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Tony Velkov - One of the best experts on this subject based on the ideXlab platform.
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Mechanisms of Polymyxin-Induced Nephrotoxicity.
Advances in experimental medicine and biology, 2019Co-Authors: Mohammad A K Azad, Roger L Nation, Tony VelkovAbstract:Polymyxin-induced nephrotoxicity is the major dose-limiting factor and can occur in up to 60% of patients after intravenous administration. This chapter reviews the latest literature on the mechanisms of Polymyxin-induced nephrotoxicity and its amelioration. After filtration by glomeruli, Polymyxins substantially accumulate in renal proximal tubules via receptor-mediated endocytosis mainly by megalin and PEPT2. It is believed that subsequently, a cascade of interconnected events occur, including the activation of death receptor and mitochondrial apoptotic pathways, mitochondrial damage, endoplasmic reticulum stress, oxidative stress and cell cycle arrest. The current literature shows that oxidative stress plays a key role in Polymyxin-induced kidney damage. Use of antioxidants have a potential in the attenuation of Polymyxin-induced nephrotoxicity, thereby widening the therapeutic window. Mechanistic findings on Polymyxin-induced nephrotoxicity are critical for the optimization of their use in the clinic and the discovery of safer Polymyxin-like antibiotics.
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comparative metabolomics and transcriptomics reveal multiple pathways associated with Polymyxin killing in pseudomonas aeruginosa
mSystems, 2019Co-Authors: Meiling Han, Darren J Creek, Yan Zhu, Yuwei Lin, Alina D Gutu, Paul J Hertzog, Tony Purcell, Hsinhui Shen, Samuel M Moskowitz, Tony VelkovAbstract:ABSTRACT Polymyxins are a last-line therapy against multidrug-resistant Pseudomonas aeruginosa; however, resistance to Polymyxins has been increasingly reported. Therefore, understanding the mechanisms of Polymyxin activity and resistance is crucial for preserving their clinical usefulness. This study employed comparative metabolomics and transcriptomics to investigate the responses of Polymyxin-susceptible P. aeruginosa PAK (Polymyxin B MIC, 1 mg/liter) and its Polymyxin-resistant pmrB mutant PAKpmrB6 (MIC, 16 mg/liter) to Polymyxin B (4, 8, and 128 mg/liter) at 1, 4, and 24 h, respectively. Our results revealed that Polymyxin B at 4 mg/liter induced different metabolic and transcriptomic responses between Polymyxin-susceptible and -resistant P. aeruginosa. In strain PAK, Polymyxin B significantly activated PmrAB and the mediated arn operon, leading to increased 4-amino-4-deoxy-L-arabinose (L-Ara4N) synthesis and the addition to lipid A. In contrast, Polymyxin B did not increase lipid A modification in strain PAKpmrB6. Moreover, the syntheses of lipopolysaccharide and peptidoglycan were significantly decreased in strain PAK but increased in strain PAKpmrB6 due to Polymyxin B treatment. In addition, 4 mg/liter Polymyxin B significantly perturbed phospholipid and fatty acid levels and induced oxidative stress in strain PAK, but not in PAKpmrB6. Notably, the increased trehalose-6-phosphate levels indicate that Polymyxin B potentially caused osmotic imbalance in both strains. Furthermore, 8 and 128 mg/liter Polymyxin B significantly elevated lipoamino acid levels and decreased phospholipid levels but without dramatic changes in lipid A modification in wild-type and mutant strains, respectively. Overall, this systems study is the first to elucidate the complex and dynamic interactions of multiple cellular pathways associated with the Polymyxin mode of action against P. aeruginosa. IMPORTANCEPseudomonas aeruginosa has been highlighted by the recent WHO Global Priority Pathogen List due to multidrug resistance. Without new antibiotics, Polymyxins remain a last-line therapeutic option for this difficult-to-treat pathogen. The emergence of Polymyxin resistance highlights the growing threat to our already very limited antibiotic armamentarium and the urgency to understand the exact mechanisms of Polymyxin activity and resistance. Integration of the correlative metabolomics and transcriptomics results in the present study discovered that Polymyxin treatment caused significant perturbations in the biosynthesis of lipids, lipopolysaccharide, and peptidoglycan, central carbon metabolism, and oxidative stress. Importantly, lipid A modifications were surprisingly rapid in response to Polymyxin treatment at clinically relevant concentrations. This is the first study to reveal the dynamics of Polymyxin-induced cellular responses at the systems level, which highlights that combination therapy should be considered to minimize resistance to the last-line Polymyxins. The results also provide much-needed mechanistic information which potentially benefits the discovery of new-generation Polymyxins.
