Rescuing the Last-Line Polymyxins: Achievements and Challenges

Abstract

Antibiotic resistance is a major global health challenge and, worryingly, several key Gram negative pathogens can become resistant to most currently available antibiotics. Polymyxins have been revived as a last-line therapeutic option for the treatment of infections caused by multidrug-resistant Gram negative bacteria, in particular Acinetobacter baumannii , Pseudomonas aeruginosa , and Enterobacterales. Polymyxins were first discovered in the late 1940s but were abandoned soon after their approval in the late 1950s as a result of toxicities (e.g., nephrotoxicity) and the availability of “safer” antibiotics approved at that time. Therefore, knowledge on polymyxins had been scarce until recently, when enormous efforts have been made by several research teams around the world to elucidate the chemical, microbiological, pharmacokinetic/pharmacodynamic, and toxicological properties of polymyxins. One of the major achievements is the development of the first scientifically based dosage regimens for colistin that are crucial to ensure its safe and effective use in patients. Although the guideline has not been developed for polymyxin B, a large clinical trial is currently being conducted to optimize its clinical use. Importantly, several novel, safer polymyxin-like lipopeptides are developed to overcome the nephrotoxicity, poor efficacy against pulmonary infections, and narrow therapeutic windows of the currently used polymyxin B and colistin. This review discusses the latest achievements on polymyxins and highlights the major challenges ahead in optimizing their clinical use and discovering new-generation polymyxins. To save lives from the deadly infections caused by Gram negative “superbugs,” every effort must be made to improve the clinical utility of the last-line polymyxins. Significance Statement Antimicrobial resistance poses a significant threat to global health. The increasing prevalence of multidrug-resistant (MDR) bacterial infections has been highlighted by leading global health organizations and authorities. Polymyxins are a last-line defense against difficult-to-treat MDR Gram negative pathogens. Unfortunately, the pharmacological information on polymyxins was very limited until recently. This review provides a comprehensive overview on the major achievements and challenges in polymyxin pharmacology and clinical use and how the recent findings have been employed to improve clinical practice worldwide.

Polymyxins, the last-resort antibiotics: Mode of action, resistance emergence, and potential solutions

“…The polymyxin group of antibiotics discovered in 1947 from the bacterium Bacillus polymyxa are one such candidate. Till now, more than fifteen varieties of polymyxins have been isolated and characterized, among which the most prominent ones are polymyxin B and polymyxin E (also known as colistin) (Mmatli et al 2020 ; Nang et al 2021 ; Poirel et al 2017a ; Trimble et al 2016 ). The polymyxins exhibit significant inhibitory effect against the Gram-negative bacterial pathogens, therefore, it has emerged as an ultimate choice to target such pathogens that have already become resistant to the frontline antibiotics such as β-lactams, aminoglycosides, and the fluoroquinolones (Biswas et al 2012 ; Landman et al 2008 ; Mmatli et al 2020 ; Nang et al 2021 ; Poirel et al 2017a ).…”

“…While the cationic peptide ring provides a hydrophilic nature to the polymyxins, the fatty acyl chain is hydrophobic. This structural feature is generally attributed to the ability of the polymyxins to insert into the cell membranes leading to its disintegration (Nang et al 2021 ; Nation et al 2014 ; Trimble et al 2016 ). This typical feature is also responsible for the observed nephrotoxicity in humans.…”

Successful Treatment With Intrathecal and Intravenous Polymyxin B-Based Combination Against MDR Acinetobacter baumannii Meningitis in Pediatric Patient: A Case Report

“…These findings are in accordance with the suspected adverse reactions observed in the present case. Moreover, recent case reports of polymyxin B-induced skin hyperpigmentation is associated with its position 6 D-Phe, because no such reports have been published on colistin to date ( 35 ). It has been reported that penetration of polymyxins into CSF is a crucial indicator for optimizing in vivo efficacy and minimizing toxicity ( 28 ).…”

Urinary Metabolomics from a Dose-Fractionated Polymyxin B Rat Model of Acute Kidney Injury

“…This metabolite, and its metabolic pathway, was identified as one of the main metabolic perturbations related to PB-induced tubular kidney cell (HK-2 and NRK-52E) damage. 29 The underlying mechanism of damage was assumed to be, among the aforementioned, oxidative and related to a loss of cellular capacity to scavenging ROS. The sharp surge of urinary taurine in all of the treated animals in our study is limited to the day 1 profile, with a return to baseline by the day 3 profile; indicative of a prompt cellular response to the accumulation of PB inside the proximal tubule cells after its administration.…”