Novel Polymyxin Combination With Antineoplastic Mitotane Improved the Bacterial Killing Against Polymyxin-Resistant Multidrug-Resistant Gram-Negative Pathogens (original) (raw)
Related papers
Development of new polymyxin derivatives for multi-drug resistant Gram-negative infections
The Journal of antibiotics, 2017
Over the last decade, there has been a resurgence of interest in polymyxins owing to the rapid rise in multi-drug resistant Gram-negative bacteria against which polymyxins offer a last-resort treatment. Although having excellent antibacterial activity, the clinical utility of polymyxins is limited by toxicity, especially renal toxicity. There is much interest therefore in developing polymyxin analogues with an improved therapeutic index. This review describes recent work aimed at improving the activity and/or reducing the toxicity of polymyxins. Consideration to providing activity against emerging strains with reduced susceptibility to polymyxins is also made.
Principles and Practice of Clinical Research
Background and aims: The emergence of infections due to multi resistant Gram negative bacteria is a major publichealth concern worldwide. Polymyxins (colistin and polymyxin B) are among the last available options for the treatment of these infections. However, when used in monotherapy, the development of polymyxin resistant strains and high mortality rates of patients has been observed. Combination of polymyxins with other antibiotic drug classes may lead to synergism enhancing its bactericidal effect and reducing the emergence of resistant strains. This review aims to analyze the main in vitro and clinical studies assessing the potential benefit of combination therapy with this class of drugs. Methods: We searched on PUBMED database for the mesh terms: "polymyxins", "polymyxin B", "colistin", "combination therapy" and their combinations. Articles published in the last 10 years (2005-2015), in English language, evaluating combination therapy of other antimicrobial classes with polymyxins were included for analyses. Results: Thirty-one' articles were selected for review. In vitro studies evaluated combinations with beta-lactams, tigecycline, rifampicin, quinolones, chloramfenicol, vancomycin and daptomycin. Clinical studies evaluated the benefit of different combinations in the treatment of Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa infections. Conclusion: Polymyxin combinations regimens seem potentially advantageous in the treatment of multi-resistant Gram-negative bacteria. Combination with beta-lactams, especially carbapenems, were the most studied and yielded positive results. However, data evaluating its benefit are mostly from in vitro and observational studies. Results are not yet conclusive and randomized clinical trials accessing this strategy are urgently needed.
Optimizing Polymyxin Combinations Against Resistant Gram-Negative Bacteria
Infectious diseases and therapy, 2015
Polymyxin combination therapy is increasingly used clinically. However, systematic investigations of such combinations are a relatively recent phenomenon. The emerging pharmacodynamic (PD) and pharmacokinetic (PK) data on CMS/colistin and polymyxin B suggest that caution is required with monotherapy. Given this situation, polymyxin combination therapy has been suggested as a possible way to increase bacterial killing and reduce the development of resistance. Considerable in vitro data have been generated in support of this view, particularly recent studies utilizing dynamic models. However, most existing animal data are of poor quality with major shortcomings in study design, while clinical data are generally limited to retrospective analysis and small, low-power, prospective studies. This article provides an overview of clinical and preclinical investigations of CMS/colistin and polymyxin B combination therapy.
Computational and Structural Biotechnology Journal, 2020
The status quo for combating uprising antibacterial resistance is to employ synergistic combinations of antibiotics. Nevertheless, the currently available combination therapies are fast becoming untenable. Combining antibiotics with various FDA-approved non-antibiotic drugs has emerged as a novel strategy against otherwise untreatable multi-drug resistant (MDR) pathogens. The apex of this study was to investigate the mechanisms of antibacterial synergy of the combination of polymyxin B with the phenothiazines against the MDR Gram-negative pathogens Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa. The synergistic antibacterial effects were tested using checkerboard and static time-kill assays. Electron microscopy (EM) and untargeted metabolomics were used to ascertain the mechanism(s) of the antibacterial synergy. The combination of polymyxin B and the phenothiazines showed synergistic antibacterial activity in checkerboard and static time-kill assays at clinically relevant concentrations against both polymyxin-susceptible and polymyxin-resistant isolates. EM revealed that the polymyxin B-prochlorperazine combination resulted in greater damage to the bacterial cell compared to each drug monotherapy. In metabolomics, at 0.5 h, polymyxin B monotherapy and the combination (to a greatest extent) disorganised the bacterial cell envelope as manifested by a major perturbation in bacterial membrane lipids (glycerophospholipids and fatty acids), peptidoglycan and lipopolysaccharide (LPS) biosynthesis. At the late time exposure (4 h), the aforementioned effects (except LPS biosynthesis) perpetuated mainly with the combination therapy, indicating the disorganising bacterial membrane biogenesis is potentially behind the mechanisms of antibacterial synergy. In conclusion, the study highlights the potential usefulness of the combination of polymyxin B with phenothiazines for the treatment of polymyxin-resistant Gram-negative infections (e.g. CNS infections).