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discovery of novel Polymyxin like antibiotics
Advances in Experimental Medicine and Biology, 2019Co-Authors: Tony Velkov, Kade D RobertsAbstract:The antimicrobial lipopeptides Polymyxin B and colistin (Polymyxin E) are used as a ‘last-line’ therapy for infections caused by multidrug-resistant (MDR) Gram-negative pathogens. However, their effective use as antibiotic drugs in the clinical setting is still plagued by significant toxicity issues, in particular their potential for nephrotoxicity. Furthermore, resistance to the Polymyxins has begun to emerge in the clinic, which implies a total lack of antibiotics for the treatment of life-threatening infections caused by the Gram-negative ‘superbugs’. This chapter details our current understanding of Polymyxin structure-activity relationships as well as recent pre-clinical and clinical drug development efforts aimed at generating new Polymyxin antibiotics with improved safety and efficacy.
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The rise and spread of mcr plasmid-mediated Polymyxin resistance
2019Co-Authors: Sue C. Nang, Tony VelkovAbstract:Polymyxins are important lipopeptide antibiotics that serve as the last-line defense against multidrug-resistant (MDR) Gram-negative bacterial infections. Worryingly, the clinical utility of Polymyxins is currently facing a serious threat with the global dissemination of mcr, plasmid-mediated Polymyxin resistance. The first plasmid-mediated Polymyxin resistance gene, termed as mcr-1 was identified in China in November 2015. Following its discovery, isolates carrying mcr, mainly mcr-1 and less commonly mcr-2 to -7, have been reported across Asia, Africa, Europe, North America, South America and Oceania. This review covers the epidemiological, microbiological and genomics aspects of this emerging threat to global human health. The mcr has been identified in various species of Gram-negative bacteria including Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Salmonella enterica, Cronobacter sakazakii, Kluyvera ascorbata, Shigella sonnei, Citrobacter freundii, Citrobacter braakii, Raoultella ornithinolytica, Proteus mirabilis, Aeromonas, Moraxella and Enterobacter species from animal, meat, food product, environment and human sources. More alarmingly is the detection of mcr in extended-spectrum-β-lactamases- and carbapenemases-producing bacteria. The mcr can be carried by different plasmids, demonstrating the high diversity of mcr plasmid reservoirs. Our review analyses the current knowledge on the emergence of mcr-mediated Polymyxin resistance.
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Intracellular localization of Polymyxins in human alveolar epithelial cells
The Journal of antimicrobial chemotherapy, 2019Co-Authors: Maizbha Uddin Ahmed, Tony Velkov, Fanfan Zhou, Qi Tony Zhou, Kim H Chan, Alex J. Fulcher, Judy M. Callaghan, Mohammad A K AzadAbstract:Background Current inhaled Polymyxin therapy is empirical and often large doses are administered, which can lead to pulmonary adverse effects. There is a dearth of information on the mechanisms of Polymyxin-induced lung toxicity and their intracellular localization in lung epithelial cells. Objectives To investigate the intracellular localization of Polymyxins in human lung epithelial A549 cells. Methods A549 cells were treated with Polymyxin B and intracellular organelles (early and late endosomes, endoplasmic reticulum, mitochondria, lysosomes and autophagosomes), ubiquitin protein and Polymyxin B were visualized using immunostaining and confocal microscopy. Fluorescence intensities of the organelles and Polymyxin B were quantified and correlated for co-localization using ImageJ and Imaris platforms. Results Polymyxin B co-localized with early endosomes, lysosomes and ubiquitin at 24 h. Significantly increased lysosomal activity and the autophagic protein LC3A were observed after 0.5 and 1.0 mM Polymyxin B treatment at 24 h. Polymyxin B also significantly co-localized with mitochondria (Pearson's R = 0.45) and led to the alteration of mitochondrial morphology from filamentous to fragmented form (n = 3, P
Roger L Nation - One of the best experts on this subject based on the ideXlab platform.
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Agents of Last Resort: An Update on Polymyxin Resistance.
