure to reduce evolution to infection as well as transmission of these bacteria between patients in intensive care unit.

PGLa-H tandem-repeat peptides active against multidrug resistant clinical bacterial isolates.

PubMed

Rončević, Tomislav; Gajski, Goran; Ilić, Nada; Goić-Barišić, Ivana; Tonkić, Marija; Zoranić, Larisa; Simunić, Juraj; Benincasa, Monica; Mijaković, Marijana; Tossi, Alessandro; Juretić, Davor

2017-02-01

Antimicrobial peptides (AMPs) are promising candidates for new antibiotic classes but often display an unacceptably high toxicity towards human cells. A naturally produced C-terminal fragment of PGLa, named PGLa-H, has been reported to have a very low haemolytic activity while maintaining a moderate antibacterial activity. A sequential tandem repeat of this fragment, diPGLa-H, was designed, as well as an analogue with a Val to Gly substitution at a key position. These peptides showed markedly improved in vitro bacteriostatic and bactericidal activity against both reference strains and multidrug resistant clinical isolates of Gram-negative and Gram-positive pathogens, with generally low toxicity for human cells as assessed by haemolysis, cell viability, and DNA damage assays. The glycine substitution analogue, kiadin, had a slightly better antibacterial activity and reduced haemolytic activity, which may correlate with an increased flexibility of its helical structure, as deduced using molecular dynamics simulations. These peptides may serve as useful lead compounds for developing anti-infective agents against resistant Gram-negative and Gram-positive species. Copyright © 2016 Elsevier B.V. All rights reserved.

Antimicrobial blue light therapy for multidrug-resistant Acinetobacter baumannii infection in a mouse burn model: implications for prophylaxis and treatment of combat-related wound infections.

PubMed

Zhang, Yunsong; Zhu, Yingbo; Gupta, Asheesh; Huang, Yingying; Murray, Clinton K; Vrahas, Mark S; Sherwood, Margaret E; Baer, David G; Hamblin, Michael R; Dai, Tianhong

2014-06-15

In this study, we investigated the utility of antimicrobial blue light therapy for multidrug-resistant Acinetobacter baumannii infection in a mouse burn model. A bioluminescent clinical isolate of multidrug-resistant A. baumannii was obtained. The susceptibility of A. baumannii to blue light (415 nm)-inactivation was compared in vitro to that of human keratinocytes. Repeated cycles of sublethal inactivation of bacterial by blue light were performed to investigate the potential resistance development of A. baumannii to blue light. A mouse model of third degree burn infected with A. baumannii was developed. A single exposure of blue light was initiated 30 minutes after bacterial inoculation to inactivate A. baumannii in mouse burns. It was found that the multidrug-resistant A. baumannii strain was significantly more susceptible than keratinocytes to blue light inactivation. Transmission electron microscopy revealed blue light-induced ultrastructural damage in A. baumannii cells. Fluorescence spectroscopy suggested that endogenous porphyrins exist in A. baumannii cells. Blue light at an exposure of 55.8 J/cm(2) significantly reduced the bacterial burden in mouse burns. No resistance development to blue light inactivation was observed in A. baumannii after 10 cycles of sublethal inactivation of bacteria. No significant DNA damage was detected in mouse skin by means of a skin TUNEL assay after a blue light exposure of 195 J/cm(2). © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Biofilm formation and multidrug-resistant Aeromonas spp. from wild animals.

PubMed

Dias, Carla; Borges, Anabela; Saavedra, Maria José; Simões, Manuel

2018-03-01

The 'One Health' concept recognises that the health of humans, animals and the environment are interconnected. Therefore, knowledge on the behaviour of micro-organisms from the most diverse environmental niches is important to prevent the emergence and dissemination of antimicrobial resistance. Wild animals are known to carry antimicrobial-resistant micro-organisms with potential public health impact. However, no data are available on the behaviour of sessile bacteria from wild animals, although antimicrobial resistance is amplified in biofilms. This study characterised the ciprofloxacin susceptibility and the adhesion and biofilm formation abilities of 14 distinct Aeromonas spp. (8 Aeromonas salmonicida, 3 Aeromonas eucrenophila, 2 Aeromonas bestiarum and 1 Aeromonas veronii) isolated from wild animals and already characterised as resistant to β-lactam antibiotics. The ciprofloxacin MIC was determined according to CLSI guidelines. A biofilm formation assay was performed by a modified microtitre plate method. Bacterial surface hydrophobicity was assessed by sessile drop contact angle measurement. All Aeromonas spp. strains were resistant to ciprofloxacin (MICs of 6-60μg/mL) and had hydrophilic surfaces (range 2-37mJ/m 2 ). These strains were able to adhere and form biofilms with distinct magnitudes. Biofilm exposure to 10×MIC of ciprofloxacin only caused low to moderate biofilm removal. This study shows that the strains tested are of potential public health concern and emphasises that wild animals are potential reservoirs of multidrug-resistant strains. In fact, Aeromonas spp. are consistently considered opportunistic pathogens. Moreover, bacterial ability to form biofilms increases antimicrobial resistance and the propensity to cause persistent infections. Copyright © 2017 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.

Increase in resistance to ceftriaxone and nonsusceptibility to ciprofloxacin and decrease in multidrug resistance among Salmonella strains, United States, 1996-2009.

PubMed

Medalla, Felicita; Hoekstra, Robert M; Whichard, Jean M; Barzilay, Ezra J; Chiller, Tom M; Joyce, Kevin; Rickert, Regan; Krueger, Amy; Stuart, Andrew; Griffin, Patricia M

2013-04-01

Salmonella is a major bacterial pathogen transmitted commonly through food. Increasing resistance to antimicrobial agents (e.g., ceftriaxone, ciprofloxacin) used to treat serious Salmonella infections threatens the utility of these agents. Infection with antimicrobial-resistant Salmonella has been associated with increased risk of severe infection, hospitalization, and death. We describe changes in antimicrobial resistance among nontyphoidal Salmonella in the United States from 1996 through 2009. The Centers for Disease Control and Prevention's National Antimicrobial Resistance Monitoring System conducts surveillance of resistance among Salmonella isolated from humans. From 1996 through 2009, public health laboratories submitted isolates for antimicrobial susceptibility testing. We used interpretive criteria from the Clinical and Laboratory Standards Institute and defined isolates with ciprofloxacin resistance or intermediate susceptibility as nonsusceptible to ciprofloxacin. Using logistic regression, we modeled annual data to assess changes in antimicrobial resistance. From 1996 through 2009, the percentage of nontyphoidal Salmonella isolates resistant to ceftriaxone increased from 0.2% to 3.4% (odds ratio [OR]=20, 95% confidence interval [CI] 6.3-64), and the percentage with nonsusceptibility to ciprofloxacin increased from 0.4% to 2.4% (OR=8.3, 95% CI 3.3-21). The percentage of isolates that were multidrug resistant (resistant to ≥3 antimicrobial classes) decreased from 17% to 9.6% (OR=0.6, 95% CI 0.5-0.7), which was driven mainly by a decline among serotype Typhimurium. However, multidrug resistance increased from 5.9% in 1996 to a peak of 31% in 2001 among serotype Newport and increased from 12% in 1996 to 26% in 2009 (OR=2.6, 95% CI 1.1-6.2) among serotype Heidelberg. We describe an increase in resistance to ceftriaxone and nonsusceptibility to ciprofloxacin and an overall decline in multidrug resistance. Trends varied by serotype. Because of evidence that

Green synthesised zinc oxide nanostructures through Periploca aphylla extract shows tremendous antibacterial potential against multidrug resistant pathogens.

PubMed

Abbas, Fazal; Maqbool, Qaisar; Nazar, Mudassar; Jabeen, Nyla; Hussain, Syed Zaheer; Anwaar, Sadaf; Mehmood, Nasir; Sheikh, Muhammad Saleem; Hussain, Talib; Iftikhar, Sidra

2017-12-01

To grapple with multidrug resistant bacterial infections, implementations of antibacterial nanomedicines have gained prime attention of the researchers across the globe. Nowadays, zinc oxide (ZnO) at nano-scale has emerged as a promising antibacterial therapeutic agent. Keeping this in view, ZnO nanostructures (ZnO-NS) have been synthesised through reduction by P. aphylla aqueous extract without the utilisation of any acid or base. Structural examinations via scanning electron microscopy (SEM) and X-ray diffraction have revealed pure phase morphology with highly homogenised average particle size of 18 nm. SEM findings were further supplemented by transmission electron microscopy examinations. The characteristic Zn-O peak has been observed around 363 nm using ultra-violet-visible spectroscopy. Fourier-transform infrared spectroscopy examination has also confirmed the formation of ZnO-NS through detection of Zn-O bond vibration frequencies. To check the superior antibacterial activity of ZnO-NS, the authors' team has performed disc diffusion assay and colony forming unit testing against multidrug resistant E. coli, S. marcescens and E. cloacae . Furthermore, protein kinase inhibition assay and cytotoxicity examinations have revealed that green fabricated ZnO-NS are non-hazardous, economical, environmental friendly and possess tremendous potential to treat lethal infections caused by multidrug resistant pathogens.

The emergence and outbreak of multidrug-resistant typhoid fever in China.

PubMed

Yan, Meiying; Li, Xinlan; Liao, Qiaohong; Li, Fang; Zhang, Jing; Kan, Biao

2016-06-22

Typhoid fever remains a severe public health problem in developing countries. The emergence of resistant typhoid, particularly multidrug-resistant typhoid infections, highlights the necessity of monitoring the resistance characteristics of this invasive pathogen. In this study, we report a typhoid fever outbreak caused by multidrug-resistant Salmonella enterica serovar Typhi strains with an ACSSxtT pattern. Resistance genes conferring these phenotypes were harbored by a large conjugative plasmid, which increases the threat of Salmonella Typhi and thus requires close surveillance for dissemination of strains containing such genes.

CD44-engineered mesoporous silica nanoparticles for overcoming multidrug resistance in breast cancer

NASA Astrophysics Data System (ADS)

Wang, Xin; Liu, Ying; Wang, Shouju; Shi, Donghong; Zhou, Xianguang; Wang, Chunyan; Wu, Jiang; Zeng, Zhiyong; Li, Yanjun; Sun, Jing; Wang, Jiandong; Zhang, Longjiang; Teng, Zhaogang; Lu, Guangming

2015-03-01

Multidrug resistance is a major impediment for the successful chemotherapy in breast cancer. CD44 is over-expressed in multidrug resistant human breast cancer cells. CD44 monoclonal antibody exhibits anticancer potential by inhibiting proliferation and regulating P-glycoprotein-mediated drug efflux activity in multidrug resistant cells. Thereby, CD44 monoclonal antibody in combination with chemotherapeutic drug might be result in enhancing chemosensitivity and overcoming multidrug resistance. The purpose of this study is to investigate the effects of the CD44 monoclonal antibody functionalized mesoporous silica nanoparticles containing doxorubicin on human breast resistant cancer MCF-7 cells. The data showed that CD44-modified mesoporous silica nanoparticles increased cytotoxicity and enhanced the downregulation of P-glycoprotein in comparison to CD44 antibody. Moreover, CD44-engineered mesoporous silica nanoparticles provided active target, which promoted more cellular uptake of DOX in the resistant cells and more retention of DOX in tumor tissues than unengineered counterpart. Animal studies of the resistant breast cancer xenografts demonstrated that CD44-engineered drug delivery system remarkably induced apoptosis and inhibited the tumor growth. Our results indicated that the CD44-engineered mesoporous silica nanoparticle-based drug delivery system offers an effective approach to overcome multidrug resistance in human breast cancer.

The emergence and outbreak of multidrug-resistant typhoid fever in China

PubMed Central

Yan, Meiying; Li, Xinlan; Liao, Qiaohong; Li, Fang; Zhang, Jing; Kan, Biao

2016-01-01

Typhoid fever remains a severe public health problem in developing countries. The emergence of resistant typhoid, particularly multidrug-resistant typhoid infections, highlights the necessity of monitoring the resistance characteristics of this invasive pathogen. In this study, we report a typhoid fever outbreak caused by multidrug-resistant Salmonella enterica serovar Typhi strains with an ACSSxtT pattern. Resistance genes conferring these phenotypes were harbored by a large conjugative plasmid, which increases the threat of Salmonella Typhi and thus requires close surveillance for dissemination of strains containing such genes. PMID:27329848

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.

Management of multidrug-resistant tuberculosis in human immunodeficiency virus patients

NASA Astrophysics Data System (ADS)

Jamil, K. F.

2018-03-01

Tuberculosis (TB) is a chronic infectious disease mainly caused by Mycobacterium tuberculosis(MTB). 10.4 million new TB cases will appear in 2015 worldwide. There were an estimated 1.4 million TB deaths in 2015, and an additional 0.4 million deaths resulting from TB disease among people living with human immunodeficiency virus (HIV). Multidrug- resistant and extensively drug-resistant tuberculosis (MDR and XDR-TB) are major public health concerns worldwide. 480.000 new cases of MDR-TB will appear in 2015 and an additional 100,000 people with rifampicin-resistant TB (RR-TB) who were also newly eligible for MDR-TB treatment. Their association with HIV infection has contributed to the slowing down of TB incidence decline over the last two decades, therefore representing one important barrier to reach TB elimination. Patients infected with MDR-TB require more expensive treatment regimens than drug-susceptible TB, with poor treatment.Patients with multidrug- resistant tuberculosis do not receive rifampin; drug interactions risk is markedly reduced. However, overlapping toxicities may limit options for co-treatment of HIV and multidrug- resistant tuberculosis.

MarA-Like Regulator of Multidrug Resistance in Yersinia pestis

PubMed Central

Udani, Rupa A.; Levy, Stuart B.

2006-01-01

MarA47Yp from Yersinia pestis, showing 47% identity to Escherichia coli MarA in its N terminus, caused resistance to antibiotics and to organic solvents when expressed in both E. coli and Y. pestis. Resistance was linked to increased expression of the AcrAB multidrug efflux pump. In four of five spontaneous multidrug-resistant mutants of Y. pestis independently selected by growth on tetracycline, the marA47Yp gene was overexpressed. The findings suggest that marA47Yp is a marA ortholog in Y. pestis. PMID:16940090

MarA-like regulator of multidrug resistance in Yersinia pestis.

PubMed

Udani, Rupa A; Levy, Stuart B

2006-09-01

MarA47(Yp) from Yersinia pestis, showing 47% identity to Escherichia coli MarA in its N terminus, caused resistance to antibiotics and to organic solvents when expressed in both E. coli and Y. pestis. Resistance was linked to increased expression of the AcrAB multidrug efflux pump. In four of five spontaneous multidrug-resistant mutants of Y. pestis independently selected by growth on tetracycline, the marA47(Yp) gene was overexpressed. The findings suggest that marA47(Yp) is a marA ortholog in Y. pestis.

Molecular characterization of multidrug-resistant Shigella spp. of food origin.

PubMed

Ahmed, Ashraf M; Shimamoto, Tadashi

2015-02-02

Shigella spp. are the causative agents of food-borne shigellosis, an acute enteric infection. The emergence of multidrug-resistant clinical isolates of Shigella presents an increasing challenge for clinicians in the treatment of shigellosis. Several studies worldwide have characterized the molecular basis of antibiotic resistance in clinical Shigella isolates of human origin, however, to date, no such characterization has been reported for Shigella spp. of food origin. In this study, we characterized the genetic basis of multidrug resistance in Shigella spp. isolated from 1600 food samples (800 meat products and 800 dairy products) collected from different street venders, butchers, retail markets, and slaughterhouses in Egypt. Twenty-four out of 27 Shigella isolates (88.9%) showed multidrug resistance phenotypes to at least three classes of antimicrobials. The multidrug-resistant Shigella spp. were as follows: Shigella flexneri (66.7%), Shigella sonnei (18.5%), and Shigella dysenteriae (3.7%). The highest resistance was to streptomycin (100.0%), then to kanamycin (95.8%), nalidixic acid (95.8%), tetracycline (95.8%), spectinomycin (93.6%), ampicillin (87.5%), and sulfamethoxazole/trimethoprim (87.5%). PCR and DNA sequencing were used to screen and characterize integrons and antibiotic resistance genes. Our results indicated that 11.1% and 74.1% of isolates were positive for class 1 and class 2 integrons, respectively. Beta-lactamase-encoding genes were identified in 77.8% of isolates, and plasmid-mediated quinolone resistance genes were identified in 44.4% of isolates. These data provide useful information to better understand the molecular basis of antimicrobial resistance in Shigella spp. To the best of our knowledge, this is the first report of the molecular characterization of antibiotic resistance in Shigella spp. isolated from food. Copyright © 2014 Elsevier B.V. All rights reserved.

Natural History of Multi-Drug Resistant Organisms in a New Military Medical Facility

DTIC Science & Technology

2013-12-01

environment plays in the transmission of multidrug- resistant Gram-negative bacteria and methicillin - resistant Staphylococcus aureus (MDRO) is increasingly...Pseudomonas aeruginosa, methicillin - resistant Staphylococcus aureus (MRSA); Klebsiella pneumoniea; and Clostridium difficile. Multidrug- resistance (MDR...target organism infection was Staphylococcus aureus (n=77), followed by E coli (56), Klebsiella pneumoniae (28), and Pseudomonas aeruginosa (11

Engineered Cationic Antimicrobial Peptides To Overcome Multidrug Resistance by ESKAPE Pathogens

PubMed Central

Deslouches, Berthony; Steckbeck, Jonathan D.; Craigo, Jodi K.; Doi, Yohei; Burns, Jane L.

2014-01-01

Multidrug resistance constitutes a threat to the medical achievements of the last 50 years. In this study, we demonstrated the abilities of two de novo engineered cationic antibiotic peptides (eCAPs), WLBU2 and WR12, to overcome resistance from 142 clinical isolates representing the most common multidrug-resistant (MDR) pathogens and to display a lower propensity to select for resistant bacteria in vitro compared to that with colistin and LL37. The results warrant an exploration of eCAPs for use in clinical settings. PMID:25421473

Multidrug-Resistant Tuberculosis, Somalia, 2010–2011

PubMed Central

Sindani, Ireneaus; Fitzpatrick, Christopher; Falzon, Dennis; Suleiman, Bashir; Arube, Peter; Adam, Ismail; Baghdadi, Samiha; Bassili, Amal

2013-01-01

In a nationwide survey in 2011, multidrug-resistant tuberculosis (MDR TB) was found in 5.2% and 40.8% of patients with new and previously treated TB, respectively. These levels of drug resistance are among the highest ever documented in Africa and the Middle East. This finding presents a serious challenge for TB control in Somalia. PMID:23621911

Synergistic effects of antimicrobial peptide DP7 combined with antibiotics against multidrug-resistant bacteria.

PubMed

Wu, Xiaozhe; Li, Zhan; Li, Xiaolu; Tian, Yaomei; Fan, Yingzi; Yu, Chaoheng; Zhou, Bailing; Liu, Yi; Xiang, Rong; Yang, Li

2017-01-01

Antibiotic-resistant bacteria present a great threat to public health. In this study, the synergistic effects of antimicrobial peptides (AMPs) and antibiotics on several multidrug-resistant bacterial strains were studied, and their synergistic effects on azithromycin (AZT)-resistance genes were analyzed to determine the relationships between antimicrobial resistance and these synergistic effects. A checkerboard method was used to evaluate the synergistic effects of AMPs (DP7 and CLS001) and several antibiotics (gentamicin, vancomycin [VAN], AZT, and amoxicillin) on clinical bacterial strains ( Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii , and Escherichia coli ). The AZT-resistance genes ( ermA, ermB, ermC, mefA , and msrA ) were identified in the resistant strains using quantitative polymerase chain reaction. For all the clinical isolates tested that were resistant to different antibiotics, DP7 had high antimicrobial activity (≤32 mg/L). When DP7 was combined with VAN or AZT, the effect was most frequently synergistic. When we studied the resistance genes of the AZT-resistant isolates, the synergistic effect of DP7-AZT occurred most frequently in highly resistant strains or strains carrying more than two AZT-resistance genes. A transmission electron microscopic analysis of the S. aureus strain synergistically affected by DP7-AZT showed no noteworthy morphological changes, suggesting that a molecular-level mechanism plays an important role in the synergistic action of DP7-AZT. AMP DP7 plus the antibiotic AZT or VAN is more effective, especially against highly antibiotic-resistant strains.

Carbon nanotubes as anti-bacterial agents.

PubMed

Mocan, Teodora; Matea, Cristian T; Pop, Teodora; Mosteanu, Ofelia; Buzoianu, Anca Dana; Suciu, Soimita; Puia, Cosmin; Zdrehus, Claudiu; Iancu, Cornel; Mocan, Lucian

2017-10-01

Multidrug-resistant bacterial infections that have evolved via natural selection have increased alarmingly at a global level. Thus, there is a strong need for the development of novel antibiotics for the treatment of these infections. Functionalized carbon nanotubes through their unique properties hold great promise in the fight against multidrug-resistant bacterial infections. This new family of nanovectors for therapeutic delivery proved to be innovative and efficient for the transport and cellular translocation of therapeutic molecules. The current review examines the latest progress in the antibacterial activity of carbon nanotubes and their composites.

Prevalence and behavior of multidrug-resistant shiga toxin-producing Escherichia coli, enteropathogenic E. coli and enterotoxigenic E. coli on coriander.

PubMed

Gómez-Aldapa, Carlos A; Segovia-Cruz, Jesús A; Cerna-Cortes, Jorge F; Rangel-Vargas, Esmeralda; Salas-Rangel, Laura P; Gutiérrez-Alcántara, Eduardo J; Castro-Rosas, Javier

2016-10-01

The prevalence and behavior of multidrug-resistant diarrheagenic Escherichia coli pathotypes on coriander was determined. One hundred coriander samples were collected from markets. Generic E. coli were determined using the most probable number procedure. Diarrheagenic E. coli pathotypes (DEPs) were identified using two multiplex polymerase chain reaction procedures. Susceptibility to sixteen antibiotics was tested for the isolated DEPs strains by standard test. The behavior of multidrug-resistant DEPs isolated from coriander was determined on coriander leaves and chopped coriander at 25°± 2 °C and 3°± 2 °C. Generic E. coli and DEPs were identified, respectively, in 43 and 7% of samples. Nine DEPs strains were isolated from positive coriander samples. The identified DEPs included Shiga toxin-producing E. coli (STEC, 4%) enterotoxigenic E. coli (ETEC, 2%) and enteropathogenic E. coli (EPEC, 1%). All isolated DEPs strains exhibited multi-resistance to antibiotics. On inoculated coriander leaves stored at 25°± 2 °C or 3°± 2 °C, no growth was observed for multidrug-resistant DEPs strains. However, multidrug-resistant DEPs strains grew in chopped coriander: after 24 h at 25° ± 2 °C, DEPs strains had grown to approximately 3 log CFU/g. However, at 3°± 2 °C the bacterial growth was inhibited. To the best of our knowledge, this is the first report of the presence and behavior of multidrug-resistant STEC, ETEC and EPEC on coriander and chopped coriander. Copyright © 2016 Elsevier Ltd. All rights reserved.

Engineered cationic antimicrobial peptides to overcome multidrug resistance by ESKAPE pathogens.

PubMed

Deslouches, Berthony; Steckbeck, Jonathan D; Craigo, Jodi K; Doi, Yohei; Burns, Jane L; Montelaro, Ronald C

2015-02-01

Multidrug resistance constitutes a threat to the medical achievements of the last 50 years. In this study, we demonstrated the abilities of two de novo engineered cationic antibiotic peptides (eCAPs), WLBU2 and WR12, to overcome resistance from 142 clinical isolates representing the most common multidrug-resistant (MDR) pathogens and to display a lower propensity to select for resistant bacteria in vitro compared to that with colistin and LL37. The results warrant an exploration of eCAPs for use in clinical settings. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Nuclear Multidrug-Resistance Related Protein 1 Contributes to Multidrug-Resistance of Mucoepidermoid Carcinoma Mainly via Regulating Multidrug-Resistance Protein 1: A Human Mucoepidermoid Carcinoma Cells Model and Spearman's Rank Correlation Analysis

PubMed Central

Liu, Yuan; Xu, Xiaofang; Guan, Sumin; Wu, Junzheng; Liu, Yanpu

2013-01-01

Background Multidrug resistance-related protein 1 (MRP1/ABCC1) and multidrug resistance protein 1 (MDR1/P-glycoprotein/ABCB1) are both membrane-bound drug transporters. In contrast to MDR1, MRP1 also transports glutathione (GSH) and drugs conjugated to GSH. Due to its extraordinary transport properties, MRP1/ABCC1 contributes to several physiological functions and pathophysiological incidents. We previously found that nuclear translocation of MRP1 contributes to multidrug-resistance (MDR) of mucoepidermoid carcinoma (MEC). The present study investigated how MRP1 contributes to MDR in the nuclei of MEC cells. Methods Western blot and RT-PCR was carried out to investigate the change of multidrug-resistance protein 1 (MDR1) in MC3/5FU cells after MRP1 was downregulated through RNA interference (RNAi). Immunohistochemistry (IHC) staining of 127 cases of MEC tissues was scored with the expression index (EI). The EI of MDR1 and MRP1 (or nuclear MRP1) was analyzed with Spearman's rank correlation analysis. Using multiple tumor tissue assays, the location of MRP1 in other tissues was checked by HIC. Luciferase reporter assays of MDR1 promoter was carried out to check the connection between MRP1 and MDR1 promoter. Results MRP1 downregulation led to a decreased MDR1 expression in MC3/5FU cells which was caused by decreased activity of MDR1 promoter. IHC study of 127 cases of MEC tissues demonstrated a strong positive correlation between nuclear MRP1 expression and MDR1 expression. Furthermore, IHC study of multiple tumor tissue array sections showed that although nuclear MRP1 widely existed in MEC tissues, it was not found in normal tissues or other tumor tissues. Conclusions Our findings indicate that nuclear MRP1 contributes to MDR mainly through regulating MDR1 expression in MEC. And the unique location of MRP1 made it an available target in identifying MEC from other tumors. PMID:24013781

An In Vitro Chicken Gut Model Demonstrates Transfer of a Multidrug Resistance Plasmid from Salmonella to Commensal Escherichia coli.

PubMed

Card, Roderick M; Cawthraw, Shaun A; Nunez-Garcia, Javier; Ellis, Richard J; Kay, Gemma; Pallen, Mark J; Woodward, Martin J; Anjum, Muna F

2017-07-18

The chicken gastrointestinal tract is richly populated by commensal bacteria that fulfill various beneficial roles for the host, including helping to resist colonization by pathogens. It can also facilitate the conjugative transfer of multidrug resistance (MDR) plasmids between commensal and pathogenic bacteria which is a significant public and animal health concern as it may affect our ability to treat bacterial infections. We used an in vitro chemostat system to approximate the chicken cecal microbiota, simulate colonization by an MDR Salmonella pathogen, and examine the dynamics of transfer of its MDR plasmid harboring several genes, including the extended-spectrum beta-lactamase bla CTX-M1 We also evaluated the impact of cefotaxime administration on plasmid transfer and microbial diversity. Bacterial community profiles obtained by culture-independent methods showed that Salmonella inoculation resulted in no significant changes to bacterial community alpha diversity and beta diversity, whereas administration of cefotaxime caused significant alterations to both measures of diversity, which largely recovered. MDR plasmid transfer from Salmonella to commensal Escherichia coli was demonstrated by PCR and whole-genome sequencing of isolates purified from agar plates containing cefotaxime. Transfer occurred to seven E. coli sequence types at high rates, even in the absence of cefotaxime, with resistant strains isolated within 3 days. Our chemostat system provides a good representation of bacterial interactions, including antibiotic resistance transfer in vivo It can be used as an ethical and relatively inexpensive approach to model dissemination of antibiotic resistance within the gut of any animal or human and refine interventions that mitigate its spread before employing in vivo studies. IMPORTANCE The spread of antimicrobial resistance presents a grave threat to public health and animal health and is affecting our ability to respond to bacterial infections

Multidrug resistant tuberculosis diagnosed by synovial fluid analysis.

PubMed

van Zeller, M; Monteiro, R; Ramalho, J; Almeida, I; Duarte, R

2012-01-01

Tuberculosis remains a major public health problem worldwide. HIV co-infection is contributing to an increased incidence of the disease, particularly that caused by multidrug resistant strains of Mycobacterium tuberculosis (MT). We describe an HIV-infected patient with pleural and lymph node tuberculosis diagnosed by pleural effusion characteristics and biopsy specimens, without MT identification, that further presented with knee-joint involvement. Arthrocentesis allowed MT isolation and drug susceptibility testing, resulting in a diagnosis of multidrug-resistant tuberculosis and an appropriate treatment regimen. MT identification and drug susceptibility tests are very important, especially for HIV co-infected patients. Copyright © 2011 Sociedade Portuguesa de Pneumologia. Published by Elsevier España. All rights reserved.

Multidrug-resistant organisms in neonatal sepsis in two tertiary neonatal ICUs, Egypt.

PubMed

Awad, Hesham A; Mohamed, Maha H; Badran, Nabil F; Mohsen, Manal; Abd-Elrhman, Al-Sayed A

2016-03-01

Neonatal sepsis remains a serious problem in any neonatal intensive care unit (NICU). Bacterial organisms have developed increased resistance to commonly used antibiotics. Because not enough data are available from Egypt, the aim of the present study was to determine the causative bacteria and the level of their resistance to commonly used antibiotics in tertiary NICUs in Cairo, Egypt. A 3.5-year retrospective study was carried out at NICUs of the Children's Hospital of Ain Shams University and that of El-Hussein Hospital, Al-Azhar University, Egypt. Records of neonates were reviewed. All neonates with culture-proven sepsis were included in the study. Almost one-third of the admitted neonates (33.4%) were diagnosed as having neonatal sepsis, 32.25% of them culture-proven. Early/late onset sepsis was found in 35.4 and 64.6%, respectively. Gram-negative/gram-positive bacteria was found in 68 to 25.6%. Fungal infection was detected in 9% of the isolates. Escherichia coli was the main pathogen isolated in both early-onset sepsis (41.2%) and late-onset sepsis (24.5%). Overall, 77% of the isolates were multidrug-resistant (60% of gram-positive bacteria and 83.4% of gram-negative bacteria). Nearly 80% (79%) of mortality was caused by multidrug-resistant organisms. Gram-positive and gram-negative bacteria showed high resistance against commonly used antibiotics such as ampicillin, amoxicillin, cefotaxime, ceftriaxone, and gentamicin. There is an alarming increase in antibiotic resistance to the commonly used antibiotics. Continuous surveillance for antibiotic susceptibility is needed to ensure proper empirical therapy. Improvement of infection control practices, avoidance of irrational use of antibiotics, and revision of the protocols are mandatory in the prevention of neonatal sepsis.

Forthcoming therapeutic perspectives for infections due to multidrug-resistant Gram-positive pathogens.

PubMed

Cornaglia, G; Rossolini, G M

2009-03-01

Multidrug resistance in Gram-positive pathogens emerged as a major therapeutic challenge over two decades ago. The worldwide spread of methicillin-resistant Staphylococcus aureus (MRSA), glycopeptide-resistant enterococci and other resistant Gram-positive pathogens had a major impact on antibiotic policies, and prompted the discovery and development of new antibiotics to combat difficult-to-treat infections caused by such pathogens. Several new antibiotics active against multidrug-resistant Gram-positive pathogens have recently been introduced into clinical practice, and the antibiotic pipeline contains additional anti-Gram-positive drugs at an advanced stage of development, including new glycopeptides (dalbavancin, oritavancin, and telavancin), new anti-MRSA beta-lactams (ceftobiprole), and new diaminopyrimidines (iclaprim). This article provides a brief overview of these upcoming agents, partially based on the material presented at the ESCMID Conference entitled 'Fighting infections due to multidrug-resistant Gram-positives' (Venice, Italy, 29-31 May 2008) and on the most recent literature.

Multidrug resistant Acinetobacter baumannii in veterinary medicine--emergence of an underestimated pathogen?

PubMed

Müller, Stefanie; Janssen, Traute; Wieler, Lothar H

2014-01-01

The proportion of multidrug resistant bacteria causing infections in animals has continuously been increasing. While the relevance of ESBL (extended spectrum beta-lactamase)-producing Enterobacteriaceae spp. and MRSA (methicillin resistant Staphylococcus aureus) is unquestionable, knowledge about multidrug resistant Acinetobacter baumannii in veterinary medicine is scarce. This is a worrisome situation, as A. baumannii are isolated from veterinary clinical specimens with rising frequency. The remarkable ability of A. baumannii to develop multidrug resistance and the high risk of transmission are known in human medicine for years. Despite this, data regarding A. baumannii isolates of animal origin are missing. Due to the changing role of companion animals with closer contact between animal and owner, veterinary intensive care medicine is steadily developing. It can be assumed that the number of "high risk" patients with an enhanced risk for hospital acquired infections will be rising simultaneously. Thus, development and spread of multidrug resistant pathogens is envisioned to rise. It is possible, that A. baumannii will evolve into a veterinary nosocomial pathogen similar to ESBL-producing Enterobacteriaceae and MRSA. The lack of attention paid to A. baumannii in veterinary medicine is even more worrying, as first reports indicate a transmission between humans and animals. Essential questions regarding the role of livestock, especially as a potential source of multidrug resistant isolates, remain unanswered. This review summarizes the current knowledge on A. baumannii in veterinary medicine for the first time. It underlines the utmost significance of further investigations of A. baumannii animal isolates, particularly concerning epidemiology and resistance mechanisms.

Multidrug-resistant organisms in military wounds from Iraq and Afghanistan.

PubMed

Calhoun, Jason H; Murray, Clinton K; Manring, M M

2008-06-01

Mortality from battlefield wounds has historically declined, thanks to better surgical management, faster transport of casualties, and improved antibiotics. Today, one of the major challenges facing U.S. military caregivers is the presence of multidrug-resistant organisms in orthopaedic extremity wounds. The most frequently identified resistant strains of bacteria are Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter calcoaceticus-baumannii complex. Overuse of broad-spectrum antibiotics may be an important factor in building resistant strains. Acinetobacter infections appear to hospital-acquired and not from an initial colonization of the injury. More research is required to give military physicians the tools they require to reduce the infection rate and defeat multidrug-resistant organisms.

Linezolid susceptibility in Helicobacter pylori, including strains with multidrug resistance.

PubMed

Boyanova, Lyudmila; Evstatiev, Ivailo; Gergova, Galina; Yaneva, Penka; Mitov, Ivan

2015-12-01

Only a few studies have evaluated Helicobacter pylori susceptibility to linezolid. The aim of the present study was to assess linezolid susceptibility in H. pylori, including strains with double/multidrug resistance. The susceptibility of 53 H. pylori strains was evaluated by Etest and a breakpoint susceptibility testing method. Helicobacter pylori resistance rates were as follows: amoxicillin, 1.9%; metronidazole, 37.7%; clarithromycin, 17.0%; tetracycline, 1.9%; levofloxacin, 24.5%; and linezolid (>4 mg/L), 39.6%. The linezolid MIC50 value was 31.2-fold higher than that of clarithromycin and 10.5-fold higher than that of levofloxacin; however, 4 of 11 strains with double/multidrug resistance were linezolid-susceptible. The MIC range of the oxazolidinone agent was larger (0.125-64 mg/L) compared with those in the previous two reports. The linezolid resistance rate was 2.2-fold higher in metronidazole-resistant strains and in strains resistant to at least one antibiotic compared with the remaining strains. Briefly, linezolid was less active against H. pylori compared with clarithromycin and levofloxacin, and linezolid resistance was linked to resistance to metronidazole as well as to resistance to at least one antibiotic. However, linezolid activity against some strains with double/multidrug resistance may render the agent appropriate to treat some associated H. pylori infections following in vitro susceptibility testing of the strains. Clinical trials are required to confirm this suggestion. Copyright © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Antibacterial and antibiotic resistance modifying activity of the extracts from Allanblackia gabonensis, Combretum molle and Gladiolus quartinianus against Gram-negative bacteria including multi-drug resistant phenotypes.

PubMed

Fankam, Aimé G; Kuiate, Jules R; Kuete, Victor

2015-06-30

Bacterial resistance to antibiotics is becoming a serious problem worldwide. The discovery of new and effective antimicrobials and/or resistance modulators is necessary to tackle the spread of resistance or to reverse the multi-drug resistance. We investigated the antibacterial and antibiotic-resistance modifying activities of the methanol extracts from Allanblackia gabonensis, Gladiolus quartinianus and Combretum molle against 29 Gram-negative bacteria including multi-drug resistant (MDR) phenotypes. The broth microdilution method was used to determine the minimal inhibitory concentrations (MIC) and minimal bactericidal concentrations (MBC) of the samples meanwhile the standard phytochemical methods were used for the preliminary phytochemical screening of the plant extracts. Phytochemical analysis showed the presence of alkaloids, flavonoids, phenols and tannins in all studied extracts. Other chemical classes of secondary metabolites were selectively presents. Extracts from A. gabonensis and C. molle displayed a broad spectrum of activity with MICs varying from 16 to 1024 μg/mL against about 72.41% of the tested bacteria. The extract from the fruits of A. gabonensis had the best activity, with MIC values below 100 μg/mL on 37.9% of tested bacteria. Percentages of antibiotic-modulating effects ranging from 67 to 100% were observed against tested MDR bacteria when combining the leaves extract from C. molle (at MIC/2 and MIC/4) with chloramphenicol, kanamycin, streptomycin and tetracycline. The overall results of the present study provide information for the possible use of the studied plant, especially Allanblackia gabonensis and Combretum molle in the control of Gram-negative bacterial infections including MDR species as antibacterials as well as resistance modulators.

Identification and characterization of multidrug-resistant Salmonella enterica serotype Albert isolates in the United States.

PubMed

Folster, Jason P; Campbell, Davina; Grass, Julian; Brown, Allison C; Bicknese, Amelia; Tolar, Beth; Joseph, Lavin A; Plumblee, Jodie R; Walker, Carrie; Fedorka-Cray, Paula J; Whichard, Jean M

2015-05-01

Salmonella enterica is one of the most common causes of bacterial foodborne illness in the United States. Although most Salmonella infections are self-limiting, antimicrobial treatment of invasive salmonellosis is critical. The primary antimicrobial treatment options include fluoroquinolones or extended-spectrum cephalosporins, and resistance to these antimicrobial drugs may complicate treatment. At present, S. enterica is composed of more than 2,600 unique serotypes, which vary greatly in geographic prevalence, ecological niche, and the ability to cause human disease, and it is important to understand and mitigate the source of human infection, particularly when antimicrobial resistance is found. In this study, we identified and characterized 19 S. enterica serotype Albert isolates collected from food animals, retail meat, and humans in the United States during 2005 to 2013. All five isolates from nonhuman sources were obtained from turkeys or ground turkey, and epidemiologic data suggest poultry consumption or live-poultry exposure as the probable source of infection. S. enterica serotype Albert also appears to be geographically localized to the midwestern United States. All 19 isolates displayed multidrug resistance, including decreased susceptibility to fluoroquinolones and resistance to extended-spectrum cephalosporins. Turkeys are a likely source of multidrug-resistant S. enterica serotype Albert, and circulation of resistance plasmids, as opposed to the expansion of a single resistant strain, is playing a role. More work is needed to understand why these resistance plasmids spread and how their presence and the serotype they reside in contribute to human disease. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Population Genetics Study of Isoniazid Resistance Mutations and Evolution of Multidrug-Resistant Mycobacterium tuberculosis†

PubMed Central

Hazbón, Manzour Hernando; Brimacombe, Michael; Bobadilla del Valle, Miriam; Cavatore, Magali; Guerrero, Marta Inírida; Varma-Basil, Mandira; Billman-Jacobe, Helen; Lavender, Caroline; Fyfe, Janet; García-García, Lourdes; León, Clara Inés; Bose, Mridula; Chaves, Fernando; Murray, Megan; Eisenach, Kathleen D.; Sifuentes-Osornio, José; Cave, M. Donald; Ponce de León, Alfredo; Alland, David

2006-01-01

The molecular basis for isoniazid resistance in Mycobacterium tuberculosis is complex. Putative isoniazid resistance mutations have been identified in katG, ahpC, inhA, kasA, and ndh. However, small sample sizes and related potential biases in sample selection have precluded the development of statistically valid and significant population genetic analyses of clinical isoniazid resistance. We present the first large-scale analysis of 240 alleles previously associated with isoniazid resistance in a diverse set of 608 isoniazid-susceptible and 403 isoniazid-resistant clinical M. tuberculosis isolates. We detected 12 mutant alleles in isoniazid-susceptible isolates, suggesting that these alleles are not involved in isoniazid resistance. However, mutations in katG, ahpC, and inhA were strongly associated with isoniazid resistance, while kasA mutations were associated with isoniazid susceptibility. Remarkably, the distribution of isoniazid resistance-associated mutations was different in isoniazid-monoresistant isolates from that in multidrug-resistant isolates, with significantly fewer isoniazid resistance mutations in the isoniazid-monoresistant group. Mutations in katG315 were significantly more common in the multidrug-resistant isolates. Conversely, mutations in the inhA promoter were significantly more common in isoniazid-monoresistant isolates. We tested for interactions among mutations and resistance to different drugs. Mutations in katG, ahpC, and inhA were associated with rifampin resistance, but only katG315 mutations were associated with ethambutol resistance. There was also a significant inverse association between katG315 mutations and mutations in ahpC or inhA and between mutations in kasA and mutations in ahpC. Our results suggest that isoniazid resistance and the evolution of multidrug-resistant strains are complex dynamic processes that may be influenced by interactions between genes and drug-resistant phenotypes. PMID:16870753

Imidazopyrazinones (IPYs): Non-Quinolone Bacterial Topoisomerase Inhibitors Showing Partial Cross-Resistance with Quinolones.

PubMed

Jeannot, Frédéric; Taillier, Thomas; Despeyroux, Pierre; Renard, Stéphane; Rey, Astrid; Mourez, Michaël; Poeverlein, Christoph; Khichane, Imène; Perrin, Marc-Antoine; Versluys, Stéphanie; Stavenger, Robert A; Huang, Jianzhong; Germe, Thomas; Maxwell, Anthony; Cao, Sha; Huseby, Douglas L; Hughes, Diarmaid; Bacqué, Eric

2018-04-26

In our quest for new antibiotics able to address the growing threat of multidrug resistant infections caused by Gram-negative bacteria, we have investigated an unprecedented series of non-quinolone bacterial topoisomerase inhibitors from the Sanofi patrimony, named IPYs for imidazopyrazinones, as part of the Innovative Medicines Initiative (IMI) European Gram Negative Antibacterial Engine (ENABLE) organization. Hybridization of these historical compounds with the quinazolinediones, a known series of topoisomerase inhibitors, led us to a novel series of tricyclic IPYs that demonstrated potential for broad spectrum activity, in vivo efficacy, and a good developability profile, although later profiling revealed a genotoxicity risk. Resistance studies revealed partial cross-resistance with fluoroquinolones (FQs) suggesting that IPYs bind to the same region of bacterial topoisomerases as FQs and interact with at least some of the keys residues involved in FQ binding.

Delamanid for multidrug-resistant pulmonary tuberculosis.

PubMed

Gler, Maria Tarcela; Skripconoka, Vija; Sanchez-Garavito, Epifanio; Xiao, Heping; Cabrera-Rivero, Jose L; Vargas-Vasquez, Dante E; Gao, Mengqiu; Awad, Mohamed; Park, Seung-Kyu; Shim, Tae Sun; Suh, Gee Young; Danilovits, Manfred; Ogata, Hideo; Kurve, Anu; Chang, Joon; Suzuki, Katsuhiro; Tupasi, Thelma; Koh, Won-Jung; Seaworth, Barbara; Geiter, Lawrence J; Wells, Charles D

2012-06-07

Delamanid (OPC-67683), a nitro-dihydro-imidazooxazole derivative, is a new antituberculosis medication that inhibits mycolic acid synthesis and has shown potent in vitro and in vivo activity against drug-resistant strains of Mycobacterium tuberculosis. In this randomized, placebo-controlled, multinational clinical trial, we assigned 481 patients (nearly all of whom were negative for the human immunodeficiency virus) with pulmonary multidrug-resistant tuberculosis to receive delamanid, at a dose of 100 mg twice daily (161 patients) or 200 mg twice daily (160 patients), or placebo (160 patients) for 2 months in combination with a background drug regimen developed according to World Health Organization guidelines. Sputum cultures were assessed weekly with the use of both liquid broth and solid medium; sputum-culture conversion was defined as a series of five or more consecutive cultures that were negative for growth of M. tuberculosis. The primary efficacy end point was the proportion of patients with sputum-culture conversion in liquid broth medium at 2 months. Among patients who received a background drug regimen plus 100 mg of delamanid twice daily, 45.4% had sputum-culture conversion in liquid broth at 2 months, as compared with 29.6% of patients who received a background drug regimen plus placebo (P=0.008). Likewise, as compared with the placebo group, the group that received the background drug regimen plus 200 mg of delamanid twice daily had a higher proportion of patients with sputum-culture conversion (41.9%, P=0.04). The findings were similar with assessment of sputum-culture conversion in solid medium. Most adverse events were mild to moderate in severity and were evenly distributed across groups. Although no clinical events due to QT prolongation on electrocardiography were observed, QT prolongation was reported significantly more frequently in the groups that received delamanid. Delamanid was associated with an increase in sputum-culture conversion at 2

High Prevalence of Multidrug-Resistant Bacteria in Libyan War Casualties Admitted to a Tertiary Care Hospital, Germany.

PubMed

Lohr, Benedikt; Pfeifer, Yvonne; Heudorf, Ursel; Rangger, Christoph; Norris, Douglas E; Hunfeld, Klaus-Peter

2018-06-01

The ongoing Libyan conflict constantly causes victims among the military and civilian population. Cross-border transfer of patients represents a high risk of introducing multidrug-resistant organisms (MDROs), for example, methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci, and carbapenem-resistant gram-negative organisms (CROs), into the country of destination. This study assessed the MDRO status in Libyan war casualties (n = 67) admitted to Northwest Medical Centre in Frankfurt/Main, Germany, from August 2016 till January 2017. Identified multidrug-resistant nonfermenters and Enterobacteriaceae were subjected to molecular detection of β-lactamases and further mechanisms of resistance. All isolates were typed by enzymatic macrorestriction and subsequent pulsed-field gel electrophoresis. MDROs were found in 40 (60%) patients, including 25 (37%) positive for at least one CRO and 11 (16%) patients with MRSA. A total of 37 isolates of Klebsiella pneumoniae, Acinetobacter baumannii, Escherichia coli, Enterobacter cloacae, and Serratia marcescens produced carbapenemases: NDM (n = 17), OXA-48 (n = 15), and OXA-23 (n = 9) in addition to other β-lactamases (with bla CTX-M-group-1 being most frequent) and plasmid-mediated quinolone resistance genes (qnrB, aac(6')Ib-cr). Bacterial strain typing revealed the presence of various clones. This high MDRO rate in Libyan war casualties demands awareness, appropriate screening, and containment measures for medical institutions involved in medical care to avoid patient-to-patient transmission.

Multidrug-resistant opportunistic pathogens challenging veterinary infection control.

PubMed

Walther, Birgit; Tedin, Karsten; Lübke-Becker, Antina

2017-02-01

Although the problems associated with healthcare-associated infections (HAI) and the emergence of zoonotic and multidrug-resistant pathogens in companion animal (dogs, cats and horses) medicine have been well-known for decades, current progress with respect to practical implementation of infection control programs in veterinary clinics has been limited. Clinical outbreak events reported for methicillin-resistant Staphylooccus aureus (MRSA) and Staphylococcus pseudintermedius (MRSP), extended spectrum beta-lactamase (ESBL)-producing Escherichia coli and multidrug-resistant (MDR) Salmonella Serovars indicate the necessity of infection control strategies for protecting animal patients at risk as well as veterinary personnel. The close bond between humans and their companion animals provides opportunities for exchange of microorganisms, including MDR pathogens. This particular aspect of the "One Health" idea requires more representative surveillance efforts and infection control strategies with respect to animal-species specific characters. Copyright © 2016 Elsevier B.V. All rights reserved.

In vitro and in vivo antimicrobial activities of gallium nitrate against multidrug-resistant Acinetobacter baumannii.

PubMed

Antunes, Luísa C S; Imperi, Francesco; Minandri, Fabrizia; Visca, Paolo

2012-11-01

Multidrug-resistant Acinetobacter baumannii poses a tremendous challenge to traditional antibiotic therapy. Due to the crucial role of iron in bacterial physiology and pathogenicity, we investigated iron metabolism as a possible target for anti-A. baumannii chemotherapy using gallium as an iron mimetic. Due to chemical similarity, gallium competes with iron for binding to several redox enzymes, thereby interfering with a number of essential biological reactions. We found that Ga(NO(3))(3), the active component of an FDA-approved drug (Ganite), inhibits the growth of a collection of 58 A. baumannii strains in both chemically defined medium and human serum, at concentrations ranging from 2 to 80 μM and from 4 to 64 μM, respectively. Ga(NO(3))(3) delayed the entry of A. baumannii into the exponential phase and drastically reduced bacterial growth rates. Ga(NO(3))(3) activity was strongly dependent on iron availability in the culture medium, though the mechanism of growth inhibition was independent of dysregulation of gene expression controlled by the ferric uptake regulator Fur. Ga(NO(3))(3) also protected Galleria mellonella larvae from lethal A. baumannii infection, with survival rates of ≥75%. At therapeutic concentrations for humans (28 μM plasma levels), Ga(NO(3))(3) inhibited the growth in human serum of 76% of the multidrug-resistant A. baumannii isolates tested by ≥90%, raising expectations on the therapeutic potential of gallium for the treatment of A. baumannii bloodstream infections. Ga(NO(3))(3) also showed strong synergism with colistin, suggesting that a colistin-gallium combination holds promise as a last-resort therapy for infections caused by pan-resistant A. baumannii.

In Vitro and In Vivo Antimicrobial Activities of Gallium Nitrate against Multidrug-Resistant Acinetobacter baumannii

PubMed Central

Antunes, Luísa C. S.; Imperi, Francesco; Minandri, Fabrizia

2012-01-01

Multidrug-resistant Acinetobacter baumannii poses a tremendous challenge to traditional antibiotic therapy. Due to the crucial role of iron in bacterial physiology and pathogenicity, we investigated iron metabolism as a possible target for anti-A. baumannii chemotherapy using gallium as an iron mimetic. Due to chemical similarity, gallium competes with iron for binding to several redox enzymes, thereby interfering with a number of essential biological reactions. We found that Ga(NO3)3, the active component of an FDA-approved drug (Ganite), inhibits the growth of a collection of 58 A. baumannii strains in both chemically defined medium and human serum, at concentrations ranging from 2 to 80 μM and from 4 to 64 μM, respectively. Ga(NO3)3 delayed the entry of A. baumannii into the exponential phase and drastically reduced bacterial growth rates. Ga(NO3)3 activity was strongly dependent on iron availability in the culture medium, though the mechanism of growth inhibition was independent of dysregulation of gene expression controlled by the ferric uptake regulator Fur. Ga(NO3)3 also protected Galleria mellonella larvae from lethal A. baumannii infection, with survival rates of ≥75%. At therapeutic concentrations for humans (28 μM plasma levels), Ga(NO3)3 inhibited the growth in human serum of 76% of the multidrug-resistant A. baumannii isolates tested by ≥90%, raising expectations on the therapeutic potential of gallium for the treatment of A. baumannii bloodstream infections. Ga(NO3)3 also showed strong synergism with colistin, suggesting that a colistin-gallium combination holds promise as a last-resort therapy for infections caused by pan-resistant A. baumannii. PMID:22964249

Mechanisms of Antibiotic Resistance

PubMed Central

Munita, Jose M.; Arias, Cesar A.

2015-01-01

Emergence of resistance among the most important bacterial pathogens is recognized as a major public health threat affecting humans worldwide. Multidrug-resistant organisms have emerged not only in the hospital environment but are now often identified in community settings, suggesting that reservoirs of antibiotic-resistant bacteria are present outside the hospital. The bacterial response to the antibiotic “attack” is the prime example of bacterial adaptation and the pinnacle of evolution. “Survival of the fittest” is a consequence of an immense genetic plasticity of bacterial pathogens that trigger specific responses that result in mutational adaptations, acquisition of genetic material or alteration of gene expression producing resistance to virtually all antibiotics currently available in clinical practice. Therefore, understanding the biochemical and genetic basis of resistance is of paramount importance to design strategies to curtail the emergence and spread of resistance and devise innovative therapeutic approaches against multidrug-resistant organisms. In this chapter, we will describe in detail the major mechanisms of antibiotic resistance encountered in clinical practice providing specific examples in relevant bacterial pathogens. PMID:27227291

Prevalence of current patterns and predictive trends of multidrug-resistant Salmonella Typhi in Sudan.

PubMed

Elshayeb, Ayman A; Ahmed, Abdelazim A; El Siddig, Marmar A; El Hussien, Adil A

2017-11-14

Enteric fever has persistence of great impact in Sudanese public health especially during rainy season when the causative agent Salmonella enterica serovar Typhi possesses pan endemic patterns in most regions of Sudan - Khartoum. The present study aims to assess the recent state of antibiotics susceptibility of Salmonella Typhi with special concern to multidrug resistance strains and predict the emergence of new resistant patterns and outbreaks. Salmonella Typhi strains were isolated and identified according to the guidelines of the International Standardization Organization and the World Health Organization. The antibiotics susceptibilities were tested using the recommendations of the Clinical Laboratories Standards Institute. Predictions of emerging resistant bacteria patterns and outbreaks in Sudan were done using logistic regression, forecasting linear equations and in silico simulations models. A total of 124 antibiotics resistant Salmonella Typhi strains categorized in 12 average groups were isolated, different patterns of resistance statistically calculated by (y = ax - b). Minimum bactericidal concentration's predication of resistance was given the exponential trend (y = n e x ) and the predictive coefficient R 2  > 0 < 1 are approximately alike. It was assumed that resistant bacteria occurred with a constant rate of antibiotic doses during the whole experimental period. Thus, the number of sensitive bacteria decreases at the same rate as resistant occur following term to the modified predictive model which solved computationally. This study assesses the prediction of multi-drug resistance among S. Typhi isolates by applying low cost materials and simple statistical methods suitable for the most frequently used antibiotics as typhoid empirical therapy. Therefore, bacterial surveillance systems should be implemented to present data on the aetiology and current antimicrobial drug resistance patterns of community-acquired agents causing outbreaks.

Biofilms and antibiotic susceptibility of multidrug-resistant bacteria from wild animals.

