Explore the vast range of titles available.

Abstract The dramatic global rise of MDR and XDR Enterobacterales in human medicine forced clinicians to the reintroduction of colistin as last-resort drug. Meanwhile, colistin is used in the veterinary medicine since its discovery, leading to a steadily increasing prevalence of resistant isolates in the livestock and meat-based food sector. Consequently, transmission of resistant isolates from animals to humans, acquisition via food and exposure to colistin in the clinic are reasons for the increased prevalence of colistin-resistant Enterobacterales in humans in the last decades. Initially, resistance mechanisms were caused by mutations in chromosomal genes. However, since the discovery in 2015, the focus has shifted exclusively to mobile colistin resistances (mcr). This review will advance the understanding of chromosomal-mediated resistance mechanisms in Enterobacterales. We provide an overview about genes involved in colistin resistance and the current global situation of colistin-resistant Enterobacterales. A comparison of the global colistin use in veterinary and human medicine highlights the effort to reduce colistin sales in veterinary medicine under the One Health approach. In contrast, it uncovers the alarming rise in colistin consumption in human medicine due to the emergence of MDR Enterobacterales, which might be an important driver for the increasing emergence of chromosome-mediated colistin resistance. Colistin resistance in Enterobacterales is highly complex and mutations in chromosomally encoded genes are of great concern due to the use of colistin as last-line drug.

Background. Intravenous colistin is difficult to use because plasma concentrations for antibacterial effect overlap those causing nephrotoxicity, and there is large interpatient variability in pharmacokinetics. The aim was to develop dosing algorithms for achievement of a clinically desirable average steady-state plasma colistin concentration (Css,avg) of 2 mg/L. Methods. Plasma concentration-time data from 214 adult critically ill patients (creatinine clearance, 0–236 mL/min; 29 receiving renal replacement therapy [RRT]) were subjected to population pharmacokinetic analysis. Development of an algorithm for patients not receiving RRT was based on the relationship between the dose of colistimethate that would be needed to achieve a desired Css,avg and creatinine clearance. The increase in colistin clearance when patients were receiving RRT was determined from the population analysis and guided the supplemental dosing needed. To balance potential antibacterial benefit against risk of nephrotoxicity the algorithms were designed to achieve target attainment rates of >80% for Css,avg ≥2 and <30% for Css,avg ≥4 mg/L. Results. When algorithm doses were applied back to individual patients not receiving RRT (including those prescribed intermittent dialysis on a nondialysis day), >80% of patients with creatinine clearance <80 mL/min achieved Css,avg ≥2 mg/L, but for patients with creatinine clearance ≥80 mL/min, the target attainment was <40%, even with the maximum allowed daily dose of 360 mg colistin base activity. For patients receiving RRT, target attainment rates were >80% with the proposed supplemental dosing. In all categories of patients, <30% of patients attained Css,avg ≥4 mg/L. Conclusions. The project has generated clinician-friendly dosing algorithms and pointed to circumstances in which intravenous monotherapy may be inadequate.

Colistin and polymyxin B have indistinguishable microbiological activity in vitro, but they differ in the form administered parenterally to patients. Polymyxin B is administered directly as the active antibiotic, whereas colistin is administered as the inactive prodrug, colistin methanesulfonate (CMS). CMS must be converted to colistin in vivo, but this occurs slowly and incompletely. Here we summarize the key differences between parenteral CMS/colistin and polymyxin B, and highlight the clinical implications. We put forth the view that overall polymyxin B has superior clinical pharmacological properties compared with CMS/colistin. We propose that in countries such as the United States where parenteral products of both colistin and polymyxin B are available, prospective studies should be conducted to formally examine their relative efficacy and safety in various types of infections and patients. In the meantime, where clinicians have access to both polymyxins, they should carefully consider the relative merits of each in a given circumstance.

In the face of diminishing therapeutic options for the treatment of infections caused by multidrug-resistant, Gram-negative bacteria, clinicians are increasingly using colistin and polymyxin B. These antibiotics became available clinically in the 1950s, when understanding of antimicrobial pharmacology and regulatory requirements for approval of drugs was substantially less than today. At the 1st International Conference on Polymyxins in Prato, Italy, 2013, participants discussed a set of key objectives that were developed to explore the factors affecting the safe and effective use of polymyxins, identify the gaps in knowledge, and set priorities for future research. Participants identified several factors that affect the optimum use of polymyxins, including: confusion caused by several different conventions used to describe doses of colistin; an absence of appropriate pharmacopoeial standards for polymyxins; outdated and diverse product information; and uncertainties about susceptibility testing and breakpoints. High-priority areas for research included: better definition of the effectiveness of polymyxin-based combination therapy compared with monotherapy via well designed, randomised controlled trials; examination of the relative merits of colistin versus polymyxin B for various types of infection; investigation of pharmacokinetics in special patient populations; and definition of the role of nebulised polymyxins alone or in combination with intravenous polymyxins for the treatment of pneumonia. The key areas identified provide a roadmap for action regarding the continued use of polymyxins, and are intended to help with the effective and safe use of these important, last-line antibiotics.