Infectious disease clinics of North America, 2020Co-Authors: Qiwen Yang, Roger L Nation, Jason M. Pogue, Keith S. KayeAbstract:Polymyxin resistance is a major public health threat, because the Polymyxins represent last-line therapeutics for gram-negative pathogens resistant to essentially all other antibiotics. Minimizing any potential emergence and dissemination of Polymyxin resistance relies on an improved understanding of mechanisms of and risk factors for Polymyxin resistance, infection prevention and stewardship strategies, together with optimization of dosing of Polymyxins (eg, combination regimens).
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Mechanisms of Polymyxin-Induced Nephrotoxicity.
Advances in experimental medicine and biology, 2019Co-Authors: Mohammad A K Azad, Roger L Nation, Tony VelkovAbstract:Polymyxin-induced nephrotoxicity is the major dose-limiting factor and can occur in up to 60% of patients after intravenous administration. This chapter reviews the latest literature on the mechanisms of Polymyxin-induced nephrotoxicity and its amelioration. After filtration by glomeruli, Polymyxins substantially accumulate in renal proximal tubules via receptor-mediated endocytosis mainly by megalin and PEPT2. It is believed that subsequently, a cascade of interconnected events occur, including the activation of death receptor and mitochondrial apoptotic pathways, mitochondrial damage, endoplasmic reticulum stress, oxidative stress and cell cycle arrest. The current literature shows that oxidative stress plays a key role in Polymyxin-induced kidney damage. Use of antioxidants have a potential in the attenuation of Polymyxin-induced nephrotoxicity, thereby widening the therapeutic window. Mechanistic findings on Polymyxin-induced nephrotoxicity are critical for the optimization of their use in the clinic and the discovery of safer Polymyxin-like antibiotics.
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Mechanism of the Antibacterial Activity and Resistance of Polymyxins
Antimicrobial Drug Resistance, 2017Co-Authors: Matthew D. Johnson, Roger L NationAbstract:Discovered in the 1940s, Polymyxins are antimicrobial peptides produced by the Gram-positive soil bacterium, Paenibacillus polymyxa, which biosynthesizes Polymyxins using non-ribosomal peptide synthetase enzymes [1–3]. Polymyxin B and E (Polymyxin E was originally named colistin but was determined to have an identical structure) were used clinically in the late 1950s against Gram-negative bacterial infections [4, 5]. However, nephrotoxic and neurotoxic effects of Polymyxin treatment became evident, causing a decline in the use of the Polymyxins in the 1970s [6]. Soon, newer antibiotics, such as the aminoglycosides, replaced Polymyxins in the clinic. However, since the early 2000s the emergence of multidrug-resistant (MDR) Gram-negative organisms, combined with a lack of novel antimicrobial agents, has led to the resurgence of interest in Polymyxins as a last-line treatment ([7–10]; Nation and Li 2009).
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high dose ampicillin sulbactam combinations combat Polymyxin resistant acinetobacter baumannii in a hollow fiber infection model
Antimicrobial Agents and Chemotherapy, 2017Co-Authors: Zackery P Bulman, Jürgen B. Bulitta, Roger L Nation, Jian Li, Visanu Thamlikitkul, Justin R Lenhard, Nicholas M Smith, Beom Soo Shin, Brian T. TsujiAbstract:Acinetobacter baumannii is emerging with resistance to Polymyxins. In 24-h time-kill experiments, high-dose ampicillin-sulbactam in combination with meropenem and Polymyxin B achieved additivity or synergy against 108 CFU/ml of two clinical A. baumannii isolates resistant to all three drugs (maximum reductions, 1.6 and 3.1 logs). In a 14-day hollow-fiber infection model, high-dose ampicillin-sulbactam (8/4 g every 8 h, respectively) in combination with meropenem (2 g every 8 h) and Polymyxin B (1.43 mg/kg of body weight every 12 h with loading dose) resulted in rapid (96 h) eradication of A. baumannii.
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Nephrotoxicity of Polymyxins: Is There Any Difference between Colistimethate and Polymyxin B?