PubMed

Dias, Carla; Borges, Anabela; Oliveira, Diana; Martinez-Murcia, Antonio; Saavedra, Maria José; Simões, Manuel

2018-01-01

The "One Health" concept recognizes that human health and animal health are interdependent and bound to the health of the ecosystem in which they (co)exist. This interconnection favors the transmission of bacteria and other infectious agents as well as the flow of genetic elements containing antibiotic resistance genes. This problem is worsened when pathogenic bacteria have the ability to establish as biofilms. Therefore, it is important to understand the characteristics and behaviour of microorganisms in both planktonic and biofilms states from the most diverse environmental niches to mitigate the emergence and dissemination of resistance. The purpose of this work was to assess the antibiotic susceptibility of four bacteria ( Acinetobacter spp., Klebsiella pneumoniae , Pseudomonas fluorescens and Shewanella putrefaciens ) isolated from wild animals and their ability to form biofilms. The effect of two antibiotics, imipenem (IPM) and ciprofloxacin (CIP), on biofilm removal was also assessed. Screening of resistance genetic determinants was performed by PCR. Biofilm tests were performed by a modified microtiter plate method. Bacterial surface hydrophobicity was determined by sessile drop contact angles. The susceptibility profile classified the bacteria as multidrug-resistant. Three genes coding for β-lactamases were detected in K. pneumoniae (TEM, SHV, OXA-aer) and one in P. fluorescens (OXA-aer). K. pneumoniae was the microorganism that carried more β-lactamase genes and it was the most proficient biofilm producer, while P. fluorescens demonstrated the highest adhesion ability. Antibiotics at their MIC, 5 × MIC and 10 × MIC were ineffective in total biofilm removal. The highest biomass reductions were found with IPM (54% at 10 × MIC) against K. pneumoniae biofilms and with CIP (40% at 10 × MIC) against P. fluorescens biofilms. The results highlight wildlife as important host reservoirs and vectors for the spread of multidrug-resistant bacteria and genetic

Biofilms and antibiotic susceptibility of multidrug-resistant bacteria from wild animals

PubMed Central

Dias, Carla; Borges, Anabela; Oliveira, Diana; Martinez-Murcia, Antonio; Saavedra, Maria José

2018-01-01

Background The “One Health” concept recognizes that human health and animal health are interdependent and bound to the health of the ecosystem in which they (co)exist. This interconnection favors the transmission of bacteria and other infectious agents as well as the flow of genetic elements containing antibiotic resistance genes. This problem is worsened when pathogenic bacteria have the ability to establish as biofilms. Therefore, it is important to understand the characteristics and behaviour of microorganisms in both planktonic and biofilms states from the most diverse environmental niches to mitigate the emergence and dissemination of resistance. Methods The purpose of this work was to assess the antibiotic susceptibility of four bacteria (Acinetobacter spp., Klebsiella pneumoniae, Pseudomonas fluorescens and Shewanella putrefaciens) isolated from wild animals and their ability to form biofilms. The effect of two antibiotics, imipenem (IPM) and ciprofloxacin (CIP), on biofilm removal was also assessed. Screening of resistance genetic determinants was performed by PCR. Biofilm tests were performed by a modified microtiter plate method. Bacterial surface hydrophobicity was determined by sessile drop contact angles. Results The susceptibility profile classified the bacteria as multidrug-resistant. Three genes coding for β-lactamases were detected in K. pneumoniae (TEM, SHV, OXA-aer) and one in P. fluorescens (OXA-aer). K. pneumoniae was the microorganism that carried more β-lactamase genes and it was the most proficient biofilm producer, while P. fluorescens demonstrated the highest adhesion ability. Antibiotics at their MIC, 5 × MIC and 10 × MIC were ineffective in total biofilm removal. The highest biomass reductions were found with IPM (54% at 10 × MIC) against K. pneumoniae biofilms and with CIP (40% at 10 × MIC) against P. fluorescens biofilms. Discussion The results highlight wildlife as important host reservoirs and vectors for the spread of

Fighting infections due to multidrug-resistant Gram-positive pathogens.

PubMed

Cornaglia, G

2009-03-01

Growing bacterial resistance in Gram-positive pathogens means that what were once effective and inexpensive treatments for infections caused by these bacteria are now being seriously questioned, including penicillin and macrolides for use against pneumococcal infections and-in hospitals-oxacillin for use against staphylococcal infections. As a whole, multidrug-resistant (MDR) Gram-positive pathogens are rapidly becoming an urgent and sometimes unmanageable clinical problem. Nevertheless, and despite decades of research into the effects of antibiotics, the actual risk posed to human health by antibiotic resistance has been poorly defined; the lack of reliable data concerning the outcomes resulting from antimicrobial resistance stems, in part, from problems with study designs and the methods used in resistence determination. Surprisingly little is known, too, about the actual effectiveness of the many types of intervention aimed at controlling antibiotic resistance. New antibiotics active against MDR Gram-positive pathogens have been recently introduced into clinical practice, and the antibiotic pipeline contains additional compounds at an advanced stage of development, including new glycopeptides, new anti-methicillin-resistant Staphylococcus aureus (MRSA) beta-lactams, and new diaminopyrimidines. Many novel antimicrobial agents are likely to be niche products, endowed with narrow antibacterial spectra and/or targeted at specific clinical problems. Therefore, an important educational goal will be to change the current, long-lasting attitudes of both physicians and customers towards broad-spectrum and multipurpose compounds. Scientific societies, such as the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), must play a leading role in this process.

Histone deacetylase inhibitor (HDACI) PCI-24781 enhances chemotherapy induced apoptosis in multidrug resistant sarcoma cell lines

PubMed Central

Yang, Cao; Choy, Edwin; Hornicek, Francis J.; Wood, Kirkham B; Schwab, Joseph H; Liu, Xianzhe; Mankin, Henry; Duan, Zhenfeng

2013-01-01

The anti-tumor activity of histone deacetylase inhibitors (HDACI) on multi-drug resistant sarcoma cell lines has never been previously described. Four multidrug resistant sarcoma cell lines treated with HDACI PCI-24781 resulted in dose-dependent accumulation of acetylated histones, p21 and PARP cleavage products. Growth of these cell lines was inhibited by PCI-24781 at IC50 of 0.43 to 2.7. When we looked for synergy of PCI-24781 with chemotherapeutic agents, we found that PCI-24781 reverses drug resistance in all four multidrug resistant sarcoma cell lines and synergizes with chemotherapeutic agents to enhance caspase-3/7 activity. Expression of RAD51 (a marker for DNA double-strand break repair) was inhibited and the expression of GADD45α (a marker for growth arrest and DNA-damage) was induced by PCI-24781 in multidrug resistant sarcoma cell lines. In conclusion, HDACI PCI-24781 synergizes with chemotherapeutic drugs to induce apoptosis and reverses drug resistance in multidrug resistant sarcoma cell lines. PMID:21508354

Determination of multidrug resistance mechanisms in Clostridium perfringens type A isolates using RNA sequencing and 2D-electrophoresis.

PubMed

Ma, Yu-Hua; Ye, Gui-Sheng

2018-06-11

In this study, we screened differentially expressed genes in a multidrug-resistant isolate strain of Clostridium perfringens by RNA sequencing. We also separated and identified differentially expressed proteins (DEPs) in the isolate strain by two-dimensional electrophoresis (2-DE) and mass spectrometry (MS). The RNA sequencing results showed that, compared with the control strain, 1128 genes were differentially expressed in the isolate strain, and these included 227 up-regulated genes and 901 down-regulated genes. Bioinformatics analysis identified the following genes and gene categories that are potentially involved in multidrug resistance (MDR) in the isolate strain: drug transport, drug response, hydrolase activity, transmembrane transporter, transferase activity, amidase transmembrane transporter, efflux transmembrane transporter, bacterial chemotaxis, ABC transporter, and others. The results of the 2-DE showed that 70 proteins were differentially expressed in the isolate strain, 45 of which were up-regulated and 25 down-regulated. Twenty-seven DEPs were identified by MS and these included the following protein categories: ribosome, antimicrobial peptide resistance, and ABC transporter, all of which may be involved in MDR in the isolate strain of C. perfringens. The results provide reference data for further investigations on the drug resistant molecular mechanisms of C. perfringens.

[Antimicrobial therapy in severe infections with multidrug-resistant Gram-negative bacterias].

PubMed

Duszyńska, Wiesława

2010-01-01

Multidrug-resistant Gram-negative bacteria pose a serious and rapidly emerging threat to patients in healthcare settings, and are especially prevalent and problematic in intensive therapy units. Recently, the emergence of pandrug-resistance in Gram-negative bacteria poses additional concerns. This review examines the clinical impact and epidemiology of multidrug-resistant Gram-negative bacteria as a cause of increased morbidity and mortality among ITU patients. Beta-lactamases, cephalosporinases and carbapenemases play the most important role in resistance to antibiotics. Despite the tendency to increased resistance, carbapenems administered by continuous infusion remain the most effective drugs in severe sepsis. Drug concentration monitoring, albeit rarely used in practice, is necessary to ensure an effective therapeutic effect.

Ugly bugs in healthy guts! Carriage of multidrug-resistant and ESBL-producing commensal Enterobacteriaceae in the intestine of healthy Nepalese adults.

PubMed

Maharjan, Anjila; Bhetwal, Anjeela; Shakya, Shreena; Satyal, Deepa; Shah, Shashikala; Joshi, Govardhan; Khanal, Puspa Raj; Parajuli, Narayan Prasad

2018-01-01

Fecal carriage of multidrug-resistant and extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae is one of the important risk factors for infection with antibiotic-resistant bacteria. In this report, we examined the prevalence of multidrug-resistant and ESBL-producing common enterobacterial strains colonizing the intestinal tract of apparently healthy adults in Kathmandu, Nepal. During a 6-month period (February-July 2016), a total of 510 stool specimens were obtained from apparently healthy students of Manmohan Memorial Institute of Health Sciences, Kathmandu, Nepal. Stool specimens were cultured, and the most common enterobacterial isolates ( Escherichia coli and Klebsiella species) were subjected to antimicrobial susceptibility tests according to the standard microbiologic guidelines. Multidrug-resistant isolates were selected for ESBL confirmation by combined disk test and E-test methods. Molecular characterization of plasmid-borne ESBL genes was performed by using specific primers of cefotaximase Munich (CTX-M), sulfhydryl variant (SHV), and temoniera (TEM) by polymerase chain reaction. Among 510 bacterial strains, E. coli (432, 84.71%) was the predominant organism followed by Klebsiella oxytoca (48, 9.41%) and K. pneumoniae (30, 5.88%). ESBLs were isolated in 9.8% of the total isolates including K. oxytoca (29.17%), E. coli (7.87%), and K. pneumoniae (6.67%). Among ESBLs, bla -TEM was the predominant type (92%) followed by bla -CTX-M (60%) and bla -SHV (4%). Multidrug-resistant and ESBL-producing enterobacterial commensal strains among healthy individuals are of serious concern. Persistent carriage of ESBL organisms in healthy individuals suggests the possibility of sustained ESBL carriage among the diseased and hospitalized patients. We recommend similar types of epidemiologic surveys in larger communities and in hospital settings to ascertain the extent of ESBL resistance.

Bacterial Profile, Antibacterial Resistance Pattern, and Associated Factors from Women Attending Postnatal Health Service at University of Gondar Teaching Hospital, Northwest Ethiopia.

PubMed

Bitew Kifilie, Abebaw; Dagnew, Mulat; Tegenie, Birhanemeskel; Yeshitela, Biruk; Howe, Rawleigh; Abate, Ebba

2018-01-01

Surgical site infection is a vital cause of maternal mortality and morbidity, especially in resource-limited countries. The rise of antibiotic resistance bacterial infection poses a big threat to this vulnerable population. However, there is lack of studies around the study area. The purpose of this study was to identify bacterial profile, antibacterial resistance pattern, and associated factors among mothers attending postnatal care health service. Institutional based cross-sectional study was conducted on 107 study participants at University of Gondar Teaching Hospital from 1 January 2016 to 30 May 2016. Wound swab, aspirate, and biopsy were collected and performed for culture and drug resistance testing. Data were entered and analyzed by using SPSS version 20. Bivariate and multivariate logistic regression models were fitted to determine the associated factors for bacterial infection. Odds ratio (95% CI) was calculated to determine the strength of statistically significant associated factors. Bacterial growth was confirmed in 90 (84.1%) of 107 study participants suspected to have surgical site infection. The predominant bacterial isolates were S. aureus (41.6%), E. coli (19.8%), K. pneumoniae (13.9%), coagulase negative Staphylococcus (12.9%), and Enterobacter spp. (4%). The majority of isolates were resistant to ampicillin, amoxicillin, and tetracycline but susceptible to ceftriaxone and amikacin. Multidrug-resistant bacteria species were isolated. Using a procedure such as cesarean section and episiotomy for delivery and premature rapture of membrane had strong association with bacterial infection. The high prevalence of bacterial profile and isolation of multidrug-resistant bacteria pose a big threat to postnatal mothers and their children. Factors such as cesarean section, episiotomy for delivery, and premature rapture of membrane were predictors for bacterial infection. Therefore, there should be done a continuous surveillance as well as rational use of

Indolcarboxamide is a preclinical candidate for treating multidrug-resistant tuberculosis.

PubMed

Rao, Srinivasa P S; Lakshminarayana, Suresh B; Kondreddi, Ravinder R; Herve, Maxime; Camacho, Luis R; Bifani, Pablo; Kalapala, Sarath K; Jiricek, Jan; Ma, Ng L; Tan, Bee H; Ng, Seow H; Nanjundappa, Mahesh; Ravindran, Sindhu; Seah, Peck G; Thayalan, Pamela; Lim, Siao H; Lee, Boon H; Goh, Anne; Barnes, Whitney S; Chen, Zhong; Gagaring, Kerstin; Chatterjee, Arnab K; Pethe, Kevin; Kuhen, Kelli; Walker, John; Feng, Gu; Babu, Sreehari; Zhang, Lijun; Blasco, Francesca; Beer, David; Weaver, Margaret; Dartois, Veronique; Glynne, Richard; Dick, Thomas; Smith, Paul W; Diagana, Thierry T; Manjunatha, Ujjini H

2013-12-04

New chemotherapeutic compounds against multidrug-resistant Mycobacterium tuberculosis (Mtb) are urgently needed to combat drug resistance in tuberculosis (TB). We have identified and characterized the indolcarboxamides as a new class of antitubercular bactericidal agent. Genetic and lipid profiling studies identified the likely molecular target of indolcarboxamides as MmpL3, a transporter of trehalose monomycolate that is essential for mycobacterial cell wall biosynthesis. Two lead candidates, NITD-304 and NITD-349, showed potent activity against both drug-sensitive and multidrug-resistant clinical isolates of Mtb. Promising pharmacokinetic profiles of both compounds after oral dosing in several species enabled further evaluation for efficacy and safety. NITD-304 and NITD-349 were efficacious in treating both acute and chronic Mtb infections in mouse efficacy models. Furthermore, dosing of NITD-304 and NITD-349 for 2 weeks in exploratory rat toxicology studies revealed a promising safety margin. Finally, neither compound inhibited the activity of major cytochrome P-450 enzymes or the hERG (human ether-a-go-go related gene) channel. These results suggest that NITD-304 and NITD-349 should undergo further development as a potential treatment for multidrug-resistant TB.

Rational design of cancer-targeted selenium nanoparticles to antagonize multidrug resistance in cancer cells.

PubMed

Liu, Ting; Zeng, Lilan; Jiang, Wenting; Fu, Yuanting; Zheng, Wenjie; Chen, Tianfeng

2015-05-01

Multidrug resistance is one of the greatest challenges in cancer therapy. Herein we described the synthesis of folate (FA)-conjugated selenium nanoparticles (SeNPs) as cancer-targeted nano-drug delivery system for ruthenium polypyridyl (RuPOP) exhibits strong fluorescence, which allows the direct imaging of the cellular trafficking of the nanosystem. This nanosystem could effectively antagonize against multidrug resistance in liver cancer. FA surface conjugation significantly enhanced the cellular uptake of SeNPs by FA receptor-mediated endocytosis through nystain-dependent lipid raft-mediated and clathrin-mediated pathways. The nanomaterials overcame the multidrug resistance in R-HepG2 cells through inhibition of ABC family proteins expression. Internalized nanoparticles triggered ROS overproduction and induced apoptosis by activating p53 and MAPKs pathways. Moreover, FA-SeNPs exhibited low in vivo acute toxicity, which verified the safety and application potential of FA-SeNPs as nanodrugs. This study provides an effective strategy for the design of cancer-targeted nanodrugs against multidrug resistant cancers. In the combat against hepatocellular carcinoma, multidrug resistance remains one of the obstacles to be overcome. The authors designed and synthesized folate (FA)-conjugated selenium nanoparticles (SeNPs) with enhanced cancer-targeting capability. This system carried ruthenium polypyridyl (RuPOP), an efficient metal-based anti-cancer drug with strong fluorescence. It was shown that this combination was effective in antagonizing against multidrug resistance in vitro. Copyright © 2015 Elsevier Inc. All rights reserved.

Effect of curcumin on human colon cancer multidrug resistance in vitro and in vivo.

PubMed

Lu, Wei-Dong; Qin, Yong; Yang, Chuang; Li, Lei; Fu, Zhong-Xue

2013-05-01

To determine whether curcumin reverses the multidrug resistance of human colon cancer cells in vitro and in vivo. In a vincristine-resistant cell line of human colon cancer, the cell viability of curcumin-treated cells was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Rhodamine123 efflux was evaluated to detect P-glycoprotein transporter activity, and expression of the multidrug resistance protein 1 and survivin genes was analyzed by reverse transcription polymerase chain reaction and western blotting. In addition, xenograft mouse tumors were grown and treated with curcumin. The morphology of the xenografts was investigated by hematoxylin-eosin staining. The in vivo expression of the multidrug resistance gene and P-glycoprotein and survivin genes and proteins was observed using reverse transcription-polymerase chain reaction and western blotting, respectively. Curcumin was not obviously toxic to the vincristine-resistant human colon cancer cells at concentrations less than 25 μM, but the growth of cells was significantly inhibited. At concentrations greater than 25 μM, curcumin was toxic in a concentration-dependent manner. The sensitivity of cells to vincristine, cisplatin, fluorouracil, and hydroxycamptothecin was enhanced, intracellular Rhodamine123 accumulation was increased (p<0.05), and the expression of the multidrug resistance gene and P-glycoprotein were significantly suppressed (p<0.05). The combination of curcumin and vincristine significantly inhibited xenograft growth. The expression of the multidrug resistance protein 1 and survivin genes was significantly reduced in xenografts of curcumin-treated mice and mice treated with both curcumin and vincristine relative to control mice. Curcumin has strong reversal effects on the multidrug resistance of human colon carcinoma in vitro and in vivo.

The secondary resistome of multidrug-resistant Klebsiella pneumoniae.

PubMed

Jana, Bimal; Cain, Amy K; Doerrler, William T; Boinett, Christine J; Fookes, Maria C; Parkhill, Julian; Guardabassi, Luca

2017-02-15

Klebsiella pneumoniae causes severe lung and bloodstream infections that are difficult to treat due to multidrug resistance. We hypothesized that antimicrobial resistance can be reversed by targeting chromosomal non-essential genes that are not responsible for acquired resistance but essential for resistant bacteria under therapeutic concentrations of antimicrobials. Conditional essentiality of individual genes to antimicrobial resistance was evaluated in an epidemic multidrug-resistant clone of K. pneumoniae (ST258). We constructed a high-density transposon mutant library of >430,000 unique Tn5 insertions and measured mutant depletion upon exposure to three clinically relevant antimicrobials (colistin, imipenem or ciprofloxacin) by Transposon Directed Insertion-site Sequencing (TraDIS). Using this high-throughput approach, we defined three sets of chromosomal non-essential genes essential for growth during exposure to colistin (n = 35), imipenem (n = 1) or ciprofloxacin (n = 1) in addition to known resistance determinants, collectively termed the "secondary resistome". As proof of principle, we demonstrated that inactivation of a non-essential gene not previously found linked to colistin resistance (dedA) restored colistin susceptibility by reducing the minimum inhibitory concentration from 8 to 0.5 μg/ml, 4-fold below the susceptibility breakpoint (S ≤ 2 μg/ml). This finding suggests that the secondary resistome is a potential target for developing antimicrobial "helper" drugs that restore the efficacy of existing antimicrobials.

Phytochemical Screening and Antimicrobial Activity of Some Medicinal Plants Against Multi-drug Resistant Bacteria from Clinical Isolates

PubMed Central

Dahiya, Praveen; Purkayastha, Sharmishtha

2012-01-01

The in vitro antibacterial activity of various solvents and water extracts of aloe vera, neem, bryophyllum, lemongrass, tulsi, oregano, rosemary and thyme was assessed on 10 multi-drug resistant clinical isolates from both Gram-positive and Gram-negative bacteria and two standard strains including Staphylococcus aureus ATCC 25923 and Escherichia coli ATCC 25922. The zone of inhibition as determined by agar well diffusion method varied with the plant extract, the solvent used for extraction, and the organism tested. Klebsiella pneumoniae 2, Escherichia coli 3 and Staphylococcus aureus 3 were resistant to the plant extracts tested. Moreover, water extracts did not restrain the growth of any tested bacteria. Ethanol and methanol extracts were found to be more potent being capable of exerting significant inhibitory activities against majority of the bacteria investigated. Staphylococcus aureus 1 was the most inhibited bacterial isolate with 24 extracts (60%) inhibiting its growth whereas Escherichia coli 2 exhibited strong resistance being inhibited by only 11 extracts (28%). The results obtained in the agar diffusion plates were in fair correlation with that obtained in the minimum inhibitory concentration tests. The minimum inhibitory concentration of tulsi, oregano, rosemary and aloe vera extracts was found in the range of 1.56-6.25 mg/ml for the multi-drug resistant Staphylococcus aureus isolates tested whereas higher values (6.25-25 mg/ml) were obtained against the multi-drug resistant isolates Klebsiella pneumoniae 1 and Escherichia coli 1 and 2. Qualitative phytochemical analysis demonstrated the presence of tannins and saponins in all plants tested. Thin layer chromatography and bioautography agar overlay assay of ethanol extracts of neem, tulsi and aloe vera indicated flavonoids and tannins as major active compounds against methicillin-resistant Staphylococcus aureus. PMID:23716873

Multidrug-resistant Salmonella Typhimurium in Four Animal Facilities

PubMed Central

Wright, Jennifer G.; Tengelsen, Leslie A.; Smith, Kirk E.; Bender, Jeff B.; Frank, Rodney K.; Grendon, John H.; Rice, Daniel H.; Thiessen, Ann Marie B.; Gilbertson, Catherine Jo; Sivapalasingam, Sumathi; Barrett, Timothy J.; Besser, Thomas E.; Hancock, Dale D.

2005-01-01

In 1999 and 2000, 3 state health departments reported 4 outbreaks of gastrointestinal illness due to Salmonella enterica serotype Typhimurium in employees, clients, and client animals from 3 companion animal veterinary clinics and 1 animal shelter. More than 45 persons and companion animals became ill. Four independent investigations resulted in the testing of 19 human samples and >200 animal samples; 18 persons and 36 animals were culture-positive for S. Typhimurium. One outbreak was due to multidrug-resistant S. Typhimurium R-type ACKSSuT, while the other 3 were due to multidrug-resistant S. Typhimurium R-type ACSSuT DT104. This report documents nosocomial transmission of S. Typhimurium and demonstrates that companion animal facilities may serve as foci of transmission for salmonellae between animals and humans if adequate precautions are not followed. PMID:16102313

Block Copolymer Nanoparticles Remove Biofilms of Drug-Resistant Gram-Positive Bacteria by Nanoscale Bacterial Debridement.

PubMed

Li, Jianghua; Zhang, Kaixi; Ruan, Lin; Chin, Seow Fong; Wickramasinghe, Nirmani; Liu, Hanbin; Ravikumar, Vikashini; Ren, Jinghua; Duan, Hongwei; Yang, Liang; Chan-Park, Mary B

2018-06-26

Biofilms and the rapid evolution of multidrug resistance complicate the treatment of bacterial infections. Antibiofilm agents such as metallic-inorganic nanoparticles or peptides act by exerting antibacterial effects and, hence, do not combat biofilms of antibiotics-resistant strains. In this Letter, we show that the block copolymer DA95B5, dextran- block-poly((3-acrylamidopropyl) trimethylammonium chloride (AMPTMA)- co-butyl methacrylate (BMA)), effectively removes preformed biofilms of various clinically relevant multidrug-resistant Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE V583), and Enteroccocus faecalis (OG1RF). DA95B5 self-assembles into core-shell nanoparticles with a nonfouling dextran shell and a cationic core. These nanoparticles diffuse into biofilms and attach to bacteria but do not kill them; instead, they promote the gradual dispersal of biofilm bacteria, probably because the solubility of the bacteria-nanoparticle complex is enhanced by the nanoparticle dextran shell. DA95B5, when applied as a solution to a hydrogel pad dressing, shows excellent in vivo MRSA biofilm removal efficacy of 3.6 log reduction in a murine excisional wound model, which is significantly superior to that for vancomycin. Furthermore, DA95B5 has very low in vitro hemolysis and negligible in vivo acute toxicity. This new strategy for biofilm removal (nanoscale bacterial debridement) is orthogonal to conventional rapidly developing resistance traits in bacteria so that it is as effective toward resistant strains as it is toward sensitive strains and may have widespread applications.

In vitro characterization of multivalent adhesion molecule 7-based inhibition of multidrug-resistant bacteria isolated from wounded military personnel.

PubMed

Krachler, Anne Marie; Mende, Katrin; Murray, Clinton; Orth, Kim

2012-07-01

Treatment of wounded military personnel at military medical centers is often complicated by colonization and infection of wounds with pathogenic bacteria. These include nosocomially transmitted, often multidrug-resistant pathogens such as Acinetobacter baumannii-calcoaceticus complex, Pseudomonas aeruginosa and extended spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae. We analyzed the efficacy of multivalent adhesion molecule (MAM) 7-based anti-adhesion treatment of host cells against aforementioned pathogens in a tissue culture infection model. Herein, we observed that a correlation between two important hallmarks of virulence, attachment and cytotoxicity, could serve as a useful predictor for the success of MAM7-based inhibition against bacterial infections. Initially, we characterized 20 patient isolates (five from each pathogen mentioned above) in terms of genotypic diversity, antimicrobial susceptibility and important hallmarks of pathogenicity (biofilm formation, attachment to and cytotoxicity toward cultured host cells). All isolates displayed a high degree of genotypic diversity, which was also reflected by large strain-to-strain variability in terms of biofilm formation, attachment and cytotoxicity within each group of pathogen. Using non-pathogenic bacteria expressing MAM7 or latex beads coated with recombinant MAM7 for anti-adhesion treatment, we showed a decrease in cytotoxicity, indicating that MAM7 has potential as a prophylactic agent to attenuate infection by multidrug-resistant bacterial pathogens.

Finding Novel Antibiotic Substances from Medicinal Plants - Antimicrobial Properties of Nigella Sativa Directed against Multidrug-resistant Bacteria.

PubMed

Bakal, Seher Nancy; Bereswill, Stefan; Heimesaat, Markus M

2017-03-01

The progressive rise in multidrug-resistant (MDR) bacterial strains poses serious problems in the treatment of infectious diseases. While the number of newly developed antimicrobial compounds has greatly fallen, the resistance of pathogens against commonly prescribed drugs is further increasing. This rise in resistance illustrates the need for developing novel therapeutic and preventive antimicrobial options. The medicinal herb Nigella sativa and its derivatives constitute promising candidates. In a comprehensive literature survey (using the PubMed data base), we searched for publications on the antimicrobial effects of N. sativa particularly directed against MDR bacterial strains. In vitro studies published between 2000 and 2015 revealed that N. sativa exerted potent antibacterial effects against both Gram-positive and Gram-negative species including resistant strains. For instance, N. sativa inhibited the growth of bacteria causing significant gastrointestinal morbidity such as Salmonella, Helicobacter pylori , and Escherichia coli . However, Listeria monocytogenes and Pseudomonas aeruginosa displayed resistance against black cumin seed extracts. In conclusion, our literature survey revealed potent antimicrobial properties of N. sativa against MDR strains in vitro that should be further investigated in order to develop novel therapeutic perspectives for combating infectious diseases particularly caused by MDR strains.

Multidrug and heavy metal-resistant Raoultella planticola isolated from surface water.

PubMed

Koc, Serkan; Kabatas, Burak; Icgen, Bulent

2013-08-01

A surface water isolate of Raoultella sp. having both multidrug- and multimetal-resistant ability was isolated and identified as Raoultella planticola. R. planticola displayed resistance to 15 drugs like ampicillin, amoxicillin/clavulanic acid, aztreonam, erythromycin, imipenem, oxacillin, pefloxacin, penicillin, piperacillin, piperacillin/tazobactam, rifampin, sulbactam/cefoperazone, ticarsillin, ticarsillin/clavulanic acid, vancomycin, and to 11 heavy metals like aluminum, barium, copper, iron, lead, lithium, manganese, nickel, silver, strontium, and tin. The multidrug and multi-metal-resistant R. planticola may remain present in the environment for a long time. Due to a possible health risk of these pathogenic bacteria, a need exists for an accurate assessment of their acquired resistance to multiple drugs and metals.

Comparison of gene expression profiles between pansensitive and multidrug-resistant strains of Mycobacterium tuberculosis.

PubMed

Peñuelas-Urquides, K; González-Escalante, L; Villarreal-Treviño, L; Silva-Ramírez, B; Gutiérrez-Fuentes, D J; Mojica-Espinosa, R; Rangel-Escareño, C; Uribe-Figueroa, L; Molina-Salinas, G M; Dávila-Velderrain, J; Castorena-Torres, F; Bermúdez de León, M; Said-Fernández, S

2013-09-01

Mycobacterium tuberculosis has developed resistance to anti-tuberculosis first-line drugs. Multidrug-resistant strains complicate the control of tuberculosis and have converted it into a worldwide public health problem. Mutational studies of target genes have tried to envisage the resistance in clinical isolates; however, detection of these mutations in some cases is not sufficient to identify drug resistance, suggesting that other mechanisms are involved. Therefore, the identification of new markers of susceptibility or resistance to first-line drugs could contribute (1) to specifically diagnose the type of M. tuberculosis strain and prescribe an appropriate therapy, and (2) to elucidate the mechanisms of resistance in multidrug-resistant strains. In order to identify specific genes related to resistance in M. tuberculosis, we compared the gene expression profiles between the pansensitive H37Rv strain and a clinical CIBIN:UMF:15:99 multidrug-resistant isolate using microarray analysis. Quantitative real-time PCR confirmed that in the clinical multidrug-resistant isolate, the esxG, esxH, rpsA, esxI, and rpmI genes were upregulated, while the lipF, groES, and narG genes were downregulated. The modified genes could be involved in the mechanisms of resistance to first-line drugs in M. tuberculosis and could contribute to increased efficiency in molecular diagnosis approaches of infections with drug-resistant strains.

Worldwide Endemicity of a Multidrug-Resistant Staphylococcus capitis Clone Involved in Neonatal Sepsis.

PubMed

Butin, Marine; Martins-Simões, Patricia; Rasigade, Jean-Philippe; Picaud, Jean-Charles; Laurent, Frédéric

2017-03-01

A multidrug-resistant Staphylococcus capitis clone, NRCS-A, has been isolated from neonatal intensive care units in 17 countries throughout the world. S. capitis NRCS-A prevalence is high in some neonatal intensive care units in France. These data highlight the worldwide endemicity and epidemiologic relevance of this multidrug-resistant, coagulase-negative staphylococci clone.

Effective Targeted Photothermal Ablation of Multidrug Resistant Bacteria and Their Biofilms with NIR-Absorbing Gold Nanocrosses.

PubMed

Teng, Choon Peng; Zhou, Tielin; Ye, Enyi; Liu, Shuhua; Koh, Leng Duei; Low, Michelle; Loh, Xian Jun; Win, Khin Yin; Zhang, Lianhui; Han, Ming-Yong

2016-08-01

With the rapid evolution of antibiotic resistance in bacteria, antibiotic-resistant bacteria (in particular, multidrug-resistant bacteria) and their biofilms have been becoming more and more difficult to be effectively treated with conventional antibiotics. As such, there is a great demand to develop a nonantibiotic approach in efficiently eliminating such bacteria. Here, multibranched gold nanocrosses with strong near-infrared absorption falling in the biological window, which heat up quickly under near-infrared-light irradiation are presented. The gold nanocrosses are conjugated to secondary and primary antibodies for targeting PcrV, a type III secretion protein, which is uniquely expressed on the bacteria superbug, Pseudomonas aeruginosa. The conjugated gold nanocrosses are capable of completely destroying P. aeruginosa and its biofilms upon near-infrared-light irradiation for 5 min with an 800 nm laser at a low power density of ≈3.0 W cm(-2) . No bacterial activity is detected after 48 h postirradiation, which indicates that the heat generated from the irradiated plasmonic gold nanocrosses attached to bacteria is effective in eliminating and preventing the re-growth of the bacteria. Overall, the conjugated gold nanocrosses allow targeted and effective photothermal ablation of multidrug-resistant bacteria and their biofilms in the localized region with reduced nonspecific damage to normal tissue. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Effect of curcumin on human colon cancer multidrug resistance in vitro and in vivo

PubMed Central

Lu, Wei-Dong; Qin, Yong; Yang, Chuang; Li, Lei

2013-01-01

OBJECTIVE: To determine whether curcumin reverses the multidrug resistance of human colon cancer cells in vitro and in vivo. METHODS: In a vincristine-resistant cell line of human colon cancer, the cell viability of curcumin-treated cells was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Rhodamine123 efflux was evaluated to detect P-glycoprotein transporter activity, and expression of the multidrug resistance protein 1 and survivin genes was analyzed by reverse transcription polymerase chain reaction and western blotting. In addition, xenograft mouse tumors were grown and treated with curcumin. The morphology of the xenografts was investigated by hematoxylin-eosin staining. The in vivo expression of the multidrug resistance gene and P-glycoprotein and survivin genes and proteins was observed using reverse transcription-polymerase chain reaction and western blotting, respectively. RESULTS: Curcumin was not obviously toxic to the vincristine-resistant human colon cancer cells at concentrations less than 25 μM, but the growth of cells was significantly inhibited. At concentrations greater than 25 μM, curcumin was toxic in a concentration-dependent manner. The sensitivity of cells to vincristine, cisplatin, fluorouracil, and hydroxycamptothecin was enhanced, intracellular Rhodamine123 accumulation was increased (p<0.05), and the expression of the multidrug resistance gene and P-glycoprotein were significantly suppressed (p<0.05). The combination of curcumin and vincristine significantly inhibited xenograft growth. The expression of the multidrug resistance protein 1 and survivin genes was significantly reduced in xenografts of curcumin-treated mice and mice treated with both curcumin and vincristine relative to control mice. CONCLUSION: Curcumin has strong reversal effects on the multidrug resistance of human colon carcinoma in vitro and in vivo. PMID:23778405

Immunoliposomal delivery of doxorubicin can overcome multidrug resistance mechanisms in EGFR-overexpressing tumor cells.

PubMed

Mamot, Christoph; Ritschard, Reto; Wicki, Andreas; Küng, Willy; Schuller, Jan; Herrmann, Richard; Rochlitz, Christoph

2012-06-01

Immunoliposomes (ILs) can be constructed to target the epidermal growth factor receptor (EGFR) to provide efficient intracellular drug delivery in tumor cells. We hypothesized that this approach might be able to overcome drug resistance mechanisms, which remain an important obstacle to better outcomes in cancer therapy. ILs were evaluated in vitro and in vivo against EGFR-overexpressing pairs of human cancer cells (HT-29 and MDA-MB-231) that either lack or feature the multidrug resistance (mdr) phenotype. In multidrug-resistant cell lines, ILs loaded with doxorubicin (DOX) produced 19-216-fold greater cytotoxicity than free DOX, whereas in nonresistant cells, immunoliposomal cytotoxicity of DOX was comparable with that of the free drug. In intracellular distribution studies, free DOX was efficiently pumped out of the multidrug-resistant tumor cells, whereas immunoliposomal DOX leads to 3.5-8 times higher accumulation of DOX in the cytoplasm and 3.5-4.9 times in the nuclei compared with the free drug. Finally, in vivo studies in the MDA-MB-231 Vb100 xenograft model confirmed the ability of anti-EGFR ILs-DOX to efficiently target multidrug-resistant cells and showed impressive antitumor effects, clearly superior to all other treatments. In conclusion, ILs provide efficient and targeted drug delivery to EGFR-overexpressing tumor cells and are capable of completely reversing the multidrug-resistant phenotype of human cancer cells.

Multidrug-resistant Neisseria gonorrhoeae failing treatment with ceftriaxone and doxycycline in France, November 2017.

PubMed

Poncin, Thibault; Fouere, Sebastien; Braille, Aymeric; Camelena, Francois; Agsous, Myriem; Bebear, Cecile; Kumanski, Sylvain; Lot, Florence; Mercier-Delarue, Severine; Ngangro, Ndeindo Ndeikoundam; Salmona, Maud; Schnepf, Nathalie; Timsit, Julie; Unemo, Magnus; Bercot, Beatrice

2018-05-01

We report a multidrug-resistant Neisseria gonorrhoeae urogenital and pharyngeal infection with ceftriaxone resistance and intermediate resistance to azithromycin in a heterosexual woman in her 20s in France. Treatment with ceftriaxone plus doxycycline failed for the pharyngeal localisation. Whole-genome sequencing of isolate F90 identified MLST 1903 , NG-MAST ST 3435 , NG-STAR 233 , and relevant resistance determinants. F90 showed phenotypic and genotypic similarities to an internationally spreading multidrug-resistant and ceftriaxone-resistant clone detected in Japan and subsequently in Australia, Canada and Denmark.

[MOLECULAR CHARACTERISTICS OF THE MULTIDRUG-RESISTANT MYCOBACTERIUM TUBERCULOSIS STRAINS IN THE NORTHWEST RUSSIA].

PubMed

Vyazovaya, A A; Mokrousov, I V; Zhuravlev, V Yu; Solovieva, N S; Otten, T F; Manicheva, O A; Vishnevsky, B I; Narvskaya, O V

2016-01-01

The goal of this work was to study the genotypic characteristics of the multidrug-resistant (MDR, i.e., resistant to at least rifampicine and isoniazid) Mycobacterium tuberculosis strains isolated in 2011-2012 from tuberculosis (TB) patients in the Northwest Russia. Spoligotyping of 195 M. tuberculosis isolates identified 14 different spoligotypes and assigned isolates to the genetic families Beijing (n = 162, 83%), LAM (n = 15), H3/URAL (n = 14), as well as T, Haarlem and X. Spoligotypes SIT1 (Beijing), SIT42 (LAM) and SIT262 (H3/URAL) were the most prevalent. Irrespective to the genotype, all the isolates were resistant to streptomycin. The multidrug resistance was accompanied by the resistance to ethionamide (56%), amikacin (31%), kanamycin (40%), and capreomycin (33%). The ethambutol resistance was found in 71% (n = 115) and 42% (n = 14) of the Beijing and non-Beijing strains, respectively (p < 0.05). In conclusion, the multidrug resistant M. tuberculosis population circulating in the Northwest Russia continues to be dominated by the Beijing family strains.

Bacillus subtilis from Soybean Food Shows Antimicrobial Activity for Multidrug-Resistant Acinetobacter baumannii by Affecting the adeS Gene.

PubMed

Wang, Tieshan; Su, Jianrong

2016-12-28

Exploring novel antibiotics is necessary for multidrug-resistant pathogenic bacteria. Because the probiotics in soybean food have antimicrobial activities, we investigated their effects on multidrug-resistant Acinetobacter baumannii . Nineteen multidrug-resistant A. baumannii strains were clinifcally isolated as an experimental group and 11 multidrug-sensitive strains as controls. The growth rates of all bacteria were determined by using the analysis for xCELLigence Real-Time Cell. The combination of antibiotics showed synergistic effects on the strains in the control group but no effect on the strains in the experimental group. Efflux pump gene adeS was absent in all the strains from the control group, whereas it exists in all the strains from the experimental group. Furthermore, all the strains lost multidrug resistance when an adeS inhibitor was used. One strain of probiotics isolated from soybean food showed high antimicrobial activity for multidrug-resistant A. baumannii . The isolated strain belongs to Bacillus subtilis according to 16S RNA analysis. Furthermore, E. coli showed multidrug resistance when it was transformed with the adeS gene from A. baumannii whereas the resistant bacteria could be inhibited completely by isolated Bacillus subtilis . Thus, probiotics from soybean food provide potential antibiotics against multidrug-resistant pathogenic bacteria.

Prevalence and risk factors for carriage of multi-drug resistant Staphylococci in healthy cats and dogs

PubMed Central

Regula, Gertraud; Petrini, Orlando; Zinsstag, Jakob; Schelling, Esther

2013-01-01

We investigated the distribution of commensal staphylococcal species and determined the prevalence of multi-drug resistance in healthy cats and dogs. Risk factors associated with the carriage of multi-drug resistant strains were explored. Isolates from 256 dogs and 277 cats were identified at the species level using matrix-assisted laser desorption ionisation-time of flight mass spectrometry. The diversity of coagulase-negative Staphylococci (CNS) was high, with 22 species in dogs and 24 in cats. Multi-drug resistance was frequent (17%) and not always associated with the presence of the mecA gene. A stay in a veterinary clinic in the last year was associated with an increased risk of colonisation by multi-drug resistant Staphylococci (OR = 2.4, 95% CI: 1.1~5.2, p value LRT = 0.04). When identifying efficient control strategies against antibiotic resistance, the presence of mechanisms other than methicillin resistance and the possible role of CNS in the spread of resistance determinants should be considered. PMID:23820161

The Growing Threat of Multidrug-Resistant Gram-Negative Infections in Patients with Hematologic Malignancies

PubMed Central

Baker, Thomas M.; Satlin, Michael J.

2016-01-01

Prolonged neutropenia and chemotherapy-induced mucositis render patients with hematologic malignancies highly vulnerable to Gram-negative bacteremia. Unfortunately, multidrug-resistant (MDR) Gram-negative bacteria are increasingly encountered globally, and current guidelines for empirical antibiotic coverage in these patients may not adequately treat these bacteria. This expansion of resistance, coupled with traditional culturing techniques requiring 2-4 days for bacterial identification and antimicrobial susceptibility results, have grave implications for these immunocompromised hosts. This review characterizes the epidemiology, risk factors, resistance mechanisms, recommended treatments, and outcomes of the MDR Gram-negative bacteria that commonly cause infections in patients with hematologic malignancies. We also examine infection prevention strategies in hematology patients, such as infection control practices, antimicrobial stewardship, and targeted decolonization. Finally, we assess strategies to improve outcomes of infected patients, including gastrointestinal screening to guide empirical antibiotic therapy, new rapid diagnostic tools for expeditious identification of MDR pathogens, and use of two new antimicrobial agents, ceftolozane/tazobactam and ceftazidime/avibactam. PMID:27339405

Genome Sequences of Multidrug-Resistant, Colistin-Susceptible and -Resistant Klebsiella pneumoniae Clinical Isolates from Pakistan

PubMed Central

Crawford, Matthew A.; Timme, Ruth; Lomonaco, Sara; Lascols, Christine; Fisher, Debra J.; Sharma, Shashi K.; Strain, Errol; Allard, Marc W.; Brown, Eric W.; McFarland, Melinda A.; Croley, Tim; Hammack, Thomas S.; Weigel, Linda M.; Anderson, Kevin; Hodge, David R.; Pillai, Segaran P.; Morse, Stephen A.; Khan, Erum

2016-01-01

The emergence and spread of colistin resistance among multidrug-resistant (MDR) Klebsiella pneumoniae represent a critical threat to global health. Here, we report the complete genome sequences of 10 MDR, colistin-susceptible and -resistant K. pneumoniae clinical isolates obtained in Pakistan between 2010 and 2013. PMID:27979956

Clonal Multidrug-Resistant Corynebacterium striatum Strains, Italy

PubMed Central

Campanile, Floriana; Carretto, Edoardo; Barbarini, Daniela; Grigis, Annalisa; Falcone, Marco; Goglio, Antonio; Venditti, Mario

2009-01-01

We assessed the clinical relevance and performed molecular characterization of 36 multidrug-resistant strains of Corynebacterium striatum. Pulsed-field gel electrophoresis confirmed a single clone, possessing erm(X), tetA/B, cmxA/B, and aphA1 genes, but few related subclones. This strain is emerging as a pathogen in Italy. PMID:19116057

Multidrug-Resistant Pathogens in Hospitalized Syrian Children.

PubMed

Kassem, Diana Faour; Hoffmann, Yoav; Shahar, Naama; Ocampo, Smadar; Salomon, Liora; Zonis, Zeev; Glikman, Daniel

2017-01-01

Since 2013, wounded and ill children from Syria have received treatment in Israel. Screening cultures indicated that multidrug-resistant (MDR) pathogens colonized 89 (83%) of 107 children. For 58% of MDR infections, the pathogen was similar to that identified during screening. MDR screening of these children is valuable for purposes of isolation and treatment.

Finding Novel Antibiotic Substances from Medicinal Plants – Antimicrobial Properties of Nigella Sativa Directed against Multidrug-resistant Bacteria

PubMed Central

Bakal, Seher Nancy; Bereswill, Stefan; Heimesaat, Markus M.

2017-01-01

The progressive rise in multidrug-resistant (MDR) bacterial strains poses serious problems in the treatment of infectious diseases. While the number of newly developed antimicrobial compounds has greatly fallen, the resistance of pathogens against commonly prescribed drugs is further increasing. This rise in resistance illustrates the need for developing novel therapeutic and preventive antimicrobial options. The medicinal herb Nigella sativa and its derivatives constitute promising candidates. In a comprehensive literature survey (using the PubMed data base), we searched for publications on the antimicrobial effects of N. sativa particularly directed against MDR bacterial strains. In vitro studies published between 2000 and 2015 revealed that N. sativa exerted potent antibacterial effects against both Gram-positive and Gram-negative species including resistant strains. For instance, N. sativa inhibited the growth of bacteria causing significant gastrointestinal morbidity such as Salmonella, Helicobacter pylori, and Escherichia coli. However, Listeria monocytogenes and Pseudomonas aeruginosa displayed resistance against black cumin seed extracts. In conclusion, our literature survey revealed potent antimicrobial properties of N. sativa against MDR strains in vitro that should be further investigated in order to develop novel therapeutic perspectives for combating infectious diseases particularly caused by MDR strains. PMID:28386474

Dental plaque bacteria with reduced susceptibility to chlorhexidine are multidrug resistant.

PubMed

Saleem, Hafiz Ghulam Murtaza; Seers, Christine Ann; Sabri, Anjum Nasim; Reynolds, Eric Charles

2016-09-15

Chlorhexidine (CHX) is used in oral care products to help control dental plaque. In this study dental plaque bacteria were grown on media containing 2 μg/ml chlorhexidine gluconate to screen for bacteria with reduced CHX susceptibility. The isolates were characterized by 16S rRNA gene sequencing and antibiotic resistance profiles were determined using the disc diffusion method. The isolates were variably resistant to multiple drugs including ampicillin, kanamycin, gentamicin and tetracycline. Two species, Chryseobacterium culicis and Chryseobacterium indologenes were able to grow planktonically and form biofilms in the presence of 32 μg/ml CHX. In the CHX and multidrug resistant C. indologenes we demonstrated a 19-fold up-regulation of expression of the HlyD-like periplasmic adaptor protein of a tripartite efflux pump upon exposure to 16 μg/ml CHX suggesting that multidrug resistance may be mediated by this system. Exposure of biofilms of these resistant species to undiluted commercial CHX mouthwash for intervals from 5 to 60 s indicated that the mouthwash was unlikely to eliminate them from dental plaque in vivo. The study highlights the requirement for increased vigilance of the presence of multidrug resistant bacteria in dental plaque and raises a potential risk of long-term use of oral care products containing antimicrobial agents for the control of dental plaque.

Induction of apoptosis and reversal of permeability glycoprotein-mediated multidrug resistance of MCF-7/ADM by ginsenoside Rh2.

PubMed

Zhang, Hui; Gong, Jian; Zhang, Huilai; Kong, Di

2015-01-01

Multidrug resistance is a phenomenon that cancer cells develop a cross-resistant phenotype against several unrelated drugs, and permeability glycoprotein derived from the overexpression of multidrug resistance gene 1 has been taken as the most significant cause of multidrug resistance. In the present study, ginsenoside Rh2 was used to reverse permeability glycoprotein-mediated multidrug resistance of MCF-7/ADM cell line. Effects of ginsenoside Rh2 on the apoptotic process and caspase-3 activity of MCF-7 and MCF-7/ADM cell lines were determined using flow cytometry and microplate reader. Methyl thiazolyl tetrazolium test was conducted to assess the IC50 values of ginsenoside Rh2 and adriamycin on MCF-7 and MCF-7/ADM cultures; Rhodamin 123 assay was used to assess the retention of permeability glycoprotein after ginsenoside Rh2 treatment; flow cytometry and real time polymerase chain reaction were used to determine the expression levels of permeability glycoprotein and multidrug resistance gene 1 in drug-resistant cells and their parental cells after exposure to ginsenoside Rh2. The results showed that ginsenoside Rh2, except for inducing apoptosis, had the ability to reverse multidrug resistance in MCF-7/ADM cell line without changing the expression levels of permeability glycoprotein and multidrug resistance gene 1. Our findings provided some valuable information for the application of ginsenoside Rh2 in cancer therapy, especially for multidrug resistance reversal in clinic.

Antimicrobial resistance determinant microarray for analysis of multi-drug resistant isolates

NASA Astrophysics Data System (ADS)

Taitt, Chris Rowe; Leski, Tomasz; Stenger, David; Vora, Gary J.; House, Brent; Nicklasson, Matilda; Pimentel, Guillermo; Zurawski, Daniel V.; Kirkup, Benjamin C.; Craft, David; Waterman, Paige E.; Lesho, Emil P.; Bangurae, Umaru; Ansumana, Rashid

2012-06-01

The prevalence of multidrug-resistant infections in personnel wounded in Iraq and Afghanistan has made it challenging for physicians to choose effective therapeutics in a timely fashion. To address the challenge of identifying the potential for drug resistance, we have developed the Antimicrobial Resistance Determinant Microarray (ARDM) to provide DNAbased analysis for over 250 resistance genes covering 12 classes of antibiotics. Over 70 drug-resistant bacteria from different geographic regions have been analyzed on ARDM, with significant differences in patterns of resistance identified: genes for resistance to sulfonamides, trimethoprim, chloramphenicol, rifampin, and macrolide-lincosamidesulfonamide drugs were more frequently identified in isolates from sources in Iraq/Afghanistan. Of particular concern was the presence of genes responsible for resistance to many of the last-resort antibiotics used to treat war traumaassociated infections.

Extra-pulmonary primary multidrug-resistant tubercular lymphadenitis in an HIV negative patient

PubMed Central

Kant, Surya; Saheer, S; Hassan, Ghulam; Parengal, Jabeed

2012-01-01

A 28-year-old woman without any history of prior antituberculosis treatment presented with cervical lymphadenopathy and a cold abscess near medial end of clavicle of 5 months duration. Pus culture and sensitivity revealed Mycobacterium tuberculosis resistant to rifampicin and isoniazid. Thus she was diagnosed as a case of primary multidrug-resistant tuberculosis and treated with second line drugs according to culture susceptibility pattern. On completion of therapy, patent showed good clinical response. This case highlights the observation that even extra-pulmonary primary multidrug-resistant tuberculosis can be successfully treated with currently available second line drugs. PMID:22605844

Multidrug-resistant tuberculosis.

PubMed

Zager, Ellen M; McNerney, Ruth

2008-01-25

With almost 9 million new cases each year, tuberculosis remains one of the most feared diseases on the planet. Led by the STOP-TB Partnership and WHO, recent efforts to combat the disease have made considerable progress in a number of countries. However, the emergence of mutated strains of Mycobacterium tuberculosis that are resistant to the major anti-tuberculosis drugs poses a deadly threat to control efforts. Multidrug-resistant tuberculosis (MDR-TB) has been reported in all regions of the world. More recently, extensively drug resistant-tuberculosis (XDR-TB) that is also resistant to second line drugs has emerged in a number of countries. To ensure that adequate resources are allocated to prevent the emergence and spread of drug resistance it is important to understand the scale of the problem. In this article we propose that current methods of describing the epidemiology of drug resistant tuberculosis are not adequate for this purpose and argue for the inclusion of population based statistics in global surveillance data. Whereas the prevalence of tuberculosis is presented as the proportion of individuals within a defined population having disease, the prevalence of drug resistant tuberculosis is usually presented as the proportion of tuberculosis cases exhibiting resistance to anti-tuberculosis drugs. Global surveillance activities have identified countries in Eastern Europe, the former Soviet Union and regions of China as having a high proportion of MDR-TB cases and international commentary has focused primarily on the urgent need to improve control in these settings. Other regions, such as sub-Saharan Africa have been observed as having a low proportion of drug resistant cases. However, if one considers the incidence of new tuberculosis cases with drug resistant disease in terms of the population then countries of sub-Saharan Africa have amongst the highest rates of transmitted MDR-TB in the world. We propose that inclusion of population based statistics in

Multidrug-Resistant Pathogens in Hospitalized Syrian Children

PubMed Central

Kassem, Diana Faour; Hoffmann, Yoav; Shahar, Naama; Ocampo, Smadar; Salomon, Liora; Zonis, Zeev

2017-01-01

Since 2013, wounded and ill children from Syria have received treatment in Israel. Screening cultures indicated that multidrug-resistant (MDR) pathogens colonized 89 (83%) of 107 children. For 58% of MDR infections, the pathogen was similar to that identified during screening. MDR screening of these children is valuable for purposes of isolation and treatment. PMID:27618479

Potential and use of bacterial small RNAs to combat drug resistance: a systematic review

PubMed Central

Liu, Xiaodong; Zhang, Lin; Wong, Sunny Hei; Chan, Matthew TV; Wu, William KK

2017-01-01

Background Over the decades, new antibacterial agents have been developed in an attempt to combat drug resistance, but they remain unsuccessful. Recently, a novel class of bacterial gene expression regulators, bacterial small RNAs (sRNAs), has received increasing attention toward their involvement in antibiotic resistance. This systematic review aimed to discuss the potential of these small molecules as antibacterial drug targets. Methods Two investigators performed a comprehensive search of MEDLINE, EmBase, and ISI Web of Knowledge from inception to October 2016, without restriction on language. We included all in vitro and in vivo studies investigating the role of bacterial sRNA in antibiotic resistance. Risk of bias of the included studies was assessed by a modified guideline of Systematic Review Center for Laboratory Animal Experimentation (SYRCLE). Results Initial search yielded 432 articles. After exclusion of non-original articles, 20 were included in this review. Of these, all studies examined bacterial-type strains only. There were neither relevant in vivo nor clinical studies. The SYRCLE scores ranged from to 5 to 7, with an average of 5.9. This implies a moderate risk of bias. sRNAs influenced the antibiotics susceptibility through modulation of gene expression relevant to efflux pumps, cell wall synthesis, and membrane proteins. Conclusion Preclinical studies on bacterial-type strains suggest that modulation of sRNAs could enhance bacterial susceptibility to antibiotics. Further studies on clinical isolates and in vivo models are needed to elucidate the therapeutic value of sRNA modulation on treatment of multidrug-resistant bacterial infection. PMID:29290689

Pathogens of Bovine Respiratory Disease in North American Feedlots Conferring Multidrug Resistance via Integrative Conjugative Elements

PubMed Central

Klima, Cassidy L.; Zaheer, Rahat; Cook, Shaun R.; Booker, Calvin W.; Hendrick, Steve

2014-01-01

In this study, we determined the prevalence of bovine respiratory disease (BRD)-associated viral and bacterial pathogens in cattle and characterized the genetic profiles, antimicrobial susceptibilities, and nature of antimicrobial resistance determinants in collected bacteria. Nasopharyngeal swab and lung tissue samples from 68 BRD mortalities in Alberta, Canada (n = 42), Texas (n = 6), and Nebraska (n = 20) were screened using PCR for bovine viral diarrhea virus (BVDV), bovine respiratory syncytial virus, bovine herpesvirus 1, parainfluenza type 3 virus, Mycoplasma bovis, Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni. Excepting bovine herpesvirus 1, all agents were detected. M. haemolytica (91%) and BVDV (69%) were the most prevalent, with cooccurrence in 63% of the cattle. Isolates of M. haemolytica (n = 55), P. multocida (n = 8), and H. somni (n = 10) from lungs were also collected. Among M. haemolytica isolates, a clonal subpopulation (n = 8) was obtained from a Nebraskan feedlot. All three bacterial pathogens exhibited a high rate of antimicrobial resistance, with 45% exhibiting resistance to three or more antimicrobials. M. haemolytica (n = 18), P. multocida (n = 3), and H. somni (n = 3) from Texas and Nebraska possessed integrative conjugative elements (ICE) that conferred resistance for up to seven different antimicrobial classes. ICE were shown to be transferred via conjugation from P. multocida to Escherichia coli and from M. haemolytica and H. somni to P. multocida. ICE-mediated multidrug-resistant profiles of bacterial BRD pathogens could be a major detriment to many of the therapeutic antimicrobial strategies currently used to control BRD. PMID:24478472

Pathogens of bovine respiratory disease in North American feedlots conferring multidrug resistance via integrative conjugative elements.

