Polymyxin combination therapy for multidrug-resistant, extensively-drug resistant, and difficult-to-treat drug-resistant gram-negative infections: is it superior to polymyxin monotherapy?

ABSTRACT

Introduction

The increasing prevalence of infections with multidrug-resistant (MDR), extensively-drug resistant (XDR) or difficult-to-treat drug resistant (DTR) Gram-negative bacilli (GNB), including Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Enterobacter species, and Escherichia coli poses a severe challenge.

Areas covered

The rapid growing of multi-resistant GNB as well as the considerable deceleration in development of new anti-infective agents have made polymyxins (e.g. polymyxin B and colistin) a mainstay in clinical practices as either monotherapy or combination therapy. However, whether the polymyxin-based combinations lead to better outcomes remains unknown. This review mainly focuses on the effect of polymyxin combination therapy versus monotherapy on treating GNB-related infections. We also provide several factors in designing studies and their impact on optimizing polymyxin combinations.

Expert opinion

An abundance of recent in vitro and preclinical in vivo data suggest clinical benefit for polymyxin-drug combination therapies, especially colistin plus meropenem and colistin plus rifampicin, with synergistic killing against MDR, XDR, and DTR P. aeruginosa, K. pneumoniae and A. baumannii. The beneficial effects of polymyxin-drug combinations (e.g. colistin or polymyxin B + carbapenem against carbapenem-resistant K. pneumoniae and carbapenem-resistant A. baumannii, polymyxin B + carbapenem + rifampin against carbapenem-resistant K. pneumoniae, and colistin + ceftolozan/tazobactam + rifampin against PDR-P. aeruginosa) have often been shown in clinical setting by retrospective studies. However, high-certainty evidence from large randomized controlled trials is necessary. These clinical trials should incorporate careful attention to patient’s sample size, characteristics of patient’s groups, PK/PD relationships and dosing, rapid detection of resistance, MIC determinations, and therapeutic drug monitoring.

KEYWORDS:

• Colistin
• combinations
• MDR/XDR/DTR gram-negative bacilli
• monotherapy
• polymyxin B

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or mending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Authors’ contributions

AA obtained data and drafted the main body of the manuscript and critically revised it. AI helped in the acquisition of data and drafting of the manuscript. MR helped in the acquisition of data, drafting the manuscript, and drawing the figures. The authors read and approved the final manuscript.

Abbreviations

AMR: Antimicrobial resistance; MDR: Multidrug-resistant; XDR: Extensively-drug resistant; DTR: Difficult-to-treat resistance; FDA: GNB: Gram-negative bacilli; LPS: Lipopolysaccharide; OM: Outer membrane; PK/PD: Pharmacokinetics (PK)/pharmacodynamics; TCS: Two-component system; CRPA; Carbapenem-resistant P. aeruginosa; CRAB: Carbapenem-resistant A. baumannii; CRE: Carbapenem-resistant Enterobacteriaceae; CMS: Colistin methanesulfonate; MIU: Million international units; CBA: Colistin base activity; CSF: Cerebrospinal fluid; ADRs: Adverse drug reactions; VCT: Validated polymyxin combination therapy; RCT: Randomized controlled trial; VABP: Ventilator-associated bacterial pneumonia; MCBT: Multiple-combination bactericidal testing; SBO: Diazabicyclooctane; MIC: Minimum inhibitory concentration; CPE: Carbapenemase-producing Enterobacteriaceae; VMEs: Very major errors; BMD: Broth microdilution; CA-MHB: Cation-adjusted Mueller-Hinton broth; WHO: World Health Organization; GNB: Gram-negative bacilli; HR: Hazard ratio; aOR: adjusted odds ratio; EU/EEA: European Union/European Economic Area; PEtN: Phosphoethanolamine; CF: Cystic fibrosis; CrCL: Creatinine clearance; AUC/MIC: Area under the curve/minimum inhibitory concentration; RRT: Renal replacement therapy; SOFA: Sequential organ failure assessment; APACHE: Acute physiology and chronic health evaluation; ICU: Intensive care unit; FIC: Fractional inhibitory concentration; cUTIs: complicated urinary tract infections; (cIAIs: complicated intra-abdominal infections; HABP: Hospital-acquired bacterial pneumonia; mMITT: microbiologic modified intent-to-treat; NARST: National Antimicrobial Resistance Surveillance Center, Thailand; UKCFR: UK cystic fibrosis registry; CRKP: Carbapenem-resistant K. pneumoniae; KPC: K. pneumoniae carbapenemases; NDM: New Delhi Metallo-β-lactamase; OXA-48: Oxacillinase-48; MBLs: Metallo-β-lactamases; OR: Odds ratio; CI: Confidence interval; BSIs: Bloodstream infections; CPE: Carbapenemase-producing Enterobacteriaceae; AIDA: Artificial Intelligence Data Analysis; HABP: Hospital-acquired bacterial pneumonia; NVCT: Non-validated polymyxin combination therapy.

Additional information

Funding

This paper was not funded.