Antimicrobial agents and chemotherapy, 2017Co-Authors: Alexandre P. Zavascki, Roger L NationAbstract:ABSTRACT Nephrotoxicity is a common adverse effect of the clinically used Polymyxins, colistin and Polymyxin B. This adverse effect is dose limiting for both Polymyxins, as the plasma Polymyxin concentrations associated with renal damage overlap those required for antibacterial effect. Since development of acute kidney injury (AKI) during therapy is highly undesirable, it is extremely important to know whether there is any difference between the nephrotoxic potential of colistin (administered as its inefficient prodrug, colistimethate) and Polymyxin B (administered as the active form). Both Polymyxins are cytotoxic to renal tubular cells and are prone to cause nephrotoxicity in vivo because of the renal handling mechanisms that facilitate accumulation of these compounds in these cells, processes that are reviewed in this article. Also reviewed are the emerging data that strongly suggest significantly higher rates of AKI in patients treated with colistimethate compared to patients treated with Polymyxin B. This finding may be due to differences in pharmacokinetics and renal handling mechanisms of colistimethate and formed colistin versus Polymyxin B, and consequently the relative amount of Polymyxin material delivered to tubular cells. A lower risk of AKI with Polymyxin B is one of several potential advantages over colistimethate. The relative safety and efficacy of the two agents require closer examination in well-designed clinical studies.
Matthew E Falagas - One of the best experts on this subject based on the ideXlab platform.
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the safety of Polymyxin antibiotics
Expert Opinion on Drug Safety, 2015Co-Authors: Theodoros Kelesidis, Matthew E FalagasAbstract:Introduction: The emergence of multidrug-resistant gram-negative bacteria has led to the increasing use of Polymyxins. Nephrotoxicity and, to a lesser degree, neurotoxicity occur often during systemic Polymyxin therapy. Scientific evidence regarding safety associated with Polymyxins remains limited.Areas covered: Case reports/case series, observational studies and clinical trials assessing safety and toxicity of Polymyxins were critically reviewed.Expert opinion: Polymyxins are drugs with a narrow therapeutic range. Nephrotoxicity is associated with both host factors and Polymyxin exposure, and recent studies suggest that the relative risk of nephrotoxicity is similar for colistin and Polymyxin B. Studies that have examined the safety of Polymyxins have several limitations. Considering the available evidence, toxicities that may develop while on Polymyxin therapy most often are mild to moderate in magnitude and reversible in nature. Strategies to minimize toxicity associated with Polymyxins have evolved a...
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Resistance to Polymyxins: Mechanisms, frequency and treatment options.
Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy, 2010Co-Authors: Matthew E Falagas, Petros I Rafailidis, Dimitrios K MatthaiouAbstract:Polymyxins act by binding to lipid A moiety of the bacterial lipopolysaccharide and subsequently disintegrating the bacterial membranes. The most important mechanism of resistance includes modifications of the bacterial outer membrane structure, including lipopolysaccharide. Lipopolysaccharide modification is mostly mediated by PmrA/PmrB and PhoP/PhoQ two-component regulatory systems. These mechanisms exist with some differences in many gram-negative bacterial species. Resistance to Polymyxins is generally less than 10%. In specific regions, such as the Mediterranean basin, Korea and Singapore, they tend to be higher. Heteroresistance to Polymyxins is associated with exposure to Polymyxins and especially suboptimal therapeutic dosage. Polymyxin combination regimens, tigecycline and fosfomycin may be useful options for the treatment of Polymyxin-resistant gram-negative infections.
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Polymyxin B: similarities to and differences from colistin (Polymyxin E).
Expert review of anti-infective therapy, 2007Co-Authors: Andrea L. Kwa, Vincent H Tam, Sofia K Kasiakou, Matthew E FalagasAbstract:Hospital-acquired infections due to multidrug-resistant gram-negative bacteria constitute major health problems, since the medical community is continuously running out of available effective antibiotics and no new agents are in the pipeline. Polymyxins, a group of antibacterials that were discovered during the late 1940s, represent some of the last treatment options for these infections. Only two Polymyxins are available commercially, Polymyxin E (colistin) and Polymyxin B. Although several reviews have been published recently regarding colistin, no review has focused on the similarities and differences between Polymyxin B and colistin. These two medications have many similarities with respect to mechanism of action, antimicrobial spectrum, clinical uses and toxicity. However, they also differ in several aspects, including chemical structure, formulation, potency, dosage and pharmacokinetic properties.