PubMed

Klima, Cassidy L; Zaheer, Rahat; Cook, Shaun R; Booker, Calvin W; Hendrick, Steve; Alexander, Trevor W; McAllister, Tim A

2014-02-01

In this study, we determined the prevalence of bovine respiratory disease (BRD)-associated viral and bacterial pathogens in cattle and characterized the genetic profiles, antimicrobial susceptibilities, and nature of antimicrobial resistance determinants in collected bacteria. Nasopharyngeal swab and lung tissue samples from 68 BRD mortalities in Alberta, Canada (n = 42), Texas (n = 6), and Nebraska (n = 20) were screened using PCR for bovine viral diarrhea virus (BVDV), bovine respiratory syncytial virus, bovine herpesvirus 1, parainfluenza type 3 virus, Mycoplasma bovis, Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni. Excepting bovine herpesvirus 1, all agents were detected. M. haemolytica (91%) and BVDV (69%) were the most prevalent, with cooccurrence in 63% of the cattle. Isolates of M. haemolytica (n = 55), P. multocida (n = 8), and H. somni (n = 10) from lungs were also collected. Among M. haemolytica isolates, a clonal subpopulation (n = 8) was obtained from a Nebraskan feedlot. All three bacterial pathogens exhibited a high rate of antimicrobial resistance, with 45% exhibiting resistance to three or more antimicrobials. M. haemolytica (n = 18), P. multocida (n = 3), and H. somni (n = 3) from Texas and Nebraska possessed integrative conjugative elements (ICE) that conferred resistance for up to seven different antimicrobial classes. ICE were shown to be transferred via conjugation from P. multocida to Escherichia coli and from M. haemolytica and H. somni to P. multocida. ICE-mediated multidrug-resistant profiles of bacterial BRD pathogens could be a major detriment to many of the therapeutic antimicrobial strategies currently used to control BRD.

Population pharmacokinetics and pharmacodynamics of fosfomycin in non-critically ill patients with bacteremic urinary infection caused by multidrug-resistant Escherichia coli.

PubMed

Merino-Bohórquez, V; Docobo-Pérez, F; Sojo, J; Morales, I; Lupión, C; Martín, D; Cameán, M; Hope, W; Pascual, Á; Rodríguez-Baño, J

2018-04-10

To describe the population pharmacokinetics of fosfomycin for patients with bacteraemic urinary tract infection (BUTI). The analysis identified optimal regimens on the basis of pharmacodynamic targets and assessed the adequacy of Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) susceptibility breakpoints for Escherichia coli. Data of 16 patients with BUTI caused by multidrug-resistant E. coli (FOREST clinical trial) received intravenous fosfomycin (4 g every 6 hours) were analysed. A population pharmacokinetic analysis was performed, and Monte Carlo simulations were undertaken using 4 g every 6 hours and 8 g every 8 hours. The probability of pharmacodynamic target attainment was assessed using pharmacodynamic targets for E. coli for static effect, 1-log drop in bacterial burden and resistance suppression. Sixty-four plasma samples were collected over a single dosing interval (day 2 or 3 after starting fosfomycin treatment). Fosfomycin concentrations were highly variable. Pharmacodynamic target attainment analysis showed mild improvement by increasing fosfomycin dosing (4 g every 6 hours vs. every 8 hours). These dosages showed success for decreasing 1-log bacterial burden in 89% to 96% (EUCAST breakpoints) and 33% to 54% (CLSI breakpoints) of patients, but they were unable to reach bacterial resistance suppression targets. Fosfomycin concentrations are highly variable-a fact partially explained by renal impairment. The present work supports the use of 4 g every 6 hours as an effective regimen for the treatment of non-critically ill patients with BUTI caused by multidrug-resistant E. coli, as higher dosages might increase toxicity but may not significantly increase efficacy. The current information may suggest that fosfomycin susceptibility breakpoints need to be reappraised. Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by

In vitro characterization of multivalent adhesion molecule 7-based inhibition of multidrug-resistant bacteria isolated from wounded military personnel

PubMed Central

Krachler, Anne Marie; Mende, Katrin; Murray, Clinton; Orth, Kim

2012-01-01

Treatment of wounded military personnel at military medical centers is often complicated by colonization and infection of wounds with pathogenic bacteria. These include nosocomially transmitted, often multidrug-resistant pathogens such as Acinetobacter baumannii-calcoaceticus complex, Pseudomonas aeruginosa and extended spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae. We analyzed the efficacy of multivalent adhesion molecule (MAM) 7-based anti-adhesion treatment of host cells against aforementioned pathogens in a tissue culture infection model. Herein, we observed that a correlation between two important hallmarks of virulence, attachment and cytotoxicity, could serve as a useful predictor for the success of MAM7-based inhibition against bacterial infections. Initially, we characterized 20 patient isolates (five from each pathogen mentioned above) in terms of genotypic diversity, antimicrobial susceptibility and important hallmarks of pathogenicity (biofilm formation, attachment to and cytotoxicity toward cultured host cells). All isolates displayed a high degree of genotypic diversity, which was also reflected by large strain-to-strain variability in terms of biofilm formation, attachment and cytotoxicity within each group of pathogen. Using non-pathogenic bacteria expressing MAM7 or latex beads coated with recombinant MAM7 for anti-adhesion treatment, we showed a decrease in cytotoxicity, indicating that MAM7 has potential as a prophylactic agent to attenuate infection by multidrug-resistant bacterial pathogens. PMID:22722243

Influx of multidrug-resistant organisms by country-to-country transfer of patients.

PubMed

Mutters, Nico T; Günther, Frank; Sander, Anja; Mischnik, Alexander; Frank, Uwe

2015-10-28

Multidrug-resistant organisms (MDRO) are a worldwide problem. International migration and travel facilitate the spread of MDRO. Therefore the goal of our study was to assess the risk of influx of MDRO from patients transferred to one of Central Europe's largest hospitals from abroad. A mono-centre study was conducted. All patients transferred from other countries were screened; additional data was collected on comorbidities, etc. Presence of carbapenemases of multidrug-resistant Gram-negatives was confirmed by PCR. The association between length of stay, being colonized and/or infected by a MDRO, country of origin, diagnosis and other factors was assessed by binomial regression analyses. From 2012 to 2013, one fifth of all patients were colonized with MDRO (Methicillin-resistant Staphylococcus aureus [4.1 %], Vancomycin-resistant Enterococci [2.9 %], multidrug-resistant Gram-negatives [12.8 %] and extensively drug-resistant Gram-negatives [3.4 %]). The Gram-negatives carried a variety of carbapenemases including OXA, VIM, KPC and NDM. The length of stay was significantly prolonged by 77.2 % in patients colonized with a MDRO, compared to those not colonized (p<0.0001). Country-to-Country transfer of patients to European hospitals represents a high risk of introduction of MDRO and infection control specialists should endorse containment and screening measures.

Multidrug and extensively drug-resistant tuberculosis.

PubMed

Maitre, T; Aubry, A; Jarlier, V; Robert, J; Veziris, N

2017-02-01

The emergence of drug-resistant tuberculosis (TB) compromises global tuberculosis control. The incidence of multidrug-resistant strains (MDR) defined as resistant to the two main antituberculosis drugs, rifampicin and isoniazid, was raised in the 1990s. Ten percent of these strains have developed additional resistance to the main second-line antituberculosis drugs: fluoroquinolones and aminoglycosides. These strains are defined as extensively drug-resistant (XDR). The prognosis of MDR-TB and XDR-TB is poor due to limited therapeutic resources. However, many new innovations may lead to a radical change in this field. Genotypic testing is now able to detect drug resistance within a few hours. Genotypic diagnosis of rifampicin resistance is now recommended in France for each new case of TB. The currently recommended treatment for MDR-TB is long (18-24 months) and toxic. It is, however, on the verge of being replaced by a 9-month treatment. New antituberculosis drugs such as bedaquiline and delamanid should also improve the prognosis of MDR-TB and XDR-TB. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Coarse-grained Simulations of Conformational Changes in Multidrug Resistance Transporters

NASA Astrophysics Data System (ADS)

Jewel, S. M. Yead; Dutta, Prashanta; Liu, Jin

2016-11-01

The overexpression of multidrug resistance (MDR) systems on the gram negative bacteria causes serious problems for treatment of bacterial infectious diseases. The system effectively pumps the antibiotic drugs out of the bacterial cells. During the pumping process one of the MDR components, AcrB undergoes a series of large-scale conformational changes which are responsible for drug recognition, binding and expelling. All-atom simulations are unable to capture those conformational changes because of computational cost. Here, we implement a hybrid coarse-grained force field that couples the united-atom protein models with the coarse-grained MARTINI water/lipid, to investigate the proton-dependent conformational changes of AcrB. The simulation results in early stage ( 100 ns) of proton-dependent conformational changes agree with all-atom simulations, validating the coarse-grained model. The coarse-grained force field allows us to explore the process in microsecond simulations. Starting from the crystal structures of Access(A)/Binding(B)/Extrusion(E) monomers in AcrB, we find that deprotonation of Asp407 and Asp408 in monomer E causes a series of large-scale conformational changes from ABE to AAA in absence of drug molecules, which is consistent with experimental findings. This work is supported by NIH Grant: 1R01GM122081-01.

Simultaneous quantification of antimicrobial agents for multidrug-resistant bacterial infections in human plasma by ultra-high-pressure liquid chromatography-tandem mass spectrometry.

PubMed

Tsai, I-Lin; Sun, Hsin-Yun; Chen, Guan-Yuan; Lin, Shu-Wen; Kuo, Ching-Hua

2013-11-15

Antibiotic-resistant bacterial infection is one of the most serious clinical problems worldwide. Vancomycin, teicoplanin, daptomycin, and colistin are glycopeptide and lipopeptide antibiotics that are frequently used to treat multidrug-resistant bacterial infections. Therapeutic drug monitoring is recommended to ensure both safety and efficacy and to improve clinical outcomes. This study developed a fast, simple, and sensitive ultra-high-pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for the simultaneous determination of the concentrations of these four drugs in human plasma. The sample preparation process includes a simple protein denaturation step using acetonitrile, followed by an 11-fold dilution with 0.1% formic acid. Eight target peaks for the four drugs can be analyzed within 3 min using a Kinetex™ 2.6 μm C18 column. The mass spectrometry parameters were optimized, and two transitions for each target peak were used for multiple reaction monitoring, which provided high sensitivity and specificity. The UHPLC-MS/MS method was validated over clinical concentration ranges. The intra-day and inter-day precisions for the ratio of the peak area of each analyte to the peak area of the internal standard were all below 12.7 and 14.7% relative standard deviations, respectively. The accuracy at low, medium, and high concentrations of the eight target peaks was between 89.3 and 110.7%. The standard curves for the analytes were linear and had coefficients of determination higher than 0.997. The limits of detection were all below 70 ng mL(-1). The use of this method to analyze patient plasma samples confirmed that it is effective for the therapeutic drug monitoring of these four drugs and can be used to improve the therapeutic efficacy and safety of treatment with antibiotics. Copyright © 2013 Elsevier B.V. All rights reserved.

Characterization of a xylose containing oligosaccharide, an inhibitor of multidrug resistance in Staphylococcus aureus, from Ipomoea pes-caprae.

PubMed

Escobedo-Martínez, Carolina; Cruz-Morales, Sara; Fragoso-Serrano, Mabel; Rahman, M Mukhlesur; Gibbons, Simon; Pereda-Miranda, Rogelio

2010-10-01

Pescaprein XVIII (1), a type of bacterial efflux pump inhibitor, was obtained from the CHCl(3)-soluble resin glycosides of beach morning glory (Ipomoea pes-caprae). The glycosidation sequence for pescaproside C, the glycosidic acid core of the lipophilic macrolactone 1 containing D-xylose and L-rhamnose, was characterized by means of several NMR techniques and FAB mass spectrometry. Recycling HPLC also yielded eight non-cytotoxic bacterial resistance modifiers, the two pescapreins XIX (2) and XX (3) as well as the known murucoidin VI (4), pecapreins II (6) and III (7), and stoloniferins III (5), IX (8) and X (9), all of which contain simonic acid B as their oligosaccharide core. Compounds 1-9 were tested for in vitro antibacterial and resistance-modifying activity against strains of Staphylococcus aureus possessing multidrug resistance efflux mechanisms. All of the pescapreins potentiated the action of norfloxacin against the NorA over-expressing strain by 4-fold (8 microg/mL from 32 microg/mL) at a concentration of 25 microg/mL. Copyright © 2010 Elsevier Ltd. All rights reserved.

Substrate-bound structure of the E. coli multidrug resistance transporter MdfA

PubMed Central

Heng, Jie; Zhao, Yan; Liu, Ming; Liu, Yue; Fan, Junping; Wang, Xianping; Zhao, Yongfang; Zhang, Xuejun C

2015-01-01

Multidrug resistance is a serious threat to public health. Proton motive force-driven antiporters from the major facilitator superfamily (MFS) constitute a major group of multidrug-resistance transporters. Currently, no reports on crystal structures of MFS antiporters in complex with their substrates exist. The E. coli MdfA transporter is a well-studied model system for biochemical analyses of multidrug-resistance MFS antiporters. Here, we report three crystal structures of MdfA-ligand complexes at resolutions up to 2.0 Å, all in the inward-facing conformation. The substrate-binding site sits proximal to the conserved acidic residue, D34. Our mutagenesis studies support the structural observations of the substrate-binding mode and the notion that D34 responds to substrate binding by adjusting its protonation status. Taken together, our data unveil the substrate-binding mode of MFS antiporters and suggest a mechanism of transport via this group of transporters. PMID:26238402

Alkanna tinctoria leaves extracts: a prospective remedy against multidrug resistant human pathogenic bacteria.

PubMed

Khan, Usman Ali; Rahman, Hazir; Qasim, Muhammad; Hussain, Anwar; Azizllah, Azizullah; Murad, Waheed; Khan, Zakir; Anees, Muhammad; Adnan, Muhammad

2015-04-23

Plants are rich source of chemical compounds that are used to accomplish biological activity. Indigenously crude extracts of plants are widely used as herbal medicine for the treatment of infections by people of different ethnic groups. The present investigation was carried out to evaluate the biological potential of Alkanna tinctoria leaves extract from district Charsadda, Pakistan against multidrug resistant human pathogenic bacteria including Acinetobacter baumannii, Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. Anti-multi-drug resistant bacterial activity of aqueous, chloroform, ethanol and hexane extracts of Alkanna tinctoria leaves were evaluated by well diffusion method. Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of different extracts were determined. Moreover qualitative phytochemicals screening of the studied extracts was performed. All four selected bacteria including A. baumannii, E. coli, P. aeruginosa and S. aureus were categorized as multi-drug resistant (MDR) as they were found to be resistant to 13, 10, 19 and 22 antibiotics belonging to different groups respectively. All the four extract showed potential activity against S. aureus as compare to positive control antibiotic (Imipenem). Similarly among the four extracts of Alkanna tinctoria leaves, aqueous extract showed best activity against A. baumannii (10±03 mm), P. aeruginosa (12±0.5 mm), and S. aureus (14±0.5 mm) as compare to Imipenem. The MICs and MBCs results also showed quantitative concentration of plant extracts to inhibit or kill MDR bacteria. When phytochemicals analysis was performed it was observed that aqueous and ethanol extracts showed phytochemicals with large number as well as volume, especially Alkaloides, Flavonoides and Charbohydrates. The undertaken study demonstrated that all the four extracts of Alkanna tinctoria leaves exhibited considerable antibacterial activity against MDR isolates. Finding from the

Challenges and Strategies for Prevention of Multidrug-Resistant Organism Transmission in Nursing Homes.

PubMed

Dumyati, Ghinwa; Stone, Nimalie D; Nace, David A; Crnich, Christopher J; Jump, Robin L P

2017-04-01

Nursing home residents are at high risk for colonization and infection with bacterial pathogens that are multidrug-resistant organisms (MDROs). We discuss challenges and potential solutions to support implementing effective infection prevention and control practices in nursing homes. Challenges include a paucity of evidence that addresses MDRO transmission during the care of nursing home residents, limited staff resources in nursing homes, insufficient infection prevention education in nursing homes, and perceptions by nursing home staff that isolation and contact precautions negatively influence the well being of their residents. A small number of studies provide evidence that specifically address these challenges. Their outcomes support a paradigm shift that moves infection prevention and control practices away from a pathogen-specific approach and toward one that focuses on resident risk factors.

Role of wild birds as carriers of multi-drug resistant Escherichia coli and Escherichia vulneris

PubMed Central

Shobrak, Mohammed Y.; Abo-Amer, Aly E.

2014-01-01

Emergence and distribution of multi-drug resistant (MDR) bacteria in environments pose a risk to human and animal health. A total of 82 isolates of Escherichia spp. were recovered from cloacal swabs of migrating and non-migrating wild birds. All bacterial isolates were identified and characterized morphologically and biochemically. 72% and 50% of isolates recovered from non-migrating and migrating birds, respectively, showed positive congo red dye binding (a virulence factor). Also, hemolysin production (a virulence factor) was showed in 8% of isolates recovered from non-migrating birds and 75% of isolates recovered from migrating birds. All isolates recovered from non-migrating birds were found resistant to Oxacillin while all isolates recovered from migrating birds demonstrated resistance to Oxacillin, Chloramphenicol, Oxytetracycline and Lincomycin. Some bacterial isolates recovered from non-migrating birds and migrating birds exhibited MDR phenotype. The MDR isolates were further characterized by API 20E and 16S rRNA as E. coli and E. vulneris. MDR Escherichia isolates contain ~1–5 plasmids of high-molecular weights. Accordingly, wild birds could create a potential threat to human and animal health by transmitting MDR bacteria to water streams and other environmental sources through their faecal residues, and to remote regions by migration. PMID:25763023

From Nano to Micro: using nanotechnology to combat microorganisms and their multidrug resistance.

PubMed

Natan, Michal; Banin, Ehud

2017-05-01

The spread of antibiotic resistance and increasing prevalence of biofilm-associated infections is driving demand for new means to treat bacterial infection. Nanotechnology provides an innovative platform for addressing this challenge, with potential to manage even infections involving multidrug-resistant (MDR) bacteria. The current review summarizes recent progress over the last 2 years in the field of antibacterial nanodrugs, and describes their unique properties, mode of action and activity against MDR bacteria and biofilms. Biocompatibility and commercialization are also discussed. As opposed to the more common division of nanoparticles (NPs) into organic- and inorganic-based materials, this review classifies NPs into two functional categories. The first includes NPs exhibiting intrinsic antibacterial properties and the second is devoted to NPs serving as a cargo for delivering antibacterial agents. Antibacterial nanomaterials used to decorate medical devices and implants are reviewed here as well. © FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

mar Operon Involved in Multidrug Resistance of Enterobacter aerogenes

PubMed Central

Chollet, Renaud; Bollet, Claude; Chevalier, Jacqueline; Malléa, Monique; Pagès, Jean-Marie; Davin-Regli, Anne

2002-01-01

We determined the sequence of the entire marRAB operon in Enterobacter aerogenes. It is functionally and structurally analogous to the Escherichia coli operon. The overexpression of E. aerogenes MarA induces a multidrug resistance phenotype in a susceptible strain, demonstrated by a noticeable resistance to various antibiotics, a decrease in immunodetected porins, and active efflux of norfloxacin. PMID:11897595

Ambulance vehicles as a source of multidrug-resistant infections: a multicenter study in Assiut City, Egypt

PubMed Central

2018-01-01

Background Ambulances may represent a potential source of infection to patients, patients’ relatives, and paramedical staffs. In this study, we analyzed the extent of bacterial contamination in ambulance vehicles and measured the degree of antimicrobial resistance among isolated pathogens. Materials and methods Twenty-five vehicles were included and 16 sampling points were swabbed in each vehicle. Then the swabs were immediately transferred to the laboratory to identify bacterial contaminants utilizing standard microbiological procedures and API® systems. Antibiotic susceptibility testing and screening for methicillin-resistant staphylococci and extended spectrum β-lactamases (ESBLs)-producing Gram-negative rods were carried out. Results A total of 400 samples were collected, 589 bacteria were isolated and 286 (48.6%) of the isolates were potentially pathogenic. The highest contamination rate with pathogenic bacteria was detected in suction devices (75.8%) and stethoscopes (67.7%). Staphylococci were the most frequently detected microorganisms (n=184) followed by Klebsiella spp. (49), Escherichia coli (40), Citrobacter spp. (7), and Proteus spp. (6). Staphylococci were mostly sensitive to vancomycin, whereas Gram-negative bacteria were sensitive to imipenem. Overall, 46.1% of Staphylococcus aureus were methicillin resistant, whereas 20.4% of the coagulase-negative staphylococci were methicillin resistant. Moreover, 36.7% of Klebsiella spp. and 27.5% of E. coli were ESBL producers. Conclusion Our study provides evidence that ambulances represent a source of prehospital multidrug-resistant infections. PMID:29731647

Rifampicin treatment of canine pyoderma due to multidrug-resistant meticillin-resistant staphylococci: a retrospective study of 32 cases.

PubMed

De Lucia, Michela; Bardagi, Mar; Fabbri, Elisabetta; Ferreira, Diana; Ferrer, Lluis; Scarampella, Fabia; Zanna, Giordana; Fondati, Alessandra

2017-04-01

Rifampicin has received increased interest in veterinary dermatology because of its activity against multidrug-resistant meticillin-resistant staphylococci (MRS). There is limited knowledge about the efficacy and safety of rifampicin in dogs. To provide information on response to treatment and adverse effects in dogs treated with rifampicin for multidrug-resistant MRS pyoderma. Thirty two dogs treated with rifampicin for rifampicin-susceptible multidrug-resistant MRS pyoderma. Retrospective review of medical records, including alanine aminotransferase (ALT) and alkaline phosphatase (ALP) serum activity levels and total bilirubin concentrations, obtained before and throughout the treatment, was performed. Oral rifampicin as sole systemic antimicrobial therapy (median dose 5 mg/kg twice daily) was effective in 71.88% of cases. Topical antimicrobials were used in most cases. Median duration of rifampicin treatment was five weeks for superficial pyoderma and four weeks for deep pyoderma. Gastrointestinal signs were reported in 15% of treated dogs. Statistically significant increases of ALT (P = 0.045) and ALP (P = 0.0002) values after 3-4 weeks of treatment was observed. The median increase was equal to 0.3 and ×1.5 the upper limit of the reference ranges for ALT and ALP, respectively. Oral rifampicin combined with topical antimicrobials can be considered an effective therapeutic option for canine superficial and deep pyoderma caused by rifampicin-susceptible multidrug-resistant MRS. Liver enzyme induction might be the most important cause of ALT and ALP increase associated with rifampicin therapy in dogs. © 2016 ESVD and ACVD.

Multidrug-resistant pathogens in the food supply.

PubMed

Doyle, Marjorie E

2015-04-01

Antimicrobial resistance, including multidrug resistance (MDR), is an increasing problem globally. MDR bacteria are frequently detected in humans and animals from both more- and less-developed countries and pose a serious concern for human health. Infections caused by MDR microbes may increase morbidity and mortality and require use of expensive drugs and prolonged hospitalization. Humans may be exposed to MDR pathogens through exposure to environments at health-care facilities and farms, livestock and companion animals, human food, and exposure to other individuals carrying MDR microbes. The Centers for Disease Control and Prevention classifies drug-resistant foodborne bacteria, including Campylobacter, Salmonella Typhi, nontyphoidal salmonellae, and Shigella, as serious threats. MDR bacteria have been detected in both meat and fresh produce. Salmonellae carrying genes coding for resistance to multiple antibiotics have caused numerous foodborne MDR outbreaks. While there is some level of resistance to antimicrobials in environmental bacteria, the widespread use of antibiotics in medicine and agriculture has driven the selection of a great variety of microbes with resistance to multiple antimicrobials. MDR bacteria on meat may have originated in veterinary health-care settings or on farms where animals are given antibiotics in feed or to treat infections. Fresh produce may be contaminated by irrigation or wash water containing MDR bacteria. Livestock, fruits, and vegetables may also be contaminated by food handlers, farmers, and animal caretakers who carry MDR bacteria. All potential sources of MDR bacteria should be considered and strategies devised to reduce their presence in foods. Surveillance studies have documented increasing trends in MDR in many pathogens, although there are a few reports of the decline of certain multidrug pathogens. Better coordination of surveillance programs and strategies for controlling use of antimicrobials need to be implemented in

Battacin (Octapeptin B5), a New Cyclic Lipopeptide Antibiotic from Paenibacillus tianmuensis Active against Multidrug-Resistant Gram-Negative Bacteria

PubMed Central

Qian, Chao-Dong; Teng, Yi; Zhao, Wen-Peng; Li, Ou; Fang, Sheng-Guo; Huang, Zhao-Hui; Gao, Hai-Chun

2012-01-01

Hospital-acquired infections caused by drug-resistant bacteria are a significant challenge to patient safety. Numerous clinical isolates resistant to almost all commercially available antibiotics have emerged. Thus, novel antimicrobial agents, specifically those for multidrug-resistant Gram-negative bacteria, are urgently needed. In the current study, we report the isolation, structure elucidation, and preliminary biological characterization of a new cationic lipopeptide antibiotic, battacin or octapeptin B5, produced from a Paenibacillus tianmuensis soil isolate. Battacin kills bacteria in vitro and has potent activity against Gram-negative bacteria, including multidrug-resistant and extremely drug-resistant clinical isolates. Hospital strains of Escherichia coli and Pseudomonas aeruginosa are the pathogens most sensitive to battacin, with MICs of 2 to 4 μg/ml. The ability of battacin to disrupt the outer membrane of Gram-negative bacteria is comparable to that of polymyxin B, the last-line therapy for infections caused by antibiotic-resistant Gram-negative bacteria. However, the capacity of battacin to permeate bacterial plasma membranes is less extensive than that of polymyxin B. The bactericidal kinetics of battacin correlate with the depolarization of the cell membrane, suggesting that battacin kills bacteria by disrupting the cytoplasmic membrane. Other studies indicate that battacin is less acutely toxic than polymyxin B and has potent in vivo biological activity against E. coli. Based on the findings of the current study, battacin may be considered a potential therapeutic agent for the treatment of infections caused by antibiotic-resistant Gram-negative bacteria. PMID:22183171

LL-37-Derived Peptides Eradicate Multidrug-Resistant Staphylococcus aureus from Thermally Wounded Human Skin Equivalents

PubMed Central

de Breij, Anna; Chan, Heelam; van Dissel, Jaap T.; Drijfhout, Jan W.; Hiemstra, Pieter S.; El Ghalbzouri, Abdoelwaheb; Nibbering, Peter H.

2014-01-01

Burn wound infections are often difficult to treat due to the presence of multidrug-resistant bacterial strains and biofilms. Currently, mupirocin is used to eradicate methicillin-resistant Staphylococcus aureus (MRSA) from colonized persons; however, mupirocin resistance is also emerging. Since we consider antimicrobial peptides to be promising candidates for the development of novel anti-infective agents, we studied the antibacterial activities of a set of synthetic peptides against different strains of S. aureus, including mupirocin-resistant MRSA strains. The peptides were derived from P60.4Ac, a peptide based on the human cathelicidin LL-37. The results showed that peptide 10 (P10) was the only peptide more efficient than P60.4Ac, which is better than LL-37, in killing MRSA strain LUH14616. All three peptides displayed good antibiofilm activities. However, both P10 and P60.4Ac were more efficient than LL-37 in eliminating biofilm-associated bacteria. No toxic effects of these three peptides on human epidermal models were detected, as observed morphologically and by staining for mitochondrial activity. In addition, P60.4Ac and P10, but not LL-37, eradicated MRSA LUH14616 and the mupirocin-resistant MRSA strain LUH15051 from thermally wounded human skin equivalents (HSE). Interestingly, P60.4Ac and P10, but not mupirocin, eradicated LUH15051 from the HSEs. None of the peptides affected the excretion of interleukin 8 (IL-8) by thermally wounded HSEs upon MRSA exposure. In conclusion, the synthetic peptides P60.4Ac and P10 appear to be attractive candidates for the development of novel local therapies to treat patients with burn wounds infected with multidrug-resistant bacteria. PMID:24841266

Genomic Definition of Hypervirulent and Multidrug-Resistant Klebsiella pneumoniae Clonal Groups

PubMed Central

Bialek-Davenet, Suzanne; Criscuolo, Alexis; Ailloud, Florent; Passet, Virginie; Jones, Louis; Delannoy-Vieillard, Anne-Sophie; Garin, Benoit; Le Hello, Simon; Arlet, Guillaume; Nicolas-Chanoine, Marie-Hélène; Decré, Dominique

2014-01-01

Multidrug-resistant and highly virulent Klebsiella pneumoniae isolates are emerging, but the clonal groups (CGs) corresponding to these high-risk strains have remained imprecisely defined. We aimed to identify K. pneumoniae CGs on the basis of genome-wide sequence variation and to provide a simple bioinformatics tool to extract virulence and resistance gene data from genomic data. We sequenced 48 K. pneumoniae isolates, mostly of serotypes K1 and K2, and compared the genomes with 119 publicly available genomes. A total of 694 highly conserved genes were included in a core-genome multilocus sequence typing scheme, and cluster analysis of the data enabled precise definition of globally distributed hypervirulent and multidrug-resistant CGs. In addition, we created a freely accessible database, BIGSdb-Kp, to enable rapid extraction of medically and epidemiologically relevant information from genomic sequences of K. pneumoniae. Although drug-resistant and virulent K. pneumoniae populations were largely nonoverlapping, isolates with combined virulence and resistance features were detected. PMID:25341126

[Multidrug-Resistant Tuberculosis by Strains of Beijing Family, in Patients from Lisbon, Portugal: Preliminary Report].

PubMed

Maltez, Fernando; Martins, Teresa; Póvoas, Diana; Cabo, João; Peres, Helena; Antunes, Francisco; Perdigão, João; Portugal, Isabel

2017-03-31

Beijing family strains of Mycobacterium tuberculosis are associated with multidrug-resistance. Although strains of the Lisboa family are the most common among multidrug-resistant and extensively drug-resistant patients in the region, several studies have reported the presence of the Beijing family. However, the features of patients from whom they were isolated, are not yet known. Retrospective study involving 104 multidrug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis, from the same number of patients, isolated and genotyped between 1993 and 2015 in Lisbon. We assessed the prevalence of strains of both families and the epidemiologic and clinical features of those infected with Beijing family strains. Seventy-four strains (71.2%) belonged to the Lisboa family, 25 (24.0%) showed a unique genotypic pattern and five (4.8%) belonged to the Beijing family, the latter identified after 2009. Those infected with Beijing family strains were angolan (n = 1), ukrainian (n = 2) and portuguese (n = 2), mainly young-aged and, four of five immunocompetent and with no past history of tuberculosis. All had multidrug-resistant tuberculosis. We did not find any distinctive clinical or radiological features, neither a predominant resistance pattern. Cure rate was high (four patients). Although the number of infected patients with Beijing strains was small, it suggests an important proportion of primary tuberculosis, a potential for transmission in the community but also a better clinical outcome when compared to other reported strains, such as W-Beijing and Lisboa. Although Lisboa family strains account for most of the multidrug and extensively drug-resistant tuberculosis cases in Lisbon area, Beijing strains are transmitted in the city and might change the local characteristics of the epidemics.

Reversal of multidrug resistance by surfactants.

PubMed Central

Woodcock, D. M.; Linsenmeyer, M. E.; Chojnowski, G.; Kriegler, A. B.; Nink, V.; Webster, L. K.; Sawyer, W. H.

1992-01-01

Cremophor EL, a pharmacologically inactive solubilising agent, has been shown to reverse multidrug resistance (MDR). Using flow cytometric evaluation of equilibrium intracellular levels of daunorubicin (DNR), we found that eight other surface active agents will also reverse MDR. All the active detergents contain polyethoxylated moieties but have no similarities in their hydrophobic components. The properties of three polyethoxylated surfactants that showed the lowest toxicities, Cremophor, Tween 80 and Solutol HS15, were examined in more detail. The concentrations of Tween 80 and Solutol required to reverse DNR exclusion were 10-fold lower than for Cremophor. However while concentrations greater than or equal to 1:10(2) of the former two surfactants resulted in breakdown of cells, even 1:10 of Cremophor did not lyse cells. Studies of the effects of Cremophor on the uptake and efflux of DNR in normal and MDR cell types showed that Cremophor increases intracellular DNR primarily by locking the rapid efflux from the cells. This blockage of drug efflux may be mediated by a substantial alteration in the fluidity of cell membranes induced by Cremophor, as shown by decreased fluorescence anisotropy of a membrane probe. Consistent with these data, coinjection of adriamycin plus Cremophor into mice carrying a multidrug resistant P388 transplantable tumour significantly increased the survival time of the mice compared with adriamycin treatment alone. PMID:1637678

Mixture model to assess the extent of cross-transmission of multidrug-resistant pathogens in hospitals.

PubMed

Mikolajczyk, Rafael T; Kauermann, Göran; Sagel, Ulrich; Kretzschmar, Mirjam

2009-08-01

Creation of a mixture model based on Poisson processes for assessment of the extent of cross-transmission of multidrug-resistant pathogens in the hospital. We propose a 2-component mixture of Poisson processes to describe the time series of detected cases of colonization. The first component describes the admission process of patients with colonization, and the second describes the cross-transmission. The data set used to illustrate the method consists of the routinely collected records for methicillin-resistant Staphylococcus aureus (MRSA), imipenem-resistant Pseudomonas aeruginosa, and multidrug-resistant Acinetobacter baumannii over a period of 3 years in a German tertiary care hospital. For MRSA and multidrug-resistant A. baumannii, cross-transmission was estimated to be responsible for more than 80% of cases; for imipenem-resistant P. aeruginosa, cross-transmission was estimated to be responsible for 59% of cases. For new cases observed within a window of less than 28 days for MRSA and multidrug-resistant A. baumannii or 40 days for imipenem-resistant P. aeruginosa, there was a 50% or greater probability that the cause was cross-transmission. The proposed method offers a solution to assessing of the extent of cross-transmission, which can be of clinical use. The method can be applied using freely available software (the package FlexMix in R) and it requires relatively little data.

Multidrug Resistance-Associated Protein 1 (MRP1) mediated vincristine resistance: effects of N-acetylcysteine and Buthionine Sulfoximine

PubMed Central

Akan, Ilhan; Akan, Selma; Akca, Hakan; Savas, Burhan; Ozben, Tomris

2005-01-01

Background Multidrug resistance mediated by the multidrug resistance-associated protein 1 (MRP1) decreases cellular drug accumulation. The exact mechanism of MRP1 involved multidrug resistance has not been clarified yet, though glutathione (GSH) is likely to have a role for the resistance to occur. N-acetylcysteine (NAC) is a pro-glutathione drug. DL-Buthionine (S,R)-sulfoximine (BSO) is an inhibitor of GSH synthesis. The aim of our study was to investigate the effect of NAC and BSO on MRP1-mediated vincristine resistance in Human Embryonic Kidney (HEK293) and its MRP1 transfected 293MRP cells. Human Embryonic Kidney (HEK293) cells were transfected with a plasmid encoding whole MRP1 gene. Both cells were incubated with vincristine in the presence or absence of NAC and/or BSO. The viability of both cells was determined under different incubation conditions. GSH, Glutathione S-Transferase (GST) and glutathione peroxidase (GPx) levels were measured in the cell extracts obtained from both cells incubated with different drugs. Results N-acetylcysteine increased the resistance of both cells against vincristine and BSO decreased NAC-enhanced MRP1-mediated vincristine resistance, indicating that induction of MRP1-mediated vincristine resistance depends on GSH. Vincristine decreased cellular GSH concentration and increased GPx activity. Glutathione S-Transferase activity was decreased by NAC. Conclusion Our results demonstrate that NAC and BSO have opposite effects in MRP1 mediated vincristine resistance and BSO seems a promising chemotherapy improving agent in MRP1 overexpressing tumor cells. PMID:16042792

Molecular screening of antibiotic-resistant determinants among multidrug-resistant clinical isolates of Proteus mirabilis from SouthWest Nigeria.

PubMed

Alabi, Olumuyiwa Samuel; Mendonça, Nuno; Adeleke, Olufemi Ezekiel; da Silva, Gabriela Jorge

2017-06-01

Globally, and particularly in developing countries, the menace of anti-microbial resistance is an accelerating problem. In Nigeria, increase in bacterial resistance has been phenotypically established but due to high cost, few molecular studies have been reported. This study screened for presence of transferable resistance genes and mobile genetic elements (MGEs) such as integron among multi-drug resistant (MDR) P. mirabilis . A total of 108 P. mirabilis strains collected from five tertiary hospitals in SouthWest Nigeria were subjected to antibiotic susceptibility study using disc-diffusion method. Transferable resistance genes and MGEs were amplified using Polymerase chain reaction (PCR) analysis and amplicons sequenced. Varied resistance was observed against all the antibiotics tested. About 56% of the isolates were MDR including those from 0-12 years old children. PCR analysis revealed the presence of aac(6')-Ib (33.3%), plasmid mediated quinolone resistance (PMQR) genes [qnrA (36.7%), acc(6')-Ib-cr (5%)], TEM (48.3%), CTX-M (6.7%) and integrons class 1 (58.3%) and class 2 (26.7%). Sequencing analysis revealed bla TEM-1 , bla CTX-M-15 associated with IS Ecp1 and eight different arrays of gene cassettes: aadA1, aadA1-qacH, aadB-aadA2, aadA5, dfrA7, dfrA15, dfrA17, dfrA17-aadA5 . Transferable resistance genes in association with MGEs are present in Nigerian P. mirabilis thus their potential in disseminating resistance.

Origin and Proliferation of Multiple-Drug Resistance in Bacterial Pathogens

PubMed Central

Chang, Hsiao-Han; Cohen, Ted; Grad, Yonatan H.; Hanage, William P.; O'Brien, Thomas F.

2015-01-01

SUMMARY Many studies report the high prevalence of multiply drug-resistant (MDR) strains. Because MDR infections are often significantly harder and more expensive to treat, they represent a growing public health threat. However, for different pathogens, different underlying mechanisms are traditionally used to explain these observations, and it is unclear whether each bacterial taxon has its own mechanism(s) for multidrug resistance or whether there are common mechanisms between distantly related pathogens. In this review, we provide a systematic overview of the causes of the excess of MDR infections and define testable predictions made by each hypothetical mechanism, including experimental, epidemiological, population genomic, and other tests of these hypotheses. Better understanding the cause(s) of the excess of MDR is the first step to rational design of more effective interventions to prevent the origin and/or proliferation of MDR. PMID:25652543

Beyond multidrug-resistant tuberculosis in Europe: a TBNET study.

PubMed

Günther, G; van Leth, F; Altet, N; Dedicoat, M; Duarte, R; Gualano, G; Kunst, H; Muylle, I; Spinu, V; Tiberi, S; Viiklepp, P; Lange, C

2015-12-01

The emergence of drug-resistant tuberculosis (TB) is a challenge to TB control in Europe. We evaluated second-line drug susceptibility testing in Mycobacterium tuberculosis isolates from patients with multidrug-resistant, pre-extensively drug-resistant (pre-XDR-TB) and XDR-TB at 23 TBNET sites in 16 European countries. Over 30% of bacilli from patients with pre-XDR-TB showed resistance to any fluoroquinolone and almost 70% to any second-line injectable drug. Respectively >90% and >80% of the XDR-TB strains tested showed phenotypic resistance to pyrazinamide and ethambutol. Resistance to prothionamide/ethionamide was high in bacilli from pre-XDR-TB patients (43%) and XDR-TB patients (49%).

Comparative genomics of the IncA/C multidrug resistance plasmid family

USDA-ARS?s Scientific Manuscript database

Multidrug resistance (MDR) plasmids belonging to the IncA/C plasmid family are widely distributed among Salmonella and other enterobacterial isolates from agricultural sources and have, at least once, also been identified in a drug resistant Yersinia pestis isolate (IP275) from Madagascar. Here, we...

Carbapenem Susceptibility and Multidrug-Resistance in Pseudomonas aeruginosa Isolates in Egypt

PubMed Central

Hashem, Hany; Hanora, Amro; Abdalla, Salah; Shawky, Alaa; Saad, Alaa

2016-01-01

Background Resistant Pseudomonas aeruginosa is a serious concern for antimicrobial therapy, as the common isolates exhibit variable grades of resistance, involving beta-lactamase enzymes, beside native defense mechanisms. Objectives The present study was designed to determine the occurrence of Metallo-β- Lactamases (MBL) and Amp C harboring P. aeruginosa isolates from Suez Canal university hospital in Ismailia, Egypt. Methods A total of 147 P. aeruginosa isolates, recovered from 311 patients during a 10-month period, were collected between May 2013 and February 2014; the isolates were collected from urine, wound and sputum. Minimum inhibitory concentration (MIC) determined by agar dilution methods was ≥2 μg/mL for meropenem and imipenem. Identification of P. aeruginosa was confirmed using API 20NE. Metallo-β- Lactamases and Amp C were detected based on different phenotypic methods. Results Overall, 26.5% of P. aeruginosa isolates (39/147) were carbapenem resistant isolates. Furthermore, 64.1% (25/39) were MBL producers, these isolates were screened by the combined disc and disc diffusion methods to determine the ability of MBL production. Both MBL and Amp C harbored P. aeruginosa isolates were 28% (7/25). Sixty-four percent of P. aeruginosa isolates were multidrug resistant (MDR) (16/25). The sensitivity toward polymyxin, imipenem, norfloxacin, piperacillin-tazobactam and gentamicin was 99%, 91%, 88%, 82% and 78%, respectively. The resistance rate towards cefotaxime, ceftazidime, cefepime, aztreonam and meropenem was 98.6%, 86%, 71.4%, 34% and 30%, respectively. Conclusions Multidrug resistance was significantly associated with MBL production in P. aeruginosa. Early detection of MBL-producing P. aeruginosa and hospital antibiotic policy prescription helps proper antimicrobial therapy and avoidance of dissemination of these multidrug resistance isolates. PMID:28138370

Carbapenem Susceptibility and Multidrug-Resistance in Pseudomonas aeruginosa Isolates in Egypt.

PubMed

Hashem, Hany; Hanora, Amro; Abdalla, Salah; Shawky, Alaa; Saad, Alaa

2016-11-01

Resistant Pseudomonas aeruginosa is a serious concern for antimicrobial therapy, as the common isolates exhibit variable grades of resistance, involving beta-lactamase enzymes, beside native defense mechanisms. The present study was designed to determine the occurrence of Metallo-β- Lactamases (MBL) and Amp C harboring P. aeruginosa isolates from Suez Canal university hospital in Ismailia, Egypt. A total of 147 P. aeruginosa isolates, recovered from 311 patients during a 10-month period, were collected between May 2013 and February 2014; the isolates were collected from urine, wound and sputum. Minimum inhibitory concentration (MIC) determined by agar dilution methods was ≥2 μg/mL for meropenem and imipenem. Identification of P. aeruginosa was confirmed using API 20NE. Metallo-β- Lactamases and Amp C were detected based on different phenotypic methods. Overall, 26.5% of P. aeruginosa isolates (39/147) were carbapenem resistant isolates. Furthermore, 64.1% (25/39) were MBL producers, these isolates were screened by the combined disc and disc diffusion methods to determine the ability of MBL production. Both MBL and Amp C harbored P. aeruginosa isolates were 28% (7/25). Sixty-four percent of P. aeruginosa isolates were multidrug resistant (MDR) (16/25). The sensitivity toward polymyxin, imipenem, norfloxacin, piperacillin-tazobactam and gentamicin was 99%, 91%, 88%, 82% and 78%, respectively. The resistance rate towards cefotaxime, ceftazidime, cefepime, aztreonam and meropenem was 98.6%, 86%, 71.4%, 34% and 30%, respectively. Multidrug resistance was significantly associated with MBL production in P. aeruginosa . Early detection of MBL-producing P. aeruginosa and hospital antibiotic policy prescription helps proper antimicrobial therapy and avoidance of dissemination of these multidrug resistance isolates.

Discovery and Optimization of Indolyl-Containing 4-Hydroxy-2-Pyridone Type II DNA Topoisomerase Inhibitors Active against Multidrug Resistant Gram-negative Bacteria.

PubMed

Gerasyuto, Aleksey I; Arnold, Michael A; Wang, Jiashi; Chen, Guangming; Zhang, Xiaoyan; Smith, Sean; Woll, Matthew G; Baird, John; Zhang, Nanjing; Almstead, Neil G; Narasimhan, Jana; Peddi, Srinivasa; Dumble, Melissa; Sheedy, Josephine; Weetall, Marla; Branstrom, Arthur A; Prasad, J V N; Karp, Gary M

2018-05-14

There exists an urgent medical need to identify new chemical entities (NCEs) targeting multidrug resistant (MDR) bacterial infections, particularly those caused by Gram-negative pathogens. 4-Hydroxy-2-pyridones represent a novel class of nonfluoroquinolone inhibitors of bacterial type II topoisomerases active against MDR Gram-negative bacteria. Herein, we report on the discovery and structure-activity relationships of a series of fused indolyl-containing 4-hydroxy-2-pyridones with improved in vitro antibacterial activity against fluoroquinolone resistant strains. Compounds 6o and 6v are representative of this class, targeting both bacterial DNA gyrase and topoisomerase IV (Topo IV). In an abbreviated susceptibility screen, compounds 6o and 6v showed improved MIC 90 values against Escherichia coli (0.5-1 μg/mL) and Acinetobacter baumannii (8-16 μg/mL) compared to the precursor compounds. In a murine septicemia model, both compounds showed complete protection in mice infected with a lethal dose of E. coli.

High Diversity of Antimicrobial Resistance Genes, Class 1 Integrons, and Genotypes of Multidrug-Resistant Escherichia coli in Beef Carcasses.

PubMed

Chen, Chih-Ming; Ke, Se-Chin; Li, Chia-Ru; Wu, Ying-Chen; Chen, Ter-Hsin; Lai, Chih-Ho; Wu, Xin-Xia; Wu, Lii-Tzu

2017-10-01

Multidrug-resistant Escherichia coli can contaminate food meat during processing and cause human infection. Phenotypic and genotypic characterization of the antimicrobial resistance were conducted for 45 multidrug-resistant E. coli isolates from 208 samples of beef carcasses. The mechanisms of resistance were evaluated using polymerase chain reaction and sequencing methods, and the clonal relationship among isolates was evaluated using multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE). Different variants of bla, tet, flo, dfrA, and aadA genes were detected in most of the strains resistant to β-lactam, tetracycline, chloramphenicol, sulfonamides, and aminoglycosides, respectively. Extended-spectrum β-lactamase (ESBL)-producing E. coli was found in 42.2% of the 45 E. coli isolates and the most commonly detected ESBL genotypes were CTX-M group 1 and 9. Class 1 integrons with nine different arrangements of gene cassettes were present in 28 of 45 E. coli isolates. Twenty-nine PFGE groups and 24 MLST types were identified in their clonal structure. This study revealed that E. coli isolates from beef contained high diversity of antimicrobial resistance genes, integrons, and genotypes. These results highlighted the role of beef meat as a potential source for multidrug-resistant E. coli strains and the need for controlling beef safety.

Secretome profile analysis of multidrug-resistant, monodrug-resistant and drug-susceptible Mycobacterium tuberculosis.

PubMed

Putim, Chanyanuch; Phaonakrop, Narumon; Jaresitthikunchai, Janthima; Gamngoen, Ratikorn; Tragoolpua, Khajornsak; Intorasoot, Sorasak; Anukool, Usanee; Tharincharoen, Chayada Sitthidet; Phunpae, Ponrut; Tayapiwatana, Chatchai; Kasinrerk, Watchara; Roytrakul, Sittiruk; Butr-Indr, Bordin

2018-03-01

The emergence of drug-resistant tuberculosis has generated great concern in the control of tuberculosis and HIV/TB patients have established severe complications that are difficult to treat. Although, the gold standard of drug-susceptibility testing is highly accurate and efficient, it is time-consuming. Diagnostic biomarkers are, therefore, necessary in discriminating between infection from drug-resistant and drug-susceptible strains. One strategy that aids to effectively control tuberculosis is understanding the function of secreting proteins that mycobacteria use to manipulate the host cellular defenses. In this study, culture filtrate proteins from Mycobacterium tuberculosis H37Rv, isoniazid-resistant, rifampicin-resistant and multidrug-resistant strains were gathered and profiled by shotgun-proteomics technique. Mass spectrometric analysis of the secreted proteome identified several proteins, of which 837, 892, 838 and 850 were found in M. tuberculosis H37Rv, isoniazid-resistant, rifampicin-resistant and multidrug-resistant strains, respectively. These proteins have been implicated in various cellular processes, including biological adhesion, biological regulation, developmental process, immune system process localization, cellular process, cellular component organization or biogenesis, metabolic process, and response to stimulus. Analysis based on STITCH database predicted the interaction of DNA topoisomerase I, 3-oxoacyl-(acyl-carrier protein) reductase, ESAT-6-like protein, putative prophage phiRv2 integrase, and 3-phosphoshikimate 1-carboxyvinyltransferase with isoniazid, rifampicin, pyrazinamide, ethambutol and streptomycin, suggesting putative roles in controlling the anti-tuberculosis ability. However, several proteins with no interaction with all first-line anti-tuberculosis drugs might be used as markers for mycobacterial identification.

Virulence properties of multidrug resistant ocular isolates of Acinetobacter baumannii.

PubMed

Talreja, Deepa; Muraleedharan, Chithra; Gunathilaka, Gayathri; Zhang, Yifan; Kaye, Keith S; Walia, Satish K; Kumar, Ashok

2014-07-01

Acinetobacter (A.) baumannii is an opportunistic pathogen and has been reported as a causative agent of ocular infections. The aim of this study is to identify virulence properties (biofilm formation, adhesion, invasion and cytotoxicity) and antibiotic resistance among A. baumannii isolates recovered from the eye. The Microscan Walk-Away®, an automated bacterial identification and susceptibility testing system was used to determine antibiotic resistance. Clonal relatedness was assessed by Pulsed-field gel electrophoresis (PFGE) and plasmid profile analysis. Conjugation experiments were carried out to determine the transfer of antibiotic resistance genes and PCR was used to confirm gene transfer. Virulence properties of the isolates were determined by biofilm formation using crystal violet and immunofluorescence staining, adherence and internalization using cultured corneal epithelial cells, and cytotoxicity by TUNEL-staining and LDH release assays. All ocular isolates (n = 12) exhibited multidrug resistant (MDR) phenotype and one of the isolate (AB12) was resistant to 18 antibiotics (β-lactam, aminoglycosides, tetracycline, chloramphenicol and quinolones). The plasmid profile analysis showed the presence of multiple plasmids in each isolate and a total of 10 different profiles were observed. However, PFGE analysis was more discriminatory which revealed 12 distinct genotypes. Antibiotic resistance (tetracycline and quinolone) was transferable from the isolate AB12 to a recipient Escherichia coli J53. Ten isolates were strong biofilm producers and the remaining two (AB5 and AB7) were moderate producers. All isolates demonstrated adherence and invasive properties towards HCECs. A similar trend was observed in their ability to cause cell death and toxicity. Our results indicate that ocular isolates of A. baumannii are biofilm producers and adherent and invasive to corneal epithelium, a first step in the pathogenesis of ocular infection. In addition, they

Multidrug resistant bacteria are sensitive to Euphorbia prostrata and six others Cameroonian medicinal plants extracts.

PubMed

Voukeng, Igor K; Beng, Veronique P; Kuete, Victor

2017-07-25

Multidrug resistant (MDR) bacteria are responsible for therapeutic failure and there is an urgent need for novels compounds efficient on them. Eleven methanol extracts from seven Cameroonian medicinal plants were tested for their antibacterial activity using broth micro-dilution method against 36 MDR bacterial strains including Escherichia coli, Enterobacter aerogenes, Enterobacter cloacae, Klebsiella pneumoniae, Providencia stuartii, Pseudomonas aeruginosa and Staphylococcus aureus. Euphorbia prostrata extract was found active against all the 36 tested bacteria including Gram-negative phenotypes over-expressing efflux pumps such as P. aeruginosa PA124, E. aerogenes CM64 and E. coli AG102. E. prostrata had minimal inhibitory concentrations values between 128 and 256 µg/mL on 55.55% of the studied microorganisms. Other plants extract displayed selective antibacterial activity. Results obtained in this study highlight the antibacterial potential of the tested plants and the possible use of E. prostrata to combat bacterial infections including MDR phenotypes.

Genetic diversity of drug and multidrug-resistant Mycobacterium tuberculosis circulating in Veracruz, Mexico

PubMed Central

Munro-Rojas, Daniela; Fernandez-Morales, Esdras; Zarrabal-Meza, José; Martínez-Cazares, Ma. Teresa; Parissi-Crivelli, Aurora; Fuentes-Domínguez, Javier; Séraphin, Marie Nancy; Lauzardo, Michael; González-y-Merchand, Jorge Alberto; Rivera-Gutierrez, Sandra

2018-01-01

Background Mexico is one of the most important contributors of drug and multidrug-resistant tuberculosis in Latin America; however, knowledge of the genetic diversity of drug-resistant tuberculosis isolates is limited. Methods In this study, the genetic structure of 112 Mycobacterium tuberculosis strains from the southeastern Mexico was determined by spoligotyping and 24-loci MIRU-VNTRs. Findings The results show eight major lineages, the most of which was T1 (24%), followed by LAM (16%) and H (15%). A total of 29 (25%) isolates were identified as orphan. The most abundant SITs were SIT53/T1 and SIT42/LAM9 with 10 isolates each and SIT50/H3 with eight isolates. Fifty-two spoligotype patterns, twenty-seven clusters and ten clonal complexes were observed, demonstrating an important genetic diversity of drug and multidrug-resistant tuberculosis isolates in circulation and transmission level of these aggravated forms of tuberculosis. Being defined as orphan or as part of an orphan cluster, was a risk factor for multidrug resistant-tuberculosis (OR 2.5, IC 1.05–5.86 and OR 3.3, IC 1–11.03, respectively). Multiple correspondence analyses showed association of some clusters and SITs with specific geographical locations. Conclusions Our study provides one of the most detailed description of the genetic structure of drug and multidrug-resistant tuberculosis strains in southeast Mexico, establishing for the first time a baseline of the genotypes observed in resistant isolates circulating, however further studies are required to better elucidate the genetic structure of tuberculosis in region and the factors that could be participating in their dispersion. PMID:29543819

Multidrug-Resistant Bacteria Isolated from Surface Water in Bassaseachic Falls National Park, Mexico.

PubMed

Delgado-Gardea, Ma Carmen E; Tamez-Guerra, Patricia; Gomez-Flores, Ricardo; Zavala-Díaz de la Serna, Francisco Javier; Eroza-de la Vega, Gilberto; Nevárez-Moorillón, Guadalupe Virginia; Pérez-Recoder, María Concepción; Sánchez-Ramírez, Blanca; González-Horta, María Del Carmen; Infante-Ramírez, Rocío

2016-06-16

Bacterial pathogens are a leading cause of waterborne disease, and may result in gastrointestinal outbreaks worldwide. Inhabitants of the Bassaseachic Falls National Park in Chihuahua, Mexico show seasonal gastroenteritis problems. This aim of this study was to detect enteropathogenic microorganisms responsible for diarrheal outbreaks in this area. In 2013, 49 surface water samples from 13 selected sampling sites along the Basaseachi waterfall and its main rivers, were collected during the spring, summer, autumn, and winter seasons. Fecal and total coliform counts were determined using standard methods; the AutoScan-4 system was used for identification of isolates and the antibiotic resistance profile by challenging each organism using 21 antibiotics. Significant differences among seasons were detected, where autumn samples resulted in the highest total (p < 0.05) and fecal (p < 0.001) coliform counts, whereas the lowest total coliform counts were recorded in spring. Significant differences between sampling sites were observed, where samples from sites 6, 8, and 11 had the highest total coliform counts (p < 0.009), whereas samples from site 9 exhibited the lowest one. From the microbiological analysis, 33 bacterial isolates from 13 different sites and four sampling seasons were selected; 53% of isolates were resistant to at least one antibiotic, and 15% exhibited a multidrug resistance (MDB) phenotype. MDB were identified as Klebsiella oxytoca (two out of four identified isolates), Escherichia coli (2/7), and Enterobacter cloacae (1/3). In addition, some water-borne microorganisms exhibited resistance to cefazoline, cefuroxime, ampicillin, and ampicillin-sulbactam. The presence of these microorganisms near rural settlements suggests that wastewater is the contamination source, providing one possible transmission mechanism for diarrheal outbreaks.