Increasing antibiotic resistance in multidrug-resistant (MDR) Gram-negative bacteria (MDR-GNB) presents significant health problems worldwide, since the vital available and effective antibiotics, including; broad-spectrum penicillins, fluoroquinolones, aminoglycosides, and β-lactams, such as; carbapenems, monobactam, and cephalosporins; often fail to fight MDR Gram-negative pathogens as well as the absence of new antibiotics that can defeat these \"superbugs\". All of these has prompted the reconsideration of old drugs such as polymyxins that were reckoned too toxic for clinical use. Only two polymyxins, polymyxin E (colistin) and polymyxin B, are currently commercially available. Colistin has re-emerged as a last-hope treatment in the mid-1990s against MDR Gram-negative pathogens due to the development of extensively drug-resistant GNB. Unfortunately, rapid global resistance towards colistin has emerged following its resurgence. Different mechanisms of colistin resistance have been characterized, including intrinsic, mutational, and transferable mechanisms. In this review, we intend to discuss the progress over the last two decades in understanding the alternative colistin mechanisms of action and different strategies used by bacteria to develop resistance against colistin, besides providing an update about what is previously recognized and what is novel concerning colistin resistance.

Abstract Background We evaluated the association between mortality and colistin resistance in Acinetobacter baumannii infections and the interaction with antibiotic therapy. Methods This is a secondary analysis of a randomized controlled trial of patients with carbapenem-resistant gram-negative bacterial infections treated with colistin or colistin-meropenem combination. We evaluated patients with infection caused by carbapenem-resistant A. baumannii (CRAB) identified as colistin susceptible (CoS) at the time of treatment and compared patients in which the isolate was confirmed as CoS with those whose isolates were retrospectively identified as colistin resistant (CoR) when tested by broth microdilution (BMD). The primary outcome was 28-day mortality. Results Data were available for 266 patients (214 CoS and 52 CoR isolates). Patients with CoR isolates had higher baseline functional capacity and lower rates of mechanical ventilation than patients with CoS isolates. All-cause 28-day mortality was 42.3% (22/52) among patients with CoR strains and 52.8% (113/214) among patients with CoS isolates (P = .174). After adjusting for variables associated with mortality, the mortality rate was lower among patients with CoR isolates (odds ratio [OR], 0.285 [95% confidence interval {CI}, .118–.686]). This difference was associated with treatment arm: Mortality rates among patients with CoR isolates were higher in those randomized to colistin-meropenem combination therapy compared to colistin monotherapy (OR, 3.065 [95% CI, 1.021–9.202]). Conclusions Colistin resistance determined by BMD was associated with lower mortality among patients with severe CRAB infections. Among patients with CoR isolates, colistin monotherapy was associated with a better outcome compared to colistin-meropenem combination therapy. Clinical Trials Registration NCT01732250 In a retrospective analysis of a randomized controlled trial, infection with carbapenem-resistant, colistin-resistant Acinetobacter baumannii was associated with lower mortality than carbapenem-resistant, colistin-susceptible Acinetobacter. Colistin-carbapenem combination therapy was associated with higher mortality than colistin monotherapy in patients with colistin-resistant isolates.

Background. With an increase in the use of colistin methansulfonate (CMS) to treat carbapenem-resistant Acinetobacter baumannii infections, colistin resistance is emerging. Methods. Patients with infection or colonization due to colistin-resistant A. baumannii were identified at a hospital system in Pennsylvania. Clinical data were collected from electronic medical records. Susceptibility testing, pulsed-field gel electrophoresis (PFGE), and multilocus sequence typing (MLST) were performed. To investigate the mechanism of colistin resistance, lipid A was subjected to matrix-assisted laser desorption/ionization mass spectrometry. Results. Twenty patients with colistin-resistant A. baumannii were identified. Ventilator-associated pneumonia was the most common type of infection. Nineteen patients had received intravenous and/or inhaled CMS for treatment of carbapenem-resistant, colistin-susceptible A. baumannii infection prior to identification of colistin-resistant isolates. The 30-day all-cause mortality rate was 30%. The treatment regimen for colistin-resistant A. baumannii infection associated with the lowest mortality rate was a combination of CMS, a carbapenem, and ampicillin-sulbactam. The colistin-susceptible and -resistant isolates from the same patients were highly related by PFGE, but isolates from different patients were not, suggesting evolution of resistance during CMS therapy. By MLST, all isolates belonged to the international clone II, the lineage that is epidemic worldwide. Phosphoethanolamine modification of lipid A was present in all colistin-resistant A. baumannii isolates. Conclusions. Colistin-resistant A. baumannii occurred almost exclusively among patients who had received CMS for treatment of carbapenem-resistant, colistin-susceptible A. baumannii infection. Lipid A modification by the addition of phosphoethanolamine accounted for colistin resistance. Susceptibility testing for colistin should be considered for A. baumannii identified from CMS-experienced patients.