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colistin the revival of Polymyxins for the management of multidrug resistant gram negative bacterial infections
Clinical Infectious Diseases, 2005Co-Authors: Matthew E Falagas, Sofia K Kasiakou, Louis D SaravolatzAbstract:The emergence of multidrug-resistant gram-negative bacteria and the lack of new antibiotics to combat them have led to the revival of Polymyxins, an old class of cationic, cyclic polypeptide antibiotics. Polymyxin B and Polymyxin E (colistin) are the 2 Polymyxins used in clinical practice. Most of the reintroduction of Polymyxins during the last few years is related to colistin. The Polymyxins are active against selected gram-negative bacteria, including Acinetobacter species, Pseudomonas aeruginosa, Klebsiella species, and Enterobacter species. These drugs have been used extensively worldwide for decades for local use. However, parenteral use of these drugs was abandoned approximately 20 years ago in most countries, except for treatment of patients with cystic fibrosis, because of reports of common and serious nephrotoxicity and neurotoxicity. Recent studies of patients who received intravenous Polymyxins for the treatment of serious P. aeruginosa and Acinetobacter baumannii infections of various types, including pneumonia, bacteremia, and urinary tract infections, have led to the conclusion that these antibiotics have acceptable effectiveness and considerably less toxicity than was reported in old studies.
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toxicity after prolonged more than four weeks administration of intravenous colistin
BMC Infectious Diseases, 2005Co-Authors: Matthew E Falagas, Sofia K Kasiakou, Michael Rizos, Ioannis A Bliziotis, Kostas Rellos, Argyris MichalopoulosAbstract:Background The intravenous use of Polymyxins has been considered to be associated with considerable nephrotoxicity and neurotoxicity. For this reason, the systemic administration of Polymyxins had been abandoned for about 20 years in most areas of the world. However, the problem of infections due to multidrug-resistant (MDR) Gram-negative bacteria such us Pseudomonas aeruginosa and Acinetobacter baumanniii has led to the re-use of Polymyxins. Our objective was to study the toxicity of prolonged intravenous administration of colistin (Polymyxin E).
Ronald N Jones - One of the best experts on this subject based on the ideXlab platform.
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Polymyxin susceptibility testing and interpretive breakpoints recommendations from the united states committee on antimicrobial susceptibility testing uscast
Antimicrobial Agents and Chemotherapy, 2019Co-Authors: Jason M. Pogue, Michael N Dudley, Ronald N Jones, John S Bradley, David R Andes, Sujata M Bhavnani, George L Drusano, Robert K Flamm, Keith A Rodvold, Paul G AmbroseAbstract:The Polymyxins are important agents for carbapenem-resistant Gram-negative bacilli. The United States Committee on Antimicrobial Susceptibility Testing breakpoint recommendations for colistin and Polymyxin B are that isolates of Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacteriaceae are considered susceptible at MIC values of ≤2 mg/liter. These recommendations are contingent upon dosing and testing strategies that are described in this commentary. Importantly, these recommendations are not applicable to lower respiratory tract infections, for which we recommend no breakpoints. Furthermore, there is no breakpoint recommendation for Polymyxin B for lower urinary tract infections.
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use of a surfactant polysorbate 80 to improve mic susceptibility testing results for Polymyxin b and colistin
Diagnostic Microbiology and Infectious Disease, 2012Co-Authors: Helio S Sader, Robert K Flamm, Paul R Rhomberg, Ronald N JonesAbstract:Abstract Accurate determination of in vitro activity for Polymyxin class agents has consistently been a problem due to their physical–chemical characteristics that can be influenced by the constituents of reference and/or standardized susceptibility testing methods. We evaluated the impact of using polysorbate 80 (P-80), a surfactant, in reference broth microdilution (BMD) methods when testing Polymyxin B and colistin against 247 clinical strains of Enterobacteriaceae (124 strains), Acinetobacter spp. (60 strains), and Pseudomonas aeruginosa (63 strains). All testing was performed in frozen-form BMD panels with and without 0.002% P-80. MIC results for both Polymyxins were generally 4- to 8-fold lower when P-80 was added to the testing broth compared to Mueller-Hinton broth without the surfactant. Decreases were greatest in organisms having MIC values at ≤2 μg/mL and among Acinetobacter spp. Polymyxins should be tested with P-80 to more accurately assess the potencies of these agents necessary to treat multidrug-resistant Gram-negative bacilli.
