Combination therapy for Gram-negative bacteria: what is the evidence?

Abstract

The treatment of infections caused by multidrug-resistant Gram-negative bacteria is challenging given the limited options for effective therapy. Combination therapy has garnered great interest recently, with the goals of ensuring appropriate therapy with at least one active agent, and achieving synergistic activity among the anti-microbials used. In this review, we evaluate the data supporting the use of combination therapy against Pseudomonas aeruginosa, carbapenem-resistant Enterobacteriaceae, Acinetobacter species and Stenotrophomonas maltophilia. Various regimens have been tried with promising results; however, the data are mostly derived from in vitro synergy studies. While these reports suggest an advantage of combination therapy over monotherapy, clinical data are scarce, and are comprised of retrospective and a few prospective observational studies. Well-designed randomized trials are needed to better elucidate the efficacy of the various combination regimens. Until then, this review offers a critical appraisal of the published literature and provides recommendations based on the available evidence.

Keywords::

• anti-microbial resistance
• carbapenems
• combination therapy
• Gram-negative
• synergy

Financial & competing interests disclosure

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 materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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

Key issues

• • Anti-microbial resistance is rapidly emerging among Gram-negative bacteria.

• • Various combination regimens have been studied in vitro.

• • Clinical data supporting the use of combination therapy for multidrug-resistant (MDR) pathogens are variable.

• • The most active combinations against MDR Pseudomonas aeruginosa are beta-lactams with an aminoglycoside or a quinolone, and colistin-based regimens.

• • Clinical evidence favoring combination therapy is strongest with carbapenem-resistant Enterobacteriaceae. The most successful regimens have been carbapenems with colistin or tigecycline.

• • MDR Acinetobacter infections are especially problematic. Promising treatment regimens include colistin, minocycline, and in one study, tigecycline, despite conflicting results from other studies.

• • Combination therapy is favored for serious infections due to Stenotrophomonas maltophilia, and when treatment with trimethoprim–sulfamethxazole is not possible due to resistance or intolerance. Ticarcillin–clavulanate, ceftazidime and ciprofloxacin have exhibited the most synergistic activity.

• • Well-designed randomized trials, albeit difficult to conduct, are needed to better evaluate the efficacy of combination therapy compared with monotherapy.