Multidrug-Resistant Bacteria Isolated from Surface Water in Bassaseachic Falls National Park, Mexico

PubMed Central

Delgado-Gardea, Ma. Carmen E.; Tamez-Guerra, Patricia; Gomez-Flores, Ricardo; Zavala-Díaz de la Serna, Francisco Javier; Eroza-de la Vega, Gilberto; Nevárez-Moorillón, Guadalupe Virginia; Pérez-Recoder, María Concepción; Sánchez-Ramírez, Blanca; González-Horta, María del Carmen; Infante-Ramírez, Rocío

2016-01-01

Bacterial pathogens are a leading cause of waterborne disease, and may result in gastrointestinal outbreaks worldwide. Inhabitants of the Bassaseachic Falls National Park in Chihuahua, Mexico show seasonal gastroenteritis problems. This aim of this study was to detect enteropathogenic microorganisms responsible for diarrheal outbreaks in this area. In 2013, 49 surface water samples from 13 selected sampling sites along the Basaseachi waterfall and its main rivers, were collected during the spring, summer, autumn, and winter seasons. Fecal and total coliform counts were determined using standard methods; the AutoScan-4 system was used for identification of isolates and the antibiotic resistance profile by challenging each organism using 21 antibiotics. Significant differences among seasons were detected, where autumn samples resulted in the highest total (p < 0.05) and fecal (p < 0.001) coliform counts, whereas the lowest total coliform counts were recorded in spring. Significant differences between sampling sites were observed, where samples from sites 6, 8, and 11 had the highest total coliform counts (p < 0.009), whereas samples from site 9 exhibited the lowest one. From the microbiological analysis, 33 bacterial isolates from 13 different sites and four sampling seasons were selected; 53% of isolates were resistant to at least one antibiotic, and 15% exhibited a multidrug resistance (MDB) phenotype. MDB were identified as Klebsiella oxytoca (two out of four identified isolates), Escherichia coli (2/7), and Enterobacter cloacae (1/3). In addition, some water-borne microorganisms exhibited resistance to cefazoline, cefuroxime, ampicillin, and ampicillin-sulbactam. The presence of these microorganisms near rural settlements suggests that wastewater is the contamination source, providing one possible transmission mechanism for diarrheal outbreaks. PMID:27322297

Modified live Edwardsiella ictaluri vaccine, AQUAVAC-ESC, lacks multidrug resistance plasmids

USDA-ARS?s Scientific Manuscript database

Plasmid mediated antibiotic resistance was first discovered in Edwardsiella ictaluri in the early 1990’s, and in 2007 an E. ictaluri isolate harboring an IncA/C plasmid was recovered from a moribund channel catfish infected with the bacterium. Due to the identification of multidrug resistance plasm...

Health system factors influencing management of multidrug-resistant tuberculosis in four European Union countries - learning from country experiences.

PubMed

de Vries, Gerard; Tsolova, Svetla; Anderson, Laura F; Gebhard, Agnes C; Heldal, Einar; Hollo, Vahur; Cejudo, Laura Sánchez-Cambronero; Schmid, Daniela; Schreuder, Bert; Varleva, Tonka; van der Werf, Marieke J

2017-04-19

In the European Union and European Economic Area only 38% of multidrug-resistant tuberculosis patients notified in 2011 completed treatment successfully at 24 months' evaluation. Socio-economic factors and patient factors such as demographic characteristics, behaviour and attitudes are associated with treatment outcomes. Characteristics of healthcare systems also affect health outcomes. This study was conducted to identify and better understand the contribution of health system components to successful treatment of multidrug-resistant tuberculosis. We selected four European Union countries to provide for a broad range of geographical locations and levels of treatment success rates of the multidrug-resistant tuberculosis cohort in 2009. We conducted semi-structured interviews following a conceptual framework with representatives from policy and planning authorities, healthcare providers and civil society organisations. Responses were organised according to the six building blocks of the World Health Organization health systems framework. In the four included countries, Austria, Bulgaria, Spain, and the United Kingdom, the following healthcare system factors were perceived as key to achieving good treatment results for patients with multidrug-resistant tuberculosis: timely diagnosis of drug-resistant tuberculosis; financial systems that ensure access to a full course of treatment and support for multidrug-resistant tuberculosis patients; patient-centred approaches with strong intersectoral collaboration that address patients' emotional and social needs; motivated and dedicated healthcare workers with sufficient mandate and means to support patients; and cross-border management of multidrug-resistant tuberculosis to secure continuum of care between countries. We suggest that the following actions may improve the success of treatment for multidrug-resistant tuberculosis patients: deployment of rapid molecular diagnostic tests; development of context-specific treatment

Characterization of multidrug-resistant diabetic foot ulcer enterococci.

PubMed

Semedo-Lemsaddek, Teresa; Mottola, Carla; Alves-Barroco, Cynthia; Cavaco-Silva, Patrícia; Tavares, Luís; Oliveira, Manuela

2016-02-01

Diabetes mellitus is a highly prevalent chronic progressive disease with complications that include diabetic-foot ulcers. Enterococci isolated from diabetic-foot infections were identified, evaluated by macro-restriction analysis, and screened for virulence traits and antimicrobial resistance. All isolates were considered multidrug-resistant, cytolysin and gelatinase producers, and the majority also demonstrated the ability to produce biofilms. These results indicate the importance of enterococci in diabetic-foot infection development and persistence, especially regarding their biofilm-forming ability and resistance to clinically relevant antibiotics. Copyright © 2015 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

Characterization and purification of a bacteriocin from Lactobacillus paracasei subsp. paracasei BMK2005, an intestinal isolate active against multidrug-resistant pathogens.

PubMed

Bendjeddou, Kamel; Fons, Michel; Strocker, Pierre; Sadoun, Djamila

2012-04-01

A strain of Lactobacillus paracasei subsp. paracasei BMK2005 isolated from healthy infant faeces has shown a remarkable antibacterial activity against 32 bacterial pathogenic strains of human clinical isolates. Among them, 13 strains belonging to species of Escherichia coli, Citrobacter freundii, Citrobacter diversus, Klebsiella oxytoca, Enterobacter cloacae and Pseudomonas aeruginosa were resistant to Cefotaxime (CTX) and Ceftazidime (CAZ), and 4 strains of Staphylococcus aureus were resistant to Methicillin (MRSA). This antibacterial activity was attributed to a bacteriocin designated as Paracaseicin A. It was heat-stable up to 120°C for 5 min and active within the pH range of 2-5. Its activity was lost when treated with proteases, which reveals its proteinaceous nature. This bacteriocin was successfully purified only by two steps of reversed phase chromatography. Its molecular mass, determined by mass spectrometry analysis, was 2,462.5 Da. To our knowledge, the present study is the first report on characterization and purification of a bacteriocin, produced by a L. paracasei subsp. paracasei strain exhibiting an antibacterial activity against various multidrug-resistant species of Gram-positive and Gram-negative bacteria, which reveals its potential for use in prevention or treatment of infections caused by multidrug-resistant species especially in cases of antibiotics-associated diarrhea (AAD).

Antibacterial and antioxidant activities of Musa sp. leaf extracts against multidrug resistant clinical pathogens causing nosocomial infection.

PubMed

Karuppiah, Ponmurugan; Mustaffa, Muhammed

2013-09-01

To investigate different Musa sp. leave extracts of hexane, ethyl acetate and methanol were evaluated for antibacterial activity against multi-drug resistant pathogens causing nosocomial infection by agar well diffusion method and also antioxidant activities. The four different Musa species leaves were extracted with hexane, ethyl acetate and methanol. Antibacterial susceptibility test, minimum inhibitory concentration and minimum inhibitory bacterial concentration were determined by agar well diffusion method. Total phenolic content and in vitro antioxidant activity was determined. All the Musa sp. extracts showed moderate antibacterial activities expect Musa paradisiaca with the inhibition zone ranging from 8.0 to 18.6 mm. Among four species ethyl acetate extracts of Musa paradisiaca showed highest activity against tested pathogens particularly E. coli, P. aeruginosa and Citrobacter sp. The minimum inhibitory concentrations were within the value of 15.63- 250 µg/mL and minimum bactericidal concentrations were ranging from 31.25- 250 µg/mL. Antioxidant activity of Musa acuminate exhibited maximum activity among other three Musa species. The present study concluded that among the different Musa species, Musa paradisiaca displayed efficient antibacterial activity followed by Musa acuminata against multi-drug resistant nosocomial infection causing pathogens. Further, an extensive study is needed to identify the bioactive compounds, mode of action and toxic effect in vivo of Musa sp.

In vitro antibacterial activity of rifampicin in combination with imipenem, meropenem and doripenem against multidrug-resistant clinical isolates of Pseudomonas aeruginosa.

PubMed

Hu, Yi-Fan; Liu, Chang-Pan; Wang, Nai-Yu; Shih, Shou-Chuan

2016-08-24

Multidrug-resistant Pseudomonas aeruginosa has emerged as one of the most important healthcare-associated pathogens. Colistin is regarded as the last-resort antibiotic for multidrug-resistant Gram-negative bacteria, but is associated with high rates of acute kidney injury. The aim of this in vitro study is to search for an alternative treatment to colistin for multidrug-resistant P. aeruginosa infections. Multidrug and carbapenem-resistant P. aeruginosa isolates were collected between January 2009 and December 2012 at MacKay Memorial Hospital. Minimal inhibitory concentrations (MICs) were determined for various antibiotic combinations. Carbapenemase-producing genes including bla VIM, other β-lactamase genes and porin mutations were screened by PCR and sequencing. The efficacy of carbapenems (imipenem, meropenem, doripenem) with or without rifampicin was correlated with the type of porin mutation (frameshift mutation, premature stop codon mutation) in multidrug-resistant P. aeruginosa isolates without carbapenemase-producing genes. Of the 71 multidrug-resistant clinical P. aeruginosa isolates, only six harboured the bla VIM gene. Imipenem, meropenem and doripenem were significantly more effective (reduced fold-change of MICs) when combined with rifampicin in bla VIM-negative isolates, especially in isolates with porin frameshift mutation. Imipenem + rifampicin combination has a low MIC against multidrug-resistant P. aeruginosa, especially in isolates with porin frameshift mutation. The imipenem + rifampicin combination may provide an alternative treatment to colistin for multidrug -resistant P. aeruginosa infections, especially for patients with renal insufficiency.

Multidrug-resistant bacteria in hematology patients: emerging threats.

PubMed

Tatarelli, Paola; Mikulska, Malgorzata

2016-06-01

Multidrug-resistant (MDR) bacteria, particularly Gram negatives, such as Enterobacteriaceae resistant to third-generation cephalosporins or carbapenems and MDR Pseudomonas aeruginosa, are increasingly frequent in hematology patients. The prevalence of different resistant species varies significantly between centers. Thus, the knowledge of local epidemiology is mandatory for deciding the most appr-opriate management protocols. In the era of increasing antibiotic resistance, empirical therapy of febrile neutropenia should be individualized. A de-escalation approach is recommended in case of severe clinical presentation in patients who are at high risk for infection with a resistant strain. Targeted therapy of an MDR Gram negative usually calls for a combination treatment, although no large randomized trials exist in this setting. Infection control measures are the cornerstone of limiting the spread of MDR pathogens in hematology units.

[Risk factors for multidrug-resistant tuberculosis in the city of Kinshasa in the Democratic Republic of Congo].

PubMed

Misombo-Kalabela, André; Nguefack-Tsague, Georges; Kalla, Ginette Claude Mireille; Ze, Emmanuel Afane; Diangs, Kimpanga; Panda, Tshapenda; Kebela, Ilunga; Fueza, Serge Bisuta; Magazani, Nzanzu; Mbopi-Kéou, François-Xavier

2016-01-01

The aim of this study was to determine the risk factors for multidrug-resistant tuberculosis (TB) in the city of Kinshasa in the Democratic Republic of Congo. This was a case control study. The cases included all TB patients notified as resistant to rifampicin and isoniazid in Kinshasa from January 2012 to June 2013. The controls included TB patients treated during the same period as the cases and declared cured at the end of treatment. For this study, we obtained ethical clearance. The sample consisted of 213 participants, 132 men (62%) and 81 women (38%). The median age was 31 years (16-73 years). Factors associated with significant (p< 0,05) multidrug-resistant tuberculosis were the non-observance of the hours of taking drugs (0R = 111) (80% cases, 4% controls), the failure of treatment (0R = 20 (76% cases, 13% controls); the concept of multidrug-resistant tuberculosis in the family (0R = 6.4) (28% cases, 6% controls); a lack of knowledge of multidrug-resistant tuberculosis (0R = 3.2) (31% cases, 59% controls); a stay in prison (0R = 7.6) (10% cases, 1% controls) and the interruption of treatment (0R = 6.1) (59% cases, 19% controls). The emergence of multidrug-resistant tuberculosis can be avoided by the installation of suitable diagnosis and treatment strategies.

Ribosomal mutations promote the evolution of antibiotic resistance in a multidrug environment.

PubMed

Gomez, James E; Kaufmann-Malaga, Benjamin B; Wivagg, Carl N; Kim, Peter B; Silvis, Melanie R; Renedo, Nikolai; Ioerger, Thomas R; Ahmad, Rushdy; Livny, Jonathan; Fishbein, Skye; Sacchettini, James C; Carr, Steven A; Hung, Deborah T

2017-02-21

Antibiotic resistance arising via chromosomal mutations is typically specific to a particular antibiotic or class of antibiotics. We have identified mutations in genes encoding ribosomal components in Mycobacterium smegmatis that confer resistance to several structurally and mechanistically unrelated classes of antibiotics and enhance survival following heat shock and membrane stress. These mutations affect ribosome assembly and cause large-scale transcriptomic and proteomic changes, including the downregulation of the catalase KatG, an activating enzyme required for isoniazid sensitivity, and upregulation of WhiB7, a transcription factor involved in innate antibiotic resistance. Importantly, while these ribosomal mutations have a fitness cost in antibiotic-free medium, in a multidrug environment they promote the evolution of high-level, target-based resistance. Further, suppressor mutations can then be easily acquired to restore wild-type growth. Thus, ribosomal mutations can serve as stepping-stones in an evolutionary path leading to the emergence of high-level, multidrug resistance.

Appropriate antimicrobial therapy in the era of multidrug-resistant human pathogens.

PubMed

Pogue, J M; Kaye, K S; Cohen, D A; Marchaim, D

2015-04-01

The past decade has brought a significant rise in antimicrobial resistance, and the ESKAPE pathogens have become a significant threat to public health. Three epidemiological features that negatively impact patients, which are consistently seen with the ESKAPE pathogens, are the following: 1) there has been a rise in incidence of these organisms as causative human pathogens, 2) there has been a significant increase in antimicrobial resistance in these bacterial species, and 3) the infections caused by these resistant strains are associated with worse outcomes when compared with infections caused by their susceptible counterparts. Significant delays in time to appropriate antimicrobial therapy of up to 5 days have been reported in infections due to these organisms and this is the strongest predictor of mortality with ESKAPE pathogens, particular in critically ill patients, where every hour delay has an incremental survival disadvantage for patients. Strategies to decrease these delays are urgently needed. Although routine broad-spectrum empiric coverage for these organisms would ideally limit this delay, agents with activity against these organisms are sometimes less effective, have significant toxicity risk, and their use can result in the development of resistance. Therefore, strategies to optimize therapy, although limiting unnecessary use of broad-spectrum antimicrobials, are urgently needed. This review will discuss potential strategies to optimize empiric therapy in the age of multi-drug resistance, the limitations of these strategies, and will discuss future directions and opportunities. Copyright © 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Molecular mechanisms of multidrug resistance in cancer chemotherapy.

PubMed

Nooter, K; Stoter, G

1996-07-01

The occurrence of multidrug resistance (MDR) is one of the main obstacles in the successful chemotherapeutic treatment of cancer. MDR cell lines are resistant to the so-called naturally occurring anti-cancer drugs, such as anthracyclines, Vinca alkaloids and epipodophyllotoxins, but are not cross-resistant to alkylating agents, antimetabolites and cisplatin. So far, three separate forms of MDR have been characterized in more detail: classical MDR, non-Pgp MDR and atypical MDR. Although all three MDR phenotypes have much in common with respect to cross-resistance patterns, the underlying mechanisms certainly differ. Atypical MDR is associated with quantitative and qualitative alterations in topoisomerase II alpha, a nuclear enzyme that actively participates in the lethal action of cytotoxic drugs. Atypical MDR cells do not overexpress P-glycoprotein, and are unaltered in their ability to accumulate drugs. In this review we will focus on classical and non-Pgp MDR. The molecular mechanism of classical and non-Pgp MDR is transcriptional activation of membrane-bound transport proteins. These transport proteins belong to the ATP-binding cassette (ABC) superfamily of transport systems. The classical MDR phenotype is characterized by a reduced ability to accumulate drugs, due to activity of an energy-dependent uni-directional, membrane-bound, drug-efflux pump with broad substrate specificity. The classical MDR drug pump is composed of a transmembrane glycoprotein (P-glyco-protein-Pgp) with a molecular weight of 170 kD, and is, in man, encoded by the so-called multidrug resistance (MDR1) gene. Typically, non-Pgp MDR has no P-gly-coprotein expression, yet has about the same cross-resistance pattern as classical MDR. This non-Pgp MDR phenotype is caused by overexpression of the multidrug resistance-associated protein (MRP) gene, which encodes a 190 kD membrane-bound glycoprotein (MRP). MRP probably works by direct extrusion of cytotoxic drugs from the cell and/or by mediating

Molecular Surveillance for Multidrug-Resistant Plasmodium falciparum, Cambodia

PubMed Central

Shah, Naman K.; Alker, Alisa P.; Sem, Rithy; Susanti, Agustina Ika; Muth, Sinuon; Maguire, Jason D.; Duong, Socheat; Ariey, Frederic; Meshnick, Steven R.

2008-01-01

We conducted surveillance for multidrug-resistant Plasmodium falciparum in Cambodia during 2004–2006 by assessing molecular changes in pfmdr1. The high prevalence of isolates with multiple pfmdr1 copies found in western Cambodia near the Thai border, where artesunate–mefloquine therapy failures occur, contrasts with isolates from eastern Cambodia, where this combination therapy remains highly effective. PMID:18826834

Preoperative biliary colonization/infection caused by multidrug-resistant (MDR) pathogens in patients undergoing major hepatectomy with extrahepatic bile duct resection.

PubMed

Sugawara, Gen; Yokoyama, Yukihiro; Ebata, Tomoki; Igami, Tsuyoshi; Yamaguchi, Junpei; Mizuno, Takashi; Yagi, Tetsuya; Nagino, Masato

2018-05-01

The aim of this study was to review the surgical outcomes of patients who underwent major hepatectomy with extrahepatic bile duct resection after preoperative biliary drainage with a particular focus on the impact of preoperative biliary colonization/infection caused by multidrug-resistant pathogens. Medical records of patients who underwent hepatobiliary resection after preoperative external biliary drainage between 2001 and 2015 were reviewed retrospectively. Prophylactic antibiotics were selected according to the results of drug susceptibility tests of surveillance bile cultures. In total, 565 patients underwent surgical resection. Based on the results of bile cultures, the patients were classified into three groups: group A, patients with negative bile cultures (n = 113); group B, patients with positive bile cultures without multidrug-resistant pathogen growth (n = 416); and group C, patients with multidrug-resistant pathogen-positive bile culture (n = 36). The incidence of organ/space surgical site infection, bacteremia, median duration of postoperative hospital stay, and the mortality rate did not differ among the three groups. The incidence of incisional surgical site infection and infectious complications caused by multidrug-resistant pathogens was significantly higher in group C than in groups A and B. Fifty-two patients had postoperative infectious complications caused by multidrug-resistant pathogens. Multivariate analysis identified preoperative multidrug-resistant pathogen-positive bile culture as a significant independent risk factor for postoperative infectious complications caused by multidrug-resistant pathogens (P< .001). Major hepatectomy with extrahepatic bile duct resection after biliary drainage can be performed with acceptable rates of morbidity and mortality using appropriate antibiotic prophylaxis, even in patients with biliary colonization/infection caused by multidrug-resistant pathogens. Copyright © 2018 Elsevier Inc. All

Multidrug Resistance among New Tuberculosis Cases: Detecting Local Variation through Lot Quality-Assurance Sampling

PubMed Central

Lynn Hedt, Bethany; van Leth, Frank; Zignol, Matteo; Cobelens, Frank; van Gemert, Wayne; Viet Nhung, Nguyen; Lyepshina, Svitlana; Egwaga, Saidi; Cohen, Ted

2012-01-01

Background Current methodology for multidrug-resistant TB (MDR TB) surveys endorsed by the World Health Organization provides estimates of MDR TB prevalence among new cases at the national level. On the aggregate, local variation in the burden of MDR TB may be masked. This paper investigates the utility of applying lot quality-assurance sampling to identify geographic heterogeneity in the proportion of new cases with multidrug resistance. Methods We simulated the performance of lot quality-assurance sampling by applying these classification-based approaches to data collected in the most recent TB drug-resistance surveys in Ukraine, Vietnam, and Tanzania. We explored three classification systems—two-way static, three-way static, and three-way truncated sequential sampling—at two sets of thresholds: low MDR TB = 2%, high MDR TB = 10%, and low MDR TB = 5%, high MDR TB = 20%. Results The lot quality-assurance sampling systems identified local variability in the prevalence of multidrug resistance in both high-resistance (Ukraine) and low-resistance settings (Vietnam). In Tanzania, prevalence was uniformly low, and the lot quality-assurance sampling approach did not reveal variability. The three-way classification systems provide additional information, but sample sizes may not be obtainable in some settings. New rapid drug-sensitivity testing methods may allow truncated sequential sampling designs and early stopping within static designs, producing even greater efficiency gains. Conclusions Lot quality-assurance sampling study designs may offer an efficient approach for collecting critical information on local variability in the burden of multidrug-resistant TB. Before this methodology is adopted, programs must determine appropriate classification thresholds, the most useful classification system, and appropriate weighting if unbiased national estimates are also desired. PMID:22249242

Multidrug resistance among new tuberculosis cases: detecting local variation through lot quality-assurance sampling.

PubMed

Hedt, Bethany Lynn; van Leth, Frank; Zignol, Matteo; Cobelens, Frank; van Gemert, Wayne; Nhung, Nguyen Viet; Lyepshina, Svitlana; Egwaga, Saidi; Cohen, Ted

2012-03-01

Current methodology for multidrug-resistant tuberculosis (MDR TB) surveys endorsed by the World Health Organization provides estimates of MDR TB prevalence among new cases at the national level. On the aggregate, local variation in the burden of MDR TB may be masked. This paper investigates the utility of applying lot quality-assurance sampling to identify geographic heterogeneity in the proportion of new cases with multidrug resistance. We simulated the performance of lot quality-assurance sampling by applying these classification-based approaches to data collected in the most recent TB drug-resistance surveys in Ukraine, Vietnam, and Tanzania. We explored 3 classification systems- two-way static, three-way static, and three-way truncated sequential sampling-at 2 sets of thresholds: low MDR TB = 2%, high MDR TB = 10%, and low MDR TB = 5%, high MDR TB = 20%. The lot quality-assurance sampling systems identified local variability in the prevalence of multidrug resistance in both high-resistance (Ukraine) and low-resistance settings (Vietnam). In Tanzania, prevalence was uniformly low, and the lot quality-assurance sampling approach did not reveal variability. The three-way classification systems provide additional information, but sample sizes may not be obtainable in some settings. New rapid drug-sensitivity testing methods may allow truncated sequential sampling designs and early stopping within static designs, producing even greater efficiency gains. Lot quality-assurance sampling study designs may offer an efficient approach for collecting critical information on local variability in the burden of multidrug-resistant TB. Before this methodology is adopted, programs must determine appropriate classification thresholds, the most useful classification system, and appropriate weighting if unbiased national estimates are also desired.

Antimicrobial multidrug resistance and coresistance patterns of Mannheimia haemolytica isolated from bovine respiratory disease cases--a three-year (2009-2011) retrospective analysis.

PubMed

Lubbers, Brian V; Hanzlicek, Gregg A

2013-05-01

Bovine respiratory disease continues to be the most important ailment of feed yard cattle. While the disease is multifactorial in nature, therapy continues to target the primary bacterial pathogens, Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni. A survey of records from a single diagnostic laboratory was conducted to evaluate the percentage of M. haemolytica isolates that were resistant to multiple antimicrobials and if coresistance patterns could be detected. All susceptibility test results for M. haemolytica recovered from lung tissues of cattle were eligible for inclusion in the survey. There were no isolates over the course of the analysis that were resistant to all 6 antimicrobials, primarily due to a lack of resistance to ceftiofur. In 2009, just over 5% of isolates were resistant to 5 or more antimicrobials (pan-resistant). In 2011, more than 35% of the M. haemolytica isolates were characterized as pan-resistant. Significant antimicrobial coresistance patterns were only seen with oxytetracycline and tilmicosin; bacterial isolates that were resistant to either oxytetracycline or tilmicosin were more likely to be resistant to at least one other antimicrobial. The mechanisms by which M. haemolytica is developing multidrug resistance warrant investigation if antimicrobial utility in the therapy of bovine respiratory disease is to be preserved.

Inhibiting fungal multidrug resistance by disrupting an activator-Mediator interaction.

PubMed

Nishikawa, Joy L; Boeszoermenyi, Andras; Vale-Silva, Luis A; Torelli, Riccardo; Posteraro, Brunella; Sohn, Yoo-Jin; Ji, Fei; Gelev, Vladimir; Sanglard, Dominique; Sanguinetti, Maurizio; Sadreyev, Ruslan I; Mukherjee, Goutam; Bhyravabhotla, Jayaram; Buhrlage, Sara J; Gray, Nathanael S; Wagner, Gerhard; Näär, Anders M; Arthanari, Haribabu

2016-02-25

Eukaryotic transcription activators stimulate the expression of specific sets of target genes through recruitment of co-activators such as the RNA polymerase II-interacting Mediator complex. Aberrant function of transcription activators has been implicated in several diseases. However, therapeutic targeting efforts have been hampered by a lack of detailed molecular knowledge of the mechanisms of gene activation by disease-associated transcription activators. We previously identified an activator-targeted three-helix bundle KIX domain in the human MED15 Mediator subunit that is structurally conserved in Gal11/Med15 Mediator subunits in fungi. The Gal11/Med15 KIX domain engages pleiotropic drug resistance transcription factor (Pdr1) orthologues, which are key regulators of the multidrug resistance pathway in Saccharomyces cerevisiae and in the clinically important human pathogen Candida glabrata. The prevalence of C. glabrata is rising, partly owing to its low intrinsic susceptibility to azoles, the most widely used antifungal agent. Drug-resistant clinical isolates of C. glabrata most commonly contain point mutations in Pdr1 that render it constitutively active, suggesting that this transcriptional activation pathway represents a linchpin in C. glabrata multidrug resistance. Here we perform sequential biochemical and in vivo high-throughput screens to identify small-molecule inhibitors of the interaction of the C. glabrata Pdr1 activation domain with the C. glabrata Gal11A KIX domain. The lead compound (iKIX1) inhibits Pdr1-dependent gene activation and re-sensitizes drug-resistant C. glabrata to azole antifungals in vitro and in animal models for disseminated and urinary tract C. glabrata infection. Determining the NMR structure of the C. glabrata Gal11A KIX domain provides a detailed understanding of the molecular mechanism of Pdr1 gene activation and multidrug resistance inhibition by iKIX1. We have demonstrated the feasibility of small-molecule targeting of a

Antibiotic-resistant bacteria show widespread collateral sensitivity to antimicrobial peptides.

PubMed

Lázár, Viktória; Martins, Ana; Spohn, Réka; Daruka, Lejla; Grézal, Gábor; Fekete, Gergely; Számel, Mónika; Jangir, Pramod K; Kintses, Bálint; Csörgő, Bálint; Nyerges, Ákos; Györkei, Ádám; Kincses, András; Dér, András; Walter, Fruzsina R; Deli, Mária A; Urbán, Edit; Hegedűs, Zsófia; Olajos, Gábor; Méhi, Orsolya; Bálint, Balázs; Nagy, István; Martinek, Tamás A; Papp, Balázs; Pál, Csaba

2018-06-01

Antimicrobial peptides are promising alternative antimicrobial agents. However, little is known about whether resistance to small-molecule antibiotics leads to cross-resistance (decreased sensitivity) or collateral sensitivity (increased sensitivity) to antimicrobial peptides. We systematically addressed this question by studying the susceptibilities of a comprehensive set of 60 antibiotic-resistant Escherichia coli strains towards 24 antimicrobial peptides. Strikingly, antibiotic-resistant bacteria show a high frequency of collateral sensitivity to antimicrobial peptides, whereas cross-resistance is relatively rare. We identify clinically relevant multidrug-resistance mutations that increase bacterial sensitivity to antimicrobial peptides. Collateral sensitivity in multidrug-resistant bacteria arises partly through regulatory changes shaping the lipopolysaccharide composition of the bacterial outer membrane. These advances allow the identification of antimicrobial peptide-antibiotic combinations that enhance antibiotic activity against multidrug-resistant bacteria and slow down de novo evolution of resistance. In particular, when co-administered as an adjuvant, the antimicrobial peptide glycine-leucine-amide caused up to 30-fold decrease in the antibiotic resistance level of resistant bacteria. Our work provides guidelines for the development of efficient peptide-based therapies of antibiotic-resistant infections.

Whole genome sequencing of multidrug-resistant Salmonella enterica serovar Typhimurium isolated from humans and poultry in Burkina Faso

USDA-ARS?s Scientific Manuscript database

Background. Multidrug-resistant Salmonella is an important cause of morbidity and mortality in developing countries. The aim of this study was to characterize and compare multidrug-resistant Salmonella enterica serovar Typhimurium isolates from patients and poultry feces. Methods. Salmonella strains...

The commensal infant gut meta-mobilome as a potential reservoir for persistent multidrug resistance integrons.

PubMed

Ravi, Anuradha; Avershina, Ekaterina; Foley, Steven L; Ludvigsen, Jane; Storrø, Ola; Øien, Torbjørn; Johnsen, Roar; McCartney, Anne L; L'Abée-Lund, Trine M; Rudi, Knut

2015-10-28

Despite the accumulating knowledge on the development and establishment of the gut microbiota, its role as a reservoir for multidrug resistance is not well understood. This study investigated the prevalence and persistence patterns of an integrase gene (int1), used as a proxy for integrons (which often carry multiple antimicrobial resistance genes), in the fecal microbiota of 147 mothers and their children sampled longitudinally from birth to 2 years. The study showed the int1 gene was detected in 15% of the study population, and apparently more persistent than the microbial community structure itself. We found int1 to be persistent throughout the first two years of life, as well as between mothers and their 2-year-old children. Metagenome sequencing revealed integrons in the gut meta-mobilome that were associated with plasmids and multidrug resistance. In conclusion, the persistent nature of integrons in the infant gut microbiota makes it a potential reservoir of mobile multidrug resistance.

The commensal infant gut meta-mobilome as a potential reservoir for persistent multidrug resistance integrons

PubMed Central

Ravi, Anuradha; Avershina, Ekaterina; Foley, Steven L.; Ludvigsen, Jane; Storrø, Ola; Øien, Torbjørn; Johnsen, Roar; McCartney, Anne L.; L’Abée-Lund, Trine M.; Rudi, Knut

2015-01-01

Despite the accumulating knowledge on the development and establishment of the gut microbiota, its role as a reservoir for multidrug resistance is not well understood. This study investigated the prevalence and persistence patterns of an integrase gene (int1), used as a proxy for integrons (which often carry multiple antimicrobial resistance genes), in the fecal microbiota of 147 mothers and their children sampled longitudinally from birth to 2 years. The study showed the int1 gene was detected in 15% of the study population, and apparently more persistent than the microbial community structure itself. We found int1 to be persistent throughout the first two years of life, as well as between mothers and their 2-year-old children. Metagenome sequencing revealed integrons in the gut meta-mobilome that were associated with plasmids and multidrug resistance. In conclusion, the persistent nature of integrons in the infant gut microbiota makes it a potential reservoir of mobile multidrug resistance. PMID:26507767

Preliminary survey of local bacteriophages with lytic activity against multi-drug resistant bacteria.

PubMed

Latz, Simone; Wahida, Adam; Arif, Assuda; Häfner, Helga; Hoß, Mareike; Ritter, Klaus; Horz, Hans-Peter

2016-10-01

Bacteriophages (phages) represent a potential alternative for combating multi-drug resistant bacteria. Because of their narrow host range and the ever emergence of novel pathogen variants the continued search for phages is a prerequisite for optimal treatment of bacterial infections. Here we performed an ad hoc survey in the surroundings of a University hospital for the presence of phages with therapeutic potential. To this end, 16 aquatic samples of different origins and locations were tested simultaneously for the presence of phages with lytic activity against five current, but distinct strains each from the ESKAPE-group (i.e., Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter cloacae). Phages could be isolated for 70% of strains, covering all bacterial species except S. aureus. Apart from samples from two lakes, freshwater samples were largely devoid of phages. By contrast, one liter of hospital effluent collected at a single time point already contained phages active against two-thirds of tested strains. In conclusion, phages with lytic activity against nosocomial pathogens are unevenly distributed across environments with the prime source being the immediate hospital vicinity. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Imipenem/cilastatin encapsulated polymeric nanoparticles for destroying carbapenem-resistant bacterial isolates.

PubMed

Shaaban, Mona I; Shaker, Mohamed A; Mady, Fatma M

2017-04-11

Carbapenem-resistance is an extremely growing medical threat in antibacterial therapy as the incurable resistant strains easily develop a multi-resistance action to other potent antimicrobial agents. Nonetheless, the protective delivery of current antibiotics using nano-carriers opens a tremendous approach in the antimicrobial therapy, allowing the nano-formulated antibiotics to beat these health threat pathogens. Herein, we encapsulated imipenem into biodegradable polymeric nanoparticles to destroy the imipenem-resistant bacteria and overcome the microbial adhesion and dissemination. Imipenem loaded poly Ɛ-caprolactone (PCL) and polylactide-co-glycolide (PLGA) nanocapsules were formulated using double emulsion evaporation method. The obtained nanocapsules were characterized for mean particle diameter, morphology, loading efficiency, and in vitro release. The in vitro antimicrobial and anti adhesion activities were evaluated against selected imipenem-resistant Klebsiella pneumoniae and Pseudomonas aeruginosa clinical isolates. The obtained results reveal that imipenem loaded PCL nano-formulation enhances the microbial susceptibility and antimicrobial activity of imipenem. The imipenem loaded PCL nanoparticles caused faster microbial killing within 2-3 h compared to the imipenem loaded PLGA and free drug. Successfully, PCL nanocapsules were able to protect imipenem from enzymatic degradation by resistant isolates and prevent the emergence of the resistant colonies, as it lowered the mutation prevention concentration of free imipenem by twofolds. Moreover, the imipenem loaded PCL eliminated bacterial attachment and the biofilm assembly of P. aeruginosa and K. pneumoniae planktonic bacteria by 74 and 78.4%, respectively. These promising results indicate that polymeric nanoparticles recover the efficacy of imipenem and can be considered as a new paradigm shift against multidrug-resistant isolates in treating severe bacterial infections.

Structural basis for the inhibition of bacterial multidrug exporters.

PubMed

Nakashima, Ryosuke; Sakurai, Keisuke; Yamasaki, Seiji; Hayashi, Katsuhiko; Nagata, Chikahiro; Hoshino, Kazuki; Onodera, Yoshikuni; Nishino, Kunihiko; Yamaguchi, Akihito

2013-08-01

The multidrug efflux transporter AcrB and its homologues are important in the multidrug resistance of Gram-negative pathogens. However, despite efforts to develop efflux inhibitors, clinically useful inhibitors are not available at present. Pyridopyrimidine derivatives are AcrB- and MexB-specific inhibitors that do not inhibit MexY; MexB and MexY are principal multidrug exporters in Pseudomonas aeruginosa. We have previously determined the crystal structure of AcrB in the absence and presence of antibiotics. Drugs were shown to be exported by a functionally rotating mechanism through tandem proximal and distal multisite drug-binding pockets. Here we describe the first inhibitor-bound structures of AcrB and MexB, in which these proteins are bound by a pyridopyrimidine derivative. The pyridopyrimidine derivative binds tightly to a narrow pit composed of a phenylalanine cluster located in the distal pocket and sterically hinders the functional rotation. This pit is a hydrophobic trap that branches off from the substrate-translocation channel. Phe 178 is located at the edge of this trap in AcrB and MexB and contributes to the tight binding of the inhibitor molecule through a π-π interaction with the pyridopyrimidine ring. The voluminous side chain of Trp 177 located at the corresponding position in MexY prevents inhibitor binding. The structure of the hydrophobic trap described in this study will contribute to the development of universal inhibitors of MexB and MexY in P. aeruginosa.

Multidrug evolutionary strategies to reverse antibiotic resistance

PubMed Central

Baym, Michael; Stone, Laura K.; Kishony, Roy

2017-01-01

Antibiotic treatment has two conflicting effects: the desired, immediate effect of inhibiting bacterial growth and the undesired, long-term effect of promoting the evolution of resistance. Although these contrasting outcomes seem inextricably linked, recent work has revealed several ways by which antibiotics can be combined to inhibit bacterial growth while, counterintuitively, selecting against resistant mutants. Decoupling treatment efficacy from the risk of resistance can be achieved by exploiting specific interactions between drugs, and the ways in which resistance mutations to a given drug can modulate these interactions or increase the sensitivity of the bacteria to other compounds. Although their practical application requires much further development and validation, and relies on advances in genomic diagnostics, these discoveries suggest novel paradigms that may restrict or even reverse the evolution of resistance. PMID:26722002

Dual Agent Loaded PLGA Nanoparticles Enhanced Antitumor Activity in a Multidrug-Resistant Breast Tumor Eenograft Model

PubMed Central

Chen, Yan; Zheng, Xue-Lian; Fang, Dai-Long; Yang, Yang; Zhang, Jin-Kun; Li, Hui-Li; Xu, Bei; Lei, Yi; Ren, Ke; Song, Xiang-Rong

2014-01-01

Multidrug-resistant breast cancers have limited and ineffective clinical treatment options. This study aimed to develop PLGA nanoparticles containing a synergistic combination of vincristine and verapamil to achieve less toxicity and enhanced efficacy on multidrug-resistant breast cancers. The 1:250 molar ratio of VCR/VRP showed strong synergism with the reversal index of approximately 130 in the multidrug-resistant MCF-7/ADR cells compared to drug-sensitive MCF-7 cells. The lyophilized nanoparticles could get dispersed quickly with the similar size distribution, zeta potential and encapsulation efficiency to the pre-lyophilized nanoparticles suspension, and maintain the synergistic in vitro release ratio of drugs. The co-encapsulated nanoparticle formulation had lower toxicity than free vincristine/verapamil combinations according to the acute-toxicity test. Furthermore, the most effective tumor growth inhibition in the MCF-7/ADR human breast tumor xenograft was observed in the co-delivery nanoparticle formulation group in comparison with saline control, free vincristine, free vincristine/verapamil combinations and single-drug nanoparticle combinations. All the data demonstrated that PLGANPs simultaneously loaded with chemotherapeutic drug and chemosensitizer might be one of the most potential formulations in the treatment of multidrug-resistant breast cancer in clinic. PMID:24552875

[Management of multidrug-resistant tuberculosis].

PubMed

Tritar, F; Daghfous, H; Ben Saad, S; Slim-Saidi, L

2015-01-01

The emergence of drug-resistant TB in many countries has become a major public health problem and an obstacle to effective tuberculosis control. Multidrug-resistant tuberculosis (MDR-TB), which is most often the result of poor adherence, is a particularly dangerous form of tuberculosis because it is caused by bacilli resistant to at least isoniazid and rifampicin, the two most effective anti-tuberculosis drugs. Techniques for rapid diagnosis of resistance have greatly improved the care of patients by allowing early treatment which remains complex and costly establishment, and requires skills and resources. The treatment is not standardized but it includes in all cases attack phase with five drugs (there must be an injectable agent and a fluoroquinolone that form the basis of the regimen) for eight months and a maintenance phase (without injectable agent) with a total duration of 20 months on average. Surgery may be beneficial as long as the lesions are localized and the patient has a good cardiorespiratory function. Evolution of MDR-TB treated is less favorable than tuberculosis with germ sensitive. The cure rate varies from 60 to 75% for MDR-TB, and drops to 30 to 40% for XDR-TB. Mortality remains high, ranging from 20 to 40% even up to 70-90% in people co-infected with HIV. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Impact of DOTS compared with DOTS-plus on multidrug resistant tuberculosis and tuberculosis deaths: decision analysis.

PubMed

Sterling, Timothy R; Lehmann, Harold P; Frieden, Thomas R

2003-03-15

This study sought to determine the impact of the World Health Organization's directly observed treatment strategy (DOTS) compared with that of DOTS-plus on tuberculosis deaths, mainly in the developing world. Decision analysis with Monte Carlo simulation of a Markov decision tree. People with smear positive pulmonary tuberculosis. Analyses modelled different levels of programme effectiveness of DOTS and DOTS-plus, and high (10%) and intermediate (3%) proportions of primary multidrug resistant tuberculosis, while accounting for exogenous reinfection. The cumulative number of tuberculosis deaths per 100 000 population over 10 years. The model predicted that under DOTS, 276 people would die from tuberculosis (24 multidrug resistant and 252 not multidrug resistant) over 10 years under optimal implementation in an area with 3% primary multidrug resistant tuberculosis. Optimal implementation of DOTS-plus would result in four (1.5%) fewer deaths. If implementation of DOTS-plus were to result in a decrease of just 5% in the effectiveness of DOTS, 16% more people would die with tuberculosis than under DOTS alone. In an area with 10% primary multidrug resistant tuberculosis, 10% fewer deaths would occur under optimal DOTS-plus than under optimal DOTS, but 16% more deaths would occur if implementation of DOTS-plus were to result in a 5% decrease in the effectiveness of DOTS CONCLUSIONS: Under optimal implementation, fewer tuberculosis deaths would occur under DOTS-plus than under DOTS. If, however, implementation of DOTS-plus were associated with even minimal decreases in the effectiveness of treatment, substantially more patients would die than under DOTS.

Characterization of Multi-Drug Resistant Enterococcus faecalis Isolated from Cephalic Recording Chambers in Research Macaques (Macaca spp.).

PubMed

Woods, Stephanie E; Lieberman, Mia T; Lebreton, Francois; Trowel, Elise; de la Fuente-Núñez, César; Dzink-Fox, Joanne; Gilmore, Michael S; Fox, James G

2017-01-01

Nonhuman primates are commonly used for cognitive neuroscience research and often surgically implanted with cephalic recording chambers for electrophysiological recording. Aerobic bacterial cultures from 25 macaques identified 72 bacterial isolates, including 15 Enterococcus faecalis isolates. The E. faecalis isolates displayed multi-drug resistant phenotypes, with resistance to ciprofloxacin, enrofloxacin, trimethoprim-sulfamethoxazole, tetracycline, chloramphenicol, bacitracin, and erythromycin, as well as high-level aminoglycoside resistance. Multi-locus sequence typing showed that most belonged to two E. faecalis sequence types (ST): ST 4 and ST 55. The genomes of three representative isolates were sequenced to identify genes encoding antimicrobial resistances and other traits. Antimicrobial resistance genes identified included aac(6')-aph(2"), aph(3')-III, str, ant(6)-Ia, tetM, tetS, tetL, ermB, bcrABR, cat, and dfrG, and polymorphisms in parC (S80I) and gyrA (S83I) were observed. These isolates also harbored virulence factors including the cytolysin toxin genes in ST 4 isolates, as well as multiple biofilm-associated genes (esp, agg, ace, SrtA, gelE, ebpABC), hyaluronidases (hylA, hylB), and other survival genes (ElrA, tpx). Crystal violet biofilm assays confirmed that ST 4 isolates produced more biofilm than ST 55 isolates. The abundance of antimicrobial resistance and virulence factor genes in the ST 4 isolates likely relates to the loss of CRISPR-cas. This macaque colony represents a unique model for studying E. faecalis infection associated with indwelling devices, and provides an opportunity to understand the basis of persistence of this pathogen in a healthcare setting.

Resistance pattern of multi-drug resistant strains of Mycobacterium tuberculosis and characteristics of patients with multi-drug resistant tuberculosis.

PubMed

Moisoiu, Adriana; Mitran, Cristina Iulia; Mitran, Mãdãlina Irina; Huhu, Mihaela Roxana; Ioghen, Octavian Costin; Gheorghe, Adelina-Silvana; Tampa, Mircea; Georgescu, Simona Roxana; Popa, Mircea Ioan

2016-01-01

Multi-drug resistant tuberculosis (MDR-TB) is a major concern in the medical community. Knowledge about the drug resistance pattern of Mycobacterium tuberculosis strains plays an essential role in the management of the disease. We conducted a retrospective, 3-year study (2009-2011), in an urban area. We collected data on the drug resistance for 497 M. tuberculosis strains, isolated from patients with pulmonary TB. Among the 497 strains, we identified 158 MDR strains. Eighty medical recorders of patients infected with MDR strains were available and we included those patients in the study group. Of the 497 analysed strains, 8% were resistant to a single anti-TB drug. We identified 5.2% polyresistant drug strains, the most frequent combination being INH+EMB (1.4%). Of the 158 MDR strains identified (31.8%), over 60% were resistant to all first line anti-TB drugs tested. Most of them presented resistance to STM (86.1%) and EMB (67.7%). With respect to second line anti-TB drugs resistance to KM (23.4%) was the most common, followed by OFX (8.2%). With respect to the patients with MDR-TB, a percentage of 61.2% of them had a history of anti-TB treatment. Regarding lifestyle habits, 61.2% of the patients were smokers and 18.8% were abusing alcohol. Out of 51 patients, for whom information was available regarding their occupation, only 33.3 % were employees. MDR strains of Mycobacterium tuberculosis display an increased resistance to first line anti-TB drugs. Extension of resistance to second line anti-TB drugs narrows the therapeutic options. Knowledge of MDR-TB risk factors is imperative for the correct and rapid initiation of the treatment.

Antibacterial and antioxidant activities of Musa sp. leaf extracts against multidrug resistant clinical pathogens causing nosocomial infection

PubMed Central

Karuppiah, Ponmurugan; Mustaffa, Muhammed

2013-01-01

Objective To investigate different Musa sp. leave extracts of hexane, ethyl acetate and methanol were evaluated for antibacterial activity against multi-drug resistant pathogens causing nosocomial infection by agar well diffusion method and also antioxidant activities. Methods The four different Musa species leaves were extracted with hexane, ethyl acetate and methanol. Antibacterial susceptibility test, minimum inhibitory concentration and minimum inhibitory bacterial concentration were determined by agar well diffusion method. Total phenolic content and in vitro antioxidant activity was determined. Results All the Musa sp. extracts showed moderate antibacterial activities expect Musa paradisiaca with the inhibition zone ranging from 8.0 to 18.6 mm. Among four species ethyl acetate extracts of Musa paradisiaca showed highest activity against tested pathogens particularly E. coli, P. aeruginosa and Citrobacter sp. The minimum inhibitory concentrations were within the value of 15.63- 250 µg/mL and minimum bactericidal concentrations were ranging from 31.25- 250 µg/mL. Antioxidant activity of Musa acuminate exhibited maximum activity among other three Musa species. Conclusions The present study concluded that among the different Musa species, Musa paradisiaca displayed efficient antibacterial activity followed by Musa acuminata against multi-drug resistant nosocomial infection causing pathogens. Further, an extensive study is needed to identify the bioactive compounds, mode of action and toxic effect in vivo of Musa sp. PMID:23998016

Directly observed treatment, short-course strategy and multidrug-resistant tuberculosis: are any modifications required?

PubMed Central

Bastian, I.; Rigouts, L.; Van Deun, A.; Portaels, F.

2000-01-01

Multidrug-resistant tuberculosis (MDRTB) should be defined as tuberculosis with resistance to at least isoniazid and rifampicin because these drugs are the cornerstone of short-course chemotherapy, and combined isoniazid and rifampicin resistance requires prolonged treatment with second-line agents. Short-course chemotherapy is a key ingredient in the tuberculosis control strategy known as directly observed treatment, short-course (DOTS). For populations in which multidrug-resistant tuberculosis is endemic, the outcome of the standard short-course chemotherapy regimen remains uncertain. Unacceptable failure rates have been reported and resistance to additional agents may be induced. As a consequence there have been calls for well-functioning DOTS programmes to provide additional services in areas with high rates of multidrug-resistant tuberculosis. These "DOTS-plus for MDRTB programmes" may need to modify all five elements of the DOTS strategy: the treatment may need to be individualized rather than standardized; laboratory services may need to provide facilities for on-site culture and antibiotic susceptibility testing; reliable supplies of a wide range of expensive second-line agents would have to be supplied; operational studies would be required to determine the indications for and format of the expanded programmes; financial and technical support from international organizations and Western governments would be needed in addition to that obtained from local governments. PMID:10743297

Multidrug-resistant tuberculosis/rifampicin-resistant tuberculosis: Principles of management

PubMed Central

Prasad, Rajendra; Gupta, Nikhil; Banka, Amitabh

2018-01-01

Multidrug-resistant tuberculosis (MDR-TB)/rifampicin-resistant TB (RR-TB) is human-made problem and emerging due to poor management of TB and is a threat to control of TB. Early suspicion and diagnosis are important. Culture and drug susceptibility testing are gold standards, but newer molecular methods help in rapid diagnosis. Once diagnosed, prompt treatment should be started, preferably under direct observation. Treatment can be standardized or individualized. Conventional regimen takes up to 24 months but recently shorter regimen of up to 12 months was introduced in specific subset of MDR-TB/RR-TB patients. Management of MDR-TB/RR-TB is complicated, costlier, and challenging and is a concern for human health worldwide. It must be emphasized that optimal treatment of MDR-TB/RR-TB alone is not sufficient. Efforts must be made to ensure effective use of first- and second-line anti-TB drugs. PMID:29319042

Multidrug-resistant tuberculosis/rifampicin-resistant tuberculosis: Principles of management.

PubMed

Prasad, Rajendra; Gupta, Nikhil; Banka, Amitabh

2018-01-01

Multidrug-resistant tuberculosis (MDR-TB)/rifampicin-resistant TB (RR-TB) is human-made problem and emerging due to poor management of TB and is a threat to control of TB. Early suspicion and diagnosis are important. Culture and drug susceptibility testing are gold standards, but newer molecular methods help in rapid diagnosis. Once diagnosed, prompt treatment should be started, preferably under direct observation. Treatment can be standardized or individualized. Conventional regimen takes up to 24 months but recently shorter regimen of up to 12 months was introduced in specific subset of MDR-TB/RR-TB patients. Management of MDR-TB/RR-TB is complicated, costlier, and challenging and is a concern for human health worldwide. It must be emphasized that optimal treatment of MDR-TB/RR-TB alone is not sufficient. Efforts must be made to ensure effective use of first- and second-line anti-TB drugs.

Antibacterial activity of exogenous glutathione and its synergism on antibiotics sensitize carbapenem-associated multidrug resistant clinical isolates of Acinetobacter baumannii.

PubMed

Alharbe, Roaa; Almansour, Ayidh; Kwon, Dong H

2017-10-01

A major clinical impact of A. baumannii is hospital-acquired infections including ventilator-associated pneumonia. The treatment of this pathogen is often difficult due to its innate and acquired resistance to almost all commercially available antibiotics. Infections with carbapenem-associated multidrug resistant A. baumannii is the most problematic. Glutathione is a tripeptide thiol-antioxidant and antibacterial activity of exogenous glutathione was reported in some bacteria. However, clinical relevance and molecular details of the antibacterial activity of glutathione are currently unclear. Seventy clinical isolates of A. baumannii including 63 carbapenem-associated multidrug resistant isolates and a type strain A. baumannii ATCC 19606 were used to determine minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). Fractional inhibitory concentration (FIC) and time-killing activity with meropenem and/or glutathione were also determined in the carbapenem-associated multidrug resistant isolates. In addition, the roles of exogenous glutathione in multidrug efflux pumps and β-lactamase production were examined. Levels of MIC and MBC were ranged from 10 to 15mM of exogenous glutathione. All tested carbapenem-associated multidrug resistant isolates were sensitized by all tested antibiotics in combination with subinhibitory concentrations of glutathione. FIC levels of glutathione with carbapenem (meropenem) were all<0.5 and the carbapenem-associated multidrug resistant isolates were killed by subinhibitory concentrations of both glutathione and meropenem at>2log10 within 12h, suggesting glutathione synergistically interacts with meropenem. The roles of multidrug efflux pumps and β-lactamase production were excluded for the glutathione-mediated antibiotic susceptibility. Overall results demonstrate that the antibacterial activity of glutathione is clinically relevant and its synergism on antibiotics sensitizes clinical isolates of A

Worldwide Occurrence of Integrative Conjugative Element Encoding Multidrug Resistance Determinants in Epidemic Vibrio cholerae O1

PubMed Central

Marin, Michel A.; Fonseca, Erica L.; Andrade, Bruno N.; Cabral, Adriana C.; Vicente, Ana Carolina P.

2014-01-01

In the last decades, there has been an increase of cholera epidemics caused by multidrug resistant strains. Particularly, the integrative and conjugative element (ICE) seems to play a major role in the emergence of multidrug resistant Vibrio cholerae. This study fully characterized, by whole genome sequencing, new ICEs carried by multidrug resistant V. cholerae O1 strains from Nigeria (2010) (ICEVchNig1) and Nepal (1994) (ICEVchNep1). The gene content and gene order of these two ICEs are the same, and identical to ICEVchInd5, ICEVchBan5 and ICEVchHai1 previously identified in multidrug resistant V. cholerae O1. This ICE is characterized by dfrA1, sul2, strAB and floR antimicrobial resistance genes, and by unique gene content in HS4 and HS5 ICE regions. Screening for ICEs, in publicly available V. cholerae genomes, revealed the occurrence and widespread distribution of this ICE among V. cholerae O1. Metagenomic analysis found segments of this ICE in marine environments far from the direct influence of the cholera epidemic. Therefore, this study revealed the epidemiology of a spatio-temporal prevalent ICE in V. cholerae O1. Its occurrence and dispersion in V. cholerae O1 strains from different continents throughout more than two decades can be indicative of its role in the fitness of the current pandemic lineage. PMID:25265418

In vitro reduction of antibacterial activity of tigecycline against multidrug-resistant Acinetobacter baumannii with host stress hormone norepinephrine.

PubMed

Inaba, Masato; Matsuda, Naoyuki; Banno, Hirotsugu; Jin, Wanchun; Wachino, Jun-Ichi; Yamada, Keiko; Kimura, Kouji; Arakawa, Yoshichika

2016-12-01

The host stress hormone norepinephrine (NE), also called noradrenaline, is reported to augment bacterial growth and pathogenicity, but few studies have focused on the effect of NE on the activity of antimicrobials. The aim of this study was to clarify whether NE affects antimicrobial activity against multidrug-resistant Acinetobacter baumannii (MDR-AB). Time-kill studies of tigecycline (TIG) and colistin (COL) against MDR-AB as well as assays for factors contributing to antibiotic resistance were performed using MDR-AB clinical strains both in the presence and absence of 10 µM NE. In addition, expression of three efflux pump genes (adeB, adeJ and adeG) in the presence and absence of NE was analysed by quantitative reverse transcription PCR. Viable bacterial cell counts in TIG-supplemented medium containing NE were significantly increased compared with those in medium without NE. In contrast, NE had little influence on viable bacterial cell counts in the presence of COL. NE-supplemented medium resulted in an ca. 2 log increase in growth and in bacterial cell numbers adhering on polyurethane, silicone and polyvinylchloride surfaces. Amounts of biofilm in the presence of NE were ca. 3-fold higher than without NE. Expression of the adeG gene was upregulated 4-6-fold in the presence of NE. In conclusion, NE augmented factors contributing to antibiotic resistance and markedly reduced the in vitro antibacterial activity of TIG against MDR-AB. These findings suggest that NE treatment may contribute to the failure of TIG therapy in patients with MDR-AB infections. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Spread of multidrug-resistant Escherichia coli harboring integron via swine farm waste water treatment plant.