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contemporary assessment of antimicrobial susceptibility testing methods for Polymyxin b and colistin review of available interpretative criteria and quality control guidelines
Journal of Clinical Microbiology, 2001Co-Authors: Ana C Gales, Adriana O Reis, Ronald N JonesAbstract:Polymyxins are a group of polycationic peptides naturally synthesized by Bacillus polymyxa, a nonactinomycete bacterium (7). Members of this class (colistin and Polymyxin B) act primarily on the gram-negative bacterial cell wall, leading to rapid permeability changes in the cytoplasmic membrane and ultimately to cell death. These drugs cross the bacterial outer membrane (self-promoted pathway) by competitive divalent cation displacement by the bulky polycations, which noncovalently cross the bridge adjacent to the polysaccharide component. Consequently, the bacterial outer membrane becomes distorted and more permeable, permitting increased uptake of the permeabilizing compounds (10, 19). Of the five recognized Polymyxins (A to E), only Polymyxins B and E (colistin) have advanced to therapeutic use. Polymyxin B and colistin have been demonstrated to be active against Pseudomonas aeruginosa. Four decades ago, Polymyxins were among the few treatments available for serious P. aeruginosa infections. Since 1980 other, less-toxic antimicrobial agents have become available, and the clinical use of Polymyxins has been limited to topical formulations for the treatment of skin, ear, and ocular diseases. Polymyxin B topical formulations also have been used prophylatically for the prevention of infection in neutropenic or cystic fibrosis patients (6, 11). Recently, the emergence of multidrug-resistant P. aeruginosa and Acinetobacter spp. isolates causing life-threatening infections has restored the potential therapeutic indication for the parenteral use of Polymyxins (1, 12, 20), usually colistin in North American medical centers. Consequently, clinical microbiology laboratories should be able to perform reliable susceptibility testing for drugs in this class. The National Committee on Clinical Laboratory Standards (NCCLS) does not provide guidance for the testing of Polymyxins. In fact, the resistance breakpoint criteria for Polymyxins were last available in the 1981 NCCLS Approved Standard M2-A2 S2 (15); however, with the very restricted use of Polymyxins, the published information was later withdrawn. In this study, the antimicrobial activities of the Polymyxins were evaluated against selected contemporary bacterial pathogens. The correlation of the broth microdilution, disk diffusion, and agar dilution methods was performed to determine the susceptibility criteria for Polymyxins. Disk diffusion quality controls for Escherichia coli ATCC 25922 and P. aeruginosa ATCC 27853 were also carried out to validate method control and the interpretation criteria only found in the disk product package insert.
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contemporary assessment of antimicrobial susceptibility testing methods for Polymyxin b and colistin review of available interpretative criteria and quality control guidelines
Journal of Clinical Microbiology, 2001Co-Authors: Ana C Gales, Adriana O Reis, Ronald N JonesAbstract:The emergence of infections caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter spp. has necessitated the search for alternative parenteral agents such as the Polymyxins. The National Committee for Clinical Laboratory Standards (NCCLS) documents do not currently provide interpretative criteria for the testing of the Polymyxins, colistin and Polymyxin B. Therefore, an evaluation of the antimicrobial activity of colistin and Polymyxin B was initiated using 200 bloodstream infection pathogens collected through the SENTRY Antimicrobial Surveillance Program. All susceptibility tests were performed according to the NCCLS recommendations. Polymyxin B and colistin displayed a nearly identical spectrum of activity, exhibiting excellent potency against P. aeruginosa (MIC(90), 2 microg/ml) and Acinetobacter sp. (MIC(90), 2 microg/ml). In contrast, they showed limited activity against some other nonfermentative bacilli such as Burkholderia cepacia (MIC(90), >/=128 microg/ml). Excellent correlation was achieved between broth microdilution and agar dilution tests (r = 0.96 to 0.98); 94.3% of the results were +/-1 log(2) dilution between the methods used for both compounds. At a resistance breakpoint of >/=4 microg/ml for both agents, unacceptable false-susceptible or very major errors were noted for colistin (5%) and Polymyxin B (6%). Modified zone criteria for colistin ( /=14 mm) and Polymyxin B ( /=14 mm) were suggested, but some degree of error persisted (>/=3.5%). It is recommended that all susceptible disk diffusion results be confirmed by MIC tests using the preferred reference NCCLS method. The quality control (QC) ranges listed in the product package insert require an adjusted range by approximately 3 mm for both NCCLS gram-negative quality control strains. This evaluation of in vitro susceptibility test methods for the Polymyxin class drugs confirmed continued serious testing error with the disk diffusion method, the possible need for breakpoint adjustments, and the recalculation of disk diffusion QC ranges. Clinical laboratories should exclusively use MIC methods to assist the therapeutic application of colistin or Polymyxin B until disk diffusion test modifications are sanctioned and published by the NCCLS.
