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.

Graphical abstract

Fig. 1.

Mechanisms of antibacterial activity of polymyxins in Gram negative bacteria via disruption of the outer membrane, vesicle-vesicle contact, inhibition of respiratory enzyme NDH-2, and hydroxyl radical formation. CoQ1, coenzyme Q1.

Fig. 2.

Mechanisms of polymyxin resistance in Gram negative bacteria via lipid A modifications with L-Ara4N, pEtN, galactosamine, and palmitoylation; efflux pump systems, capsule shielding, loss of LPS, and polymyxin dependence.

Fig. 3.

Two-component systems regulating polymyxin resistance in E. coli, S. enterica, K. pneumoniae, A. baumannii, and P. aeruginosa.

Fig. 4.

Steady-state plasma concentrations of colistimethate (A) and formed colistin (B) across a dosage interval in 215 critically ill patients. Patients were receiving colistimethate every 8, 12, or 24 hours. Each symbol represents the data from an individual. Permission obtained from Oxford University Press (Nation et al., 2017).

Fig. 5.

Linear (A) and log-linear (B) plots of the relationship between the daily dose of CBA needed for each 1 mg/l of the average steady-state plasma concentration of colistin (C_ss,avg) and creatinine clearance. The regression equation in (B) with the intercept adjusted from 1.667 to 1.825 is the renally based dosing algorithm. Permission obtained from Oxford University Press (Nation et al., 2017).

Fig. 6.

Plasma concentration-time profiles of polymyxin B in 24 critically ill patients. Permission obtained from Oxford University Press (Sandri et al., 2013a).

Fig. 7.

Individual polymyxin B clearance estimates vs. creatinine clearance in critically ill patients. Polymyxin B clearance was scaled by total body weight (liters per hour per kilogram). Open circles represent patients not on hemodialysis, the filled diamond represents the continuous venovenous hemodialysis patient who weighed 250 kg, and the filled triangle represents the lean continuous venovenous hemodialysis patient. Permission obtained from Oxford University Press (Sandri et al., 2013a).

Fig. 8.

The proposed mechanisms of polymyxin-induced apoptotic cell death in renal tubular cells. AIF, apoptosis-induced factor; CAT, catalase; CDK2, cyclin-dependent kinase 2; cytC, cytochrome C; MAPK, mitogen-activated protein kinase; MDA, malondialdehyde; MR, endocytic receptor megalin; OCTN1, organic cation transporter 1; SOD, superoxide dismutase; tBid, truncated Bax-inhibiting peptide . Reproduced with permission (Dai et al., 2014). Copyright © American Society for Microbiology.