PubMed

Park, Jin-Hyeong; Kim, Young-Ji; Binn-Kim; Seo, Kun-Ho

2018-03-01

Wastewater treatment plants (WWTPs) that release treated wastewater into the environment have emerged as a major threat to public health. In this study, we investigated Escherichia coli load and antibiotic-resistance profiles across different treatment processes at a swine farm WWTP. The frequency of the detection of class 1 and 2 integrons, and their association with antibiotic resistance, were also analyzed. Samples were obtained at each of five sampling sites that represented each processing step within the WWTP. The largest decrease in E. coli load was observed during the anaerobic digestion step (from 4.86 to 2.89log CFU/mL). Isolates resistant to β-lactam antibiotics were efficiently removed after a series of treatment steps, whereas the proportions of isolates resistant to non-β-lactam antibiotics and multidrug-resistant strains were maintained across treatments. The occurrence of integron-positive strains was not significantly different at the various sampling sites (43.4-70%; p>0.05). Of the class 1 integron-positive isolates, 17.9% harbored the integron-associated gene cassettes aadA2, aadA12, aadA22, and dfrA15. To the best of our knowledge, this is the first description of a class 1 integron containing the aadA12 gene cassette from a swine farm and the presence of a class 1 integron containing dfrA15 in E. coli. This suggests that novel antibiotic-resistance gene cassette arrays could be generated in swine farm WWTPs. Moreover, 75% of integron-positive strains were categorized as multidrug resistant, whereas only 15.4% of integron-negative strains were multidrug resistant (p<0.05), indicating that integrons may be responsible for mediating resistance in WWTPs. With regard to the occurrence of multidrug-resistant, integron-positive E. coli recovered from the final effluent, our results highlighted the potential risks associated with wastewater discharge from swine farm WWTPs in terms of the spread of antibiotic-resistant bacteria to the aquatic

Whole Genome Sequencing and Plasmid Genomics of Antimicrobial Resistance – Salmonella’s mobile genetic elements and the antimicrobial resistance genes they carry

USDA-ARS?s Scientific Manuscript database

With the emergence of antibiotic resistance (AR), multidrug resistance (MDR), and carbapenem resistant Enterobacteriaceae (CRE), the specter of widespread untreatable bacterial infections threatens human and animal health. The ability of these emerging resistances to transfer between bacteria on mob...

Genome Evolution and Plasticity of Serratia marcescens, an Important Multidrug-Resistant Nosocomial Pathogen

PubMed Central

Iguchi, Atsushi; Nagaya, Yutaka; Pradel, Elizabeth; Ooka, Tadasuke; Ogura, Yoshitoshi; Katsura, Keisuke; Kurokawa, Ken; Oshima, Kenshiro; Hattori, Masahira; Parkhill, Julian; Sebaihia, Mohamed; Coulthurst, Sarah J.; Gotoh, Naomasa; Thomson, Nicholas R.; Ewbank, Jonathan J.; Hayashi, Tetsuya

2014-01-01

Serratia marcescens is an important nosocomial pathogen that can cause an array of infections, most notably of the urinary tract and bloodstream. Naturally, it is found in many environmental niches, and is capable of infecting plants and animals. The emergence and spread of multidrug-resistant strains producing extended-spectrum or metallo beta-lactamases now pose a threat to public health worldwide. Here we report the complete genome sequences of two carefully selected S. marcescens strains, a multidrug-resistant clinical isolate (strain SM39) and an insect isolate (strain Db11). Our comparative analyses reveal the core genome of S. marcescens and define the potential metabolic capacity, virulence, and multidrug resistance of this species. We show a remarkable intraspecies genetic diversity, both at the sequence level and with regards genome flexibility, which may reflect the diversity of niches inhabited by members of this species. A broader analysis with other Serratia species identifies a set of approximately 3,000 genes that characterize the genus. Within this apparent genetic diversity, we identified many genes implicated in the high virulence potential and antibiotic resistance of SM39, including the metallo beta-lactamase and multiple other drug resistance determinants carried on plasmid pSMC1. We further show that pSMC1 is most closely related to plasmids circulating in Pseudomonas species. Our data will provide a valuable basis for future studies on S. marcescens and new insights into the genetic mechanisms that underlie the emergence of pathogens highly resistant to multiple antimicrobial agents. PMID:25070509

Phenolic composition, antioxidant capacity of Salvia verticcilata and effect on multidrug resistant bacteria by flow-cytometry.

PubMed

Tekeli, Yener; Karpuz, Esra; Danahaliloglu, Hatice; Bucak, Serbay; Guzel, Yelda; Erdmann, Helmuth

2014-01-01

Antioxidants are of great importance for preventing oxidative stress that may cause several degenerative diseases. Studies have indicated phytochemicals have high free-radical scavenging activity, which helps to reduce the risk of chronic diseases. The aim of the present study is the determination of antioxidant properties, polyphenolic content and multidrug resistant bacteria of Salvia verticcilata L. Methanol was used as the extraction solvent. The total phenolic content was calculated using Folin-Ciocalteau method and phenolic composition was determined by HPLC. The radical scavenging activity of plant was evaluated in vitro based on the reduction of the stable DPPH free radical. The reducing capacity was identified by using the FRAP method. The ability of Salvia verticcilata L. to increase the permeability of multidrug resistant bacterial cells was conducted by flow cytometric assay on Listeria innocua and E-coli. The amount of total phenolics was found to be 347.5 mg GA/g extract. The IC50 value and FRAP assay are 0.61, and 0.944 respectively, Free radical scavenging effect and FRAP values are less than synthetic antioxidant compounds (BHA and BHT). Eight phenolic compounds were found in Salvia verticcilata L. Intense concentration of S. verticcilata L. has destroyed 97 % of living cells for Listeria innocua and 94.86% for E-coli. This study shows that methanolic extracts of Salvia verticcilata L. is a potential source of natural antioxidants and antimicrobial agent and can form the basis for pharmacological studies.

Quantifying the Evolutionary Conservation of Genes Encoding Multidrug Efflux Pumps in the ESKAPE Pathogens To Identify Antimicrobial Drug Targets.

PubMed

Brooks, Lauren E; Ul-Hasan, Sabah; Chan, Benjamin K; Sistrom, Mark J

2018-01-01

Increasing rates of antibiotic-resistant bacterial infection are one of the most pressing contemporary global health concerns. The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) have been identified as the leading global cause of multidrug-resistant bacterial infections, and overexpression of multidrug efflux (MEX) transport systems has been identified as one of the most critical mechanisms facilitating the evolution of multidrug resistance in ESKAPE pathogens. Despite efforts to develop efflux pump inhibitors to combat antibiotic resistance, the need persists to identify additional targets for future investigations. We evaluated evolutionary pressures on 110 MEX-encoding genes from all annotated ESKAPE organism genomes. We identify several MEX genes under stabilizing selection-representing targets which can facilitate broad-spectrum treatments with evolutionary constraints limiting the potential emergence of escape mutants. We also examine MEX systems being evaluated as drug targets, demonstrating that divergent selection may underlie some of the problems encountered in the development of effective treatments-specifically in relation to the NorA system in S. aureus. This study provides a comprehensive evolutionary context to efflux in the ESKAPE pathogens, which will provide critical context to the evaluation of efflux systems as antibiotic targets. IMPORTANCE Increasing rates of antibiotic-resistant bacterial infection are one of the most pressing contemporary global health concerns. The ESKAPE pathogen group represents the leading cause of these infections, and upregulation of efflux pump expression is a significant mechanism of resistance in these pathogens. This has resulted in substantial interest in the development of efflux pump inhibitors to combat antibiotic-resistant infections; however, no widespread treatments have been developed to date

Multidrug-Resistant Escherichia fergusonii: a Case of Acute Cystitis▿

PubMed Central

Savini, Vincenzo; Catavitello, Chiara; Talia, Marzia; Manna, Assunta; Pompetti, Franca; Favaro, Marco; Fontana, Carla; Febbo, Fabio; Balbinot, Andrea; Di Berardino, Fabio; Di Bonaventura, Giovanni; Di Zacomo, Silvia; Esattore, Francesca; D'Antonio, Domenico

2008-01-01

We report a case in which Escherichia fergusonii, an emerging pathogen in various types of infections, was associated with cystitis in a 52-year-old woman. The offending strain was found to be multidrug resistant. Despite in vitro activity, beta-lactam treatment failed because of a lack of patient compliance with therapy. The work confirms the pathogenic potential of E. fergusonii. PMID:18256229

[Study on active constituents of traditional Chinese medicine reversing multidrug resistance of tumor cells in vitro].

PubMed

Zhang, H; Yang, L; Liu, S; Ren, L

2001-09-01

To screen drugs reversing multidrug resistance of tumor cells from active constituents of traditional Chinese medicine and to study the reversal action. The kill effects of the drugs on tumor cell lines in vitro were determined with MTT method. The Jin's formula was used to analyse the effect of drug combination. 5 micrograms/ml rhynchophylline, 2 micrograms/ml jatrorrhizine and 1.25 micrograms/ml indirulin could reverse multidrug resistance for vincristine on KBv200 cell line by 16.8, 5.1 and 4 fold respectively. 1.56-12.5 micrograms/ml curcumine combining with vincristine could sensitize antitumor effect both on KB and KBv200 cell lines. All rhynchophylline, jatrorrhizine and indirulin could reverse multidrug resistance for vincristine on KBv200 cell line. Curcumine combinating vincristine could sensitize antitumor effect both on kB and kBv200 cell lines.

Outbreak of multidrug-resistant acute postoperative endophthalmitis due to Enterobacter aerogenes.

PubMed

Bhat, Shailaja S; Undrakonda, Vivekanand; Mukhopadhyay, Chiranjay; Parmar, Prachi Vikramsinh

2014-04-01

To report the clinical features, management, and outcome of 7 cases of culture-proven multidrug-resistant Enterobacter postoperative endophthalmitis following cataract surgery. Medical records of 7 cases of acute postoperative endophthalmitis after uneventful cataract surgery were reviewed. Details regarding age, gender, visual acuity and clinical features at presentation, microbiological profile, treatment interventions, and visual acuity and clinical features at 1 week, 1 month, and 3 months follow-up were collected. All patients reported decreased visual acuity and pain as presenting symptoms. All patients were resistant to intravitreal antibiotics such as vancomycin (1 mg/0.1 mL) and ceftazidime (2.25 mg/0.1 mL). Culture of aqueous and vitreous sample was positive for Enterobacter aerogenes and sensitive to co-trimoxazole, cefoperazone-sulbactam, imipenem-meropenem, and piperacillin-tazobactem. Two patients with panophthalmitis and no perception of light underwent evisceration. Three patients had visual acuity of ≥6/24 at the final follow-up. Multidrug-resistant Enterobacter acute postoperative endophthalmitis has a poor prognosis if not intercepted early.

Multidrug resistance in amoebiasis patients.

PubMed

Bansal, Devendra; Sehgal, Rakesh; Chawla, Yogesh; Malla, Nancy; Mahajan, R C

2006-08-01

Amoebiasis, caused by Entamoeba sp. a protozoan parasite, is a major public health problem in tropical and subtropical countries. The symptomatic patients are treated by specific chemotherapy. However, there are reports of treatment failure in some cases suggesting the possibility of drug resistance. The present study was therefore planned to assess the presence and expression of mRNA of multidrug resistance (MDR) gene in clinical isolates of Entamoeba histolytica and E. dispar. Forty five clinical isolates of Entamoeba sp. [E. histolytica (15) and E. dispar (30)] were maintained in polyxenic followed by monoxenic medium. DNA and total RNA were extracted from clinical isolates of Entamoeba sp. and from sensitive strain of E. histolytica (HM1: IMSS) and subjected to polymerase chain reaction (PCR) and multiplex reverse transcription (RT)-PCR techniques. The 344 bp segment of E. histolytica DNA was seen by PCR using primers specific to EhPgp1 in all clinical isolates and sensitive strain of E. histolytica. Over expression of EhPgp1 was observed only in resistant mutant of E. histolytica; however, transcription of EhPgp1 was not seen in any clinical isolates and sensitive strain of E. histolytica. The findings of the present study indicate that, so far, drug resistance in clinical isolates of E. histolytica does not seem to be a major problem in this country. However, susceptibility of clinical isolates of E. histolytica against various antiamoebic drugs needs to be investigated for better management.

Genomic analysis of globally diverse Mycobacterium tuberculosis strains provides insights into the emergence and spread of multidrug resistance.

PubMed

Manson, Abigail L; Cohen, Keira A; Abeel, Thomas; Desjardins, Christopher A; Armstrong, Derek T; Barry, Clifton E; Brand, Jeannette; Chapman, Sinéad B; Cho, Sang-Nae; Gabrielian, Andrei; Gomez, James; Jodals, Andreea M; Joloba, Moses; Jureen, Pontus; Lee, Jong Seok; Malinga, Lesibana; Maiga, Mamoudou; Nordenberg, Dale; Noroc, Ecaterina; Romancenco, Elena; Salazar, Alex; Ssengooba, Willy; Velayati, A A; Winglee, Kathryn; Zalutskaya, Aksana; Via, Laura E; Cassell, Gail H; Dorman, Susan E; Ellner, Jerrold; Farnia, Parissa; Galagan, James E; Rosenthal, Alex; Crudu, Valeriu; Homorodean, Daniela; Hsueh, Po-Ren; Narayanan, Sujatha; Pym, Alexander S; Skrahina, Alena; Swaminathan, Soumya; Van der Walt, Martie; Alland, David; Bishai, William R; Cohen, Ted; Hoffner, Sven; Birren, Bruce W; Earl, Ashlee M

2017-03-01

Multidrug-resistant tuberculosis (MDR-TB), caused by drug-resistant strains of Mycobacterium tuberculosis, is an increasingly serious problem worldwide. Here we examined a data set of whole-genome sequences from 5,310 M. tuberculosis isolates from five continents. Despite the great diversity of these isolates with respect to geographical point of isolation, genetic background and drug resistance, the patterns for the emergence of drug resistance were conserved globally. We have identified harbinger mutations that often precede multidrug resistance. In particular, the katG mutation encoding p.Ser315Thr, which confers resistance to isoniazid, overwhelmingly arose before mutations that conferred rifampicin resistance across all of the lineages, geographical regions and time periods. Therefore, molecular diagnostics that include markers for rifampicin resistance alone will be insufficient to identify pre-MDR strains. Incorporating knowledge of polymorphisms that occur before the emergence of multidrug resistance, particularly katG p.Ser315Thr, into molecular diagnostics should enable targeted treatment of patients with pre-MDR-TB to prevent further development of MDR-TB.

Sequence- and structure-based computational analyses of Gram-negative tripartite efflux pumps in the context of bacterial membranes

DOE PAGES

Travers, Timothy; Wang, Katherine J.; Lopez, Cesar A.; ...

2018-02-09

Gram-negative multidrug resistance currently presents a serious threat to public health with infections effectively rendered untreatable. Multiple molecular mechanisms exist that cause antibiotic resistance and in addition, the last three decades have seen slowing rates of new drug development. In this paper, we summarize the use of various computational techniques for investigating the mechanisms of multidrug resistance mediated by Gram-negative tripartite efflux pumps and membranes. Recent work in our lab combines data-driven sequence and structure analyses to study the interactions and dynamics of these bacterial components. Computational studies can complement experimental methodologies for gaining crucial insights into combatting multidrug resistance.

Sequence- and structure-based computational analyses of Gram-negative tripartite efflux pumps in the context of bacterial membranes

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

Travers, Timothy; Wang, Katherine J.; Lopez, Cesar A.

Gram-negative multidrug resistance currently presents a serious threat to public health with infections effectively rendered untreatable. Multiple molecular mechanisms exist that cause antibiotic resistance and in addition, the last three decades have seen slowing rates of new drug development. In this paper, we summarize the use of various computational techniques for investigating the mechanisms of multidrug resistance mediated by Gram-negative tripartite efflux pumps and membranes. Recent work in our lab combines data-driven sequence and structure analyses to study the interactions and dynamics of these bacterial components. Computational studies can complement experimental methodologies for gaining crucial insights into combatting multidrug resistance.

Nanodrug delivery in reversing multidrug resistance in cancer cells

PubMed Central

Kapse-Mistry, Sonali; Govender, Thirumala; Srivastava, Rohit; Yergeri, Mayur

2014-01-01

Different mechanisms in cancer cells become resistant to one or more chemotherapeutics is known as multidrug resistance (MDR) which hinders chemotherapy efficacy. Potential factors for MDR includes enhanced drug detoxification, decreased drug uptake, increased intracellular nucleophiles levels, enhanced repair of drug induced DNA damage, overexpression of drug transporter such as P-glycoprotein(P-gp), multidrug resistance-associated proteins (MRP1, MRP2), and breast cancer resistance protein (BCRP). Currently nanoassemblies such as polymeric/solid lipid/inorganic/metal nanoparticles, quantum dots, dendrimers, liposomes, micelles has emerged as an innovative, effective, and promising platforms for treatment of drug resistant cancer cells. Nanocarriers have potential to improve drug therapeutic index, ability for multifunctionality, divert ABC-transporter mediated drug efflux mechanism and selective targeting to tumor cells, cancer stem cells, tumor initiating cells, or cancer microenvironment. Selective nanocarrier targeting to tumor overcomes dose-limiting side effects, lack of selectivity, tissue toxicity, limited drug access to tumor tissues, high drug doses, and emergence of multiple drug resistance with conventional or combination chemotherapy. Current review highlights various nanodrug delivery systems to overcome mechanism of MDR by neutralizing, evading, or exploiting the drug efflux pumps and those independent of drug efflux pump mechanism by silencing Bcl-2 and HIF1α gene expressions by siRNA and miRNA, modulating ceramide levels and targeting NF-κB. “Theragnostics” combining a cytotoxic agent, targeting moiety, chemosensitizing agent, and diagnostic imaging aid are highlighted as effective and innovative systems for tumor localization and overcoming MDR. Physical approaches such as combination of drug with thermal/ultrasound/photodynamic therapies to overcome MDR are focused. The review focuses on newer drug delivery systems developed to overcome

Antibiotic Resistant Bacterial Isolates from Captive Green Turtles and In Vitro Sensitivity to Bacteriophages

PubMed Central

Ariel, Ellen; Picard, Jacqueline; Elliott, Lisa

2017-01-01

This study aimed to test multidrug resistant isolates from hospitalised green turtles (Chelonia mydas) and their environment in North Queensland, Australia, for in vitro susceptibility to bacteriophages. Seventy-one Gram-negative bacteria were isolated from green turtle eye swabs and water samples. Broth microdilution tests were used to determine antibiotic susceptibility. All isolates were resistant to at least two antibiotics, with 24% being resistant to seven of the eight antibiotics. Highest resistance rates were detected to enrofloxacin (77%) and ampicillin (69.2%). More than 50% resistance was also found to amoxicillin/clavulanic acid (62.5%), ceftiofur (53.8%), and erythromycin (53.3%). All the enriched phage filtrate mixtures resulted in the lysis of one or more of the multidrug resistant bacteria, including Vibrio harveyi and V. parahaemolyticus. These results indicate that antibiotic resistance is common in Gram-negative bacteria isolated from hospitalised sea turtles and their marine environment in North Queensland, supporting global concern over the rapid evolution of multidrug resistant genes in the environment. Using virulent bacteriophages as antibiotic alternatives would not only be beneficial to turtle health but also prevent further addition of multidrug resistant genes to coastal waters. PMID:29147114

Epidemic Typhoid in Vietnam: Molecular Typing of Multiple-Antibiotic-Resistant Salmonella enterica Serotype Typhi from Four Outbreaks

PubMed Central

Connerton, Phillippa; Wain, John; Hien, Tran T.; Ali, Tahir; Parry, Christopher; Chinh, Nguyen T.; Vinh, Ha; Ho, Vo A.; Diep, To S.; Day, Nicholas P. J.; White, Nicholas J.; Dougan, Gordon; Farrar, Jeremy J.

2000-01-01

Multidrug-resistant Salmonella enterica serotype Typhi isolates from four outbreaks of typhoid fever in southern Vietnam between 1993 and 1997 were compared. Pulsed-field gel electrophoresis, bacteriophage and plasmid typing, and antibiotic susceptibilities showed that independent outbreaks of multidrug-resistant typhoid fever in southern Vietnam are caused by single bacterial strains. However, different outbreaks do not derive from the clonal expansion of a single multidrug-resistant serotype Typhi strain. PMID:10655411

Phosphate-Containing Polyethylene Glycol Polymers Prevent Lethal Sepsis by Multidrug-Resistant Pathogens

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

Zaborin, Alexander; Defazio, Jennifer; Kade, Matthew

The gastrointestinal tract is the primary site of colonization for multi-drug resistant healthcare associated pathogens (HAPs) that are the principal source and cause of life-threatening infections in critically ill patients. We previously identified a high molecular weight co-polymer (PEG15-20) with mucoadhesive and cytoprotective actions on the intestinal epithelium. In this report we covalently bonded phosphate (Pi) to PEG15-20 ( termed Pi-PEG15-20) to enhance its cytoprotective activity against microbial virulence activation and invasion based on our previous work showing that Pi is a key environmental cue regulating microbial virulence across pathogens of clinical importance to hospitalized patients. We demonstrated that Pi-PEG15-20more » can suppress phosphate-, iron-, and quorum sensing signal- mediated activation of bacterial virulence as well as inhibit intestinal epithelial IL-8 release during lipopolysaccharide (LPS) exposure. Pi-PEG15-20 also prevented mortality in C. elegans and mice exposed to several highly virulent and antibiotic(?)-resistant health care acquired pathogens (HAPs) while preserving the normal microbiota. Intestinal application Pi-PEG 15-20 has the potential to be a useful agent to prevent the pathogenic activation of microbes during critical illness where exposure to HAPs is ubiquitous.« less

Intravenous immunoglobulin enhances the killing activity and autophagy of neutrophils isolated from immunocompromised patients against multidrug-resistant bacteria.

PubMed

Matsuo, Hidemasa; Itoh, Hiroshi; Kitamura, Naoko; Kamikubo, Yasuhiko; Higuchi, Takeshi; Shiga, Shuichi; Ichiyama, Satoshi; Kondo, Tadakazu; Takaori-Kondo, Akifumi; Adachi, Souichi

2015-08-14

Intravenous immunoglobulin (IVIG) is periodically administered to immunocompromised patients together with antimicrobial agents. The evidence that supports the effectiveness of IVIG is mostly based on data from randomized clinical trials; the underlying mechanisms are poorly understood. A recent study revealed that killing of multidrug-resistant bacteria and drug-sensitive strains by neutrophils isolated from healthy donors is enhanced by an IVIG preparation. However, the effectiveness of IVIG in immunocompromised patients remains unclear. The present study found that IVIG increased both killing activity and O2(-) release by neutrophils isolated from six patients receiving immune-suppressive drugs after hematopoietic stem cell transplantation (HSCT); these neutrophils killed both multidrug-resistant extended-spectrum β-lactamase-producing Escherichia coli (E. coli) and multidrug-resistant Pseudomonas aeruginosa (P. aeruginosa). Moreover, IVIG increased the autophagy of the neutrophils, which is known to play an important role in innate immunity. These results suggest that IVIG promotes both the killing activity and autophagy of neutrophils isolated from immunocompromised patients against multidrug-resistant bacteria. Copyright © 2015 Elsevier Inc. All rights reserved.

Plasma membrane microorganization of LR73 multidrug-resistant cells revealed by FCS

NASA Astrophysics Data System (ADS)

Winckler, Pascale; Jaffiol, Rodolphe; Cailler, Aurélie; Morjani, Hamid; Jeannesson, Pierre; Deturche, Régis

2011-03-01

Tumoral cells could present a multidrug resistance (MDR) to chemotherapeutic treatments. This drug resistance would be associated to biomechanisms occurring at the plasma membrane level, involving modification of membrane fluidity, drug permeability, presence of microdomains (rafts, caveolae...), and membrane proteins overexpression such as Pglycoprotein. Fluorescence correlation spectroscopy (FCS) is the relevant method to investigate locally the fluidity of biological membranes through the lateral diffusion of a fluorescent membrane probe. Thus, we use FCS to monitor the plasma membrane local organization of LR73 carcinoma cells and three derived multidrug-resistant cancer cells lines. Measurements were conducted at the single cell level, which enabled us to get a detailed overview of the plasma membrane microviscosity distribution of each cell line studied. Moreover, we propose 2D diffusion simulation based on a Monte Carlo model to investigate the membrane organisation in terms of microdomains. This simulation allows us to relate the differences in the fluidity distributions with microorganization changes in plasma membrane of MDR cells.

Quantifying the Evolutionary Conservation of Genes Encoding Multidrug Efflux Pumps in the ESKAPE Pathogens To Identify Antimicrobial Drug Targets

PubMed Central

Ul-Hasan, Sabah; Chan, Benjamin K.; Sistrom, Mark J.

2018-01-01

ABSTRACT Increasing rates of antibiotic-resistant bacterial infection are one of the most pressing contemporary global health concerns. The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) have been identified as the leading global cause of multidrug-resistant bacterial infections, and overexpression of multidrug efflux (MEX) transport systems has been identified as one of the most critical mechanisms facilitating the evolution of multidrug resistance in ESKAPE pathogens. Despite efforts to develop efflux pump inhibitors to combat antibiotic resistance, the need persists to identify additional targets for future investigations. We evaluated evolutionary pressures on 110 MEX-encoding genes from all annotated ESKAPE organism genomes. We identify several MEX genes under stabilizing selection—representing targets which can facilitate broad-spectrum treatments with evolutionary constraints limiting the potential emergence of escape mutants. We also examine MEX systems being evaluated as drug targets, demonstrating that divergent selection may underlie some of the problems encountered in the development of effective treatments—specifically in relation to the NorA system in S. aureus. This study provides a comprehensive evolutionary context to efflux in the ESKAPE pathogens, which will provide critical context to the evaluation of efflux systems as antibiotic targets. IMPORTANCE Increasing rates of antibiotic-resistant bacterial infection are one of the most pressing contemporary global health concerns. The ESKAPE pathogen group represents the leading cause of these infections, and upregulation of efflux pump expression is a significant mechanism of resistance in these pathogens. This has resulted in substantial interest in the development of efflux pump inhibitors to combat antibiotic-resistant infections; however, no widespread treatments have been

A Bactericidal Guanidinomethyl Biaryl That Alters the Dynamics of Bacterial FtsZ Polymerization

PubMed Central

Kaul, Malvika; Parhi, Ajit K.; Zhang, Yongzheng; LaVoie, Edmond J.; Tuske, Steve; Arnold, Eddy; Kerrigan, John E.; Pilch, Daniel S.

2014-01-01

The prevalence of multidrug resistance among clinically significant bacterial pathogens underscores a critical need for the development of new classes of antibiotics with novel mechanisms of action. Here we describe the synthesis and evaluation of a guanidinomethyl biaryl compound {1-((4′-(tert-butyl)-[1,1′-biphenyl]-3-yl)methyl)guanidine} that targets the bacterial cell division protein FtsZ. In vitro studies with various bacterial FtsZ proteins reveal that the compound alters the dynamics of FtsZ self-polymerization via a stimulatory mechanism, while minimally impacting the polymerization of tubulin, the closest mammalian homologue of FtsZ. The FtsZ binding site of the compound is identified through a combination of computational and mutational approaches. The compound exhibits a broad spectrum of bactericidal activity, including activity against the multidrug-resistant pathogens methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE), while also exhibiting a minimal potential to induce resistance. Taken together, our results highlight the compound as a promising new FtsZ-targeting bactericidal agent. PMID:23050700

Overcoming Multidrug Resistance in Human Cancer Cells by Natural Compounds

PubMed Central

Nabekura, Tomohiro

2010-01-01

Multidrug resistance is a phenomenon whereby tumors become resistant to structurally unrelated anticancer drugs. P-glycoprotein belongs to the large ATP-binding cassette (ABC) transporter superfamily of membrane transport proteins. P-glycoprotein mediates resistance to various classes of anticancer drugs including vinblastine, daunorubicin, and paclitaxel, by actively extruding the drugs from the cells. The quest for inhibitors of anticancer drug efflux transporters has uncovered natural compounds, including (-)-epigallocatechin gallate, curcumin, capsaicin, and guggulsterone, as promising candidates. In this review, studies on the effects of natural compounds on P-glycoprotein and anticancer drug efflux transporters are summarized. PMID:22069634

Reversal effect of a macrocyclic bisbibenzyl plagiochin E on multidrug resistance in adriamycin-resistant K562/A02 cells.

PubMed

Shi, Yan-Qiu; Qu, Xian-Jun; Liao, Yong-Xiang; Xie, Chun-Feng; Cheng, Yan-Na; Li, Song; Lou, Hong-Xiang

2008-04-14

Plagiochin E is a new macrocyclic bisbibenzyl compound isolated from Marchantia polymorpha. In the previous studies, we reported that when combined with fluconazole, plagiochin E had synergetic effects against the resistant strain of Candida albicans. Herein, we examined the reversal effect of plagiochin E on multidrug resistance in adriamycin-induced resistant K562/A02 cells and the parental K562 cells. Its cytotoxicity and reversal effects on multidrug resistance were assessed by MTT (3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl-tetrazolium bromide) assay. Apoptosis percentage of cells was obtained from Annexin V/fluorescein isothiocyanate (FITC) and propridium iodide (PI) double-staining. The effects of plagiochin E on P-glycoprotein activity were evaluated by measuring rhodamine 123 (Rh123)-associated mean fluorescence intensity and P-glycoprotein expression on the basis of the flow cytometric technology, respectively. The results showed that plagiochin E ranging from 2 to 12 mug/ml had little cytotoxicity against K562/A02 cells. When combined with adriamycin, it significantly promoted the sensitivity of K562/A02 cells toward adriamycin through increasing intracellular accumulation of adriamycin in a dose-dependent manner. Further study demonstrated that the inhibitory effect of plagiochin E on P-glycoprotein activity was the major cause of increased stagnation of adriamycin inside K562/A02 cells, indicating that plagiochin E, as a new class of mutidrug resistance inhibitor, may effectively reverse the multidrug resistance in K562/A02 cells via inhibiting expression and drug-transport function of P-glycoprotein.

[Molecular characterization of resistance mechanisms: methicillin resistance Staphylococcus aureus, extended spectrum β-lactamases and carbapenemases].

PubMed

Oteo, Jesús; Belén Aracil, María

2015-07-01

Multi-drug resistance in bacterial pathogens increases morbidity and mortality in infected patients and it is a threat to public health concern by their high capacity to spread. For both reasons, the rapid detection of multi-drug resistant bacteria is critical. Standard microbiological procedures require 48-72 h to provide the antimicrobial susceptibility results, thus there is emerging interest in the development of rapid detection techniques. In recent years, the use of selective and differential culture-based methods has widely spread. However, the capacity for detecting antibiotic resistance genes and their low turnaround times has made molecular methods a reference for diagnosis of multidrug resistance. This review focusses on the molecular methods for detecting some mechanisms of antibiotic resistance with a high clinical and epidemiological impact: a) Enzymatic resistance to broad spectrum β-lactam antibiotics in Enterobacteriaceae, mainly extended spectrum β-lactamases (ESBL) and carbapenemases; and b) methicillin resistance in Staphylococcus aureus. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

Rapid increase in multidrug-resistant enteric bacilli blood stream infection after prostate biopsy - A 10-year population-based cohort study.

PubMed

Aly, Markus; Dyrdak, Robert; Nordström, Tobias; Jalal, Shah; Weibull, Caroline E; Giske, Christian G; Grönberg, Henrik

2015-06-15

Bloodstream infection following a transrectal prostate biopsy is a well-known and feared complication. Previous studies have shown an increase in multi-resistant bacterial infections as a consequence of higher usage of antibiotics in investigated populations. Our aim was to analyze bacterial resistance patterns in positive blood cultures, after prostate biopsies in Stockholm, Sweden, where the use of antibiotics has been low and decreasing during the last 10 years. From the three pathology laboratories in Stockholm, reports of prostate examinations were retrieved (n = 56,076) from 2003 to 2012. By linking men to the National Patient Register all but prostate core biopsies were excluded (n = 12,024). Prostate biopsies in men younger than 30 years of age were excluded (n = 5) leaving 44,047 biopsies for analysis. From laboratory information systems data regarding blood cultures were retrieved. Proportions of blood cultures within 30 days by year were calculated. Crude and adjusted logistic regression models were used to estimate ORs. In total, 44,047 prostate biopsies were performed in 32,916 men over 10 years. On 620 occasions a blood culture was drawn within 30 days of the biopsy; 266 of these were positive. The proportions with positive blood cultures in 2003 and 2012 were 0.38 and 1.14%, respectively. The proportion of multidrug-resistant bacteria increased significantly during the study. In the crude and the adjusted analysis, the year of biopsy and Charlson Comorbidity Index were associated with the risk of having a positive blood culture. Multidrug-resistant enteric bacilli are becoming a problem in Sweden, despite low antimicrobial use. Men need to be informed about the increasing risks of infectious complications of transrectal prostate biopsy. One out of 50 men undergoing a prostate biopsy will develop symptoms suggestive of a bloodstream infection after the biopsy and one in 100 men will have a positive blood culture. © 2015 Wiley Periodicals

ATP-binding cassette transporters are enriched in non-caveolar detergent-insoluble glycosphingolipid-enriched membrane domains (DIGs) in human multidrug-resistant cancer cells.

PubMed

Hinrichs, John W J; Klappe, Karin; Hummel, Ina; Kok, Jan W

2004-02-13

In this study we show that P-glycoprotein in multidrug-resistant 2780AD human ovarian carcinoma cells and multidrug resistance-associated protein 1 in multidrug-resistant HT29col human colon carcinoma cells are predominantly located in Lubrol-based detergent-insoluble glycosphingolipid-enriched membrane domains. This localization is independent of caveolae, since 2780AD cells do not express caveolin-1. Although HT29col cells do express caveolin-1, the ATP-binding cassette transporter and caveolin-1 were dissociated on the basis of differential solubility in Triton X-100 and absence of microscopical colocalization. While both the multidrug resistance-associated protein 1 and caveolin-1 are located in Lubrol-based membrane domains, they occupy different regions of these domains.

Antibacterial and Antibiotic-Modifying Activity of Methanol Extracts from Six Cameroonian Food Plants against Multidrug-Resistant Enteric Bacteria

PubMed Central

Dzotam, Joachim K.

2017-01-01

The present work was designed to investigate the antibacterial activities of methanol extracts from six Cameroonian edible plants and their synergistic effects with some commonly used antibiotics against multidrug-resistant (MDR) Gram-negative bacteria expressing active efflux pumps. The extracts were subjected to qualitative phytochemical screening and the microdilution broth method was used for antibacterial assays. The results of phytochemical tests indicate that all tested crude extracts contained polyphenols, flavonoids, triterpenes, and steroids. Extracts displayed selective antibacterial activities with the minimal inhibitory concentration (MIC) values ranging from 32 to 1024 μg/mL. The lowest MIC value (32 μg/mL) was recorded with Coula edulis extract against E. coli AG102 and K. pneumoniae K2 and with Mangifera indica bark extract against P. aeruginosa PA01 and Citrus sinensis extract against E. coli W3110 which also displayed the best MBC (256 μg/mL) value against E. coli ATCC8739. In combination with antibiotics, extracts from M. indica leaves showed synergistic effects with 75% (6/8) of the tested antibiotics against more than 80% of the tested bacteria. The findings of the present work indicate that the tested plants may be used alone or in combination in the treatment of bacterial infections including the multidrug-resistant bacteria. PMID:28904944

Antibacterial and Antibiotic-Modifying Activity of Methanol Extracts from Six Cameroonian Food Plants against Multidrug-Resistant Enteric Bacteria.

PubMed

Dzotam, Joachim K; Kuete, Victor

2017-01-01

The present work was designed to investigate the antibacterial activities of methanol extracts from six Cameroonian edible plants and their synergistic effects with some commonly used antibiotics against multidrug-resistant (MDR) Gram-negative bacteria expressing active efflux pumps. The extracts were subjected to qualitative phytochemical screening and the microdilution broth method was used for antibacterial assays. The results of phytochemical tests indicate that all tested crude extracts contained polyphenols, flavonoids, triterpenes, and steroids. Extracts displayed selective antibacterial activities with the minimal inhibitory concentration (MIC) values ranging from 32 to 1024  μ g/mL. The lowest MIC value (32  μ g/mL) was recorded with Coula edulis extract against E. coli AG102 and K. pneumoniae K2 and with Mangifera indica bark extract against P. aeruginosa PA01 and Citrus sinensis extract against E. coli W3110 which also displayed the best MBC (256  μ g/mL) value against E. coli ATCC8739. In combination with antibiotics, extracts from M. indica leaves showed synergistic effects with 75% (6/8) of the tested antibiotics against more than 80% of the tested bacteria. The findings of the present work indicate that the tested plants may be used alone or in combination in the treatment of bacterial infections including the multidrug-resistant bacteria.

Burden of Multidrug Resistant Mycobacterium tuberculosis Among New Cases in Al-Madinah Al-Monawarah, Saudi Arabia.

PubMed

Elhassan, Mogahid M; Hemeg, Hassan A; Elmekki, Miskelyemen A; Turkistani, Khalid A; Abdul-Aziz, Ahmed A

2017-01-01

The pattern of Mycobacterium tuberculosis susceptibility to first line drugs and multidrug resistance in Al-Madinah Al-Munawarah, a seasonally overcrowded are during Hajj and Omrah, is not well studied. This study aimed to investigate anti-tuberculosis drug resistance and its distribution among new cases in Al-Madinah Al-Monawarah. Study subjects included 622 patients with first time confirmed TB referred to the central tuberculosis laboratory in Al-Madinah between January 2012 and December 2014. Out of the 622 isolates, 99 (15.9%) were Mycobacteria Other Than Tuberculosis (MOTTS) and 25 (4.0%), three of which (12%) were children under five years of age, revealed multidrug resistance (MDR). Monoresistance to isoniazid (H) was (1.8%), to rifampin (R) was (1.4%), to streptomycin (S) was (1.9 %) to ethambutol (E) was (1.1 %) and to pyrazinamide (Z) was (2.1%). Being among the new cases, multidrug resistant tuberculosis (MDR TB) is supposed to be caused by strains which are originally multidrug resistant. Neither nationality nor gender was found to be associated with MDR TB. Since 12% of MDR cases were among children, a probability of primary infection with MDR strains is to be considered. Moreover, mass gathering during Hajj and Omrah seasons does not seem to increase the burden of MDR in the region. However, further investigation is needed to molecularly characterize MDR isolates and their phylogenetics and geographical origin. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Incidence of Multidrug-Resistant Pseudomonas Spp. in ICU Patients with Special Reference to ESBL, AMPC, MBL and Biofilm Production

PubMed Central

Gupta, Richa; Malik, Abida; Rizvi, Meher; Ahmed, S. Moied

2016-01-01

Background: Multidrug-resistant (MDR) Pseudomonas spp. have been reported to be the important cause of ICU infections. The appearance of ESBL, AmpC and MBL genes and their spread among bacterial pathogens is a matter of great concern. Biofilm production also attributes to antimicrobial resistance due to close cell to cell contact that permits bacteria to more effectively transfer plasmids to one another. This study aimed at determining the incidence of ESBL, AmpC, MBL and biofilm producing Pseudomonas spp. in ICU patients. Material and Methods: The clinical specimens were collected aseptically from 150 ICU patients from February 2012 to October 2013. Identification and antimicrobial susceptibility was performed according to Clinical and Laboratory Standards Institute (CLSI) guidelines. ESBLs and AmpC were detected phenotypically and genotypically. MBL was detected by modified Hodge and imipenem-EDTA double-disk synergy test. Results: Pseudomonas spp. 35(28%) were the most prevalent pathogen in ICU infections. Multidrug resistance and biofilm production was observed in 80.1% and 60.4% isolates, respectively. Prevalence of ESBL, AmpC and MBL was 22.9%, 42.8% and 14.4%, respectively. The average hospital stay was 25 days and was associated with 20% mortality. Conclusions: A regular surveillance is required to detect ESBL, AmpC and MBL producers especially in ICU patients. Carbapenems should be judiciously used to prevent their spread. The effective antibiotics, such as fluoroquinolones and piperacillin-tazobactum should be used after sensitivity testing. PMID:27013841

Genome evolution and plasticity of Serratia marcescens, an important multidrug-resistant nosocomial pathogen.

PubMed

Iguchi, Atsushi; Nagaya, Yutaka; Pradel, Elizabeth; Ooka, Tadasuke; Ogura, Yoshitoshi; Katsura, Keisuke; Kurokawa, Ken; Oshima, Kenshiro; Hattori, Masahira; Parkhill, Julian; Sebaihia, Mohamed; Coulthurst, Sarah J; Gotoh, Naomasa; Thomson, Nicholas R; Ewbank, Jonathan J; Hayashi, Tetsuya

2014-08-01

Serratia marcescens is an important nosocomial pathogen that can cause an array of infections, most notably of the urinary tract and bloodstream. Naturally, it is found in many environmental niches, and is capable of infecting plants and animals. The emergence and spread of multidrug-resistant strains producing extended-spectrum or metallo beta-lactamases now pose a threat to public health worldwide. Here we report the complete genome sequences of two carefully selected S. marcescens strains, a multidrug-resistant clinical isolate (strain SM39) and an insect isolate (strain Db11). Our comparative analyses reveal the core genome of S. marcescens and define the potential metabolic capacity, virulence, and multidrug resistance of this species. We show a remarkable intraspecies genetic diversity, both at the sequence level and with regards genome flexibility, which may reflect the diversity of niches inhabited by members of this species. A broader analysis with other Serratia species identifies a set of approximately 3,000 genes that characterize the genus. Within this apparent genetic diversity, we identified many genes implicated in the high virulence potential and antibiotic resistance of SM39, including the metallo beta-lactamase and multiple other drug resistance determinants carried on plasmid pSMC1. We further show that pSMC1 is most closely related to plasmids circulating in Pseudomonas species. Our data will provide a valuable basis for future studies on S. marcescens and new insights into the genetic mechanisms that underlie the emergence of pathogens highly resistant to multiple antimicrobial agents. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Molecular detection of multidrug-resistant Mycobacterium leprae from Indian leprosy patients.

PubMed

Lavania, Mallika; Singh, Itu; Turankar, Ravindra P; Ahuja, Madhvi; Pathak, Vinay; Sengupta, Utpal; Das, Loretta; Kumar, Archana; Darlong, Joydeepa; Nathan, Rajeev; Maseey, Asha

2018-03-01

The emergence of multidrug-resistant (MDR) organisms for any infectious disease is a public health concern. Global efforts to control leprosy by intensive chemotherapy have led to a significant decrease in the number of registered patients. Currently recommended control measures for treating leprosy with multidrug therapy (MDT) were designed to prevent the spread of dapsone-resistant Mycobacterium leprae strains. Here we report the identification of MDR M. leprae from relapse leprosy patients from endemic regions in India. Resistance profiles to rifampicin, dapsone and ofloxacin of the isolated strains were confirmed by identification of mutations in genes previously shown to be associated with resistance to each drug. Between 2009-2016, slit-skin smear samples were collected from 239 relapse and 11 new leprosy cases from hospitals of The Leprosy Mission across India. DNA was extracted from the samples and was analysed by PCR targeting the rpoB, folP and gyrA genes associated with resistance to rifampicin, dapsone and ofloxacin, respectively, in M. leprae. M. leprae Thai-53 (wild-type) and Zensho-4 (MDR) were used as reference strains. Fifteen strains showed representative mutations in at least two resistance genes. Two strains showed mutations in all three genes responsible for drug resistance. Seven, seven and one strain, respectively, showed mutations in genes responsible for rifampicin and dapsone resistance, for dapsone and ofloxacin resistance and for rifampicin and ofloxacin resistance. This study showed the emergence of MDR M. leprae in MDT-treated leprosy patients from endemic regions of India. Copyright © 2017 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.

Anethole inhibits growth of recently emerged multidrug resistant toxigenic Vibrio cholerae O1 El Tor variant strains in vitro

PubMed Central

ZAHID, M. Shamim Hasan; AWASTHI, Sharda Prasad; HINENOYA, Atsushi; YAMASAKI, Shinji

2015-01-01

To search natural compounds having inhibitory effect on bacterial growth is important, particularly in view of growing multidrug resistant (MDR) strains of bacterial pathogens. Like other bacterial pathogens, MDR Vibrio cholerae, the causative agent of diarrheal disease cholera, is becoming a great concern. As an approach of searching new antimicrobial agents, here, we show that anethole, a well-studied natural component of sweet fennel and star anise seeds, could potentially inhibit the growth of MDR O1 El Tor biotype, the ongoing 7th cholera pandemic variant strains of toxigenic V. cholerae. The minimum inhibitory concentration (MIC) of anethole against diverse O1 El Tor biotype strains is evaluated as 200 µg/ml. Moreover, the effect of anethole is bactericidal and exerts rapid-killing action on V. cholerae cells. This study is the first report which demonstrates that anethole, purified from natural compound, is a potent inhibitor of growth of toxigenic V. cholerae. Our data suggest that anethole could be a potential antimicrobial drug candidate, particularly against MDR V. cholerae mediated infections. PMID:25648987

Anethole inhibits growth of recently emerged multidrug resistant toxigenic Vibrio cholerae O1 El Tor variant strains in vitro.

PubMed

Zahid, M Shamim Hasan; Awasthi, Sharda Prasad; Hinenoya, Atsushi; Yamasaki, Shinji

2015-05-01

To search natural compounds having inhibitory effect on bacterial growth is important, particularly in view of growing multidrug resistant (MDR) strains of bacterial pathogens. Like other bacterial pathogens, MDR Vibrio cholerae, the causative agent of diarrheal disease cholera, is becoming a great concern. As an approach of searching new antimicrobial agents, here, we show that anethole, a well-studied natural component of sweet fennel and star anise seeds, could potentially inhibit the growth of MDR O1 El Tor biotype, the ongoing 7th cholera pandemic variant strains of toxigenic V. cholerae. The minimum inhibitory concentration (MIC) of anethole against diverse O1 El Tor biotype strains is evaluated as 200 µg/ml. Moreover, the effect of anethole is bactericidal and exerts rapid-killing action on V. cholerae cells. This study is the first report which demonstrates that anethole, purified from natural compound, is a potent inhibitor of growth of toxigenic V. cholerae. Our data suggest that anethole could be a potential antimicrobial drug candidate, particularly against MDR V. cholerae mediated infections.

Non-p-glycoprotein-mediated multidrug resistance in detransformed rat cells selected for resistance to methylglyoxal bis(guanylhydrazone).

PubMed

Weber, J M; Sircar, S; Horvath, J; Dion, P

1989-11-01

Three independent variants (G2, G4, G5), resistant to methylglyoxal bis(guanylhydrazone), an anticancer drug, have been isolated by single step selection from an adenovirus-transformed rat brain cell line (1). These variants display selective cross-resistance to several natural product drugs of dissimilar structure and action. Multidrug resistance has recently been shown to be caused by overexpression of the membrane-associated p-glycoprotein, most often caused by amplification of the mdr gene. Several types of experiments were conducted to determine whether the observed drug resistance in our cell lines could be due to changes at the mdr locus. The following results were obtained: (a) the mdr locus was not amplified; (b) transcription of the mdr gene and p-glycoprotein synthesis were not increased; (c) multidrug resistance cell lines, which carry an amplified mdr locus, were not cross-resistant to methylglyoxal bis(guanylhydrazone); (d) verapamil did not reverse the resistance of G cells or mdr cells to methylglyoxal bis(guanylhydrazone), nor that of G cells to vincristine; and (e) methylglyoxal bis(guanylhydrazone) resistance was recessive and depended on a block to drug uptake, as opposed to mdr cells which are dominant and express increased drug efflux. The results obtained suggest that the drug resistance in the G2, G4, and G5 cells was atypical and may be due to a mechanism distinct from that mediated by the mdr locus.

Isolation and in vitro evaluation of bacteriophages against MDR-bacterial isolates from septic wound infections.

PubMed

Pallavali, Roja Rani; Degati, Vijaya Lakshmi; Lomada, Dakshayani; Reddy, Madhava C; Durbaka, Vijaya Raghava Prasad

2017-01-01

Multi-drug resistance has become a major problem for the treatment of pathogenic bacterial infections. The use of bacteriophages is an attractive approach to overcome the problem of drug resistance in several pathogens that cause fatal diseases. Our study aimed to isolate multi drug resistant bacteria from patients with septic wounds and then isolate and apply bacteriophages in vitro as alternative therapeutic agents. Pus samples were aseptically collected from Rajiv Gandhi Institute of Medical Science (RIMS), Kadapa, A.P., and samples were analyzed by gram staining, evaluating morphological characteristics, and biochemical methods. MDR-bacterial strains were collected using the Kirby-Bauer disk diffusion method against a variety of antibiotics. Bacteriophages were collected and tested in vitro for lytic activity against MDR-bacterial isolates. Analysis of the pus swab samples revealed that the most of the isolates detected had Pseudomonas aeruginosa as the predominant bacterium, followed by Staphylococcus aureus, Klebsiella pneumoniae and Escherichia coli. Our results suggested that gram-negative bacteria were more predominant than gram-positive bacteria in septic wounds; most of these isolates were resistant to ampicillin, amoxicillin, penicillin, vancomycin and tetracycline. All the gram-positive isolates (100%) were multi-drug resistant, whereas 86% of the gram-negative isolates had a drug resistant nature. Further bacteriophages isolated from sewage demonstrated perfect lytic activity against the multi-drug resistant bacteria causing septic wounds. In vitro analysis of the isolated bacteriophages demonstrated perfect lysis against the corresponding MDR-bacteria, and these isolated phages may be promising as a first choice for prophylaxis against wound sepsis, Moreover, phage therapy does not enhance multi-drug resistance in bacteria and could work simultaneously on a wide variety of MDR-bacteria when used in a bacteriophage cocktail. Hence, our results suggest

Control of metazoan heme homeostasis by a conserved multidrug resistance protein

PubMed Central

Korolnek, Tamara; Zhang, Jianbing; Beardsley, Simon; Scheffer, George L; Hamza, Iqbal

2014-01-01

Several lines of evidence predict that specific pathways must exist in metazoans for the escorted movement of heme, an essential but cytotoxic iron-containing organic ring, within and between cells and tissues, but these pathways remain obscure. In Caenorhabditis elegans, embryonic development is inextricably dependent on both maternally-derived heme and environmentally-acquired heme. Here, we show that the multidrug resistance protein, MRP-5/ABCC5, likely acts as a heme exporter and targeted depletion of mrp-5 in the intestine causes embryonic lethality. Transient knockdown of mrp5 in zebrafish leads to morphological defects and failure to hemoglobinize red blood cells. MRP5 resides on the plasma membrane and endosomal compartments and regulates export of cytosolic heme. Together, our genetic studies in worms, yeast, zebrafish, and mammalian cells identify a conserved, physiological role for a multidrug resistance protein in regulating systemic heme homeostasis. We envision other MRP family members may play similar unanticipated physiological roles in animal development. PMID:24836561

Putative histidine kinase inhibitors with antibacterial effect against multi-drug resistant clinical isolates identified by in vitro and in silico screens

NASA Astrophysics Data System (ADS)

Velikova, Nadya; Fulle, Simone; Manso, Ana Sousa; Mechkarska, Milena; Finn, Paul; Conlon, J. Michael; Oggioni, Marco Rinaldo; Wells, Jerry M.; Marina, Alberto

2016-05-01

Novel antibacterials are urgently needed to address the growing problem of bacterial resistance to conventional antibiotics. Two-component systems (TCS) are widely used by bacteria to regulate gene expression in response to various environmental stimuli and physiological stress and have been previously proposed as promising antibacterial targets. TCS consist of a sensor histidine kinase (HK) and an effector response regulator. The HK component contains a highly conserved ATP-binding site that is considered to be a promising target for broad-spectrum antibacterial drugs. Here, we describe the identification of putative HK autophosphorylation inhibitors following two independent experimental approaches: in vitro fragment-based screen via differential scanning fluorimetry and in silico structure-based screening, each followed up by the exploration of analogue compounds as identified by ligand-based similarity searches. Nine of the tested compounds showed antibacterial effect against multi-drug resistant clinical isolates of bacterial pathogens and include three novel scaffolds, which have not been explored so far in other antibacterial compounds. Overall, putative HK autophosphorylation inhibitors were found that together provide a promising starting point for further optimization as antibacterials.

Cytotoxicity of South-African medicinal plants towards sensitive and multidrug-resistant cancer cells.

PubMed

Saeed, Mohamed E M; Meyer, Marion; Hussein, Ahmed; Efferth, Thomas

2016-06-20

Traditional medicine plays a major role for primary health care worldwide. Cancer belongs to the leading disease burden in industrialized and developing countries. Successful cancer therapy is hampered by the development of resistance towards established anticancer drugs. In the present study, we investigated the cytotoxicity of 29 extracts from 26 medicinal plants of South-Africa against leukemia cell lines, most of which are used traditionally to treat cancer and related symptoms. We have investigated the plant extracts for their cytotoxic activity towards drug-sensitive parental CCRF-CEM leukemia cells and their multidrug-resistant P-glycoprotein-overexpressing subline, CEM/ADR5000 by means of the resazurin assay. A panel of 60 NCI tumor cell lines have been investigated for correlations between selected phytochemicals from medicinal plants and the expression of resistance-conferring genes (ABC-transporters, oncogenes, tumor suppressor genes). Seven extracts inhibited both cell lines (Acokanthera oppositifolia, Hypoestes aristata, Laurus nobilis, Leonotis leonurus, Plectranthus barbatus, Plectranthus ciliates, Salvia apiana). CEM/ADR5000 cells exhibited a low degree of cross-resistance (3.35-fold) towards the L. leonurus extract, while no cross-resistance was observed to other plant extracts, although CEM/ADR5000 cells were highly resistant to clinically established drugs. The log10IC50 values for two out of 14 selected phytochemicals from these plants (acovenoside A and ouabain) of 60 tumor cell lines were correlated to the expression of ABC-transporters (ABCB1, ABCB5, ABCC1, ABCG2), oncogenes (EGFR, RAS) and tumor suppressors (TP53). Sensitivity or resistance of the cell lines were not statistically associated with the expression of these genes, indicating that multidrug-resistant, refractory tumors expressing these genes may still respond to acovenoside A and ouabain. The bioactivity of South African medicinal plants may represent a basis for the development

Multidrug-resistant enterococci lack CRISPR-cas.

PubMed

Palmer, Kelli L; Gilmore, Michael S

2010-10-12

Clustered, regularly interspaced short palindromic repeats (CRISPR) provide bacteria and archaea with sequence-specific, acquired defense against plasmids and phage. Because mobile elements constitute up to 25% of the genome of multidrug-resistant (MDR) enterococci, it was of interest to examine the codistribution of CRISPR and acquired antibiotic resistance in enterococcal lineages. A database was built from 16 Enterococcus faecalis draft genome sequences to identify commonalities and polymorphisms in the location and content of CRISPR loci. With this data set, we were able to detect identities between CRISPR spacers and sequences from mobile elements, including pheromone-responsive plasmids and phage, suggesting that CRISPR regulates the flux of these elements through the E. faecalis species. Based on conserved locations of CRISPR and CRISPR-cas loci and the discovery of a new CRISPR locus with associated functional genes, CRISPR3-cas, we screened additional E. faecalis strains for CRISPR content, including isolates predating the use of antibiotics. We found a highly significant inverse correlation between the presence of a CRISPR-cas locus and acquired antibiotic resistance in E. faecalis, and examination of an additional eight E. faecium genomes yielded similar results for that species. A mechanism for CRISPR-cas loss in E. faecalis was identified. The inverse relationship between CRISPR-cas and antibiotic resistance suggests that antibiotic use inadvertently selects for enterococcal strains with compromised genome defense.