Alan Forrest - One of the best experts on this subject based on the ideXlab platform.
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Polymyxin b in combination with enrofloxacin exerts synergistic killing against extensively drug resistant pseudomonas aeruginosa
Antimicrobial Agents and Chemotherapy, 2018Co-Authors: Heidi H Yu, Alan Forrest, Tony Velkov, Jinxin Zhao, Jesmin Akter, Hasini Wickremasinghe, Hasini Walpola, Veronika Wirth, Jian LiAbstract:: Polymyxins are increasingly used as a last-resort class of antibiotics against extensively drug-resistant (XDR) Gram-negative bacteria. However, resistance to Polymyxins can emerge with monotherapy. As nephrotoxicity is the major dose-limiting factor for Polymyxin monotherapy, dose escalation to suppress the emergence of Polymyxin resistance is not a viable option. Therefore, novel approaches are needed to preserve this last-line class of antibiotics. This study aimed to investigate the antimicrobial synergy of Polymyxin B combined with enrofloxacin against Pseudomonas aeruginosa Static time-kill studies were conducted over 24 h with Polymyxin B (1 to 4 mg/liter) and enrofloxacin (1 to 4 mg/liter) alone or in combination. Additionally, in vitro one-compartment model (IVM) and hollow-fiber infection model (HFIM) experiments were performed against P. aeruginosa 12196. Polymyxin B and enrofloxacin in monotherapy were ineffective against all of the P. aeruginosa isolates examined, whereas Polymyxin B-enrofloxacin in combination was synergistic against P. aeruginosa, with ≥2 to 4 log10 kill at 24 h in the static time-kill studies. In both IVM and HFIM, the combination was synergistic, and the bacterial counting values were below the limit of quantification on day 5 in the HFIM. A population analysis profile indicated that the combination inhibited the emergence of Polymyxin resistance in P. aeruginosa 12196. The mechanism-based modeling suggests that the synergistic killing is a result of the combination of mechanistic and subpopulation synergy. Overall, this is the first preclinical study to demonstrate that the Polymyxin-enrofloxacin combination is of considerable utility for the treatment of XDR P. aeruginosa infections and warrants future clinical evaluations.
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pharmacokinetics pharmacodynamics of colistin and Polymyxin b are we there yet
International Journal of Antimicrobial Agents, 2016Co-Authors: Thien B. Tran, Alan Forrest, Tony Velkov, Roger L Nation, Brian T. Tsuji, Phillip J. BergenAbstract:The Polymyxin antibiotics [colistin and Polymyxin B (PMB)] are increasingly used as a last-line option for the treatment of infections caused by extensively drug-resistant Gram-negative bacteria. Despite having similar structures and antibacterial activity in vitro, the two clinically available Polymyxins have very different pharmacological properties, as colistin (Polymyxin E) is intravenously administered to patients in the form of an inactive prodrug colistin methanesulphonate (sodium). This review will discuss recent progress in the pharmacokinetics/pharmacodynamics and toxicity of colistin and PMB, the factors that affect their pharmacological profiles, and the challenges for the effective use of both Polymyxins. Strategies are proposed for optimising their clinical utility based upon the recent pharmacological studies in vitro, in animals and patients. In the 'Bad Bugs, No Drugs' era, Polymyxins are a critically important component of the antibiotic armamentarium against difficult-to-treat Gram-negative 'superbugs'. Rational approaches to the use of Polymyxins must be pursued to increase their effectiveness and to minimise resistance and toxicity.
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Pharmacokinetics/pharmacodynamics of colistin and Polymyxin B: are we there yet?