Background. Polymyxins including colistin are an important \"last-line\" treatment for infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKp). Increasing use of colistin has led to resistance to this cationic antimicrobial peptide. Methods. A cohort nested within the Consortium on Resistance against Carbapenems in Klebsiella pneumoniae (CRACKLE) was constructed of patients with infection, or colonization with CRKp isolates tested for colistin susceptibility during the study period of December, 2011 to October, 2014. Reference colistin resistance determination as performed by broth macrodilution was compared to results from clinical microbiology laboratories (Etest) and to polymyxin resistance testing. Each patient was included once, at the time of their first colistin-tested CRKp positive culture. Time to 30-day in-hospital all-cause mortality was evaluated by Kaplan-Meier curves and Cox proportional hazard modeling. Results. In 246 patients with CRKp, 13% possessed ColR CRKp. ColR was underestimated by Etest (very major error rate = 35%, major error rate = 0.4%). A variety of rep-PCR strain types were encountered in both the ColS and the ColR groups. Carbapenem resistance was mediated primarily by blaKPC-2 (46%) and blaKPC-3 (50%). ColR was associated with increased hazard for in-hospital mortality (aHR 3.48; 95% confidence interval, 1.73–6.57; P < .001). The plasmid-associated ColR genes, mcr-1 and mcr-2 were not detected in any of the ColR CRKp. Conclusions. In this cohort, 13% of patients with CRKp presented with ColR CRKp. The apparent polyclonal nature of the isolates suggests de novo emergence of ColR in this cohort as the primary factor driving ColR. Importantly, mortality was increased in patients with ColR isolates.

Until now, polymyxin resistance has involved chromosomal mutations but has never been reported via horizontal gene transfer. During a routine surveillance project on antimicrobial resistance in commensal Escherichia coli from food animals in China, a major increase of colistin resistance was observed. When an E coli strain, SHP45, possessing colistin resistance that could be transferred to another strain, was isolated from a pig, we conducted further analysis of possible plasmid-mediated polymyxin resistance. Herein, we report the emergence of the first plasmid-mediated polymyxin resistance mechanism, MCR-1, in Enterobacteriaceae. The mcr-1 gene in E coli strain SHP45 was identified by whole plasmid sequencing and subcloning. MCR-1 mechanistic studies were done with sequence comparisons, homology modelling, and electrospray ionisation mass spectrometry. The prevalence of mcr-1 was investigated in E coli and Klebsiella pneumoniae strains collected from five provinces between April, 2011, and November, 2014. The ability of MCR-1 to confer polymyxin resistance in vivo was examined in a murine thigh model. Polymyxin resistance was shown to be singularly due to the plasmid-mediated mcr-1 gene. The plasmid carrying mcr-1 was mobilised to an E coli recipient at a frequency of 10−1 to 10−3 cells per recipient cell by conjugation, and maintained in K pneumoniae and Pseudomonas aeruginosa. In an in-vivo model, production of MCR-1 negated the efficacy of colistin. MCR-1 is a member of the phosphoethanolamine transferase enzyme family, with expression in E coli resulting in the addition of phosphoethanolamine to lipid A. We observed mcr-1 carriage in E coli isolates collected from 78 (15%) of 523 samples of raw meat and 166 (21%) of 804 animals during 2011–14, and 16 (1%) of 1322 samples from inpatients with infection. The emergence of MCR-1 heralds the breach of the last group of antibiotics, polymyxins, by plasmid-mediated resistance. Although currently confined to China, MCR-1 is likely to emulate other global resistance mechanisms such as NDM-1. Our findings emphasise the urgent need for coordinated global action in the fight against pan-drug-resistant Gram-negative bacteria. Ministry of Science and Technology of China, National Natural Science Foundation of China.

This report compared plazomicin with colistin for the treatment of severe (bloodstream or pneumonia) infection with carbapenem-resistant Enterobacteriaceae. The trial was stopped early for futility, but a suggestion of activity of plazomicin was identified.