Multidrug-Resistant TB

PubMed Central

Cox, Helen; Coomans, Fons

2016-01-01

Abstract The right to enjoy the benefits of scientific progress (REBSP) is a little-known but potentially valuable right that can contribute to rights-based approaches to addressing multidrug-resistant TB (MDR-TB). We argue that better understanding of the REBSP may help to advance legal and civil society action for health rights. While the REBSP does not provide an individual entitlement to have a new drug developed for MDR-TB, it sets up entitlements to expect a state to establish a legislative and policy framework aimed at developing scientific capacity to address the most important health issues and at disseminating the outcomes of scientific research. By making scientific findings available and accessible, people can be enabled to claim the use of science for social benefits. Inasmuch as the market fails to address neglected diseases such as MDR-TB, the REBSP provides a potential counterbalance to frame a positive obligation on states to both marshal their own resources and to coordinate the actions of multiple other actors towards this goal, including non-state actors. While the latter do not hold the same level of accountability as states, the REBSP can still enable the recognition of obligations at a level of “soft law” responsibilities. PMID:27780997

Antibacterial activity of Limonium brasiliense (Baicuru) against multidrug-resistant bacteria using a statistical mixture design.

PubMed

Blainski, Andressa; Gionco, Barbara; Oliveira, Admilton G; Andrade, Galdino; Scarminio, Ieda S; Silva, Denise B; Lopes, Norberto P; Mello, João C P

2017-02-23

Limonium brasiliense (Boiss.) Kuntze (Plumbaginaceae) is commonly known as "baicuru" or "guaicuru" and preparations of its dried rhizomes have been popularly used in the treatment of premenstrual syndrome and menstrual disorder, and as an antiseptic in genito-urinary infections. This study evaluated the potential antibacterial activity of rhizome extracts against multidrug-resistant bacterial strains using statistical mixture design. The statistical design of four components (water, methanol, acetone, and ethanol) produced 15 different extracts and also a confirmatory experiment, which was performed using water:acetone (3:7, v/v). The crude extracts and their ethyl-acetate fractions were tested against vancomycin-resistant Enterococcus faecium (VREfm), methicillin-resistant Staphylococcus aureus (MRSA) and Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae, all of which have been implicated in hospital and community-acquired infections. The dry residue, total polyphenol, gallocatechin and epigallocatechin contents of the extracts were also tested and statistical analysis was applied in order to define the fit models to predict the result of each parameter for any mixture of components. The principal component and hierarchical clustering analyses (PCA and HCA) of chromatographic data, as well as mass spectrometry (MS) analysis were performanced to determine the main compounds present in the extracts. The Gram-positive bacteria were susceptible to inhibition of bacterial growth, in special the ethyl-acetate fraction of ternary extracts from water:acetone:ethanol and methanol:acetone:ethanol against, respectively, VREfm (MIC=19µg/mL) and MRSA (MIC=39µg/mL). On the other hand, moderate activity of the ethyl-acetate fractions from primary (except water), secondary and ternary extracts (MIC=625µg/mL) was noted against KPC. The quadratic and special cubic models were significant for polyphenols and gallocatechin contents, respectively. Fit models to dry

Activity of Topical Antimicrobial Agents Against Multidrug-Resistant Bacteria Recovered from Burn Patients

DTIC Science & Technology

2010-01-01

produced by Pseudomonas fluorescens [19] Inhibition of RNA and protein synthesis by targeting the isoleucine-binding site on the isoleucyl-transfer-RNA...multidrug-resistant (MDR) bacteria. We compared two methods of determining topical antimicrobial susceptibilities. Methods: Isolates of Pseudomonas ...aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA), extended spectrum beta-lactamase (ESBL) producing Klebsiella pneumoniae, and

Draft Genome Sequences of Six Multidrug-Resistant Clinical Strains of Acinetobacter baumannii, Isolated at Two Major Hospitals in Kuwait.

PubMed

Nasser, Kother; Mustafa, Abu Salim; Khan, Mohd Wasif; Purohit, Prashant; Al-Obaid, Inaam; Dhar, Rita; Al-Fouzan, Wadha

2018-04-19

Acinetobacter baumannii is an important opportunistic pathogen in global health care settings. Its dissemination and multidrug resistance pose an issue with treatment and outbreak control. Here, we present draft genome assemblies of six multidrug-resistant clinical strains of A. baumannii isolated from patients admitted to one of two major hospitals in Kuwait. Copyright © 2018 Nasser et al.

Multidrug-resistant Pulmonary Tuberculosis Among Young Korean Soldiers in a Communal Setting

PubMed Central

Lee, Sei Won; Kim, Kwang Hyun; Min, Kyung Hoon

2009-01-01

The goal of this study was to evaluate the prevalence of first-line anti-tuberculosis drug resistance and risk factors associated with multidrug-resistant tuberculosis (MDR TB) among young soldiers in the Korean military, which has a strict tuberculosis control program. All patients with culture-confirmed pulmonary tuberculosis during their service at the Armed Forces Capital Hospital from January 2001 to December 2006 were enrolled in the study. Drug resistant Mycobacterium tuberculosis was isolated from 18 patients (12.2%) and multidrug-resistant M. tuberculosis was isolated from 12 patients (8.1%). Previous treatment of tuberculosis and the presence of a cavity on the patient's chest computed tomography scan were associated with MDR TB; military rank, smoking habits, and positive acid-fast bacilli smears were not associated with MDR TB. In a multiple logistic regression analysis, previous treatment of tuberculosis was a significant independent risk factor for MDR TB (odds ratio 6.12, 95% confidence interval 1.53-24.46). The prevalence of drug resistant tuberculosis among young soldiers in the Korean military was moderately high and the majority of resistant cases were found in patients who had undergone previous treatment of tuberculosis. Based on our results, we suggest that relapsed tuberculosis cases within communal settings should be cautiously managed until the drug susceptibility tests report is completed, even if previous treatment results were satisfactory. PMID:19654938

Prevalence and characterization of multidrug-resistant zoonotic Enterobacter spp. in poultry of Bangladesh.

PubMed

Nandi, Shuvro Prokash; Sultana, Munawar; Hossain, M Anwar

2013-05-01

Poultry and poultry products are major contributors of zoonotic pathogens. Limited data are available on Enterobacter spp. as a potent zoonotic pathogen in poultry. The present study is a first endeavor on the emergence of multidrug-resistant zoonotic Enterobacter spp. and its prevalence arising from poultry in Bangladesh. Cloacal swabs from poultry samples of five different farms at Savar, Dhaka, Bangladesh were collected and from 106 isolates, 18 presumptive Enterobacter spp. were obtained. Antibiogram using 19 used antibiotics belonging to 15 major groups revealed that all of the 18 isolates were completely resistant to penicillin and rifampicin, but differed in their drug resistance pattern against ampicillin (94.4%), clindamycin (94.4%), erythromycin (94.4%), vancomycin (88.9%), sulfonamides (72.2%), imipenem (66.6%), streptomycin (55.6%), nitrofurantoin (33.3%), doxycycline (33.3%), tetracyclines (33.3%), cefepime (11.1%), and gentamicin (5.6%). All Enterobacter spp. were found to be plasmid free, implying that multidrug-resistant properties are chromosomal borne. The vanA and sulI were detected by polymerase chain reaction assay in 17 and 13 isolates, respectively. Amplified ribosomal DNA restriction analysis and randomly amplified polymorphic DNA distributed the 18 multidrug-resistant Enterobacter spp. into three genotypes. Phylogenetic analysis of the representatives of the three genotypes using partial 16S rRNA gene sequence (approximately 900 bp) showed that the genotypically diverse groups belonged to Enterobacter hormaechei, E. cloacae, and E. cancerogenus, respectively. The clinical significance of the close relative Enterobacter spp. is indicative of their zoonotic potential. Therefore, urgent intervention is required to limit the emergence and spread of these bacteria in poultry feed as well as prudent use of antibiotics among poultry farmers in Bangladesh.

Biofilm Formation Potential of Heat-Resistant Escherichia coli Dairy Isolates and the Complete Genome of Multidrug-Resistant, Heat-Resistant Strain FAM21845

PubMed Central

Schmid, Michael; Kulli, Sandra; Schneeberger, Kerstin; Naskova, Javorka; Knøchel, Susanne; Ahrens, Christian H.

2017-01-01

ABSTRACT We tested the biofilm formation potential of 30 heat-resistant and 6 heat-sensitive Escherichia coli dairy isolates. Production of curli and cellulose, static biofilm formation on polystyrene (PS) and stainless steel surfaces, biofilm formation under dynamic conditions (Bioflux), and initial adhesion rates (IAR) were evaluated. Biofilm formation varied greatly between strains, media, and assays. Our results highlight the importance of the experimental setup in determining biofilm formation under conditions of interest, as correlation between different assays was often not a given. The heat-resistant, multidrug-resistant (MDR) strain FAM21845 showed the strongest biofilm formation on PS and the highest IAR and was the only strain that formed significant biofilms on stainless steel under conditions relevant to the dairy industry, and it was therefore fully sequenced. Its chromosome is 4.9 Mb long, and it harbors a total of five plasmids (147.2, 54.2, 5.8, 2.5, and 1.9 kb). The strain carries a broad range of genes relevant to antimicrobial resistance and biofilm formation, including some on its two large conjugative plasmids, as demonstrated in plate mating assays. IMPORTANCE In biofilms, cells are embedded in an extracellular matrix that protects them from stresses, such as UV radiation, osmotic shock, desiccation, antibiotics, and predation. Biofilm formation is a major bacterial persistence factor of great concern in the clinic and the food industry. Many tested strains formed strong biofilms, and especially strains such as the heat-resistant, MDR strain FAM21845 may pose a serious issue for food production. Strong biofilm formation combined with diverse resistances (some encoded on conjugative plasmids) may allow for increased persistence, coselection, and possible transfer of these resistance factors. Horizontal gene transfer may conceivably occur in the food production setting or the gastrointestinal tract after consumption. PMID:28550056

Biofilm Formation Potential of Heat-Resistant Escherichia coli Dairy Isolates and the Complete Genome of Multidrug-Resistant, Heat-Resistant Strain FAM21845.

PubMed

Marti, Roger; Schmid, Michael; Kulli, Sandra; Schneeberger, Kerstin; Naskova, Javorka; Knøchel, Susanne; Ahrens, Christian H; Hummerjohann, Jörg

2017-08-01

We tested the biofilm formation potential of 30 heat-resistant and 6 heat-sensitive Escherichia coli dairy isolates. Production of curli and cellulose, static biofilm formation on polystyrene (PS) and stainless steel surfaces, biofilm formation under dynamic conditions (Bioflux), and initial adhesion rates (IAR) were evaluated. Biofilm formation varied greatly between strains, media, and assays. Our results highlight the importance of the experimental setup in determining biofilm formation under conditions of interest, as correlation between different assays was often not a given. The heat-resistant, multidrug-resistant (MDR) strain FAM21845 showed the strongest biofilm formation on PS and the highest IAR and was the only strain that formed significant biofilms on stainless steel under conditions relevant to the dairy industry, and it was therefore fully sequenced. Its chromosome is 4.9 Mb long, and it harbors a total of five plasmids (147.2, 54.2, 5.8, 2.5, and 1.9 kb). The strain carries a broad range of genes relevant to antimicrobial resistance and biofilm formation, including some on its two large conjugative plasmids, as demonstrated in plate mating assays. IMPORTANCE In biofilms, cells are embedded in an extracellular matrix that protects them from stresses, such as UV radiation, osmotic shock, desiccation, antibiotics, and predation. Biofilm formation is a major bacterial persistence factor of great concern in the clinic and the food industry. Many tested strains formed strong biofilms, and especially strains such as the heat-resistant, MDR strain FAM21845 may pose a serious issue for food production. Strong biofilm formation combined with diverse resistances (some encoded on conjugative plasmids) may allow for increased persistence, coselection, and possible transfer of these resistance factors. Horizontal gene transfer may conceivably occur in the food production setting or the gastrointestinal tract after consumption. Copyright © 2017 Marti et al.

Extensive Drug Resistance Acquired During Treatment of Multidrug-Resistant Tuberculosis

PubMed Central

Cegielski, J. Peter; Dalton, Tracy; Yagui, Martin; Wattanaamornkiet, Wanpen; Volchenkov, Grigory V.; Via, Laura E.; Van Der Walt, Martie; Tupasi, Thelma; Smith, Sarah E.; Odendaal, Ronel; Leimane, Vaira; Kvasnovsky, Charlotte; Kuznetsova, Tatiana; Kurbatova, Ekaterina; Kummik, Tiina; Kuksa, Liga; Kliiman, Kai; Kiryanova, Elena V.; Kim, HeeJin; Kim, Chang-ki; Kazennyy, Boris Y.; Jou, Ruwen; Huang, Wei-Lun; Ershova, Julia; Erokhin, Vladislav V.; Diem, Lois; Contreras, Carmen; Cho, Sang Nae; Chernousova, Larisa N.; Chen, Michael P.; Caoili, Janice Campos; Bayona, Jaime; Akksilp, Somsak; Calahuanca, Gloria Yale; Wolfgang, Melanie; Viiklepp, Piret; Vasilieva, Irina A.; Taylor, Allison; Tan, Kathrine; Suarez, Carmen; Sture, Ingrida; Somova, Tatiana; Smirnova, Tatyana G.; Sigman, Erika; Skenders, Girts; Sitti, Wanlaya; Shamputa, Isdore C.; Riekstina, Vija; Pua, Kristine Rose; Therese, M.; Perez, C.; Park, Seungkyu; Norvaisha, Inga; Nemtsova, Evgenia S.; Min, Seonyeong; Metchock, Beverly; Levina, Klavdia; Lei, Yung-Chao; Lee, Jongseok; Larionova, Elena E.; Lancaster, Joey; Jeon, Doosoo; Jave, Oswaldo; Khorosheva, Tatiana; Hwang, Soo Hee; Huang, Angela Song-En; Gler, M. Tarcela; Dravniece, Gunta; Eum, Seokyong; Demikhova, Olga V.; Degtyareva, Irina; Danilovits, Manfred; Cirula, Anda; Cho, Eunjin; Cai, Ying; Brand, Jeanette; Bonilla, Cesar; Barry, Clifton E.; Asencios, Luis; Andreevskaya, Sofia N.; Akksilp, Rattanawadee

2014-01-01

Background. Increasing access to drugs for the treatment of multidrug-resistant (MDR) tuberculosis is crucial but could lead to increasing resistance to these same drugs. In 2000, the international Green Light Committee (GLC) initiative began to increase access while attempting to prevent acquired resistance. Methods. To assess the GLC's impact, we followed adults with pulmonary MDR tuberculosis from the start to the end of treatment with monthly sputum cultures, drug susceptibility testing, and genotyping. We compared the frequency and predictors of acquired resistance to second-line drugs (SLDs) in 9 countries that volunteered to participate, 5 countries that met GLC criteria, and 4 countries that did not apply to the GLC. Results. In total, 832 subjects were enrolled. Of those without baseline resistance to specific SLDs, 68 (8.9%) acquired extensively drug-resistant (XDR) tuberculosis, 79 (11.2%) acquired fluoroquinolone (FQ) resistance, and 56 (7.8%) acquired resistance to second-line injectable drugs (SLIs). The relative risk (95% confidence interval [CI]) of acquired resistance was lower at GLC-approved sites: 0.27 (.16–.47) for XDR tuberculosis, 0.28 (.17–.45) for FQ, and 0.15 (.06–.39) to 0.60 (.34–1.05) for 3 different SLIs. The risk increased as the number of potentially effective drugs decreased. Controlling for baseline drug resistance and differences between sites, the odds ratios (95% CIs) were 0.21 (.07–.62) for acquired XDR tuberculosis and 0.23 (.09–.59) for acquired FQ resistance. Conclusions. Treatment of MDR tuberculosis involves substantial risk of acquired resistance to SLDs, increasing as baseline drug resistance increases. The risk was significantly lower in programs documented by the GLC to meet specific standards. PMID:25057101

Efflux-mediated antimicrobial resistance.

PubMed

Poole, Keith

2005-07-01

Antibiotic resistance continues to plague antimicrobial chemotherapy of infectious disease. And while true biocide resistance is as yet unrealized, in vitro and in vivo episodes of reduced biocide susceptibility are common and the history of antibiotic resistance should not be ignored in the development and use of biocidal agents. Efflux mechanisms of resistance, both drug specific and multidrug, are important determinants of intrinsic and/or acquired resistance to these antimicrobials, with some accommodating both antibiotics and biocides. This latter raises the spectre (as yet generally unrealized) of biocide selection of multiple antibiotic-resistant organisms. Multidrug efflux mechanisms are broadly conserved in bacteria, are almost invariably chromosome-encoded and their expression in many instances results from mutations in regulatory genes. In contrast, drug-specific efflux mechanisms are generally encoded by plasmids and/or other mobile genetic elements (transposons, integrons) that carry additional resistance genes, and so their ready acquisition is compounded by their association with multidrug resistance. While there is some support for the latter efflux systems arising from efflux determinants of self-protection in antibiotic-producing Streptomyces spp. and, thus, intended as drug exporters, increasingly, chromosomal multidrug efflux determinants, at least in Gram-negative bacteria, appear not to be intended as drug exporters but as exporters with, perhaps, a variety of other roles in bacterial cells. Still, given the clinical significance of multidrug (and drug-specific) exporters, efflux must be considered in formulating strategies/approaches to treating drug-resistant infections, both in the development of new agents, for example, less impacted by efflux and in targeting efflux directly with efflux inhibitors.

Dextrin-colistin conjugates as a model bioresponsive treatment for multidrug resistant bacterial infections.

PubMed

Ferguson, Elaine L; Azzopardi, Ernest; Roberts, Jessica L; Walsh, Timothy R; Thomas, David W

2014-12-01

Polymer therapeutics offer potential benefits in the treatment of multidrug resistant (MDR) infections; affording targeted delivery of biologically active agents to the site of inflammation, potential decreases in systemic toxicity, and the retention of antimicrobial activity at the target site. As a prototype model, these studies developed and characterized a library of dextrin-colistin conjugates (dextrin molecular weight: 7500-48,000 g/mol) as a means of targeting the delivery of colistin. Optimum colistin release kinetics (following dextrin degradation by physiological concentrations of amylase (100 IU/L)) were observed in conjugates containing low molecular weight (∼7500 g/mol) dextrin with ∼1 mol % succinoylation (∼80% drug release within 48 h, compared to ∼33% from sodium colistin methanesulfonate (CMS, Colomycin)). These conjugates exhibited comparable antimicrobial activity to CMS in conventional MIC assays against a range of Gram-negative pathogens, but with significantly reduced in vitro toxicity toward kidney (IC₅₀ = CMS, 15.4 μg/mL; dextrin-colistin, 63.9 μg/mL) and macrophage (IC₅₀ = CMS, 111.3 μg/mL; dextrin-colistin, 303.9 μg/mL) cells. In vivo dose-escalation studies in rats demonstrated improved pharmacokinetics of the conjugates, with prolonged plasma levels of colistin (t₁/₂ 135-1271 min vs 53 min) and decreased toxicity, compared to colistin sulfate. These studies highlight the potential utility of "nanoantibiotic" polymer therapeutics to aid the safe, effective, and targeted delivery of colistin in the management of MDR infections.

Genome-wide re-sequencing of multidrug-resistant Mycobacterium leprae Airaku-3.

PubMed

Singh, P; Benjak, A; Carat, S; Kai, M; Busso, P; Avanzi, C; Paniz-Mondolfi, A; Peter, C; Harshman, K; Rougemont, J; Matsuoka, M; Cole, S T

2014-10-01

Genotyping and molecular characterization of drug resistance mechanisms in Mycobacterium leprae enables disease transmission and drug resistance trends to be monitored. In the present study, we performed genome-wide analysis of Airaku-3, a multidrug-resistant strain with an unknown mechanism of resistance to rifampicin. We identified 12 unique non-synonymous single-nucleotide polymorphisms (SNPs) including two in the transporter-encoding ctpC and ctpI genes. In addition, two SNPs were found that improve the resolution of SNP-based genotyping, particularly for Venezuelan and South East Asian strains of M. leprae. © 2014 The Authors Clinical Microbiology and Infection © 2014 European Society of Clinical Microbiology and Infectious Diseases.

[Potential antimicrobial drug interactions in clinical practice: consequences of polypharmacy and multidrug resistance].

PubMed

Martínez-Múgica, Cristina

2015-12-01

Polypharmacy is a growing problem nowadays, which can increase the risk of potential drug interactions, and result in a loss of effectiveness. This is particularly relevant to the anti-infective therapy, especially when infection is produced by resistant bacteria, because therapeutic options are limited and interactions can cause treatment failure. All antimicrobial prescriptions were retrospectively reviewed during a week in the Pharmacy Department, in order to detect potential drug-interactions and analysing their clinical significance. A total of 314 antimicrobial prescriptions from 151 patients were checked. There was at least one potential interaction detected in 40% of patients, being more frequent and severe in those infected with multidrug-resistant microorganisms. Drugs most commonly involved were quinolones, azoles, linezolid and vancomycin. Potential drug interactions with antimicrobial agents are a frequent problem that can result in a loss of effectiveness. This is why they should be detected and avoided when possible, in order to optimize antimicrobial therapy, especially in case of multidrug resistant infections.

Marine sponge alkaloids as a source of anti-bacterial adjuvants

PubMed Central

Melander, Roberta J.; Liu, Hong-bing; Stephens, Matthew D.; Bewley, Carole A.; Melander, Christian

2018-01-01

Novel approaches that do not rely upon developing microbicidal compounds are sorely needed to combat multidrug resistant (MDR) bacteria. The potential of marine secondary metabolites to serve as a source of non-traditional anti-bacterial agents is demonstrated by showing that pyrrole-imidazole alkaloids inhibit biofilm formation and suppress antibiotic resistance. PMID:27876320

Multidrug-resistant Gram-negative bacteria: a product of globalization.

PubMed

Hawkey, P M

2015-04-01

Global trade and mobility of people has increased rapidly over the last 20 years. This has had profound consequences for the evolution and the movement of antibiotic resistance genes. There is increasing exposure of populations all around the world to resistant bacteria arising in the emerging economies. Arguably the most important development of the last two decades in the field of antibiotic resistance is the emergence and spread of extended-spectrum β-lactamases (ESBLs) of the CTX-M group. A consequence of the very high rates of ESBL production among Enterobacteriaceae in Asian countries is that there is a substantial use of carbapenem antibiotics, resulting in the emergence of plasmid-mediated resistance to carbapenems. This article reviews the emergence and spread of multidrug-resistant Gram-negative bacteria, focuses on three particular carbapenemases--imipenem carbapenemases, Klebsiella pneumoniae carbapenemase, and New Delhi metallo-β-lactamase--and highlights the importance of control of antibiotic use. Copyright © 2015. Published by Elsevier Ltd.

Essential Oil from Origanum vulgare Completely Inhibits the Growth of Multidrug-Resistant Cystic Fibrosis Pathogens.

PubMed

Pesavento, Giovanna; Maggini, Valentina; Maida, Isabel; Lo Nostro, Antonella; Calonico, Carmela; Sassoli, Chiara; Perrin, Elena; Fondi, Marco; Mengoni, Alessio; Chiellini, Carolina; Vannacci, Alfredo; Gallo, Eugenia; Gori, Luigi; Bogani, Patrizia; Bilia, Anna Rita; Campana, Silvia; Ravenni, Novella; Dolce, Daniela; Firenzuoli, Fabio; Fani, Renato

2016-06-01

Essential oils (EOs) are known to inhibit the growth of a wide range of microorganisms. Particularly interesting is the possible use of EOs to treat multidrug-resistant cystic fibrosis (CF) pathogens. We tested the essential oil (EO) from Origanum vulgare for in vitro antimicrobial activity, against three of the major human opportunistic pathogens responsible for respiratory infections in CF patients; these are methicillin-resistant Staphylococcus aureus, Stenotrophomonas maltophilia and Achromobacter xylosoxidans. Antibiotic susceptibility of each strain was previously tested by the standard disk diffusion method. Most strains were resistant to multiple antibiotics and could be defined as multi-drug-resistant (MDR). The antibacterial activity of O. vulgare EO (OEO) against a panel of 59 bacterial strains was evaluated, with MIC and MBC determined at 24, 48 and 72 hours by a microdilution method. The OEO was effective against all tested strains, although to a different extent. The MBC and MIC of OEO for S. aureus strains were either lower or equal to 0.50%, v/v, for A. xylosoxidans strains were lower or equal to 1% and 0.50%, v/v, respectively; and for S. maltophilia strains were lower or equal to 0.25%, v/v. The results from this study suggest that OEO might exert a role as an antimicrobial in the treatment of CF infections.

Identification of multidrug-resistant Salmonella enterica serovar typhimurium isolates that have an antibiotic-induced invasion phenotype

USDA-ARS?s Scientific Manuscript database

Multidrug-resistant (MDR) Salmonella is an important food safety issue in humans and animals. The National Antimicrobial Resistance Monitoring System (NARMS) has reported that 27.3% of Salmonella enterica serotype Typhimurium isolates in humans were resistant to three or more classes of antibiotics...

First Genome Sequence of a Mexican Multidrug-Resistant Acinetobacter baumannii Isolate

PubMed Central

Graña-Miraglia, Lucía; Lozano, Luis; Castro-Jaimes, Semiramis; Cevallos, Miguel A.; Volkow, Patricia

2016-01-01

Acinetobacter baumannii has emerged as an important nosocomial pathogen worldwide. Here, we present the draft genome of the first multidrug-resistant A. baumannii isolate, sampled from a tertiary hospital in Mexico City. This genome will provide a starting point for studying the genomic diversity of this species in Mexico. PMID:27013043

Chemical Countermeasures for Antibiotic Resistance

DTIC Science & Technology

2012-04-01

INTRODUCTION: New approaches are required to control multi-drug resistant (MDR) bacterial infections in military medical facilities, as injured...Warfighters are highly susceptible to such infections . MDR bacterial infections can cause sepsis, cellulitis and skin abscesses, pneumonia, toxic shock...syndrome, osteomyelitis, and endocarditis among other symptoms. Serious cases result in organ failure (especially kidney), loss of limbs (via amputation

Management of multi-drug resistant Helicobacter pylori infection by supplementary, complementary and alternative medicine; a review

PubMed Central

Rezaeimanesh, Nasim; Farzi, Nastaran; Pirmanesh, Samira; Emami, Saeed; Yadegar, Abbas

2017-01-01

Helicobacter pylori is recognized as the most common bacterial pathogens colonizing the gastric epithelium of nearly half of the world’s population. This bacterium is the main etiological cause of gastroduodenal ulcers, and more importantly as the substantial risk factor for development of gastric cancer. The emergence and rapid increase in the prevalence of multi-drug resistant phenotypes have posed major pitfalls in effectiveness of various treatment regimens and eradication strategies against H. pylori infections. Several natural products and supplementary food components have been reported to have established anti-H. pylori activity. Herein, we review the application and efficacy of some specific natural products and foodstuffs such as milk, bee products (honey and propolis), fish oil, vitamins C and E, and also a nickel free-diet used as anti-H. pylori alternative treatment regimens. PMID:29511465

Outbreak of mastitis in sheep caused by multi-drug resistant Enterococcus faecalis in Sardinia, Italy.

PubMed

Sanciu, G; Marogna, G; Paglietti, B; Cappuccinelli, P; Leori, G; Rappelli, P

2013-03-01

An outbreak of infective mastitis due to Enterococcus faecalis occurred in an intensive sheep farm in north Sardinia (Italy). E. faecalis, which is only rarely isolated from sheep milk, was unexpectedly found in 22·3% of positive samples at microbiological examination. Forty-five out of the 48 E. faecalis isolates showed the same multi-drug resistance pattern (cloxacillin, streptomycin, kanamycin, clindamycin, oxytetracycline). E. faecalis isolates were analysed by pulsed-field gel electrophoresis, and all 45 multi-drug resistant strains showed an indistinguishable macrorestiction profile, indicating their clonal origin. To our knowledge, this is the first report of an outbreak of mastitis in sheep caused by E. faecalis.

Antimicrobial utilization and bacterial resistance at three different hospitals.

PubMed

Vlahović-Palcevski, V; Morović, M; Palcevski, G; Betica-Radić, L

2001-01-01

It has been generally recognized that the prevalence of bacterial resistance among bacteria is an unavoidable consequence of antibiotic use and is positively linked to the overall use of antibacterial drugs. The purpose of this study was to investigate the extent of antimicrobial usage and to evaluate the antimicrobial resistance at three different hospital settings in Croatia: a clinical hospital, a general hospital and a specialized clinic for infectious diseases. In this survey the antimicrobial drug consumption and antimicrobial susceptibility test results were analyzed for the first 6 months of 1997 in three different hospitals in Croatia: the University Hospital Center (UHC), Rijeka, the Clinic for Infectious Diseases 'Dr Fran Mihaljević', Zagreb and the Dubrovnik General Hospital. The data were collected from corresponding hospital pharmacy records and microbiology laboratories. Antimicrobial drug utilization was expressed in number of defined daily doses (DDDs) per 100 bed days. High antimicrobial utilization and high resistance rates were found in all three hospitals. At the Clinic for Infectious Diseases, the most frequently used antimicrobials where those of narrow spectrum while at the UHC Rijeka and the Dubrovnik General Hospital the broad spectrum antimicrobials were mostly used. The highest antimicrobial consumption was noted at the Susak locality of the UHC, Rijeka, where the highest resistance rates of bacteria to antimicrobials were also found. Results of this observational study indicate that attempts should be made to reduce the influence of factors that may lead to emergent resistance. The most effective approach to the prevention of transmission of multidrug-resistant pathogens is preventing the initial emergence of resistance. A rational and strict antibiotic policy is thus of great importance for the optimal use of these agents.

The demise of multidrug-resistant HIV-1: the national time trend in Portugal.

PubMed

Vercauteren, Jurgen; Theys, Kristof; Carvalho, Ana Patricia; Valadas, Emília; Duque, Luis Miguel; Teófilo, Eugénio; Faria, Telo; Faria, Domitília; Vera, José; Aguas, Maria João; Peres, Susana; Mansinho, Kamal; Vandamme, Anne-Mieke; Camacho, Ricardo Jorge

2013-04-01

Despite a decreasing mortality and morbidity in treated HIV-1 patients, highly active antiretroviral treatment (HAART) can still fail due to the development of drug resistance. Especially, multidrug-resistant viruses pose a threat to efficient therapy. We studied the changing prevalence of multidrug resistance (MDR) over time in a cohort of HIV-1-infected patients in Portugal. We used data of 8065 HIV-1-infected patients followed from July 2001 up to April 2012 in 22 hospitals located in Portugal. MDR at a specific date of sampling was defined as no more than one fully active drug (excluding integrase and entry inhibitors) at that time authorized by the Portuguese National Authority of Medicines and Health Products (INFARMED), as interpreted with the Rega algorithm version 8.0.2. A generalized linear mixed model was used to study the time trend of the prevalence of MDR. We observed a statistically significant decrease in the prevalence of MDR over the last decade, from 6.9% (95% CI: 5.7-8.4) in 2001-03, 6.0% (95% CI: 4.9-7.2) in 2003-05, 3.7% (95% CI: 2.8-4.8) in 2005-07 and 1.6% (95% CI: 1.1-2.2) in 2007-09 down to 0.6% (95% CI: 0.3-0.9) in 2009-12 [OR=0.80 (95% CI: 0.75-0.86); P<0.001]. In July 2011 the last new case of MDR was seen. The prevalence of multidrug-resistant HIV-1 is decreasing over time in Portugal, reflecting the increasing efficiency of HAART and the availability of new drugs. Therefore, in designing a new drug, safety and practical aspects, e.g. less toxicity and ease of use, may need more attention than focusing mainly on efficacy against resistant strains.

Conspicuous multidrug-resistant Mycobacterium tuberculosis cluster strains do not trespass country borders in Latin America and Spain.

PubMed

Ritacco, Viviana; Iglesias, María-José; Ferrazoli, Lucilaine; Monteserin, Johana; Dalla Costa, Elis R; Cebollada, Alberto; Morcillo, Nora; Robledo, Jaime; de Waard, Jacobus H; Araya, Pamela; Aristimuño, Liselotte; Díaz, Raúl; Gavin, Patricia; Imperiale, Belen; Simonsen, Vera; Zapata, Elsa M; Jiménez, María S; Rossetti, Maria L; Martin, Carlos; Barrera, Lucía; Samper, Sofia

2012-06-01

Multidrug-resistant Mycobacterium tuberculosis strain diversity in Ibero-America was examined by comparing extant genotype collections in national or state tuberculosis networks. To this end, genotypes from over 1000 patients with multidrug-resistant tuberculosis diagnosed from 2004 through 2008 in Argentina, Brazil, Chile, Colombia, Venezuela and Spain were compared in a database constructed ad hoc. Most of the 116 clusters identified by IS6110 restriction fragment length polymorphism were small and restricted to individual countries. The three largest clusters, of 116, 49 and 25 patients, were found in Argentina and corresponded to previously documented locally-epidemic strains. Only 13 small clusters involved more than one country, altogether accounting for 41 patients, of whom 13 were, in turn, immigrants from Latin American countries different from those participating in the study (Peru, Ecuador and Bolivia). Most of these international clusters belonged either to the emerging RD(Rio) LAM lineage or to the Haarlem family of M. tuberculosis and four were further split by country when analyzed with spoligotyping and rifampin resistance-conferring mutations, suggesting that they did not represent ongoing transnational transmission events. The Beijing genotype accounted for 1.3% and 10.2% of patients with multidrug-resistant tuberculosis in Latin America and Spain, respectively, including one international cluster of two cases. In brief, Euro-American genotypes were widely predominant among multidrug-resistant M. tuberculosis strains in Ibero-America, reflecting closely their predominance in the general M. tuberculosis population in the region, and no evidence was found of acknowledged outbreak strains trespassing country borders. Copyright © 2011 Elsevier B.V. All rights reserved.

Multidrug-resistant Salmonella enterica serovar Typhimurium isolates are resistant to antibiotics that influence their swimming and swarming motility

USDA-ARS?s Scientific Manuscript database

Motile bacteria utilize one or more strategies for movement, such as darting, gliding, sliding, swarming, swimming, and twitching. The ability to move is considered a virulence factor in many pathogenic bacteria, including Salmonella. Multidrug-resistant (MDR) Salmonella encodes acquired factors t...

Antimicrobial activity of five essential oils from lamiaceae against multidrug-resistant Staphylococcus aureus.

PubMed

Kot, Barbara; Wierzchowska, Kamila; Piechota, Małgorzata; Czerniewicz, Paweł; Chrzanowski, Grzegorz

2018-06-11

Analysis of Lamiaceae essential oils (EOs) by GC-FID-MS revealed the presence as the major constituents of linalool (16.8%), linalyl acetate (15.7%) in Lavandula angustifolia, menthol (29.0%), menthone (22.7%), menthyl acetate (19.2%) in Mentha x piperita, terpinen-4-ol (27.1%), (E)-sabinene hydrate (12.1%), γ-terpinene (10.0%) in Origanum majorana, α-thujone (19.5%), camphor (19.0%), viridiflorol (13.5%) in Salvia officinalis, thymol (61.9%), p-cymene (10.0%), γ-terpinene (10.0%) in Thymus vulgaris. Based on the MIC and MBC values (0.09-0.78 mg/mL) and ratio MBC/MIC showed that EO from T. vulgaris (TO) had the strong inhibitory and bactericidal effect against multidrug-resistant Staphylococcus aureus. The bacterial cells were total killed by TO at 2MIC concentration after 6 h. The higher concentrations of other EOs were needed to achieve bactericidal effects. The strong bactericidal effect of TO against these bacteria indicates the possibility of topical use of TO but it requires research under clinical conditions.

Antibiotic resistance: What is so special about multidrug-resistant Gram-negative bacteria?

PubMed Central

Exner, Martin; Bhattacharya, Sanjay; Christiansen, Bärbel; Gebel, Jürgen; Goroncy-Bermes, Peter; Hartemann, Philippe; Heeg, Peter; Ilschner, Carola; Kramer, Axel; Larson, Elaine; Merkens, Wolfgang; Mielke, Martin; Oltmanns, Peter; Ross, Birgit; Rotter, Manfred; Schmithausen, Ricarda Maria; Sonntag, Hans-Günther; Trautmann, Matthias

2017-01-01

In the past years infections caused by multidrug-resistant Gram-negative bacteria have dramatically increased in all parts of the world. This consensus paper is based on presentations, subsequent discussions and an appraisal of current literature by a panel of international experts invited by the Rudolf Schülke Stiftung, Hamburg. It deals with the epidemiology and the inherent properties of Gram-negative bacteria, elucidating the patterns of the spread of antibiotic resistance, highlighting reservoirs as well as transmission pathways and risk factors for infection, mortality, treatment and prevention options as well as the consequences of their prevalence in livestock. Following a global, One Health approach and based on the evaluation of the existing knowledge about these pathogens, this paper gives recommendations for prevention and infection control measures as well as proposals for various target groups to tackle the threats posed by Gram-negative bacteria and prevent the spread and emergence of new antibiotic resistances. PMID:28451516

Polyclonal Pulmonary Tuberculosis Infections and Risk for Multidrug Resistance, Lima, Peru

PubMed Central

Shi, Cynthia X.; Chindelevitch, Leonid; Calderon, Roger; Zhang, Zibiao; Galea, Jerome T.; Contreras, Carmen; Yataco, Rosa; Lecca, Leonid; Becerra, Mercedes C.; Murray, Megan B.; Cohen, Ted

2017-01-01

Because within-host Mycobacterium tuberculosis diversity complicates diagnosis and treatment of tuberculosis (TB), we measured diversity prevalence and associated factors among 3,098 pulmonary TB patients in Lima, Peru. The 161 patients with polyclonal infection were more likely than the 115 with clonal or the 2,822 with simple infections to have multidrug-resistant TB. PMID:29048297

Antibacterial activities of the methanol extracts of Albizia adianthifolia, Alchornea laxiflora, Laportea ovalifolia and three other Cameroonian plants against multi-drug resistant Gram-negative bacteria.

PubMed

Tchinda, Cedric F; Voukeng, Igor K; Beng, Veronique P; Kuete, Victor

2017-05-01

In the last 10 years, resistance in Gram-negative bacteria has been increasing. The present study was designed to evaluate the in vitro antibacterial activities of the methanol extracts of six Cameroonian medicinal plants Albizia adianthifolia , Alchornea laxiflora , Boerhavia diffusa , Combretum hispidum , Laportea ovalifolia and Scoparia dulcis against a panel of 15 multidrug resistant Gram-negative bacterial strains. The broth microdilution was used to determine the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of the extracts. The preliminary phytochemical screening of the extracts was conducted according to the reference qualitative phytochemical methods. Results showed that all extracts contained compounds belonging to the classes of polyphenols and triterpenes, other classes of chemicals being selectively distributed. The best antibacterial activities were recorded with bark and root extracts of A. adianthifolia as well as with L. ovalifolia extract, with MIC values ranging from 64 to 1024 μg/mL on 93.3% of the fifteen tested bacteria. The lowest MIC value of 64 μg/mL was recorded with A. laxiflora bark extract against Enterobacter aerogenes EA289. Finally, the results of this study provide evidence of the antibacterial activity of the tested plants and suggest their possible use in the control of multidrug resistant phenotypes.

Mesoporous silica nanoparticles loading doxorubicin reverse multidrug resistance: performance and mechanism

NASA Astrophysics Data System (ADS)

Shen, Jianan; He, Qianjun; Gao, Yu; Shi, Jianlin; Li, Yaping

2011-10-01

Multidrug resistance (MDR) is one of the major obstacles for successful chemotherapy in cancer. One of the effective approaches to overcome MDR is to use nanoparticle-mediated drug delivery to increase drug accumulation in drug resistant cancer cells. In this work, we first report that the performance and mechanism of an inorganic engineered delivery system based on mesoporous silica nanoparticles (MSNs) loading doxorubicin (DMNs) to overcome the MDR of MCF-7/ADR (a DOX-resistant and P-glycoprotein (P-gp) over-expression cancer cell line). The experimental results showed that DMNs could enhance the cellular uptake of doxorubicin (DOX) and increase the cell proliferation suppression effect of DOX against MCF-7/ADR cells. The IC50 of DMNs against MCF-7/ADR cells was 8-fold lower than that of free DOX. However, an improved effect of DOX in DMNs against MCF-7 cells (a DOX-sensitive cancer cell line) was not found. The increased cellular uptake and nuclear accumulation of DOX delivered by DMNs in MCF-7/ADR cells was confirmed by confocal laser scanning microscopy, and could result from the down-regulation of P-gp and bypassing the efflux action by MSNs themselves. The cellular uptake mechanism of DMNs indicated that the macropinocytosis was one of the pathways for the uptake of DMNs by MCF-7/ADR cells. The in vivo biodistribution showed that DMNs induced a higher accumulation of DOX in drug resistant tumors than free DOX. These results suggested that MSNs could be an effective delivery system to overcome multidrug resistance.

Previous treatment, sputum-smear nonconversion, and suburban living: The risk factors of multidrug-resistant tuberculosis among Malaysians.

PubMed

Mohd Shariff, Noorsuzana; Shah, Shamsul Azhar; Kamaludin, Fadzilah

2016-03-01

The number of multidrug-resistant tuberculosis patients is increasing each year in many countries all around the globe. Malaysia has no exception in facing this burdensome health problem. We aimed to investigate the factors that contribute to the occurrence of multidrug-resistant tuberculosis among Malaysian tuberculosis patients. An unmatched case-control study was conducted among tuberculosis patients who received antituberculosis treatments from April 2013 until April 2014. Cases are those diagnosed as pulmonary tuberculosis patients clinically, radiologically, and/or bacteriologically, and who were confirmed to be resistant to both isoniazid and rifampicin through drug-sensitivity testing. On the other hand, pulmonary tuberculosis patients who were sensitive to all first-line antituberculosis drugs and were treated during the same time period served as controls. A total of 150 tuberculosis patients were studied, of which the susceptible cases were 120. Factors found to be significantly associated with the occurrence of multidrug-resistant tuberculosis are being Indian or Chinese (odds ratio 3.17, 95% confidence interval 1.04-9.68; and odds ratio 6.23, 95% confidence interval 2.24-17.35, respectively), unmarried (odds ratio 2.58, 95% confidence interval 1.09-6.09), living in suburban areas (odds ratio 2.58, 95% confidence interval 1.08-6.19), are noncompliant (odds ratio 4.50, 95% confidence interval 1.71-11.82), were treated previously (odds ratio 8.91, 95% confidence interval 3.66-21.67), and showed positive sputum smears at the 2nd (odds ratio 7.00, 95% confidence interval 2.46-19.89) and 6th months of treatment (odds ratio 17.96, 95% confidence interval 3.51-91.99). Living in suburban areas, positive sputum smears in the 2nd month of treatment, and was treated previously are factors that independently contribute to the occurrence of multidrug-resistant tuberculosis. Those with positive smears in the second month of treatment, have a history of previous

Simple Method for Markerless Gene Deletion in Multidrug-Resistant Acinetobacter baumannii

PubMed Central

Oh, Man Hwan; Lee, Je Chul; Kim, Jungmin

2015-01-01

The traditional markerless gene deletion technique based on overlap extension PCR has been used for generating gene deletions in multidrug-resistant Acinetobacter baumannii. However, the method is time-consuming because it requires restriction digestion of the PCR products in DNA cloning and the construction of new vectors containing a suitable antibiotic resistance cassette for the selection of A. baumannii merodiploids. Moreover, the availability of restriction sites and the selection of recombinant bacteria harboring the desired chimeric plasmid are limited, making the construction of a chimeric plasmid more difficult. We describe a rapid and easy cloning method for markerless gene deletion in A. baumannii, which has no limitation in the availability of restriction sites and allows for easy selection of the clones carrying the desired chimeric plasmid. Notably, it is not necessary to construct new vectors in our method. This method utilizes direct cloning of blunt-end DNA fragments, in which upstream and downstream regions of the target gene are fused with an antibiotic resistance cassette via overlap extension PCR and are inserted into a blunt-end suicide vector developed for blunt-end cloning. Importantly, the antibiotic resistance cassette is placed outside the downstream region in order to enable easy selection of the recombinants carrying the desired plasmid, to eliminate the antibiotic resistance cassette via homologous recombination, and to avoid the necessity of constructing new vectors. This strategy was successfully applied to functional analysis of the genes associated with iron acquisition by A. baumannii ATCC 19606 and to ompA gene deletion in other A. baumannii strains. Consequently, the proposed method is invaluable for markerless gene deletion in multidrug-resistant A. baumannii. PMID:25746991

Antimicrobial activity of the bioactive components of essential oils from Pakistani spices against Salmonella and other multi-drug resistant bacteria

PubMed Central

2013-01-01

Background The main objective of this study was the phytochemical characterization of four indigenous essential oils obtained from spices and their antibacterial activities against the multidrug resistant clinical and soil isolates prevalent in Pakistan, and ATCC reference strains. Methods Chemical composition of essential oils from four Pakistani spices cumin (Cuminum cyminum), cinnamon (Cinnamomum verum), cardamom (Amomum subulatum) and clove (Syzygium aromaticum) were analyzed on GC/MS. Their antibacterial activities were investigated by minimum inhibitory concentration (MIC) and Thin-Layer Chromatography-Bioautographic (TLC-Bioautographic) assays against pathogenic strains Salmonella typhi (D1 Vi-positive), Salmonella typhi (G7 Vi-negative), Salmonella paratyphi A, Escherichia coli (SS1), Staphylococcus aureus, Pseudomonas fluorescens and Bacillus licheniformis (ATCC 14580). The data were statistically analyzed by using Analysis of Variance (ANOVA) and Least Significant Difference (LSD) method to find out significant relationship of essential oils biological activities at p <0.05. Results Among all the tested essential oils, oil from the bark of C. verum showed best antibacterial activities against all selected bacterial strains in the MIC assay, especially with 2.9 mg/ml concentration against S. typhi G7 Vi-negative and P. fluorescens strains. TLC-bioautography confirmed the presence of biologically active anti-microbial components in all tested essential oils. P. fluorescens was found susceptible to C. verum essential oil while E. coli SS1 and S. aureus were resistant to C. verum and A. subulatum essential oils, respectively, as determined in bioautography assay. The GC/MS analysis revealed that essential oils of C. cyminum, C. verum, A. subulatum, and S. aromaticum contain 17.2% cuminaldehyde, 4.3% t-cinnamaldehyde, 5.2% eucalyptol and 0.73% eugenol, respectively. Conclusions Most of the essential oils included in this study possessed good antibacterial

Reducing the price of treatment for multidrug-resistant tuberculosis through the Global Drug Facility.

PubMed

Lunte, Kaspars; Cordier-Lassalle, Thierry; Keravec, Joel

2015-04-01

Many countries have limited experience of securing the best prices for drugs and have little negotiating power. This is particularly true for the complex, lengthy and expensive regimens used to treat multidrug-resistant tuberculosis. The Stop TB Partnership's Global Drug Facility is dedicated to improving worldwide access to antituberculosis medicines and diagnostic techniques that meet international quality standards. The Global Drug Facility is able to secure price reductions through competitive tendering among prequalified drug manufacturers and by consolidating orders to achieve large purchase volumes. Consolidating the market in this way increases the incentives for suppliers of quality-assured medicines. In 2013 the Global Drug Facility reduced the price of the second-line drugs it supplies for multidrug-resistant tuberculosis: the overall cost of the longest and most expensive treatment regimen for a patient decreased by 26% - from 7890 United States dollars (US$) in 2011 to US$ 5822 in 2013. The price of treatment for multidrug-resistant tuberculosis supplied by the Global Drug Facility was reduced by consolidating orders to achieve large purchase volumes, by international, competitive bidding and by the existence of donor-funded medicine stockpiles. The rise in the number of suppliers of internationally quality-assured drugs was also important. The savings achieved from lower drug costs could be used to increase the number of patients on high-quality treatment.

Antimicrobial activity of some essential oils against oral multidrug-resistant Enterococcus faecalis in both planktonic and biofilm state

PubMed Central

Benbelaïd, Fethi; Khadir, Abdelmounaïm; Abdoune, Mohamed Amine; Bendahou, Mourad; Muselli, Alain; Costa, Jean

2014-01-01

Objective To evaluate some essential oils in treatment of intractable oral infections, principally caused by biofilm of multidrug-resistant Enterococcus faecalis (E. faecalis), such as persistent endodontic infections in which their treatment exhibits a real challenge for dentists. Methods Ten chemically analyzed essential oils by gas chromatography-mass spectrometry were evaluated for antimicrobial activity against sensitive and resistant clinical strains of E. faecalis in both planktonic and biofilm state using two methods, disk diffusion and broth micro-dilution. Results Studied essential oils showed a good antimicrobial activity and high ability in E. faecalis biofilm eradication, whether for sensitive or multidrug-resistant strains, especially those of Origanum glandulosum and Thymbra capitata with interesting minimum inhibitory concentration, biofilm inhibitory concentration, and biofilm eradication concentration values which doesn't exceed 0.063%, 0.75%, and 1.5%, respectively. Conclusions Findings of this study indicate that essential oils extracted from aromatic plants can be used in treatment of intractable oral infections, especially caused by biofilm of multidrug-resistant E. faecalis. PMID:25182948

Cell biological mechanisms of multidrug resistance in tumors.

PubMed

Simon, S M; Schindler, M

1994-04-26

Multidrug resistance (MDR) is a generic term for the variety of strategies tumor cells use to evade the cytotoxic effects of anticancer drugs. MDR is characterized by a decreased sensitivity of tumor cells not only to the drug employed for chemotherapy but also to a broad spectrum of drugs with neither obvious structural homology nor common targets. This pleiotropic resistance is one of the major obstacles to the successful treatment of tumors. MDR may result from structural or functional changes at the plasma membrane or within the cytoplasm, cellular compartments, or nucleus. Molecular mechanisms of MDR are discussed in terms of modifications in detoxification and DNA repair pathways, changes in cellular sites of drug sequestration, decreases in drug-target affinity, synthesis of specific drug inhibitors within cells, altered or inappropriate targeting of proteins, and accelerated removal or secretion of drugs.

20(S)-Protopanaxadiol (PPD) analogues chemosensitize multidrug-resistant cancer cells to clinical anticancer drugs.

PubMed

Liu, Junhua; Wang, Xu; Liu, Peng; Deng, Rongxin; Lei, Min; Chen, Wantao; Hu, Lihong

2013-07-15

Novel 20(S)-protopanoxadiol (PPD) analogues were designed, synthesized, and evaluated for the chemosensitizing activity against a multidrug resistant (MDR) cell line (KBvcr) overexpressing P-glycoprotein (P-gp). Structure-activity relationship analysis showed that aromatic substituted aliphatic amine at the 24-positions (groups V) effectively and significantly sensitized P-gp overexpressing multidrug resistant (MDR) cells to anticancer drugs, such as docetaxel (DOC), vincristine (VCR), and adriamycin (ADM). PPD derivatives 12 and 18 showed 1.3-2.6 times more effective reversal ability than verapamil (VER) for DOC and VCR. Importantly, no cytotoxicity was observed by the active PPD analogues (5μM) against both non-MDR and MDR cells, suggesting that PPD analogues serve as novel lead compounds toward a potent and safe resistance modulator. Moreover, a preliminary mechanism study demonstrated that the chemosensitizing activity of PPD analogues results from inhibition of P-glycoprotein (P-gp) overexpressed in MDR cancer cells. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Multidrug-resistant Commensal Escherichia coli in Children, Peru and Bolivia

PubMed Central

Pallecchi, Lucia; Benedetti, Marta; Fernandez, Connie; Vallejos, Yolanda; Guzman, Elisa; Villagran, Ana Liz; Mantella, Antonia; Lucchetti, Chiara; Bartalesi, Filippo; Strohmeyer, Marianne; Bechini, Angela; Gamboa, Herlan; Rodríguez, Hugo; Falkenberg, Torkel; Kronvall, Göran; Gotuzzo, Eduardo; Paradisi, Franco; Rossolini, Gian Maria

2006-01-01

Using a rapid screening method, we investigated the prevalence of fecal carriage of antimicrobial drug–resistant Escherichia coli in 3,174 healthy children from 4 urban settings in Peru and Bolivia. High resistance rates were observed for ampicillin (95%), trimethoprim-sulfamethoxazole (94%), tetracycline (93%), streptomycin (82%), and chloramphenicol (70%). Lower resistance rates were observed for nalidixic acid (35%), kanamycin (28%), gentamicin (21%), and ciprofloxacin (18%); resistance to ceftriaxone and amikacin was uncommon (<0.5%). In a random sample of 1,080 resistant E. coli isolates, 90% exhibited a multidrug-resistance (MDR) phenotype. The 2 most common MDR phenotypes (ampicillin/tetracycline/trimethoprim-sulfamethoxazole and ampicillin/tetracycline/trimethoprim-sulfamethoxazole/chloramphenicol) could be transferred en bloc in conjugation experiments. The most common acquired resistance genes were blaTEM, tet(A), tet(B), drfA8, sul1, sul2, and catI. These findings underscore the magnitude of the problem of antimicrobial drug resistance in low-resource settings and the urgent need for surveillance and control of this phenomenon. PMID:16707045

Phylogenetic diversity of ceftriaxone resistance and the presence of extended-spectrum β-lactamase genes in the culturable soil resistome.

PubMed

Pagaling, Eulyn; Gatica, Joao; Yang, Kun; Cytryn, Eddie; Yan, Tao

2016-09-01

The aim of this study was to determine the phylogenetic diversity of ceftriaxone resistance and the presence of known extended-spectrum β-lactamase (ESBL) genes in culturable soil resistomes. Libraries of soil bacterial isolates resistant to ceftriaxone were established from six physicochemically diverse soils collected in Hawaii (USA) and Israel. The phylogenetic affiliation, ceftriaxone and multidrug resistance levels, and presence of known ESBL genes of the isolates were determined. The soil bacterial isolates were phylogenetically grouped with the Alphaproteobacteria, Betaproteobacteria, Gammaproteobacteria, Actinobacteria, Firmicutes and Bacteroidetes. Ceftriaxone minimum inhibitory concentrations (MICs) largely followed the phylogeny structure and higher levels of ceftriaxone resistance corresponded to higher multidrug resistance. Three distinct blaTEM variants were detected in soil bacterial isolates belonging to nine different genera. In conclusion, the culturable soil resistomes for ceftriaxone exhibited high phylogenetic diversity and multidrug resistance. blaTEM was the only known ESBL detected in the soil resistomes, and its distribution in different phylogenetic groups suggests its ubiquitous presence and/or possible horizontal gene transfer within the soil microbiomes. Copyright © 2016 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.

Multifunctional magnetic Fe3O4 nanoparticles combined with chemotherapy and hyperthermia to overcome multidrug resistance

PubMed Central

Ren, Yanyan; Zhang, Haijun; Chen, Baoan; Cheng, Jian; Cai, Xiaohui; Liu, Ran; Xia, Guohua; Wu, Weiwei; Wang, Shuai; Ding, Jiahua; Gao, Chong; Wang, Jun; Bao, Wen; Wang, Lei; Tian, Liang; Song, Huihui; Wang, Xuemei

2012-01-01

Background Multidrug resistance in cancer is a major obstacle for clinical therapeutics, and is the reason for 90% of treatment failures. This study investigated the efficiency of novel multifunctional Fe3O4 magnetic nanoparticles (Fe3O4-MNP) combined with chemotherapy and hyperthermia for overcoming multidrug resistance in an in vivo model of leukemia. Methods Nude mice with tumor xenografts were randomly divided into a control group, and the treatment groups were allocated to receive daunorubicin, 5-bromotetrandrine (5-BrTet) and daunorubicin, Fe3O4-MNP, and Fe3O4-MNP coloaded with daunorubicin and 5-bromotetrandrine (Fe3O4-MNP-DNR-5-BrTet), with hyperthermia in an alternating magnetic field. We investigated tumor volume and pathology, as well as P-glycoprotein, Bcl-2, Bax, and caspase-3 protein expression to elucidate the effect of multimodal treatment on overcoming multidrug resistance. Results Fe3O4-MNP played a role in increasing tumor temperature during hyperthermia. Tumors became significantly smaller, and apoptosis of cells was observed in both the Fe3O4-MNP and Fe3O4-MNP-DNR-5-BrTet groups, especially in the Fe3O4-MNP-DNR-5-BrTet group, while tumor volumes in the other groups had increased after treatment for 12 days. Furthermore, Fe3O4-MNP-DNR-5-BrTet with hyperthermia noticeably decreased P-glycoprotein and Bcl-2 expression, and markedly increased Bax and caspase-3 expression. Conclusion Fe3O4-MNP-DNR-5-BrTet with hyperthermia may be a potential approach for reversal of multidrug resistance in the treatment of leukemia. PMID:22619560

Multifunctional magnetic Fe3O4 nanoparticles combined with chemotherapy and hyperthermia to overcome multidrug resistance.