International Journal of Antimicrobial Agents, 2016Co-Authors: Thien B. Tran, Phillip J. Bergen, Alan Forrest, Tony Velkov, Roger L Nation, Brian T. Tsuji, Jian LiAbstract:Abstract The Polymyxin antibiotics [colistin and Polymyxin B (PMB)] are increasingly used as a last-line option for the treatment of infections caused by extensively drug-resistant Gram-negative bacteria. Despite having similar structures and antibacterial activity in vitro, the two clinically available Polymyxins have very different pharmacological properties, as colistin (Polymyxin E) is intravenously administered to patients in the form of an inactive prodrug colistin methanesulphonate (sodium). This review will discuss recent progress in the pharmacokinetics/pharmacodynamics and toxicity of colistin and PMB, the factors that affect their pharmacological profiles, and the challenges for the effective use of both Polymyxins. Strategies are proposed for optimising their clinical utility based upon the recent pharmacological studies in vitro, in animals and patients. In the ‘Bad Bugs, No Drugs’ era, Polymyxins are a critically important component of the antibiotic armamentarium against difficult-to-treat Gram-negative ‘superbugs’. Rational approaches to the use of Polymyxins must be pursued to increase their effectiveness and to minimise resistance and toxicity.
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colistin and Polymyxin b dosage regimens against acinetobacter baumannii differences in activity and the emergence of resistance
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Soon-ee Cheah, Jürgen B. Bulitta, Alan Forrest, Brian T. Tsuji, Roger L NationAbstract:Infections caused by multidrug-resistant Acinetobacter baumannii are a major public health problem, and Polymyxins are often the last line of therapy for recalcitrant infections by such isolates. The pharmacokinetics of the two clinically used Polymyxins, Polymyxin B and colistin, differ considerably, since colistin is administered as an inactive prodrug that undergoes slow conversion to colistin. However, the impact of these substantial pharmacokinetic differences on bacterial killing and resistance emergence is poorly understood. We assessed clinically relevant Polymyxin B and colistin dosage regimens against one reference and three clinical A. baumannii strains in a dynamic one-compartment in vitro model. A new mechanism-based pharmacodynamic model was developed to describe and predict the drug concentrations and viable counts of the total and resistant populations. Rapid attainment of target concentrations was shown to be critical for Polymyxin-induced bacterial killing. All Polymyxin B regimens achieved peak concentrations of at least 1 mg/liter within 1 h and caused ≥4 log10 killing at 1 h. In contrast, the slow rise of colistin concentrations to 3 mg/liter over 48 h resulted in markedly reduced bacterial killing. A significant (4 to 6 log10 CFU/ml) amplification of resistant bacterial populations was common to all dosage regimens. The developed mechanism-based model explained the observed bacterial killing, regrowth, and resistance. The model also implicated adaptive Polymyxin resistance as a key driver of bacterial regrowth and predicted the amplification of preexisting, highly Polymyxin-resistant bacterial populations following Polymyxin treatment. Antibiotic combination therapies seem the most promising option for minimizing the emergence of Polymyxin resistance.
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Anthelmintic closantel enhances bacterial killing of Polymyxin B against multidrug-resistant Acinetobacter baumannii
The Journal of Antibiotics, 2016Co-Authors: Thien B. Tran, Phillip J. Bergen, Alan Forrest, Roger L Nation, Soon-ee Cheah, Heidi H Yu, Darren J Creek, Anthony Purcell, Jiangning Song, Tony VelkovAbstract:Polymyxins, an old class of antibiotics, are currently used as the last resort for the treatment of multidrug-resistant (MDR) Acinetobacter baumannii . However, recent pharmacokinetic and pharmacodynamic data indicate that monotherapy can lead to the development of resistance. Novel approaches are urgently needed to preserve and improve the efficacy of this last-line class of antibiotics. This study examined the antimicrobial activity of novel combination of Polymyxin B with anthelmintic closantel against A. baumannii . Closantel monotherapy (16 mg l^−1) was ineffective against most tested A. baumannii isolates. However, closantel at 4–16 mg l^−1 with a clinically achievable concentration of Polymyxin B (2 mg l^−1) successfully inhibited the development of Polymyxin resistance in Polymyxin-susceptible isolates, and provided synergistic killing against Polymyxin-resistant isolates (MIC ⩾4 mg l^−1). Our findings suggest that the combination of Polymyxin B with closantel could be potentially useful for the treatment of MDR, including Polymyxin-resistant, A. baumannii infections. The repositioning of non-antibiotic drugs to treat bacterial infections may significantly expedite discovery of new treatment options for bacterial ‘superbugs’.