Antibiotics, 2021
The emergence of antibiotic resistance has severely impaired the treatment of chronic respiratory infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa. Since the reintroduction of polymyxins as a last-line therapy against MDR Gram-negative bacteria, resistance to its monotherapy and recurrent infections continue to be reported and synergistic antibiotic combinations have been investigated. In this study, comprehensive in vitro microbiological evaluations including synergy panel screening, population analysis profiling, time-kill kinetics, anti-biofilm formation and membrane damage analysis studies were conducted to evaluate the combination of polymyxin B and meropenem against biofilm-producing, polymyxin-resistant MDR P. aeruginosa. Two phylogenetically unrelated MDR P. aeruginosa strains, FADDI-PA060 (MIC of polymyxin B [MICpolymyxin B], 64 mg/L; MICmeropenem, 64 mg/L) and FADDI-PA107 (MICpolymyxin B, 32 mg/L; MICmeropenem, 4 mg/L) were investigated. Genome sequenc...
Journal of Biosciences, 2021
Infections caused by multi-drug resistant (MDR) bacterial pathogens are a leading cause of mortality and morbidity across the world. Indiscriminate use of broad-spectrum antibiotics has seriously affected this situation. With the diminishing discovery of novel antibiotics, new treatment methods are urgently required to combat MDR pathogens. Polymyxins, the cationic lipopeptide antibiotics, discovered more than half a century ago, are considered to be the last-line of antibiotics available at the moment. This antibiotic shows a great bactericidal effect against Gram-negative bacteria. Polymyxins primarily target the bacterial membrane and disrupt them, causing lethality. Because of their membrane interacting mode of action, polymyxins cause nephrotoxicity and neurotoxicity in humans, limiting their usability. However, recent modifications in their chemical structure have been able to reduce the toxic effects. The development of better dosing regimens has also helped in getting better clinical outcomes in the infections caused by MDR pathogens. Since the mid-1990s the use of polymyxins has increased manifold in clinical settings, resulting in the emergence of polymyxin-resistant strains. The risk posed by the polymyxin-resistant nosocomial pathogens such as the Enterobacteriaceae group, Pseudomonas aeruginosa, and Acinetobacter baumannii, etc. is very serious considering these pathogens are resistant to almost all available antibacterial drugs. In this review article, the mode of action of the polymyxins and the genetic regulatory mechanism responsible for the emergence of resistance are discussed. Specifically, this review aims to update our current understanding in the field and suggest possible solutions that can be pursued for future antibiotic development. As polymyxins primarily target the bacterial membranes, resistance to polymyxins arises primarily by the modification of the lipopolysaccharides (LPS) in the outer membrane (OM). The LPS modification pathways are largely regulated by the bacterial two-component signal transduction (TCS) systems. Therefore, targeting or modulating the TCS signalling mechanisms can be pursued as an alternative to treat the infections caused by polymyxin-resistant MDR pathogens. In this review article, this aspect is also highlighted.
Clinical Infectious Diseases, 2005
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 ∼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.
Antimicrobial agents and chemotherapy, 2016
Polymyxins have emerged as a last-resort treatment against the growing threat of extensively drug-resistant (XDR) gram negative bacilli (GNB) infections. Individualized polymyxin-based antibiotic combinations selected based onin vitrocombination testing results may be required to optimize therapy. A retrospective cohort study of hospitalized patients receiving polymyxins for XDR GNB infections from 2009 - 2014 was conducted to compare treatment outcomes between patients receiving polymyxin monotherapy (MT), non-validated polymyxin combination therapy (NVCT), andin vitrocombination testing validated polymyxin combination therapy (VCT). The primary and secondary outcomes were infection-related mortality and microbiological eradication respectively. Adverse drug reactions (ADRs) between treatment groups were assessed. A total of 291 patients (MT: n = 58; NVCT: n = 203; VCT: n = 30) were included. The overall infection-related mortality was 23.0% (67 patients). In the multivariable anal...
mBio, 2017
The rapid increase of carbapenem resistance in Gram-negative bacteria has resurrected the importance of the polymyxin antibiotics. The recent discovery of plasmid-mediated polymyxin resistance (mcr-1) in carbapenem-resistant Enterobacteriaceae serves as an important indicator that the golden era of antibiotics is under serious threat. We assessed the bacterial killing of 15 different FDA-approved antibiotics alone and in combination with polymyxin B in time-killing experiments against Escherichia coli MCR1_NJ, the first reported isolate in the United States to coharbor mcr-1 and a New Delhi metallo-β-lactamase gene (blaNDM-5). The most promising regimens were advanced to the hollow-fiber infection model (HFIM), where human pharmacokinetics for polymyxin B, aztreonam, and amikacin were simulated over 240 h. Exposure to polymyxin B monotherapy was accompanied by MCR1_NJ regrowth but not resistance amplification (polymyxin B MIC from 0 to 240 h [MIC0h to MIC240h] of 4 mg/liter), wherea...
The Journal of antimicrobial chemotherapy, 2016
The objective of this study was to summarize available data on polymyxin-based combination therapy or monotherapy for carbapenem-resistant Gram-negative bacteria. This is a systematic review. We included observational studies and randomized controlled trials (RCTs) comparing polymyxin monotherapy versus polymyxin-based combination therapy in adult patients with infections caused by carbapenem-resistant or carbapenemase-producing Gram-negative bacteria. Only named antibiotic regimens were included. The primary outcome was 30 day mortality. Unadjusted OR (uOR) and adjusted OR where available with 95% CI were pooled in random-effects meta-analyses. Twenty-two studies including 28 comparisons were included. Polymyxin monotherapy was associated with a uOR of 1.58 (95% CI = 1.03-2.42) for mortality compared with polymyxin/carbapenem combination therapy (seven observational studies, 537 patients), without heterogeneity. Subgrouping studies to serious and critical risk of bias resulted in u...