PubMed

Ren, Yanyan; Zhang, Haijun; Chen, Baoan; Cheng, Jian; Cai, Xiaohui; Liu, Ran; Xia, Guohua; Wu, Weiwei; Wang, Shuai; Ding, Jiahua; Gao, Chong; Wang, Jun; Bao, Wen; Wang, Lei; Tian, Liang; Song, Huihui; Wang, Xuemei

2012-01-01

Multidrug resistance in cancer is a major obstacle for clinical therapeutics, and is the reason for 90% of treatment failures. This study investigated the efficiency of novel multifunctional Fe(3)O(4) magnetic nanoparticles (Fe(3)O(4)-MNP) combined with chemotherapy and hyperthermia for overcoming multidrug resistance in an in vivo model of leukemia. Nude mice with tumor xenografts were randomly divided into a control group, and the treatment groups were allocated to receive daunorubicin, 5-bromotetrandrine (5-BrTet) and daunorubicin, Fe(3)O(4)-MNP, and Fe(3)O(4)-MNP coloaded with daunorubicin and 5-bromotetrandrine (Fe(3)O(4)-MNP-DNR-5-BrTet), with hyperthermia in an alternating magnetic field. We investigated tumor volume and pathology, as well as P-glycoprotein, Bcl-2, Bax, and caspase-3 protein expression to elucidate the effect of multimodal treatment on overcoming multidrug resistance. Fe(3)O(4)-MNP played a role in increasing tumor temperature during hyperthermia. Tumors became significantly smaller, and apoptosis of cells was observed in both the Fe(3)O(4)-MNP and Fe(3)O(4)-MNP-DNR-5-BrTet groups, especially in the Fe(3)O(4)-MNP-DNR-5-BrTet group, while tumor volumes in the other groups had increased after treatment for 12 days. Furthermore, Fe(3)O(4)-MNP-DNR-5-BrTet with hyperthermia noticeably decreased P-glycoprotein and Bcl-2 expression, and markedly increased Bax and caspase-3 expression. Fe(3)O(4)-MNP-DNR-5-BrTet with hyperthermia may be a potential approach for reversal of multidrug resistance in the treatment of leukemia.

The intrinsic resistome of bacterial pathogens

PubMed Central

Olivares, Jorge; Bernardini, Alejandra; Garcia-Leon, Guillermo; Corona, Fernando; B. Sanchez, Maria; Martinez, Jose L.

2013-01-01

Intrinsically resistant bacteria have emerged as a relevant health problem in the last years. Those bacterial species, several of them with an environmental origin, present naturally low-level susceptibility to several drugs. It has been proposed that intrinsic resistance is mainly the consequence of the impermeability of cellular envelopes, the activity of multidrug efflux pumps or the lack of appropriate targets for a given family of drugs. However, recently published articles indicate that the characteristic phenotype of susceptibility to antibiotics of a given bacterial species depends on the concerted activity of several elements, what has been named as intrinsic resistome. These determinants comprise not just classical resistance genes. Other elements, several of them involved in basic bacterial metabolic processes, are of relevance for the intrinsic resistance of bacterial pathogens. In the present review we analyze recent publications on the intrinsic resistomes of Escherichia coli and Pseudomonas aeruginosa. We present as well information on the role that global regulators of bacterial metabolism, as Crc from P. aeruginosa, may have on modulating bacterial susceptibility to antibiotics. Finally, we discuss the possibility of searching inhibitors of the intrinsic resistome in the aim of improving the activity of drugs currently in use for clinical practice. PMID:23641241

The intrinsic resistome of bacterial pathogens.

PubMed

Olivares, Jorge; Bernardini, Alejandra; Garcia-Leon, Guillermo; Corona, Fernando; B Sanchez, Maria; Martinez, Jose L

2013-01-01

Intrinsically resistant bacteria have emerged as a relevant health problem in the last years. Those bacterial species, several of them with an environmental origin, present naturally low-level susceptibility to several drugs. It has been proposed that intrinsic resistance is mainly the consequence of the impermeability of cellular envelopes, the activity of multidrug efflux pumps or the lack of appropriate targets for a given family of drugs. However, recently published articles indicate that the characteristic phenotype of susceptibility to antibiotics of a given bacterial species depends on the concerted activity of several elements, what has been named as intrinsic resistome. These determinants comprise not just classical resistance genes. Other elements, several of them involved in basic bacterial metabolic processes, are of relevance for the intrinsic resistance of bacterial pathogens. In the present review we analyze recent publications on the intrinsic resistomes of Escherichia coli and Pseudomonas aeruginosa. We present as well information on the role that global regulators of bacterial metabolism, as Crc from P. aeruginosa, may have on modulating bacterial susceptibility to antibiotics. Finally, we discuss the possibility of searching inhibitors of the intrinsic resistome in the aim of improving the activity of drugs currently in use for clinical practice.

Transferability of antimicrobial resistance from multidrug-resistant Escherichia coli isolated from cattle in the USA to E. coli and Salmonella Newport recipients

USDA-ARS?s Scientific Manuscript database

The objective of this study was to evaluate conjugative transfer of cephalosporin resistance among (n=100) strains of multi-drug resistant Escherichia coli (MDRE) to Salmonella Newport and E. coli DH5-alpha recipients. To accomplish this, phenotypic and genotypic profiles were determined for MDRE, ...

Cloacael Carriage and Multidrug Resistance Escherichia coli O157:H7 from Poultry Farms, Eastern Ethiopia

PubMed Central

Shecho, Mude; Muktar, Yimer

2017-01-01

A cross-sectional study was carried out to determine antimicrobial drug resistance patterns of E. coli O157:H7 isolates and estimate the level of the pathogen. A total of 194 cloacae swab samples were collected randomly in two poultry farms. Standard cultural, biochemical, and serological (latex agglutination) methods were used to isolate E. coli O157:H7. The isolates were subjected to antimicrobial susceptibility testing using disc diffusion method. Out of 194 cloacae samples examined, 13.4% (n = 26) were found to be positive for E. coli O157:H7. The finding indicated differences in E. coli O157:H7 infection among the different risk factors. Chicken from Adele Poultry Farm showed higher E. coli O157:H7 infection (OR = 3.89) than Haramaya University poultry farm and young birds had more infection (OR = 4.62) than adult birds. Of the total 14 antimicrobials included in the panel of study, the susceptibility results were varied with 96.15% and 0% E. coli O157:H7 isolates expressing resistance to erythromycin, clindamycin, spectinomycin, and ciprofloxacin, respectively. Multidrug resistance to more than two antimicrobial agents was detected in 24 (92.30%) of the isolates. The study showed high presence of antimicrobial resistant isolates of E. coli O157:H7. Further study is required to better understand the ecology and evolution of bacterial resistance to antimicrobial agents. PMID:28349121

Cloacael Carriage and Multidrug Resistance Escherichia coli O157:H7 from Poultry Farms, Eastern Ethiopia.

PubMed

Shecho, Mude; Thomas, Naod; Kemal, Jelalu; Muktar, Yimer

2017-01-01

A cross-sectional study was carried out to determine antimicrobial drug resistance patterns of E. coli O157:H7 isolates and estimate the level of the pathogen. A total of 194 cloacae swab samples were collected randomly in two poultry farms. Standard cultural, biochemical, and serological (latex agglutination) methods were used to isolate E. coli O157:H7. The isolates were subjected to antimicrobial susceptibility testing using disc diffusion method. Out of 194 cloacae samples examined, 13.4% ( n = 26) were found to be positive for E. coli O157:H7. The finding indicated differences in E. coli O157:H7 infection among the different risk factors. Chicken from Adele Poultry Farm showed higher E. coli O157:H7 infection (OR = 3.89) than Haramaya University poultry farm and young birds had more infection (OR = 4.62) than adult birds. Of the total 14 antimicrobials included in the panel of study, the susceptibility results were varied with 96.15% and 0% E. coli O157:H7 isolates expressing resistance to erythromycin, clindamycin, spectinomycin, and ciprofloxacin, respectively. Multidrug resistance to more than two antimicrobial agents was detected in 24 (92.30%) of the isolates. The study showed high presence of antimicrobial resistant isolates of E. coli O157:H7. Further study is required to better understand the ecology and evolution of bacterial resistance to antimicrobial agents.

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.

Disinfection of Multidrug Resistant Escherichia coli by Solar-Photocatalysis using Fe-doped ZnO Nanoparticles.

PubMed

Das, Sourav; Sinha, Sayantan; Das, Bhaskar; Jayabalan, R; Suar, Mrutyunjay; Mishra, Amrita; Tamhankar, Ashok J; Stålsby Lundborg, Cecilia; Tripathy, Suraj K

2017-03-07

Spread of antibiotic resistant bacteria through water, is a threat to global public health. Here, we report Fe-doped ZnO nanoparticles (Fe/ZnO NPs) based solar-photocatalytic disinfection (PCD) of multidrug resistant Escherichia coli (MDR E. coli). Fe/ZnO NPs were synthesized by chemical precipitation technique, and when used as photocatalyst for disinfection, proved to be more effective (time for complete disinfection = 90 min) than ZnO (150 min) and TiO 2 (180 min). Lipid peroxidation and potassium (K + ) ion leakage studies indicated compromisation of bacterial cell membrane and electron microscopy and live-dead staining confirmed the detrimental effects on membrane integrity. Investigations indicated that H 2 O 2 was the key species involved in solar-PCD of MDR E. coli by Fe/ZnO NPs. X-ray diffraction and atomic absorption spectroscopy studies showed that the Fe/ZnO NPs system remained stable during the photocatalytic process. The Fe/ZnO NPs based solar-PCD process proved successful in the disinfection of MDR E. coli in real water samples collected from river, pond and municipal tap. The Fe/ZnO NPs catalyst made from low cost materials and with high efficacy under solar light may have potential for real world applications, to help reduce the spread of resistant bacteria.

[Multidrug resistant tuberculosis among health personnel in Côte d'Ivoire].

PubMed

Bakayoko, A S; Ahui, B J M; Nguessan, R; Kone, A; Kone, Z; Daix, A T; Badoum, G; Adou, G; Kouakou, O A; Kouakou, J; Coulibaly, G; Domoua, K; Aka-Danguy, E

2016-04-01

Multidrug resistance tuberculosis (MDR-TB) of health workers raises the question of hospital-borne transmission of infection. We report 4 cases of MDR-TB confirmed at the health workers over a period of 8 years (January, 2005 to December 2012), in the 2 services of pulmonology from Abidjan to Côte d'Ivoire). It was about young grown-up patients (aged between 28 and 39 years), all HIV negatives, in a no-win situation of antituberculosis treatment (3 patients/4). The most concerned staffs were the male nurses (2/4). Two agents worked in general hospital and the only one in a pulmonology department at the time of the diagnosis. The tuberculosis was of lung seat with bilateral radiographic hurt (3/4) and multiples excavations (4/4). The case index, when it was identified (2/2), was a family case. Among 3 agents who benefited from a second line treatment, 1 died further to an extensive drug resistance and 2 are declared to be cured. The fourth died before the beginning of the treatment. These cases of cure were in touch with a premature care. Multidrug resistant tuberculosis at the health workers could have a negative impact on the antituberculosis fight imposing rigorous measures of infection control and better implication of the occupational medicine. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Nanomedicine to Deal With Cancer Cell Biology in Multi-Drug Resistance.

PubMed

Tekchandani, Pawan; Kurmi, Balak Das; Paliwal, Shivani Rai

2017-01-01

Today Cancer still remains a major cause of mortality and death worldwide, in humans. Chemotherapy, a key treatment strategy in cancer, has significant hurdles such as the occurrence of chemoresistance in cancer, which is inherent unresponsiveness or acquired upon exposure to chemotherapeutics. The resistance of cancer cells to an antineoplastic agent accompanied to other chemotherapeutic drugs with different structures and mechanisms of action called multi-drug resistance (MDR) plays an important role in the failure of chemo- therapeutics. MDR is primarily based on the overexpression of drug efflux pumps in the cellular membrane, which belongs to the ATP-binding cassette (ABC) superfamily of proteins, are P-gp (P-glycoprotein) and multidrug resistance-associated protein (MRP). Over the years, various strategies have been evaluated to overcome MDR, based not only on the use of MDR modulators but also on the implementation an innovative approach and advanced nanosized drug delivery systems. Nanomedicine is an emerging tool of chemotherapy that focuses on alternative drug delivery for improvement of the treatment efficacy and reducing side effects to normal tissues. This review aims to focus on the details biology, reversal strategies option with the limitation of MDR and various advantages of the present medical science nanotechnology with intracellular delivery aspects for overcoming the significant potential for improving the treatment of MDR malignancies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Multidrug Resistance Protein 1 (MRP1, ABCC1), a “Multitasking” ATP-binding Cassette (ABC) Transporter*

PubMed Central

Cole, Susan P. C.

2014-01-01

The multidrug resistance protein 1 (MRP1) encoded by ABCC1 was originally discovered as a cause of multidrug resistance in tumor cells. However, it is now clear that MRP1 serves a broader role than simply mediating the ATP-dependent efflux of drugs from cells. The antioxidant GSH and the pro-inflammatory cysteinyl leukotriene C4 have been identified as key physiological organic anions effluxed by MRP1, and an ever growing body of evidence indicates that additional lipid-derived mediators are also substrates of this transporter. As such, MRP1 is a multitasking transporter that likely influences the etiology and progression of a host of human diseases. PMID:25281745

Draft Genome Sequence of a Multidrug-Resistant Klebsiella quasipneumoniae subsp. similipneumoniae Isolate from a Clinical Source

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

Ozer, Egon A.; Morris, Andrew R.; Krapp, Fiorella

We report here the draft genome sequence of a multidrug-resistant clinical isolate ofKlebsiella quasipneumoniaesubsp.similipneumoniae, KP_Z4175. This strain, isolated as part of a hospital infection-control screening program, is resistant to multiple β-lactam antibiotics, aminoglycosides, and trimethoprim-sulfamethoxazole.

Nasal carriage of multi-drug resistant Panton-Valentine leucocidin-positive methicillin-resistant Staphylococcus aureus in children in Tripoli-Libya.

PubMed

Al-haddad, Omaima H; Zorgani, Abdulaziz; Ghenghesh, Khalifa Sifaw

2014-04-01

Methicillin-resistant Staphylococcus aureus (MRSA) colonized children are at an increased risk of developing infections than methicillin-sensitive S. aureus colonized children. Nasal specimens from inpatient children, mothers of inpatient children, healthcare workers, and outpatient children at Tripoli Children Hospital (TCH) were examined for MRSA by chromogenic MRSA ID medium. Susceptibility of MRSA isolates to antibiotics was determined by the disc diffusion method. The nasal carriage rate of MRSA among inpatient children (8.3%, 24 of 289), their mothers (11%, 22 of 200), and healthcare workers (12.4%, 22 of 178) was significantly higher than among outpatient children (2.2%, 2 of 91) (P < 0.05, P < 0.02, and P < 0.006, respectively). Of the examined MRSA isolates (N = 35) 10 (28.6%) were positive for Panton-Valentine leucocidin genes by polymerase chain reaction. Multidrug resistance was found in 24.3% (17 of 70) of MRSA isolates. Nasal carriage of multidrug-resistant Panton-Valentine leucocidin-positive MRSA is not uncommon among inpatient children and their mothers in Tripoli.

Jatrophane diterpenoids from Euphorbia sororia as potent modulators against P-glycoprotein-based multidrug resistance.

PubMed

Hu, Rui; Gao, Jie; Rozimamat, Rushangul; Aisa, Haji Akber

2018-02-25

Five new (1-5) and ten known (6-15) jatrophane diterpenoids were isolated from the fructus of Euphorbia sororia and their structures were elucidated by extensive spectroscopic analysis. The absolute configurations of compounds 1 and 4 were confirmed by X-ray crystallographic analysis. Cytotoxicity and anti-multidrug resistance effects of these jatrophane diterpenoids were evaluated in multidrug-resistant MCF-7/ADR breast cancer cells with an overexpression of P-glycoprotein (P-gp). Eight compounds (1, 2, 4, 6, 8, 10, 11, and 15) showed promising chemoreversal abilities compared to verapamil (VRP). The most potent compound, Euphosorophane A (1), possessed many advantages, including (1) high potency (EC 50  = 92.68 ± 18.28 nM) in reversing P-gp-mediated resistance to doxorubicin (DOX), low cytotoxicity, and a high therapeutic index, (2) potency in reversing resistance to other cytotoxic agents associated with MDR, and (3) inhibition of P-gp-mediated Rhodamine123 (Rh123) efflux function in MCF-7/ADR cells. The results of the Western blot analysis indicated that the multidrug resistance (MDR) reversal induced by 1 was not due to the inhibiton of P-gp expression. Compound 1 stimulated P-gp-ATPase activity and caused the dose-dependent inhibition of DOX transport activity. Lineweaver-Burk and Dixon plots implied that 1 was a competitive inhibitor to DOX in the binding site of P-gp with a Ki of 0.49-0.50 μM. Our data suggested that 1 had a high binding affinity toward the DOX recognition site of P-gp. This resulted in inhibiting DOX transport, increasing intracellular DOX concentration, and finally resensitizing MCF-7/ADR to DOX. In addition, we discussed some added contents in the structure-activity relationship (SAR) of jatrophane diterpenoids. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

High prevalence of multidrug resistant tuberculosis in Djibouti: a retrospective study.

PubMed

Boyer-Cazajous, Géraldine; Martinaud, Christophe; Déhan, Céline; Hassan, Mohammed Osman; Gaas, Yassin; Chenilleau-Vidal, Marie-Caroline; Soler, Charles

2014-02-13

The Republic of Djibouti is an African country that exhibits one of the highest incidence rate of tuberculosis in the world. The aim of this study was to evaluate the prevalence of multidrug-resistant tuberculosis among new cases. We studied retrospectively every tuberculosis case diagnosed over a 12-month period in patients hospitalized at the French Military Hospital of Bouffard. During this period, 1,274 samples from 675 patients were tested. We isolated 266 mycobacteria corresponding to 180 cases of tuberculosis. Thirty-three were fully susceptible and 57% met the tuberculosis criteria, with 46% primary resistance. No extensively-drug-resistant tuberculosis was found. Our results highlight a major concern about the situation in this part of the world.

In Vitro Activity and MIC of Sitafloxacin against Multidrug-Resistant and Extensively Drug-Resistant Mycobacterium tuberculosis Isolated in Thailand

PubMed Central

Leechawengwongs, Manoon; Prammananan, Therdsak; Jaitrong, Sarinya; Billamas, Pamaree; Makhao, Nampueng; Thamnongdee, Nongnard; Thanormchat, Arirat; Phurattanakornkul, Arisa; Rattanarangsee, Somcharn; Ratanajaraya, Chate; Disratthakit, Areeya

2017-01-01

ABSTRACT New fluoroquinolones (FQs) have been shown to be more active against drug-resistant Mycobacterium tuberculosis strains than early FQs, such as ofloxacin. Sitafloxacin (STFX) is a new fluoroquinolone with in vitro activity against a broad range of bacteria, including M. tuberculosis. This study aimed to determine the in vitro activity of STFX against all groups of drug-resistant strains, including multidrug-resistant M. tuberculosis (MDR M. tuberculosis), MDR M. tuberculosis with quinolone resistance (pre-XDR), and extensively drug-resistant (XDR) strains. A total of 374 drug-resistant M. tuberculosis strains were tested for drug susceptibility by the conventional proportion method, and 95 strains were randomly submitted for MIC determination using the microplate alamarBlue assay (MABA). The results revealed that all the drug-resistant strains were susceptible to STFX at a critical concentration of 2 μg/ml. Determination of the MIC90s of the strains showed different MIC levels; MDR M. tuberculosis strains had a MIC90 of 0.0625 μg/ml, whereas pre-XDR and XDR M. tuberculosis strains had identical MIC90s of 0.5 μg/ml. Common mutations within the quinolone resistance-determining region (QRDR) of gyrA and/or gyrB did not confer resistance to STFX, except that double mutations of GyrA at Ala90Val and Asp94Ala were found in strains with a MIC of 1.0 μg/ml. The results indicated that STFX had potent in vitro activity against all the groups of drug-resistant M. tuberculosis strains and should be considered a new repurposed drug for treatment of multidrug-resistant and extensively drug-resistant TB. PMID:29061759

Antibacterial effect of Allium sativum cloves and Zingiber officinale rhizomes against multiple-drug resistant clinical pathogens.

PubMed

Karuppiah, Ponmurugan; Rajaram, Shyamkumar

2012-08-01

To evaluate the antibacterial properties of Allium sativum (garlic) cloves and Zingiber officinale (ginger) rhizomes against multi-drug resistant clinical pathogens causing nosocomial infection. The cloves of garlic and rhizomes of ginger were extracted with 95% (v/v) ethanol. The ethanolic extracts were subjected to antibacterial sensitivity test against clinical pathogens. Anti-bacterial potentials of the extracts of two crude garlic cloves and ginger rhizomes were tested against five gram negative and two gram positive multi-drug resistant bacteria isolates. All the bacterial isolates were susceptible to crude extracts of both plants extracts. Except Enterobacter sp. and Klebsiella sp., all other isolates were susceptible when subjected to ethanolic extracts of garlic and ginger. The highest inhibition zone was observed with garlic (19.45 mm) against Pseudomonas aeruginosa (P. aeruginosa). The minimal inhibitory concentration was as low as 67.00 µg/mL against P. aeruginosa. Natural spices of garlic and ginger possess effective anti-bacterial activity against multi-drug clinical pathogens and can be used for prevention of drug resistant microbial diseases and further evaluation is necessary.

Tetracycline can induce the expression of invasion factors in multidrug-resistant Salmonella during early-log phase

USDA-ARS?s Scientific Manuscript database

The prevalence of multidrug-resistant (MDR) Salmonella continues to be an important health and safety concern in both humans and animals worldwide. Because the response of drug resistant bacteria exposed to antibiotics can affect a variety of cellular processes, such as motility, attachment, and in...

Temporal Fluctuation of Multidrug Resistant Salmonella Typhi Haplotypes in the Mekong River Delta Region of Vietnam

PubMed Central

Chau, Tran Thuy; Duy, Pham Thanh; La, Tran Thi Phi; Hoang, Nguyen Van Minh; Nga, Tran Vu Thieu; Campbell, James I.; Manh, Bui Huu; Vinh Chau, Nguyen Van; Hien, Tran Tinh; Farrar, Jeremy; Dougan, Gordon; Baker, Stephen

2011-01-01

Background Typhoid fever remains a public health problem in Vietnam, with a significant burden in the Mekong River delta region. Typhoid fever is caused by the bacterial pathogen Salmonella enterica serovar Typhi (S. Typhi), which is frequently multidrug resistant with reduced susceptibility to fluoroquinolone-based drugs, the first choice for the treatment of typhoid fever. We used a GoldenGate (Illumina) assay to type 1,500 single nucleotide polymorphisms (SNPs) and analyse the genetic variation of S. Typhi isolated from 267 typhoid fever patients in the Mekong delta region participating in a randomized trial conducted between 2004 and 2005. Principal Findings The population of S. Typhi circulating during the study was highly clonal, with 91% of isolates belonging to a single clonal complex of the S. Typhi H58 haplogroup. The patterns of disease were consistent with the presence of an endemic haplotype H58-C and a localised outbreak of S. Typhi haplotype H58-E2 in 2004. H58-E2-associated typhoid fever cases exhibited evidence of significant geo-spatial clustering along the Sông H u branch of the Mekong River. Multidrug resistance was common in the established clone H58-C but not in the outbreak clone H58-E2, however all H58 S. Typhi were nalidixic acid resistant and carried a Ser83Phe amino acid substitution in the gyrA gene. Significance The H58 haplogroup dominates S. Typhi populations in other endemic areas, but the population described here was more homogeneous than previously examined populations, and the dominant clonal complex (H58-C, -E1, -E2) observed in this study has not been detected outside Vietnam. IncHI1 plasmid-bearing S. Typhi H58-C was endemic during the study period whilst H58-E2, which rarely carried the plasmid, was only transient, suggesting a selective advantage for the plasmid. These data add insight into the outbreak dynamics and local molecular epidemiology of S. Typhi in southern Vietnam. PMID:21245916

The demise of multidrug-resistant HIV-1: the national time trend in Portugal

PubMed Central

Vercauteren, Jurgen; Theys, Kristof; Carvalho, Ana Patricia; Valadas, Emília; Duque, Luis Miguel; Teófilo, Eugénio; Faria, Telo; Faria, Domitília; Vera, José; Águas, Maria João; Peres, Susana; Mansinho, Kamal; Vandamme, Anne-Mieke; Camacho, Ricardo Jorge; Mansinho, Kamal; Cláudia Miranda, Ana; Aldir, Isabel; Ventura, Fernando; Nina, Jaime; Borges, Fernando; Valadas, Emília; Doroana, Manuela; Antunes, Francisco; João Aleixo, Maria; João Águas, Maria; Botas, Júlio; Branco, Teresa; Vera, José; Vaz Pinto, Inês; Poças, José; Sá, Joana; Duque, Luis; Diniz, António; Mineiro, Ana; Gomes, Flora; Santos, Carlos; Faria, Domitília; Fonseca, Paula; Proença, Paula; Tavares, Luís; Guerreiro, Cristina; Narciso, Jorge; Faria, Telo; Teófilo, Eugénio; Pinheiro, Sofia; Germano, Isabel; Caixas, Umbelina; Faria, Nancy; Paula Reis, Ana; Bentes Jesus, Margarida; Amaro, Graça; Roxo, Fausto; Abreu, Ricardo; Neves, Isabel

2013-01-01

Objectives Despite a decreasing mortality and morbidity in treated HIV-1 patients, highly active antiretroviral treatment (HAART) can still fail due to the development of drug resistance. Especially, multidrug-resistant viruses pose a threat to efficient therapy. We studied the changing prevalence of multidrug resistance (MDR) over time in a cohort of HIV-1-infected patients in Portugal. Patients and methods We used data of 8065 HIV-1-infected patients followed from July 2001 up to April 2012 in 22 hospitals located in Portugal. MDR at a specific date of sampling was defined as no more than one fully active drug (excluding integrase and entry inhibitors) at that time authorized by the Portuguese National Authority of Medicines and Health Products (INFARMED), as interpreted with the Rega algorithm version 8.0.2. A generalized linear mixed model was used to study the time trend of the prevalence of MDR. Results We observed a statistically significant decrease in the prevalence of MDR over the last decade, from 6.9% (95% CI: 5.7–8.4) in 2001–03, 6.0% (95% CI: 4.9–7.2) in 2003–05, 3.7% (95% CI: 2.8–4.8) in 2005–07 and 1.6% (95% CI: 1.1–2.2) in 2007–09 down to 0.6% (95% CI: 0.3–0.9) in 2009–12 [OR = 0.80 (95% CI: 0.75–0.86); P < 0.001]. In July 2011 the last new case of MDR was seen. Conclusions The prevalence of multidrug-resistant HIV-1 is decreasing over time in Portugal, reflecting the increasing efficiency of HAART and the availability of new drugs. Therefore, in designing a new drug, safety and practical aspects, e.g. less toxicity and ease of use, may need more attention than focusing mainly on efficacy against resistant strains. PMID:23228933

MRP1 and glucosylceramide are coordinately over expressed and enriched in rafts during multidrug resistance acquisition in colon cancer cells.

PubMed

Klappe, Karin; Hinrichs, John W J; Kroesen, Bart-Jan; Sietsma, Hannie; Kok, Jan Willem

2004-07-01

Previously we have described a novel multidrug-resistant cell line, HT29(col), which displayed over expression of the multidrug-resistance protein 1 (MRP1) and an altered sphingolipid composition, including enhanced levels of glucosylceramide (GlcCer; Kok JW, Veldman RJ, Klappe K, Koning H, Filipeanu C, Muller M. Int J Cancer 2000;87:172-8). In our study, long-term screening revealed that, during colchicine-induced acquisition of multidrug resistance in a new HT29(col) cell line, increases in GlcCer occurred concomitantly with upregulation of MRP1 expression. Both MRP1 and GlcCer were found enriched in Lubrol-insoluble membrane domains. The expression of MRP1 and GlcCer were tightly correlated, as indicated also by a reversal of both at the later stage of colchicine consolidation. Resistance to colchicine was determined by MRP1, while glucosylceramide synthase (GCS) did not contribute: 1). Resistance was fully inhibited by MK571. 2). GCS expression and activity were not upregulated in HT29(col) cells. 3). Inhibition of GCS did not affect MRP1-mediated efflux function or sensitivity to colchicine. Instead, overall sphingolipid metabolism was upregulated through an increased rate of ceramide biosynthesis. In conclusion, upregulation of MRP1 occurs in concert with upregulation of GlcCer during multidrug-resistance acquisition, and both are enriched in rafts. The increased GlcCer pool does not directly modulate MRP1 function and cell survival. Copyright 2004 Wiley-Liss, Inc.

Characterization of Multidrug Resistant E. faecalis Strains from Pigs of Local Origin by ADSRRS-Fingerprinting and MALDI -TOF MS; Evaluation of the Compatibility of Methods Employed for Multidrug Resistance Analysis

PubMed Central

Nowakiewicz, Aneta; Ziółkowska, Grażyna; Zięba, Przemysław; Gnat, Sebastian; Trościańczyk, Aleksandra; Adaszek, Łukasz

2017-01-01

The aim of this study was to characterize multidrug resistant E. faecalis strains from pigs of local origin and to analyse the relationship between resistance and genotypic and proteomic profiles by amplification of DNA fragments surrounding rare restriction sites (ADSRRS-fingerprinting) and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI -TOF MS). From the total pool of Enterococcus spp. isolated from 90 pigs, we selected 36 multidrug resistant E. faecalis strains, which represented three different phenotypic resistance profiles. Phenotypic resistance to tetracycline, macrolides, phenicols, and lincomycin and high-level resistance to aminoglycosides were confirmed by the occurrence of at least one corresponding resistance gene in each strain. Based on the analysis of the genotypic and phenotypic resistance of the strains tested, five distinct resistance profiles were generated. As a complement of this analysis, profiles of virulence genes were determined and these profiles corresponded to the phenotypic resistance profiles. The demonstration of resistance to a wide panel of antimicrobials by the strains tested in this study indicates the need of typing to determine the spread of resistance also at the local level. It seems that in the case of E. faecalis, type and scope of resistance strongly determines the genotypic pattern obtained with the ADSRRS-fingerprinting method. The ADSRRS-fingerprinting analysis showed consistency of the genetic profiles with the resistance profiles, while analysis of data with the use of the MALDI- TOF MS method did not demonstrate direct reproduction of the clustering pattern obtained with this method. Our observations were confirmed by statistical analysis (Simpson’s index of diversity, Rand and Wallace coefficients). Even though the MALDI -TOF MS method showed slightly higher discrimination power than ADSRRS-fingerprinting, only the latter method allowed reproduction of the clustering pattern of

Python Cathelicidin CATHPb1 Protects against Multidrug-Resistant Staphylococcal Infections by Antimicrobial-Immunomodulatory Duality.

PubMed

Cai, Shasha; Qiao, Xue; Feng, Lan; Shi, Nannan; Wang, Hui; Yang, Huaixin; Guo, Zhilai; Wang, Mengke; Chen, Yan; Wang, Yipeng; Yu, Haining

2018-03-08

Multidrug-resistant Staphylococcus aureus, including MRSA (methicillin-resistant) and VRSA (vancomycin-resistant), causes serious healthcare-associated infections, even sepsis and death. Here, we identified six novel cathelicidins (CATHPb1-6) from Python bivittatu, and CATHPb1 displayed the best in vitro pharmacological and toxicological profile. We further show that CATHPb1 exhibited evident protection in mice MRSA/VRSA infection models, given either 24 h before or 4 h after infection. The protection was all effective through different administration routes, but was blocked by in vivo depletion of monocyte/macrophages or neutrophils. CATHPb1 can rapidly and massively modulate macrophages/monocytes and neutrophils trafficking to the infection site, and potentiate their bactericidal functions. Meanwhile, CATHPb1 remarkably augmented neutrophil-mediated bacteria killing by facilitating neutrophil extracellular traps (NETs) formation and preventing its degradation. Acting through MAPKs and NF-κB pathways, CATHPb1 selectively enhanced the levels of chemokines while reducing the production of pro-inflammatory cytokines without undesirable toxicities. The much improved serum half-life and stabilities confer CATHPb1 an excellent prospect to become a novel therapeutic agent against multidrug-resistant staphylococcal infections.

A Potato cDNA Encoding a Homologue of Mammalian Multidrug Resistant P-Glycoprotein

NASA Technical Reports Server (NTRS)

Wang, W.; Takezawa, D.; Poovaiah, B. W.

1996-01-01

A homologue of the multidrug resistance (MDR) gene was obtained while screening a potato stolon tip cDNA expression library with S-15-labeled calmodulin. The mammalian MDR gene codes for a membrane-bound P-glycoprotein (170-180 kDa) which imparts multidrug resistance to cancerous cells. The potato cDNA (PMDR1) codes for a polypeptide of 1313 amino acid residues (ca. 144 kDa) and its structural features are very similar to the MDR P-glycoprotein. The N-terminal half of the PMDR1-encoded protein shares striking homology with its C-terminal half, and each half contains a conserved ATP-binding site and six putative transmembrane domains. Southern blot analysis indicated that potato has one or two MDR-like genes. PMDR1 mRNA is constitutively expressed in all organs studied with higher expression in the stem and stolon tip. The PMDR1 expression was highest during tuber initiation and decreased during tuber development.

Targeting multidrug resistance protein 1 (MRP1, ABCC1): past, present, and future.

PubMed

Cole, Susan P C

2014-01-01

The human ATP-binding cassette transporter multidrug resistance protein 1 (MRP1), encoded by ABCC1, was initially identified because of its ability to confer multidrug resistance in lung cancer cells. It is now established that MRP1 plays a role in protecting certain tissues from xenobiotic insults and that it mediates the cellular efflux of the proinflammatory cysteinyl leukotriene C4 as well as a vast array of other endo- and xenobiotic organic anions. Many of these are glutathione (GSH) or glucuronide conjugates, the products of Phase II drug metabolism. MRP1 also plays a role in the cellular efflux of the reduced and oxidized forms of GSH and thus contributes to the many physiological and pathophysiological processes influenced by these small peptides, including oxidative stress. In this review, the pharmacological and physiological aspects of MRP1 are considered in the context of the current status and future prospects of pharmacological and genetic modulation of MRP1 activity.

Capreomycin-induced optic neuritis in a case of multidrug resistant pulmonary tuberculosis

PubMed Central

Magazine, Rahul; Pal, Mahuya; Chogtu, Bharti; Nayak, Veena

2010-01-01

A patient of multidrug-resistant pulmonary tuberculosis was prescribed an anti-tubercular regimen containing capreomycin. Patient developed optic neuritis 3 months after starting treatment. Investigations did not reveal any specific cause for this ocular condition and on discontinuing capreomycin his vision recovered. We conclude that capreomycin is the cause of reversible optic neuritis in our case. PMID:20927254

Synthesis and Characterization of Cefotaxime Conjugated Gold Nanoparticles and Their Use to Target Drug-Resistant CTX-M-Producing Bacterial Pathogens.

PubMed

Shaikh, Sibhghatulla; Rizvi, Syed Mohd Danish; Shakil, Shazi; Hussain, Talib; Alshammari, Thamir M; Ahmad, Waseem; Tabrez, Shams; Al-Qahtani, Mohammad H; Abuzenadah, Adel M

2017-09-01

Multidrug-resistance due to "β lactamases having the expanded spectrum" (ESBLs) in members of Enterobacteriaceae is a matter of continued clinical concern. CTX-M is among the most common ESBLs in Enterobacteriaceae family. In the present study, a nanoformulation of cefotaxime was prepared using gold nanoparticles to combat drug-resistance in ESBL producing strains. Here, two CTX-M-15 positive cefotaxime resistant bacterial strains (i.e., one Escherichia coli and one Klebsiella pneumoniae strain) were used for testing the efficacy of "cefotaxime loaded gold-nanoparticles." Bromelain was used for both reduction and capping in the process of synthesis of gold-nanoparticles. Thereafter, cefotaxime was conjugated onto it with the help of activator 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide. For characterization of both unconjugated and cefotaxime conjugated gold nanoparticles; UV-Visible spectroscopy, Scanning, and Transmission type Electron Microscopy methods accompanied with Dynamic Light Scattering were used. We used agar diffusion method plus microbroth-dilution method for the estimation of the antibacterial-activity and determination of minimum inhibitory concentration or MIC values, respectively. MIC values of cefotaxime loaded gold nanoparticles against E. coli and K. pneumoniae were obtained as 1.009 and 2.018 mg/L, respectively. These bacterial strains were completely resistant to cefotaxime alone. These results reinforce the utility of conjugating an old unresponsive antibiotic with gold nanoparticles to restore its efficacy against otherwise resistant bacterial pathogens. J. Cell. Biochem. 118: 2802-2808, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Horizontal gene transfer and antibiotic resistance plasmids in multi-drug resistant Salmonella enterica serovars

USDA-ARS?s Scientific Manuscript database

Antibiotic resistant foodborne pathogens pose serious public health concerns and increase the burden of disease treatment. Antibiotic resistance genes can reside on the bacterial chromosome or on other self-replicating DNA molecules such as plasmids. The resistance genes/DNA can be transferred int...

Intensive care unit environmental surfaces are contaminated by multidrug-resistant bacteria in biofilms: combined results of conventional culture, pyrosequencing, scanning electron microscopy, and confocal laser microscopy.

PubMed

Hu, H; Johani, K; Gosbell, I B; Jacombs, A S W; Almatroudi, A; Whiteley, G S; Deva, A K; Jensen, S; Vickery, K

2015-09-01

Hospital-associated infections cause considerable morbidity and mortality, and are expensive to treat. Organisms causing these infections can be sourced from the inanimate environment around a patient. Could the difficulty in eradicating these organisms from the environment be because they reside in dry surface biofilms? The intensive care unit (ICU) of a tertiary referral hospital was decommissioned and the opportunity to destructively sample clinical surfaces was taken in order to investigate whether multidrug-resistant organisms (MDROs) had survived the decommissioning process and whether they were present in biofilms. The ICU had two 'terminal cleans' with 500 ppm free chlorine solution; items from bedding, surrounds, and furnishings were then sampled with cutting implements. Sections were sonicated in tryptone soya broth and inoculated on to chromogenic plates to demonstrate MDROs, which were confirmed with the Vitek2 system. Genomic DNA was extracted directly from ICU samples, and subjected to polymerase chain reaction (PCR) for femA to detect Staphylococcus aureus and the microbiome by bacterial tag-encoded FLX amplicon pyrosequencing. Confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM) were performed on environmental samples. Multidrug-resistant bacteria were cultured from 52% (23/44) of samples cultured. S. aureus PCR was positive in 50%. Biofilm was demonstrated in 93% (41/44) of samples by CLSM and/or SEM. Pyrosequencing demonstrated that the biofilms were polymicrobial and contained species that had multidrug-resistant strains. Dry surface biofilms containing MDROs are found on ICU surfaces despite terminal cleaning with chlorine solution. How these arise and how they might be removed requires further study. Copyright © 2015 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

Comparative genomics of multidrug resistance in Acinetobacter baumannii.

PubMed

Fournier, Pierre-Edouard; Vallenet, David; Barbe, Valérie; Audic, Stéphane; Ogata, Hiroyuki; Poirel, Laurent; Richet, Hervé; Robert, Catherine; Mangenot, Sophie; Abergel, Chantal; Nordmann, Patrice; Weissenbach, Jean; Raoult, Didier; Claverie, Jean-Michel

2006-01-01

Acinetobacter baumannii is a species of nonfermentative gram-negative bacteria commonly found in water and soil. This organism was susceptible to most antibiotics in the 1970s. It has now become a major cause of hospital-acquired infections worldwide due to its remarkable propensity to rapidly acquire resistance determinants to a wide range of antibacterial agents. Here we use a comparative genomic approach to identify the complete repertoire of resistance genes exhibited by the multidrug-resistant A. baumannii strain AYE, which is epidemic in France, as well as to investigate the mechanisms of their acquisition by comparison with the fully susceptible A. baumannii strain SDF, which is associated with human body lice. The assembly of the whole shotgun genome sequences of the strains AYE and SDF gave an estimated size of 3.9 and 3.2 Mb, respectively. A. baumannii strain AYE exhibits an 86-kb genomic region termed a resistance island--the largest identified to date--in which 45 resistance genes are clustered. At the homologous location, the SDF strain exhibits a 20 kb-genomic island flanked by transposases but devoid of resistance markers. Such a switching genomic structure might be a hotspot that could explain the rapid acquisition of resistance markers under antimicrobial pressure. Sequence similarity and phylogenetic analyses confirm that most of the resistance genes found in the A. baumannii strain AYE have been recently acquired from bacteria of the genera Pseudomonas, Salmonella, or Escherichia. This study also resulted in the discovery of 19 new putative resistance genes. Whole-genome sequencing appears to be a fast and efficient approach to the exhaustive identification of resistance genes in epidemic infectious agents of clinical significance.

Bacterial Adaptation to Antibiotics through Regulatory RNAs.

PubMed

Felden, Brice; Cattoir, Vincent

2018-05-01

The extensive use of antibiotics has resulted in a situation where multidrug-resistant pathogens have become a severe menace to human health worldwide. A deeper understanding of the principles used by pathogens to adapt to, respond to, and resist antibiotics would pave the road to the discovery of drugs with novel mechanisms. For bacteria, antibiotics represent clinically relevant stresses that induce protective responses. The recent implication of regulatory RNAs (small RNAs [sRNAs]) in antibiotic response and resistance in several bacterial pathogens suggests that they should be considered innovative drug targets. This minireview discusses sRNA-mediated mechanisms exploited by bacterial pathogens to fight against antibiotics. A critical discussion of the newest findings in the field is provided, with emphasis on the implication of sRNAs in major mechanisms leading to antibiotic resistance, including drug uptake, active drug efflux, drug target modifications, biofilms, cell walls, and lipopolysaccharide (LPS) biosynthesis. Of interest is the lack of knowledge about sRNAs implicated in Gram-positive compared to Gram-negative bacterial resistance. Copyright © 2018 American Society for Microbiology.

High Prevalence of Multidrug-Resistant Tuberculosis, Swaziland, 2009–2010

PubMed Central

Dlamini, Themba; Ascorra, Alexandra; Rüsch-Gerdes, Sabine; Tefera, Zerihun Demissie; Calain, Philippe; de la Tour, Roberto; Jochims, Frauke; Richter, Elvira; Bonnet, Maryline

2012-01-01

In Africa, although emergence of multidrug-resistant (MDR) tuberculosis (TB) represents a serious threat in countries severely affected by the HIV epidemic, most countries lack drug-resistant TB data. This finding was particularly true in the Kingdom of Swaziland, which has the world’s highest HIV and TB prevalences. Therefore, we conducted a national survey in 2009–2010 to measure prevalence of drug-resistant TB. Of 988 patients screened, 420 new case-patients and 420 previously treated case-patients met the study criteria. Among culture-positive patients, 15.3% new case-patients and 49.5% previously treated case-patients harbored drug-resistant strains. MDR TB prevalence was 7.7% and 33.8% among new case-patients and previously treated case-patients, respectively. HIV infection and past TB treatment were independently associated with MDR TB. The findings assert the need for wide-scale intervention in resource-limited contexts such as Swaziland, where diagnostic and treatment facilities and health personnel are lacking. PMID:22260950

Chitosan as an effective inhibitor of multidrug resistant Acinetobacter baumannii.

PubMed

Costa, E M; Silva, S; Vicente, S; Veiga, M; Tavaria, F; Pintado, M M

2017-12-15

Over the last two decades worldwide levels of antibiotic resistance have risen leading to the appearance of multidrug resistant microorganisms. Acinetobacter baumannii is a known skin pathogen which has emerged as a major cause of nosocomial outbreaks due to its capacity to colonize indwelling medical devices and natural antibiotic resistance. With chitosan being an effective antimicrobial agent against antibiotic resistant microorganisms, the aim of this work was to access its potential as an alternative to traditional antimicrobials in the management of A. baumannii growth. What the results showed was that both chitosan MW's tested were active upon A. baumannii's planktonic and sessile growth. For planktonic growth MICs and MBCs were obtained at relatively low concentrations (0.5-2mg/mL) while for sessile growth chitosan proved to be an effective inhibitor of A. baumannii's adhesion and biofilm formation. Considering these results chitosan shows a high potential for control of A. baumannii infections. Copyright © 2017 Elsevier Ltd. All rights reserved.

Multidrug-Resistant Salmonella enterica Serotype Typhi, Gulf of Guinea Region, Africa

PubMed Central

Baltazar, Murielle; Ngandjio, Antoinette; Holt, Kathryn Elizabeth; Lepillet, Elodie; Pardos de la Gandara, Maria; Collard, Jean-Marc; Bercion, Raymond; Nzouankeu, Ariane; Le Hello, Simon; Dougan, Gordon; Fonkoua, Marie-Christine

2015-01-01

We identified 3 lineages among multidrug-resistant (MDR) Salmonella enterica serotype Typhi isolates in the Gulf of Guinea region in Africa during the 2000s. However, the MDR H58 haplotype, which predominates in southern Asia and Kenya, was not identified. MDR quinolone-susceptible isolates contained a 190-kb incHI1 pST2 plasmid or a 50-kb incN pST3 plasmid. PMID:25811307

5-Episinuleptolide Decreases the Expression of the Extracellular Matrix in Early Biofilm Formation of Multi-Drug Resistant Acinetobacter baumannii.

PubMed

Tseng, Sung-Pin; Hung, Wei-Chun; Huang, Chiung-Yao; Lin, Yin-Shiou; Chan, Min-Yu; Lu, Po-Liang; Lin, Lin; Sheu, Jyh-Horng

2016-07-29

Nosocomial infections and increasing multi-drug resistance caused by Acinetobacter baumannii have been recognized as emerging problems worldwide. Moreover, A. baumannii is able to colonize various abiotic materials and medical devices, making it difficult to eradicate and leading to ventilator-associated pneumonia, and bacteremia. Development of novel molecules that inhibit bacterial biofilm formation may be an alternative prophylactic option for the treatment of biofilm-associated A. baumannii infections. Marine environments, which are unlike their terrestrial counterparts, harbor an abundant biodiversity of marine organisms that produce novel bioactive natural products with pharmaceutical potential. In this study, we identified 5-episinuleptolide, which was isolated from Sinularia leptoclados, as an inhibitor of biofilm formation in ATCC 19606 and three multi-drug resistant A. baumannii strains. In addition, the anti-biofilm activities of 5-episinuleptolide were observed for Gram-negative bacteria but not for Gram-positive bacteria, indicating that the inhibition mechanism of 5-episinuleptolide is effective against only Gram-negative bacteria. The mechanism of biofilm inhibition was demonstrated to correlate to decreased gene expression from the pgaABCD locus, which encodes the extracellular polysaccharide poly-β-(1,6)-N-acetylglucosamine (PNAG). Scanning electron microscopy (SEM) indicated that extracellular matrix of the biofilm was dramatically decreased by treatment with 5-episinuleptolide. Our study showed potentially synergistic activity of combination therapy with 5-episinuleptolide and levofloxacin against biofilm formation and biofilm cells. These data indicate that inhibition of biofilm formation via 5-episinuleptolide may represent another prophylactic option for solving the persistent problem of biofilm-associated A. baumannii infections.

Perspectives on multidrug-resistant organisms at the end of life : A focus group study of staff members and institutional stakeholders.

PubMed

Herbst, Franziska A; Heckel, Maria; Tiedtke, Johanna M; Adelhardt, Thomas; Sturm, Alexander; Stiel, Stephanie; Ostgathe, Christoph

2018-03-16

There is a lack of research into how hospital staff and institutional stakeholders (i. e. institutional representatives from public health authorities, hospital hygiene, and the departments of microbiology, palliative care, and geriatrics) engage with patients who are carriers of multidrug-resistant organisms and receiving end-of-life care. Knowledge of their experiences, workload, and needs should be considered in dealing with hospitalized carriers of multidrug-resistant organisms as well as staff education. This study explored and compared staff members' and stakeholders' perspectives on multidrug-resistant organisms and on provision of end-of-life care to carrier patients. In this study four focus groups consisting of hospital staff members and institutional stakeholders were formed within a mixed-methods parent study in a palliative care unit at a university clinic and a geriatric ward of a Catholic and academic teaching hospital. Participants discussed results from staff and stakeholder interviews from a former study phase. Data were analyzed according to Grounded Theory and perspectives of staff members and institutional stakeholders were compared and contrasted. Key issues debated by staff members (N = 19) and institutional stakeholders (N = 10) were 1) the additional workload, 2) reasons for uncertainty about handling carrier patients, 3) the format of continuing education, and 4) the preferred management approach for dealing with multidrug-resistant organism carrier patients. Although similar barriers (e. g. colleagues' ambiguous opinions) were identified, both groups drew different conclusions concerning the management of these barriers. While institutional stakeholders recommended making decisions on hygiene measures under consideration of the specific patient situation, staff members preferred the use of standardized hygiene measures which should be applied uniformly to all patients. Staff members and institutional stakeholders

Reduced susceptibility to chlorhexidine disinfectant among New Delhi metallo-beta-lactamase-1 positive Enterobacteriaceae and other multidrug-resistant organisms: Report from a tertiary care hospital in Karachi, Pakistan.

PubMed

Mal, P B; Farooqi, J; Irfan, S; Hughes, M A; Khan, E

2016-01-01

We analysed susceptibility of multidrug-resistant organisms (MDROs) including New Delhi metallo-beta-lactamase-1 positive Enterobacteriaceae to chlorhexidine and compared results to their susceptible counterparts. Susceptibilities of chlorhexidine digluconate in a standard (CHX-S) preparation and two commercial disinfectants containing different CHX concentrations (2% w/v and 4% w/w) were performed. MDROs had narrower range of higher CHX-S minimum inhibitory concentrations (MICs) as compared to pan-sensitive organisms. The MIC values for commercial disinfectants products for MDROs were many folds higher (20-600 times), than CHX-S for in vitro use. Increasing antibiotic resistance among bacterial isolates can be an indirect marker of reduced susceptibility to chlorhexidine in hospital setting.

Emergence of Multidrug-Resistant New Delhi Metallo-β-Lactamase-1-Producing Klebsiella pneumoniae in Egypt.

PubMed

Khalil, Mahmoud A F; Elgaml, Abdelaziz; El-Mowafy, Mohammed

2017-06-01

Despite expansion of the New Delhi metallo-β-lactamase-1 (NDM-1) worldwide, the incident of outbreaks regarding Egypt is still uncommon. In this survey, we denounce the emanation of multidrug-resistant NDM-1-producing Klebsiella pneumoniae in Egypt. We have reclaimed 46 unrepeatable carbapenem-resistant K. pneumoniae isolates at El-demerdash hospital, Ain Shams University, Cairo, Egypt. All the isolates showed a decreased sensitivity to imipenem and meropenem via the disc diffusion method. Among the isolates, 10 were proven as NDM-1 producers by utilizing the phenotypic methods (modified Hodge test and EDTA synergistic test) and specific PCR detection of NDM-1 encoding gene, bla NDM-1 . The isolates hosting the bla NDM-1 showed an elevated resistance to several classes of β-lactam and non β-lactam antibiotics. All bla NDM-1 -harboring isolates have showed positivity for one or more other plasmid-mediated bla genes; in addition, the isolates carried class 1 integron. Enterobacterial repetitive intergenic consensus (ERIC)-PCR results revealed that majority of the isolates, including the NDM-1 producers, are unrelated to each other. This highlights the danger of horizontal transfer of plasmids encoding for such carbapenemases, including NDM-1, between the isolates of K. pneumoniae. In summary, this study has confirmed the incidence of bla NDM-1 together with other bla genes among the K. pneumoniae isolates in Egypt. Control and prevention of infection can be achieved through early detection of resistance genes among bacterial isolates; through limiting the dispersal of these organisms.

Comparison of methods to detect the in vitro activity of silver nanoparticles (AgNP) against multidrug resistant bacteria.

PubMed

Cavassin, Emerson Danguy; de Figueiredo, Luiz Francisco Poli; Otoch, José Pinhata; Seckler, Marcelo Martins; de Oliveira, Roberto Angelo; Franco, Fabiane Fantinelli; Marangoni, Valeria Spolon; Zucolotto, Valtencir; Levin, Anna Sara Shafferman; Costa, Silvia Figueiredo

2015-10-05

Multidrug resistant microorganisms are a growing challenge and new substances that can be useful to treat infections due to these microorganisms are needed. Silver nanoparticle may be a future option for treatment of these infections, however, the methods described in vitro to evaluate the inhibitory effect are controversial. This study evaluated the in vitro activity of silver nanoparticles against 36 susceptible and 54 multidrug resistant Gram-positive and Gram-negative bacteria from clinical sources. The multidrug resistant bacteria were oxacilin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus spp., carbapenem- and polymyxin B-resistant A. baumannii, carbapenem-resistant P. aeruginosa and carbapenem-resistant Enterobacteriaceae. We analyzed silver nanoparticles stabilized with citrate, chitosan and polyvinyl alcohol and commercial silver nanoparticle. Silver sulfadiazine and silver nitrate were used as control. Different methods were used: agar diffusion, minimum inhibitory concentration, minimum bactericidal concentration and time-kill. The activity of AgNPs using diffusion in solid media and the MIC methods showed similar effect against MDR and antimicrobial-susceptible isolates, with a higher effect against Gram-negative isolates. The better results were achieved with citrate and chitosan silver nanoparticle, both with MIC90 of 6.75 μg mL(-1), which can be due the lower stability of these particles and, consequently, release of Ag(+) ions as revealed by X-ray diffraction (XRD). The bactericidal effect was higher against antimicrobial-susceptible bacteria. It seems that agar diffusion method can be used as screening test, minimum inhibitory concentration/minimum bactericidal concentration and time kill showed to be useful methods. The activity of commercial silver nanoparticle and silver controls did not exceed the activity of the citrate and chitosan silver nanoparticles. The in vitro inhibitory effect was stronger against Gram

Multidrug Efflux Systems in Microaerobic and Anaerobic Bacteria

PubMed Central

Xu, Zeling; Yan, Aixin

2015-01-01

Active drug efflux constitutes an important mechanism of antibiotic and multidrug resistance in bacteria. Understanding the distribution, expression, and physiological functions of multidrug efflux pumps, especially under physiologically and clinically relevant conditions of the pathogens, is the key to combat drug resistance. In animal hosts, most wounded, infected and inflamed tissues display low oxygen tensions. In this article, we summarize research development on multidrug efflux pumps in the medicinally relevant microaerobic and anaerobic pathogens and their implications in the effort to combat drug-resistant infections. PMID:27025630

Haemophilus parasuis CpxRA two-component system confers bacterial tolerance to environmental stresses and macrolide resistance.

PubMed

Cao, Qi; Feng, Fenfen; Wang, Huan; Xu, Xiaojuan; Chen, Huanchun; Cai, Xuwang; Wang, Xiangru

2018-01-01

Haemophilus parasuis is an opportunistic pathogen localized in the upper respiratory tracts of pigs, its infection begins from bacterial survival under complex conditions, like hyperosmosis, oxidative stress, phagocytosis, and sometimes antibiotics as well. The two-component signal transduction (TCST) system serves as a common stimulus-response mechanism that allows microbes to sense and respond to diverse environmental conditions via a series of phosphorylation reactions. In this study, we investigated the role of TCST system CpxRA in H. parasuis in response to different environmental stimuli by constructing the ΔcpxA and ΔcpxR single deletion mutants as well as the ΔcpxRA double deletion mutant from H. parasuis serotype 4 isolate JS0135. We demonstrated that H. parasuis TCST system CpxRA confers bacterial tolerance to stresses and bactericidal antibiotics. The CpxR was found to play essential roles in mediating oxidative stress, osmotic stresses and alkaline pH stress tolerance, as well as macrolide resistance (i.e. erythromycin), but the CpxA deletion did not decrease bacterial resistance to abovementioned stresses. Moreover, we found via RT-qPCR approach that HAPS_RS00160 and HAPS_RS09425, both encoding multidrug efflux pumps, were significantly decreased in erythromycin challenged ΔcpxR and ΔcpxRA mutants compared with wild-type strain JS0135. These findings characterize the role of the TCST system CpxRA in H. parasuis conferring stress response tolerance and bactericidal resistance, which will deepen our understanding of the pathogenic mechanism in H. parasuis. Copyright © 2017 Elsevier GmbH. All rights reserved.

