Combination therapy for carbapenem-resistant Gram-negative bacteria

Abstract

The emergence of resistant to carbapenems Gram-negative bacteria (CR GNB) has severely challenged antimicrobial therapy. Many CR GNB isolates are only susceptible to polymyxins; however, therapy with polymyxins and other potentially active antibiotics presents some drawbacks, which have discouraged their use in monotherapy. In this context, along with strong pre-clinical evidence of benefit in combining antimicrobials against CR GNB, the clinical use of combination therapy has been raised as an interesting strategy to overcome these potential limitations of a single agent. Polymyxins, tigecycline and even carbapenems are usually the cornerstone agents in combination schemes. Optimization of the probability to attain the pharmacokinetic/pharmacodynamic targets by both cornerstone drug and adjuvant drug is of paramount importance to achieve better clinical and microbiological outcomes. Clinical evidence of the major drugs utilized in combination schemes and how they should be prescribed considering pharmacokinetic/pharmacodynamic characteristics against CR GNB will be reviewed in this article.

Keywords::

• aminoglycosides
• carbapenem-resistance
• colistin
• doripenem
• fosfomycin
• imipenem
• meropenem
• pharmacodynamics
• pharmacokinetics
• polymyxin B
• rifampicin
• sulbactam
• tigecycline

Financial and competing interests disclosure

AP Zavascki is a research fellow from the National Council for Scientific and Technological Development, Ministry of Science and Technology, Brazil. He has received consultancy fees from Pfizer, Eurofarma, and Forest Laboratories. JB Bulitta is supported by a DECRA fellowship (DE120103084) from the Australian Research Council. JB Bulitta and CB Landersdorfer obtained research funding from Pfizer, Trius, Cempra, CSL, Cubist and Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Resistance to carbapenems in Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacteriaceae, mainly determined by the production of carbapenem-hydrolyzing β-lactamases, has emerged worldwide and is severely challenging antimicrobial therapy against these pathogens.

• • Most resistant to carbapenems Gram-negative bacteria isolates are only susceptible to polymyxins, which are commonly the main antibiotic class used against these isolates.

• • Some shortcomings of polymyxins, as well as other potentially active agents, for use in monotherapy against infections by CR GNB have been raised, including emergence of resistance during monotherapy and possible lower clinical efficacy. Combined with strong pre-clinical evidence supporting the use of antibiotic combinations, this has led to the common practice of prescribing two or more agents, even without solid clinical evidence for this practice.

• • Combination schemes usually rely on a cornerstone drug, most often polymyxin B or colistin, but also tigecycline and even a carbapenem, plus an adjuvant agent, which may or may not present in vitro susceptibility against the carbapenems Gram-negative bacteria (CR GNB) isolate considering the current clinical and Laboratory Standards Institute and European Committee on Antimicrobial Susceptibility Testing breakpoints.

• • Optimization of pharmacokinetic/pharmacodynamic target attainment both with the cornerstone and the adjuvant antibiotic should be attempted to improve clinical and microbiologic outcomes. More systematic studies to rationally optimize combination therapies against resistant to carbapenems Gram-negative bacteria are urgently needed.