Anesthesia in patients with infectious disease caused by multi-drug resistant bacteria.

PubMed

Einav, Sharon; Wiener-Well, Yonit

2017-06-01

Up to 50% of specific bacterial strains in healthcare admission facilities are multi-drug resistant organisms (MDROs). Involvement of anesthesiologists in management of patients carrying/at risk of carrying MDROs may decrease transmission in the Operating Room (OR). Anesthesiologists, their work area and tools have all been implicated in MDRO outbreaks. Causes include contamination of external ventilation circuits and noncontribution of filters to prevention, inappropriate decontamination procedures for nondisposable equipment (e.g. laryngoscopes, bronchoscopes and stethoscopes) and the anesthesia workplace (e.g. external surfaces of cart and anesthesia machine, telephones and computer keyboards) during OR cleaning and lack of training in sterile drug management. Discussions regarding the management of potential MDRO carriers must include anesthesia providers to optimize infection control interventions as well as the anesthesia method, the location of surgery and recovery and the details of patient transport. Anesthesia staff must learn to identify patients at risk for MDRO infection. Antibiotic prophylaxis, although not evidence based, should adhere to known best practices. Adjuvant therapies (e.g. intranasal Mupirocin and bathing with antiseptics) should be considered. Addition of nonmanual OR cleaning methods such as ultraviolet irradiation or gaseous decontamination is encouraged. Anesthesiologists must undergo formal training in sterile drug preparation and administration.

Targeted nanoparticles for enhanced X-ray radiation killing of multidrug-resistant bacteria.

PubMed

Luo, Yang; Hossain, Mainul; Wang, Chaoming; Qiao, Yong; An, Jincui; Ma, Liyuan; Su, Ming

2013-01-21

This paper describes a nanoparticle enhanced X-ray irradiation based strategy that can be used to kill multidrug resistant (MDR) bacteria. In the proof-of-concept experiment using MDR Pseudomonas aeruginosa (P. aeruginosa) as an example, polyclonal antibody modified bismuth nanoparticles are introduced into bacterial culture to specifically target P. aeruginosa. After washing off uncombined bismuth nanoparticles, the bacteria are irradiated with X-rays, using a setup that mimics a deeply buried wound in humans. Results show that up to 90% of MDR P. aeruginosa are killed in the presence of 200 μg ml(-1) bismuth nanoparticles, whereas only ∼6% are killed in the absence of bismuth nanoparticles when exposed to 40 kVp X-rays for 10 min. The 200 μg ml(-1) bismuth nanoparticles enhance localized X-ray dose by 35 times higher than the control with no nanoparticles. In addition, no significant harmful effects on human cells (HeLa and MG-63 cells) have been observed with 200 μg ml(-1) bismuth nanoparticles and 10 min 40 kVp X-ray irradiation exposures, rendering the potential for future clinical use. Since X-rays can easily penetrate human tissues, this bactericidal strategy has the potential to be used in effectively killing deeply buried MDR bacteria in vivo.

A treatment plant receiving waste water from multiple bulk drug manufacturers is a reservoir for highly multi-drug resistant integron-bearing bacteria.

PubMed

Marathe, Nachiket P; Regina, Viduthalai R; Walujkar, Sandeep A; Charan, Shakti Singh; Moore, Edward R B; Larsson, D G Joakim; Shouche, Yogesh S

2013-01-01

The arenas and detailed mechanisms for transfer of antibiotic resistance genes between environmental bacteria and pathogens are largely unclear. Selection pressures from antibiotics in situations where environmental bacteria and human pathogens meet are expected to increase the risks for such gene transfer events. We hypothesize that waste-water treatment plants (WWTPs) serving antibiotic manufacturing industries may provide such spawning grounds, given the high bacterial densities present there together with exceptionally strong and persistent selection pressures from the antibiotic-contaminated waste. Previous analyses of effluent from an Indian industrial WWTP that processes waste from bulk drug production revealed the presence of a range of drugs, including broad spectrum antibiotics at extremely high concentrations (mg/L range). In this study, we have characterized the antibiotic resistance profiles of 93 bacterial strains sampled at different stages of the treatment process from the WWTP against 39 antibiotics belonging to 12 different classes. A large majority (86%) of the strains were resistant to 20 or more antibiotics. Although there were no classically-recognized human pathogens among the 93 isolated strains, opportunistic pathogens such as Ochrobactrum intermedium, Providencia rettgeri, vancomycin resistant Enterococci (VRE), Aerococcus sp. and Citrobacter freundii were found to be highly resistant. One of the O. intermedium strains (ER1) was resistant to 36 antibiotics, while P. rettgeri (OSR3) was resistant to 35 antibiotics. Class 1 and 2 integrons were detected in 74/93 (80%) strains each, and 88/93 (95%) strains harbored at least one type of integron. The qPCR analysis of community DNA also showed an unprecedented high prevalence of integrons, suggesting that the bacteria living under such high selective pressure have an appreciable potential for genetic exchange of resistance genes via mobile gene cassettes. The present study provides insight into

Recycling antibiotics into GUMBOS: A new combination strategy to combat multi-drug resistant bacteria

USDA-ARS?s Scientific Manuscript database

The emergence of multi-drug resistant bacteria, coupled with the lack of new antibiotics in development, is fast evolving into a global crisis. New strategies utilizing existing antibacterial agents are urgently needed. We propose one such strategy in which four outmoded ß-lactam antibiotics (amp...

Multidrug resistance reversal and apoptosis induction in human colon cancer cells by some flavonoids present in citrus plants.

PubMed

Wesołowska, Olga; Wiśniewski, Jerzy; Sroda-Pomianek, Kamila; Bielawska-Pohl, Aleksandra; Paprocka, Maria; Duś, Danuta; Duarte, Noélia; Ferreira, Maria-José U; Michalak, Krystyna

2012-11-26

Multidrug resistance (MDR) of cancer cells constitutes one of the main reasons for chemotherapy failure. The search for nontoxic modulators that reduce MDR is a task of great importance. An ability to enhance apoptosis of resistant cells would also be beneficial. In the present study, the MDR reversal and apoptosis-inducing potency of three flavonoids produced by Citrus plants, namely, naringenin (1a), aromadendrin (2), and tangeretin (3), and the methylated naringenin derivatives (1b, 1c), have been studied in sensitive (LoVo) and multidrug-resistant (LoVo/Dx) human colon adenocarcinoma cells. Cytotoxicity of methoxylated flavonoids was higher as compared to hydroxylated analogues. Only 3 turned out to inhibit P-glycoprotein, as demonstrated by a rhodamine 123 accumulation assay. It also increased doxorubicin accumulation in LoVo/Dx cells and enabled doxorubicin to enter cellular nuclei. In addition, 3 was found to be an effective MDR modulator in resistant cells by sensitizing them to doxorubicin. Tangeretin-induced caspase-3 activation and elevated surface phosphatidylserine exposure demonstrated its apoptosis-inducing activity in LoVo/Dx cells, while the other flavonoids evaluated were not active. Additionally, 3 was more toxic to resistant rather than to sensitive cancer cells. Its apoptosis-inducing activity was also higher in LoVo/Dx than in LoVo cells. It was concluded that the activity of 3 against multidrug-resistant cancer cells may be enhanced by its apoptosis-inducing activity.

The drinking water treatment process as a potential source of affecting the bacterial antibiotic resistance.

PubMed

Bai, Xiaohui; Ma, Xiaolin; Xu, Fengming; Li, Jing; Zhang, Hang; Xiao, Xiang

2015-11-15

Two waterworks, with source water derived from the Huangpu or Yangtze River in Shanghai, were investigated, and the effluents were plate-screened for antibiotic-resistant bacteria (ARB) using five antibiotics: ampicillin (AMP), kanamycin (KAN), rifampicin (RFP), chloramphenicol (CM) and streptomycin (STR). The influence of water treatment procedures on the bacterial antibiotic resistance rate and the changes that bacteria underwent when exposed to the five antibiotics at concentration levels ranging from 1 to 100 μg/mL were studied. Multi-drug resistance was also analyzed using drug sensitivity tests. The results indicated that bacteria derived from water treatment plant effluent that used the Huangpu River rather than the Yangtze River as source water exhibited higher antibiotic resistance rates against AMP, STR, RFP and CM but lower antibiotic resistance rates against KAN. When the antibiotic concentration levels ranged from 1 to 10 μg/mL, the antibiotic resistance rates of the bacteria in the water increased as water treatment progressed. Biological activated carbon (BAC) filtration played a key role in increasing the antibiotic resistance rate of bacteria. Chloramine disinfection can enhance antibiotic resistance. Among the isolated ARB, 75% were resistant to multiple antibiotics. Ozone oxidation, BAC filtration and chloramine disinfection can greatly affect the relative abundance of bacteria in the community. Copyright © 2015 Elsevier B.V. All rights reserved.

Screening dietary flavonoids for the reversal of P-glycoprotein-mediated multidrug resistance in cancer

PubMed Central

Mohana, S; Ganesan, M; Agilan, B; Karthikeyan, R; Srithar, G; Beaulah Mary, R; Ananthakrishnan, D; Velmurugan, D; Rajendra Prasad, N; Ambudkar, Suresh V.

2016-01-01

P-glycoprotein (P-gp) serves as a therapeutic target for the development of inhibitors to overcome multidrug resistance in cancer cells. Although various approaches of virtual screening procedures have been practiced so far to develop first three generations of P-gp inhibitors, their toxicity and drug interaction profiles are still a matter of concern. To address the above important problem of developing safe and effective P-gp inhibitors, we have made systematic computational and experimental studies on the interaction of natural phytochemicals with human P-gp. Molecular docking and QSAR studies were carried out for 40 dietary phytochemicals in the drug-binding site of the transmembrane domains (TMDs) of P-gp. Dietary flavonoids exhibit better interactions with homology modeled human P-gp. Based on the computational analysis, selected flavonoids were tested for their inhibitory potential against P-gp transport function in drug resistant cell lines using calcein-AM and rhodamine 123 efflux assays. It has been found that quercetin and rutin were the highly desirable flavonoids for the inhibition of P-gp transport function and significantly reduced resistance in cytotoxicity assay to paclitaxel in P-gp overexpressing MDR cell lines. Hence, quercetin and rutin may be considered as potential chemosensitizing agents to overcome multidrug resistance in cancer. PMID:27216424

Screening dietary flavonoids for the reversal of P-glycoprotein-mediated multidrug resistance in cancer.

PubMed

Mohana, S; Ganesan, M; Agilan, B; Karthikeyan, R; Srithar, G; Beaulah Mary, R; Ananthakrishnan, D; Velmurugan, D; Rajendra Prasad, N; Ambudkar, Suresh V

2016-07-19

P-Glycoprotein (P-gp) serves as a therapeutic target for the development of inhibitors to overcome multidrug resistance in cancer cells. Although various screening procedures have been practiced so far to develop first three generations of P-gp inhibitors, their toxicity and drug interaction profiles are still a matter of concern. To address the above important problem of developing safe and effective P-gp inhibitors, we have made systematic computational and experimental studies on the interaction of natural phytochemicals with human P-gp. Molecular docking and QSAR studies were carried out for 40 dietary phytochemicals in the drug-binding site of the transmembrane domains (TMDs) of P-gp. Dietary flavonoids exhibit better interactions with homology modeled human P-gp. Based on the computational analysis, selected flavonoids were tested for their inhibitory potential against P-gp transport function in drug resistant cell lines using calcein-AM and rhodamine 123 efflux assays. It has been found that quercetin and rutin were the highly desirable flavonoids for the inhibition of P-gp transport function and they significantly reduced resistance in cytotoxicity assays to paclitaxel in P-gp overexpressing MDR cell lines. Hence, quercetin and rutin may be considered as potential chemosensitizing agents to overcome multidrug resistance in cancer.

Bacterial strategies of resistance to antimicrobial peptides.

PubMed

Joo, Hwang-Soo; Fu, Chih-Iung; Otto, Michael

2016-05-26

Antimicrobial peptides (AMPs) are a key component of the host's innate immune system, targeting invasive and colonizing bacteria. For successful survival and colonization of the host, bacteria have a series of mechanisms to interfere with AMP activity, and AMP resistance is intimately connected with the virulence potential of bacterial pathogens. In particular, because AMPs are considered as potential novel antimicrobial drugs, it is vital to understand bacterial AMP resistance mechanisms. This review gives a comparative overview of Gram-positive and Gram-negative bacterial strategies of resistance to various AMPs, such as repulsion or sequestration by bacterial surface structures, alteration of membrane charge or fluidity, degradation and removal by efflux pumps.This article is part of the themed issue 'Evolutionary ecology of arthropod antimicrobial peptides'. © 2016 The Author(s).

Green Tea Catechin-Based Complex Micelles Combined with Doxorubicin to Overcome Cardiotoxicity and Multidrug Resistance

PubMed Central

Cheng, Tangjian; Liu, Jinjian; Ren, Jie; Huang, Fan; Ou, Hanlin; Ding, Yuxun; Zhang, Yumin; Ma, Rujiang; An, Yingli; Liu, Jianfeng; Shi, Linqi

2016-01-01

Chemotherapy for cancer treatment has been demonstrated to cause some side effects on healthy tissues and multidrug resistance of the tumor cells, which greatly limits therapeutic efficacy. To address these limitations and achieve better therapeutic efficacy, combination therapy based on nanoparticle platforms provides a promising approach through delivering different agents simultaneously to the same destination with synergistic effect. In this study, a novel green tea catechin-based polyion complex (PIC) micelle loaded with doxorubicin (DOX) and (-)-Epigallocatechin-3-O-gallate (EGCG) was constructed through electrostatic interaction and phenylboronic acid-catechol interaction between poly(ethylene glycol)-block-poly(lysine-co-lysine-phenylboronic acid) (PEG-PLys/PBA) and EGCG. DOX was co-loaded in the PIC micelles through π-π stacking interaction with EGCG. The phenylboronic acid-catechol interaction endowed the PIC micelles with high stability under physiological condition. Moreover, acid cleavability of phenylboronic acid-catechol interaction in the micelle core has significant benefits for delivering EGCG and DOX to same destination with synergistic effects. In addition, benefiting from the oxygen free radicals scavenging activity of EGCG, combination therapy with EGCG and DOX in the micelle core could protect the cardiomyocytes from DOX-mediated cardiotoxicity according to the histopathologic analysis of hearts. Attributed to modulation of EGCG on P-glycoprotein (P-gp) activity, this kind of PIC micelles could effectively reverse multidrug resistance of cancer cells. These results suggested that EGCG based PIC micelles could effectively overcome DOX induced cardiotoxicity and multidrug resistance. PMID:27375779

Green Tea Catechin-Based Complex Micelles Combined with Doxorubicin to Overcome Cardiotoxicity and Multidrug Resistance.

PubMed

Cheng, Tangjian; Liu, Jinjian; Ren, Jie; Huang, Fan; Ou, Hanlin; Ding, Yuxun; Zhang, Yumin; Ma, Rujiang; An, Yingli; Liu, Jianfeng; Shi, Linqi

2016-01-01

Chemotherapy for cancer treatment has been demonstrated to cause some side effects on healthy tissues and multidrug resistance of the tumor cells, which greatly limits therapeutic efficacy. To address these limitations and achieve better therapeutic efficacy, combination therapy based on nanoparticle platforms provides a promising approach through delivering different agents simultaneously to the same destination with synergistic effect. In this study, a novel green tea catechin-based polyion complex (PIC) micelle loaded with doxorubicin (DOX) and (-)-Epigallocatechin-3-O-gallate (EGCG) was constructed through electrostatic interaction and phenylboronic acid-catechol interaction between poly(ethylene glycol)-block-poly(lysine-co-lysine-phenylboronic acid) (PEG-PLys/PBA) and EGCG. DOX was co-loaded in the PIC micelles through π-π stacking interaction with EGCG. The phenylboronic acid-catechol interaction endowed the PIC micelles with high stability under physiological condition. Moreover, acid cleavability of phenylboronic acid-catechol interaction in the micelle core has significant benefits for delivering EGCG and DOX to same destination with synergistic effects. In addition, benefiting from the oxygen free radicals scavenging activity of EGCG, combination therapy with EGCG and DOX in the micelle core could protect the cardiomyocytes from DOX-mediated cardiotoxicity according to the histopathologic analysis of hearts. Attributed to modulation of EGCG on P-glycoprotein (P-gp) activity, this kind of PIC micelles could effectively reverse multidrug resistance of cancer cells. These results suggested that EGCG based PIC micelles could effectively overcome DOX induced cardiotoxicity and multidrug resistance.

Diverse targeted approaches to battle multidrug resistance in cancer.

PubMed

Shankaraiah, Nagula; Nekkanti, Shalini; Ommi, Ojaswitha; Lakshmi, P S Soukya

2018-04-09

The efficacy of successful cancer therapies is frequently hindered by the development of drug resistance in the tumor. The term 'drug resistance' is used to illustrate the decreased effectiveness of a drug in curing a disease or alleviating the symptoms of the patient. This phenomenon helps tumors to survive the damage caused by a specific drug or group of drugs. In this context, studying the mechanisms of drug resistance and applying this information to design customized treatment regimens can improve therapeutic efficacy as well as the curative outcome. Over the years, numerous multidrug resistance (MDR) mechanisms have been recognized and tremendous effort has been put into developing agents to address them. The integration of data emerging from the elucidation of molecular and biochemical pathways and specific tumor-associated factors has shown tremendous promise within the oncology community for improving patient outcomes. In this review, we provide an overview of the utility of these molecular and biochemical signaling processes as well as tumor-associated factors associated with MDR, for the rational selection of cancer treatment strategies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

[Opportunistic pathogen Candida glabrata and the mechanisms of its resistance to antifungal drugs].

PubMed

Berila, N; Subík, J

2010-04-01

Treatment of not only bacterial but also fungal infections is currently a growing concern. A major reason is the acquisition of multidrug resistance in both prokaryotic and human cells. The multidrug resistance phenotype is a cellular response to the presence of cytotoxic substances in the environment. The basic mechanism of multidrug resistance is overexpression of the membrane proteins involved in the extrusion of toxic substances outside the cell. The resistance mechanism based on the efflux of inhibitors as a result of the overproduction of transport proteins was also observed in some plant and animal pathogens and human tumour cells. The phenomenon of multidrug resistance associated with an excessive and long-term use of antifungals, in particular of azole derivatives, was also confirmed in the yeast Candida glabrata which is becoming a growing concern for health care professionals. Reduced susceptibility to azole derivatives in particular, a high potential for adapting to stressors, and multiple mechanisms of resistance to structurally and functionally unrelated antifungal drugs make the species C. glabrata a potential threat to hospital patients.

An allosteric transport mechanism for the AcrAB-TolC multidrug efflux pump

PubMed Central

Wang, Zhao; Fan, Guizhen; Hryc, Corey F; Blaza, James N; Serysheva, Irina I; Schmid, Michael F; Chiu, Wah; Luisi, Ben F; Du, Dijun

2017-01-01

Bacterial efflux pumps confer multidrug resistance by transporting diverse antibiotics from the cell. In Gram-negative bacteria, some of these pumps form multi-protein assemblies that span the cell envelope. Here, we report the near-atomic resolution cryoEM structures of the Escherichia coli AcrAB-TolC multidrug efflux pump in resting and drug transport states, revealing a quaternary structural switch that allosterically couples and synchronizes initial ligand binding with channel opening. Within the transport-activated state, the channel remains open even though the pump cycles through three distinct conformations. Collectively, our data provide a dynamic mechanism for the assembly and operation of the AcrAB-TolC pump. DOI: http://dx.doi.org/10.7554/eLife.24905.001 PMID:28355133

Isolation and characterization of a bacteriophage phiEap-2 infecting multidrug resistant Enterobacter aerogenes

PubMed Central

Li, Erna; Wei, Xiao; Ma, Yanyan; Yin, Zhe; Li, Huan; Lin, Weishi; Wang, Xuesong; Li, Chao; Shen, Zhiqiang; Zhao, Ruixiang; Yang, Huiying; Jiang, Aimin; Yang, Wenhui; Yuan, Jing; Zhao, Xiangna

2016-01-01

Enterobacter aerogenes (Enterobacteriaceae) is an important opportunistic pathogen that causes hospital-acquired pneumonia, bacteremia, and urinary tract infections. Recently, multidrug-resistant E. aerogenes have been a public health problem. To develop an effective antimicrobial agent, bacteriophage phiEap-2 was isolated from sewage and its genome was sequenced because of its ability to lyse the multidrug-resistant clinical E. aerogenes strain 3-SP. Morphological observations suggested that the phage belongs to the Siphoviridae family. Comparative genome analysis revealed that phage phiEap-2 is related to the Salmonella phage FSL SP-031 (KC139518). All of the structural gene products (except capsid protein) encoded by phiEap-2 had orthologous gene products in FSL SP-031 and Serratia phage Eta (KC460990). Here, we report the complete genome sequence of phiEap-2 and major findings from the genomic analysis. Knowledge of this phage might be helpful for developing therapeutic strategies against E. aerogenes. PMID:27320081

Isolation and characterization of a bacteriophage phiEap-2 infecting multidrug resistant Enterobacter aerogenes.

PubMed

Li, Erna; Wei, Xiao; Ma, Yanyan; Yin, Zhe; Li, Huan; Lin, Weishi; Wang, Xuesong; Li, Chao; Shen, Zhiqiang; Zhao, Ruixiang; Yang, Huiying; Jiang, Aimin; Yang, Wenhui; Yuan, Jing; Zhao, Xiangna

2016-06-20

Enterobacter aerogenes (Enterobacteriaceae) is an important opportunistic pathogen that causes hospital-acquired pneumonia, bacteremia, and urinary tract infections. Recently, multidrug-resistant E. aerogenes have been a public health problem. To develop an effective antimicrobial agent, bacteriophage phiEap-2 was isolated from sewage and its genome was sequenced because of its ability to lyse the multidrug-resistant clinical E. aerogenes strain 3-SP. Morphological observations suggested that the phage belongs to the Siphoviridae family. Comparative genome analysis revealed that phage phiEap-2 is related to the Salmonella phage FSL SP-031 (KC139518). All of the structural gene products (except capsid protein) encoded by phiEap-2 had orthologous gene products in FSL SP-031 and Serratia phage Eta (KC460990). Here, we report the complete genome sequence of phiEap-2 and major findings from the genomic analysis. Knowledge of this phage might be helpful for developing therapeutic strategies against E. aerogenes.

The Incidence of Amikacin Ototoxicity in Multidrug-ResistantTuberculosis Patients

PubMed Central

Javadi, Mohammad Reza; Abtahi, Bahareh; Gholami, Kheirollah; Safari Moghadam, Behzad; Tabarsi, Payam; Salamzadeh, Jamshid

2011-01-01

Amikacin has been shown to irreversibly suppressCochlear activity.The aim of this study is to assess the incidence of amikacinototoxicity in multidrug-resistant tuberculosis patients and riskfactors associated withthis ototoxicity.In this cross-sectional study, 41 patientswith multidrug-resistant tuberculosis (MDR-TB) were included.All patients received fixed dose of intravenous amikacin(500 mg/day) and anti-TB medications for six months. Baseline Pure-Tone Audiometry (PTA) was performed on all patients,before and during the drug treatment with the frequency range between 250 Hz and 8000 Hz. Patients were closely observed for the occurrence of symptomatic ototoxicity using a questionnaire .To find an association between the incidence of cochlear damage and patients’ demographics, all patients’ data were recorded. A total of 29 patients suffered from hearing loss (70.1%) (Male: n = 18; Female: n = 20).Using logistic regression, the incidence ofamikacinototoxicity was higher in men than in women. There was a negative correlation between the duration of the amikacin treatment and the difference in hearing thresholds(r = -0.34, p = 0.03). The mean of hearing threshold was significantly increased before and after the amikacin treatment((23.68 ± 19.26 vs. 38.93 ± 22.80) (p < 0.0001)). The incidence of hearing loss was remarkable in MDR-TB patients treating with amikacin. However, risk factors’ determination and monitoring of audiometric result variations could haveinfluenced the incidence of the amikacin ototoxicity. PMID:24250429

Recent independent emergence of multiple multidrug-resistant Serratia marcescens clones within the United Kingdom and Ireland

PubMed Central

Moradigaravand, Danesh; Boinett, Christine J.; Martin, Veronique; Peacock, Sharon J.; Parkhill, Julian

2016-01-01

Serratia marcescens, a member of the Enterobacteriaceae family, is a Gram-negative bacterium responsible for a wide range of nosocomial infections. The emergence of multidrug-resistant strains is an increasing danger to public health. To design effective means to control the dissemination of S. marcescens, an in-depth analysis of the population structure and variation is required. Utilizing whole-genome sequencing, we characterized the population structure and variation, as well as the antimicrobial resistance determinants, of a systematic collection of antimicrobial-resistant S. marcescens associated with bloodstream infections in hospitals across the United Kingdom and Ireland between 2001 and 2011. Our results show that S. marcescens is a diverse species with a high level of genomic variation. However, the collection was largely composed of a limited number of clones that emerged from this diverse background within the past few decades. We identified potential recent transmissions of these clones, within and between hospitals, and showed that they have acquired antimicrobial resistance determinants for different beta-lactams, ciprofloxacin, and tetracyclines on multiple occasions. The expansion of these multidrug-resistant clones suggests that the treatment of S. marcescens infections will become increasingly difficult in the future. PMID:27432456

Role of FKS Mutations in Candida glabrata: MIC Values, Echinocandin Resistance, and Multidrug Resistance

PubMed Central

Pham, Cau D.; Iqbal, Naureen; Bolden, Carol B.; Kuykendall, Randall J.; Harrison, Lee H.; Farley, Monica M.; Schaffner, William; Beldavs, Zintars G.; Chiller, Tom M.; Park, Benjamin J.; Cleveland, Angela A.

2014-01-01

Candida glabrata is the second leading cause of candidemia in U.S. hospitals. Current guidelines suggest that an echinocandin be used as the primary therapy for the treatment of C. glabrata disease due to the high rate of resistance to fluconazole. Recent case reports indicate that C. glabrata resistance to echinocandins may be increasing. We performed susceptibility testing on 1,380 isolates of C. glabrata collected between 2008 and 2013 from four U.S. cities, Atlanta, Baltimore, Knoxville, and Portland. Our analysis showed that 3.1%, 3.3%, and 3.6% of the isolates were resistant to anidulafungin, caspofungin, and micafungin, respectively. We screened 1,032 of these isolates, including all 77 that had either a resistant or intermediate MIC value with respect to at least one echinocandin, for mutations in the hot spot regions of FKS1 and FKS2, the major mechanism of echinocandin resistance. Fifty-one isolates were identified with hot spot mutations, 16 in FKS1 and 35 in FKS2. All of the isolates with an FKS mutation except one were resistant to at least one echinocandin by susceptibility testing. Of the isolates resistant to at least one echinocandin, 36% were also resistant to fluconazole. Echinocandin resistance among U.S. C. glabrata isolates is a concern, especially in light of the fact that one-third of those isolates may be multidrug resistant. Further monitoring of U.S. C. glabrata isolates for echinocandin resistance is warranted. PMID:24890592

A simple reduction-sensitive micelles co-delivery of paclitaxel and dasatinib to overcome tumor multidrug resistance

PubMed Central

Lu, Xiao; He, Jing; Jin, Shidai

2017-01-01

Multidrug resistance (MDR) is one of the major obstacles in successful chemotherapy. The combination of chemotherapy drugs and multidrug-resistant reversing agents for treating MDR tumor is a good strategy to overcome MDR. In this work, we prepared the simple redox-responsive micelles based on mPEG-SS-C18 as a co-delivery system to load the paclitaxel (PTX) and dasatinib (DAS) for treatment of MCF-7/ADR cells. The co-loaded micelles had a good dispersity and a spherical shape with a uniform size distribution, and they could quickly disassemble and rapidly release drugs under the reduction environment. Compared with MCF-7 cells, the DAS and PTX co-loaded redox-sensitive micelle (SS-PDNPs) showed stronger cytotoxicity and a more improving intracellular drug concentration than other drug formulations in MCF-7/ADR cells. In summary, the results suggested that the simple co-delivery micelles of PTX and DAS possessed significant potential to overcome drug resistance in cancer therapy. PMID:29138561

Investigation of the Diversity of Antibiotic Resistance Genes and Mobile Genetic Elements in Salmonella associated with U.S. Food Animals

USDA-ARS?s Scientific Manuscript database

With the emergence of antibiotic resistance (AR), multidrug resistance (MDR), and carbapenem resistant Enterobacteriaceae (CRE), the specter of widespread untreatable bacterial infections threatens human and animal health. The ability of these emerging resistances to transfer between bacteria on mob...

Investigation of the diversity of antibiotic resistance genes and mobile genetic elements in Salmonella associated with U.S. food animals

USDA-ARS?s Scientific Manuscript database

With the emergence of antibiotic resistance (AR), multidrug resistance (MDR), and carbapenem resistant Enterobacteriaceae (CRE), the specter of widespread untreatable bacterial infections threatens human and animal health. The ability of these emerging resistances to transfer between bacteria on mob...

Bloodstream infections caused by multi-drug resistant Proteus mirabilis: Epidemiology, risk factors and impact of multi-drug resistance.

PubMed

Korytny, Alexander; Riesenberg, Klaris; Saidel-Odes, Lisa; Schlaeffer, Fransisc; Borer, Abraham

2016-01-01

The prevalence of antimicrobial co-resistance among ESBL-producing Enterobactereaceae is extremely high in Israel. Multidrug-resistant Proteus mirabilis strains (MDR-PM), resistant to almost all antibiotic classes have been described. The aim was to determine the risk factors for bloodstream infections caused by MDR-PM and clinical outcomes. A retrospective case-control study. Adult patients with PM bacteremia during 7 years were identified retrospectively and their files reviewed for demographics, underlying diseases, Charlson Comorbidity Index, treatment and outcome. One hundred and eighty patients with PM-bloodstream infection (BSI) were included; 90 cases with MDR-PM and 90 controls with sensitive PM (S-PM). Compared to controls, cases more frequently were from nursing homes, had recurrent hospital admissions in the past year and received antibiotic therapy in the previous 3 months, were bedridden and suffered from peripheral vascular disease and peptic ulcer disease (p < 0.001). Two-thirds of the MDR-PM isolates were ESBL-producers vs 4.4% of S-PM isolates (p < 0.001, OR = 47.6, 95% CI = 15.9-142.6). In-hospital crude mortality rate of patients with MDR-PM BSI was 37.7% vs 23.3% in those with S-PM BSI (p = 0.0359, OR = 2, 95% CI = 1.4-3.81). PM bacteremia in elderly and functionally-dependent patients is likely to be caused by nearly pan-resistant PM strains in the institution; 51.8% of the patients received inappropriate empiric antibiotic treatment. The crude mortality rate of patients with MDR-PM BSI was significantly higher than that of patients with S-PM BSI.

Contamination of the Clinical Microbiology Laboratory with Vancomycin-Resistant Enterococci and Multidrug- Resistant Enterobacteriaceae: Implications for Hospital and Laboratory Workers

PubMed Central

Collins, Susan M.; Hacek, Donna M.; Degen, Lisa A.; Wright, Marc O.; Noskin, Gary A.; Peterson, Lance R.

2001-01-01

We surveyed environmental surfaces in our clinical microbiology laboratory to determine the prevalence of vancomycin-resistant enterococci (VRE) and multidrug-resistant Enterobacteriaceae (MDRE) during a routine working day. From a total of 193 surfaces, VRE were present on 20 (10%) and MDRE were present on 4 (2%) of the surfaces tested. In a subsequent survey after routine cleaning, all of the 24 prior positive surfaces were found to be negative. Thus, those in the laboratory should recognize that many surfaces may be contaminated by resistant organisms during routine processing of patient specimens. PMID:11574615

Genomic Characterization of Nonclonal mcr-1-Positive Multidrug-Resistant Klebsiella pneumoniae from Clinical Samples in Thailand

PubMed Central

Srijan, Apichai; Ruekit, Sirigade; Snesrud, Erik; Maybank, Rosslyn; Serichantalergs, Oralak; Kormanee, Rosarin; Sukhchat, Prawet; Sriyabhaya, Jossin; Hinkle, Mary; Crawford, John M.; McGann, Patrick; Swierczewski, Brett E.

2018-01-01

Multidrug-resistant Klebsiella pneumoniae strains are one of the most prevalent causes of nosocomial infections and pose an increasingly dangerous public health threat. The lack of remaining treatment options has resulted in the utilization of older drug classes, including colistin. As a drug of last resort, the discovery of plasmid-mediated colistin resistance by mcr-1 denotes the potential development of pandrug-resistant bacterial pathogens. To address the emergence of the mcr-1 gene, 118 gram-negative Enterobacteriaceae isolated from clinical samples collected at Queen Sirikit Naval Hospital in Chonburi, Thailand were screened for colistin resistance using automated antimicrobial susceptibility testing and conventional PCR screening. Two K. pneumoniae strains, QS17-0029 and QS17-0161, were positive for mcr-1, and both isolates were sequenced to closure using short- and long-read whole-genome sequencing. QS17-0029 carried 16 antibiotic resistance genes in addition to mcr-1, including 2 carbapenemases, blaNDM-1 and blaOXA-232. QS17-0161 carried 13 antibiotic resistance genes in addition to mcr-1, including the extended-spectrum β-lactamase blaCTX-M-55. Both isolates carried multiple plasmids, but mcr-1 was located alone on highly similar 33.9 Kb IncX4 plasmids in both isolates. The IncX4 plasmid shared considerable homology to other mcr-1-containing IncX4 plasmids. This is the first report of a clinical K. pneumoniae strain from Thailand carrying mcr-1 as well as the first strain to simultaneously carry mcr-1 and multiple carbapenemase genes (QS17-0029). The identification and characterization of these isolates serves to highlight the urgent need for continued surveillance and intervention in Southeast Asia, where extensively drug-resistant pathogens are being increasingly identified in hospital-associated infections. PMID:29688801

Genomic Characterization of Nonclonal mcr-1-Positive Multidrug-Resistant Klebsiella pneumoniae from Clinical Samples in Thailand.

PubMed

Srijan, Apichai; Margulieux, Katie R; Ruekit, Sirigade; Snesrud, Erik; Maybank, Rosslyn; Serichantalergs, Oralak; Kormanee, Rosarin; Sukhchat, Prawet; Sriyabhaya, Jossin; Hinkle, Mary; Crawford, John M; McGann, Patrick; Swierczewski, Brett E

2018-05-01

Multidrug-resistant Klebsiella pneumoniae strains are one of the most prevalent causes of nosocomial infections and pose an increasingly dangerous public health threat. The lack of remaining treatment options has resulted in the utilization of older drug classes, including colistin. As a drug of last resort, the discovery of plasmid-mediated colistin resistance by mcr-1 denotes the potential development of pandrug-resistant bacterial pathogens. To address the emergence of the mcr-1 gene, 118 gram-negative Enterobacteriaceae isolated from clinical samples collected at Queen Sirikit Naval Hospital in Chonburi, Thailand were screened for colistin resistance using automated antimicrobial susceptibility testing and conventional PCR screening. Two K. pneumoniae strains, QS17-0029 and QS17-0161, were positive for mcr-1, and both isolates were sequenced to closure using short- and long-read whole-genome sequencing. QS17-0029 carried 16 antibiotic resistance genes in addition to mcr-1, including 2 carbapenemases, bla NDM-1 and bla OXA-232 . QS17-0161 carried 13 antibiotic resistance genes in addition to mcr-1, including the extended-spectrum β-lactamase bla CTX-M-55 . Both isolates carried multiple plasmids, but mcr-1 was located alone on highly similar 33.9 Kb IncX4 plasmids in both isolates. The IncX4 plasmid shared considerable homology to other mcr-1-containing IncX4 plasmids. This is the first report of a clinical K. pneumoniae strain from Thailand carrying mcr-1 as well as the first strain to simultaneously carry mcr-1 and multiple carbapenemase genes (QS17-0029). The identification and characterization of these isolates serves to highlight the urgent need for continued surveillance and intervention in Southeast Asia, where extensively drug-resistant pathogens are being increasingly identified in hospital-associated infections.

Risk Factors for Acquisition of Drug Resistance during Multidrug-Resistant Tuberculosis Treatment, Arkhangelsk Oblast, Russia, 2005–2010

PubMed Central

Ershova, Julia; Vlasova, Natalia; Nikishova, Elena; Tarasova, Irina; Eliseev, Platon; Maryandyshev, Andrey O.; Shemyakin, Igor G.; Kurbatova, Ekaterina; Cegielski, J. Peter

2015-01-01

Acquired resistance to antituberculosis drugs decreases effective treatment options and the likelihood of treatment success. We identified risk factors for acquisition of drug resistance during treatment for multidrug-resistant tuberculosis (MDR TB) and evaluated the effect on treatment outcomes. Data were collected prospectively from adults from Arkhangelsk Oblast, Russia, who had pulmonary MDR TB during 2005–2008. Acquisition of resistance to capreomycin and of extensively drug-resistant TB were more likely among patients who received <3 effective drugs than among patients who received >3 effective drugs (9.4% vs. 0% and 8.6% vs. 0.8%, respectively). Poor outcomes were more likely among patients with acquired capreomycin resistance (100% vs. 25.9%), acquired ofloxacin resistance (83.6% vs. 22.7%), or acquired extensive drug resistance (100% vs. 24.4%). To prevent acquired drug resistance and poor outcomes, baseline susceptibility to first- and second-line drugs should be determined quickly, and treatment should be adjusted to contain >3 effective drugs. PMID:25988954

Strategies to overcome or circumvent P-glycoprotein mediated multidrug resistance.

PubMed

Yuan, Hongyu; Li, Xun; Wu, Jifeng; Li, Jinpei; Qu, Xianjun; Xu, Wenfang; Tang, Wei

2008-01-01

Cancer patients who receive chemotherapy often experience intrinsic or acquired resistance to a broad spectrum of chemotherapeutic agents. The phenomenon, termed multidrug resistance (MDR), is often associated with the over-expression of P-glycoprotein, a transmembrane protein pump, which can enhance efflux of a various chemicals structurally unrelated at the expense of ATP depletion, resulting in decrease of the intracellular cytotoxic drug accumulation. The MDR has been a big threaten to the human health and the war fight for it continues. Although several other mechanisms for MDR are elucidated in recent years, considerable efforts attempting to inverse MDR are involved in exploring P-glycoprotein modulators and suppressing P-glycoprotein expression. In this review, we will report on the recent advances in various strategies for overcoming or circumventing MDR mediated by P-glycoprotein.

MRJP1-containing glycoproteins isolated from honey, a novel antibacterial drug candidate with broad spectrum activity against multi-drug resistant clinical isolates

PubMed Central

Brudzynski, Katrina; Sjaarda, Calvin; Lannigan, Robert

2015-01-01

The emergence of extended- spectrum β-lactamase (ESBL) is the underlying cause of growing antibiotic resistance among Gram-negative bacteria to β-lactam antibiotics. We recently reported the discovery of honey glycoproteins (glps) that exhibited a rapid, concentration-dependent antibacterial activity against both Gram-positive Bacillus subtilis and Gram-negative Escherichia coli that resembled action of cell wall-active β-lactam drugs. Glps showed sequence identity with the Major Royal Jelly Protein 1 (MRJP1) precursor that harbors three antimicrobial peptides: Jelleins 1, 2, and 4. Here, we used semi-quantitative radial diffusion assay and broth microdilution assay to evaluate susceptibility of a number of multi-drug resistant (MDR) clinical isolates to the MRJP1-contaning honey glycoproteins. The MDR bacterial strains comprised three methicillin-resistant Staphylococcus aureus (MRSA), four Pseudomonas aeruginosa, two Klebsiella pneumoniae, two vancomycin-resistant Enterococci (VRE), and five ESBL identified as one Proteus mirabilis, three E. coli, and one E. coli NDM. Their resistance to different classes of antibiotics was confirmed using automated system Vitek 2. MDR isolates differed in their susceptibility to glps with MIC90 values ranging from 4.8 μg/ml against B. subtilis to 14.4 μg/ml against ESBL K. pneumoniae, Klebsiella spp. ESBL and E. coli and up to 33 μg/ml against highly resistant strains of P. aeruginosa. Glps isolated from different honeys showed a similar ability to overcome bacterial resistance to β-lactams suggesting that (a) their mode of action is distinct from other classes of β-lactams and that (b) the common glps structure was the lead structure responsible for the activity. The results of the current study together with our previous evidence of a rapid bactericidal activity of glps demonstrate that glps possess suitable characteristics to be considered a novel antibacterial drug candidate. PMID:26217333

The agricultural antibiotic carbadox induces prophage and antibiotic resistance gene transfer in multidrug-resistant salmonella enterica serovar typhimurium DT104

USDA-ARS?s Scientific Manuscript database

Non-typhoidal Salmonella strains cause ~1 million cases of foodborne disease each year in the U.S. and are a leading cause of food-related deaths. The prevalence of multidrug-resistant (MDR) Salmonella serovars has increased over the last few decades, and infection with these strains has an increase...

Efficacy of surface disinfectant cleaners against emerging highly resistant gram-negative bacteria

PubMed Central

2014-01-01

Background Worldwide, the emergence of multidrug-resistant gram-negative bacteria is a clinical problem. Surface disinfectant cleaners (SDCs) that are effective against these bacteria are needed for use in high risk areas around patients and on multi-touch surfaces. We determined the efficacy of several SDCs against clinically relevant bacterial species with and without common types of multidrug resistance. Methods Bacteria species used were ATCC strains; clinical isolates classified as antibiotic-susceptible; and multi-resistant clinical isolates from Klebsiella oxytoca, Klebsiella pneumoniae, and Serratia marcescens (all OXA-48 and KPC-2); Acinetobacter baumannii (OXA-23); Pseudomonas aeruginosa (VIM-1); and Achromobacter xylosoxidans (ATCC strain). Experiments were carried out according to EN 13727:2012 in quadruplicate under dirty conditions. The five evaluated SDCs were based on alcohol and an amphoteric substance (AAS), an oxygen-releaser (OR), surface-active substances (SAS), or surface-active-substances plus aldehydes (SASA; two formulations). Bactericidal concentrations of SDCs were determined at two different contact times. Efficacy was defined as a log10 ≥ 5 reduction in bacterial cell count. Results SDCs based on AAS, OR, and SAS were effective against all six species irrespective of the degree of multi-resistance. The SASA formulations were effective against the bacteria irrespective of degree of multi-resistance except for one of the four P. aeruginosa isolates (VIM-1). We found no general correlation between SDC efficacy and degree of antibiotic resistance. Conclusions SDCs were generally effective against gram-negative bacteria with and without multidrug resistance. SDCs are therefore suitable for surface disinfection in the immediate proximity of patients. Single bacterial isolates, however, might have reduced susceptibility to selected biocidal agents. PMID:24885029

Fecal Microbiota Transfer for Multidrug-Resistant Gram-Negatives: A Clinical Success Combined With Microbiological Failure.

PubMed

Stalenhoef, Janneke E; Terveer, Elisabeth M; Knetsch, Cornelis W; Van't Hof, Peter J; Vlasveld, Imro N; Keller, Josbert J; Visser, Leo G; Kuijper, Eduard J

2017-01-01

Combined fecal microbiota transfer and antibiotic treatment prevented recurrences of urinary tract infections with multidrug-resistant (MDR) Pseudomonas aeruginosa , but it failed to eradicate intestinal colonization with MDR Escherichia coli . Based on microbiota analysis, failure was not associated with distinct diminished microbiota diversity.

Drug Resistance and Gene Transfer Mechanisms in Respiratory/Oral Bacteria.

PubMed

Jiang, S; Zeng, J; Zhou, X; Li, Y

2018-06-01

Growing evidence suggests the existence of new antibiotic resistance mechanisms. Recent studies have revealed that quorum-quenching enzymes, such as MacQ, are involved in both antibiotic resistance and cell-cell communication. Furthermore, some small bacterial regulatory RNAs, classified into RNA attenuators and small RNAs, modulate the expression of resistance genes. For example, small RNA sprX, can shape bacterial resistance to glycopeptide antibiotics via specific downregulation of protein SpoVG. Moreover, some bacterial lipocalins capture antibiotics in the extracellular space, contributing to severe multidrug resistance. But this defense mechanism may be influenced by Agr-regulated toxins and liposoluble vitamins. Outer membrane porin proteins and efflux pumps can influence intracellular concentrations of antibiotics. Alterations in target enzymes or antibiotics prevent binding to targets, which act to confer high levels of resistance in respiratory/oral bacteria. As described recently, horizontal gene transfer, including conjugation, transduction and transformation, is common in respiratory/oral microflora. Many conjugative transposons and plasmids discovered to date encode antibiotic resistance proteins and can be transferred from donor bacteria to transient recipient bacteria. New classes of mobile genetic elements are also being identified. For example, nucleic acids that circulate in the bloodstream (circulating nucleic acids) can integrate into the host cell genome by up-regulation of DNA damage and repair pathways. With multidrug resistant bacteria on the rise, new drugs have been developed to combate bacterial antibiotic resistance, such as innate defense regulators, reactive oxygen species and microbial volatile compounds. This review summaries various aspects and mechanisms of antibiotic resistance in the respiratory/oral microbiota. A better understanding of these mechanisms will facilitate minimization of the emergence of antibiotic resistance.

Amide side chain amphiphilic polymers disrupt surface established bacterial bio-films and protect mice from chronic Acinetobacter baumannii infection.

PubMed

Uppu, Divakara S S M; Samaddar, Sandip; Ghosh, Chandradhish; Paramanandham, Krishnamoorthy; Shome, Bibek R; Haldar, Jayanta

2016-01-01

Bacterial biofilms represent the root-cause of chronic or persistent infections in humans. Gram-negative bacterial infections due to nosocomial and opportunistic pathogens such as Acinetobacter baumannii are more difficult to treat because of their inherent and rapidly acquiring resistance to antibiotics. Due to biofilm formation, A. baumannii has been noted for its apparent ability to survive on artificial surfaces for an extended period of time, therefore allowing it to persist in the hospital environment. Here we report, maleic anhydride based novel cationic polymers appended with amide side chains that disrupt surface established multi-drug resistant A. baumannii biofilms. More importantly, these polymers significantly (p < 0.0001) decrease the bacterial burden in mice with chronic A. baumannii burn wound infection. The polymers also show potent antibacterial efficacy against methicillin resistant Staphylococcus aureus (MRSA), vancomycin resistant Enterococci (VRE) and multi-drug resistant clinical isolates of A. baumannii with minimal toxicity to mammalian cells. We observe that optimal hydrophobicity dependent on the side chain chemical structure of these polymers dictate the selective toxicity to bacteria. Polymers interact with the bacterial cell membranes by causing membrane depolarization, permeabilization and energy depletion. Bacteria develop rapid resistance to erythromycin and colistin whereas no detectable development of resistance occurs against these polymers even after several passages. These results suggest the potential use of these polymeric biomaterials in disinfecting biomedical device surfaces after the infection has become established and also for the topical treatment of chronic bacterial infections. Copyright © 2015 Elsevier Ltd. All rights reserved.

Multidrug Resistance Proteins (MRPs/ABCCs) in Cancer Chemotherapy and Genetic Diseases

PubMed Central

Chen, Zhe-Sheng; Tiwari, Amit K.

2011-01-01

The ATP-binding cassette (ABC) transporters are a superfamily of membrane proteins that are best known for their ability to transport a wide variety of exogenous and endogenous substances across membranes against a concentration gradient via ATP hydrolysis. There are seven subfamilies of human ABC transporters, one of the largest being the ‘C’ subfamily (gene symbol ABCC). Nine ABCC subfamily members, the so-called Multidrug Resistance Proteins (MRPs) 1-9, have been implicated in mediating multidrug resistance in tumor cells to varying degrees as the efflux extrude chemotherapeutic compounds (or their metabolites) from malignant cells. Some of the MRPs are also known to either influence drug disposition in normal tissues or modulate the elimination of drugs (or their metabolites) via hepatobiliary or renal excretory pathways. In addition, the cellular efflux of physiologically important organic anions such as leukotriene C4 and cAMP is mediated by one or more of the MRPs. Finally, mutations in several MRPs are associated with human genetic disorders. In this review article, the current biochemical and physiological knowledge of MRP1-MRP9 in cancer chemotherapy and human genetic disease is summarized. The mutations in MRP2/ABCC2 leading to conjugated hyperbilirubinemia (Dubin-Johnson syndrome) and in MRP6/ABCC6 leading to the connective tissue disorder Pseudoxanthoma elasticum are also discussed. PMID:21740521

The prevention and management of infections due to multidrug resistant organisms in haematology patients

PubMed Central

Trubiano, Jason A; Worth, Leon J; Thursky, Karin A; Slavin, Monica A

2015-01-01

Infections due to resistant and multidrug resistant (MDR) organisms in haematology patients and haematopoietic stem cell transplant recipients are an increasingly complex problem of global concern. We outline the burden of illness and epidemiology of resistant organisms such as gram-negative pathogens, vancomycin-resistant Enterococcus faecium (VRE), and Clostridium difficile in haematology cohorts. Intervention strategies aimed at reducing the impact of these organisms are reviewed: infection prevention programmes, screening and fluoroquinolone prophylaxis. The role of newer therapies (e.g. linezolid, daptomycin and tigecycline) for treatment of resistant and MDR organisms in haematology populations is evaluated, in addition to the mobilization of older agents (e.g. colistin, pristinamycin and fosfomycin) and the potential benefit of combination regimens. PMID:24341410

The prevalence and clinical features of multi-drug resistant Salmonella typhi infections in Baluchistan, Pakistan.

PubMed

Mirza, S H; Beeching, N J; Hart, C A

1995-10-01

Between January and July 1994, a prospective study of bacteraemia in 692 patients with fever without localizing signs was undertaken at the Quetta Military Hospital in Baluchistan, Pakistan. Salmonella spp. were isolated from 76 (11%) of the patients; 62 had S. typhi and 14 had S. paratyphi A. Significantly more isolations of S. typhi were made in the hot dry months of May and June than in the earlier months. Although multi-drug resistance (to chloramphenicol ampicillin and cotrimoxazole) was detected in 43 (69%) of the S. typhi isolates, it was not found in any of the S. paratyphi A. Defervescence of patients with chloramphenicol-sensitive S. typhi took 7-10 days of chloramphenicol therapy. In contrast, most (91%) of the patients infected with multi-drug resistant S. typhi who were treated with fluoroquinolones achieved defervescence in 1-3 days; the remainder took 4-6 days.

Bacterial cheating limits antibiotic resistance

NASA Astrophysics Data System (ADS)

Xiao Chao, Hui; Yurtsev, Eugene; Datta, Manoshi; Artemova, Tanya; Gore, Jeff

2012-02-01

The widespread use of antibiotics has led to the evolution of resistance in bacteria. Bacteria can gain resistance to the antibiotic ampicillin by acquiring a plasmid carrying the gene beta-lactamase, which inactivates the antibiotic. This inactivation may represent a cooperative behavior, as the entire bacterial population benefits from removing the antibiotic. The cooperative nature of this growth suggests that a cheater strain---which does not contribute to breaking down the antibiotic---may be able to take advantage of cells cooperatively inactivating the antibiotic. Here we find experimentally that a ``sensitive'' bacterial strain lacking the plasmid conferring resistance can invade a population of resistant bacteria, even in antibiotic concentrations that should kill the sensitive strain. We observe stable coexistence between the two strains and find that a simple model successfully explains the behavior as a function of antibiotic concentration and cell density. We anticipate that our results will provide insight into the evolutionary origin of phenotypic diversity and cooperative behaviors.

Complete genome sequence of new bacteriophage phiE142, which causes simultaneously lysis of multidrug-resistant Escherichia coli O157:H7 and Salmonella enterica.

PubMed

Amarillas, Luis; Chaidez, Cristobal; González-Robles, Arturo; León-Félix, Josefina

2016-01-01

The emergence of antibiotic-resistant foodborne bacteria is a global health problem that requires immediate attention. Bacteriophages are a promising biotechnological alternative approach against bacterial pathogens. However, a detailed analysis of phage genomes is essential to assess the safety of the phages prior to their use as biocontrol agents. Therefore, here we report the complete genome sequence of bacteriophage phiE142, which is able to lyse Salmonella and multidrug-resistant Escherichia coli O157:H7 strains. Bacteriophage phiE142 belongs to the Myoviridae family due to the presence of long non-flexible tail and icosahedral head. The genome is composed of 121,442 bp and contains 194 ORFs, and 2 tRNAs. Furthermore, the phiE142 genome does not contain any genes coding for food-borne allergens, antibiotics resistance, virulence factors, or associated with lysogenic conversion. The bacteriophage phiE142 is characterized by broad host range and compelling genetic attributes making them potential candidates as a biocontrol agent.

Evaluation of the Bactericidal Activity of Plazomicin and Comparators against Multidrug-resistant Enterobacteriaceae.

PubMed

Thwaites, M; Hall, D; Shinabarger, D; Serio, A W; Krause, K M; Marra, A; Pillar, C

2018-06-04

The next-generation aminoglycoside plazomicin, in development for infections due to multi-drug resistant (MDR) Enterobacteriaceae, was evaluated alongside comparators for bactericidal activity in minimum bactericidal concentration (MBC) and time-kill (TK) assays against MDR Enterobacteriaceae isolates with characterized aminoglycoside and β-lactam resistance mechanisms. Overall, plazomicin and colistin were the most potent, with plazomicin demonstrating an MBC 50/90 of 0.5/4 μg/mL and sustained 3-log 10 kill against MDR Escherichia coli , Klebsiella pneumoniae and Enterobacter spp. Copyright © 2018 Thwaites et al.

Multidrug-resistant tuberculosis (MDR-TB) in India: an attempt to link biosocial determinants.

PubMed

Atre, Sachin R; Mistry, Nerges F

2005-04-01

Multidrug-resistant tuberculosis (MDR-TB) has emerged as a possible threat to global tuberculosis control efforts in recent years. It is a challenge not only from a public health point of view but also in the context of global economy, especially in the absence of treatment for MDR-TB at national-level programs in developing countries. Biological accounts are insufficient to understand the emergence and dynamics of drug resistance. This article focuses essentially on the need for a holistic perspective, linking biosocial determinants that would probably lead to better insights into MDR-TB control strategies.

Multidrug resistance characterization in multicellular tumour spheroids from two human lung cancer cell lines.

PubMed

Barrera-Rodríguez, Raúl; Fuentes, Jorge Morales

2015-01-01

Most of the knowledge about the mechanisms of multidrug resistance in lung cancer has been achieved through the use of cell lines isolated from tumours cultivated either in suspensions of isolated cells or in monolayers and following exposition to different cytostatic agents. However, tumour cell lines growing as multicellular tumour spheroids (MTS) frequently develop multicellular resistance in a drug-independent form. The aim of this study was to characterize the phenotypic and functional differences between two human NSCLC cell lines (INER-37 and INER-51) grown as traditional monolayer cultures versus as MTS. After 72 hours treatment with anticancer drugs, chemosensitivity in monolayers and tumour spheroids cultures was assessed using MTT assay. Reverse transcription-polymerase chain reaction was employed to detect the mRNAs of multidrug resistance-related genes. The expression of P-gp was analyzed by immunohistochemical staining and cell cycle profiles were analyzed using FACS. The results indicate that when grown as MTS each lung cancer cell line had different morphologies as well as and abrogation of cell proliferation with decrease of the G2/M phase. Also, MTS acquired multicellular resistance to several chemotherapeutic agents in only a few days of culture which were accomplished by significant changes in the expression of MDR-related genes. Overall, the MTS culture changed the cellular response to drugs nevertheless each of the cell lines studied seems to implement different mechanisms to acquire multicellular resistance.

Omega 3 fatty acids chemosensitize multidrug resistant colon cancer cells by down-regulating cholesterol synthesis and altering detergent resistant membranes composition