Colistin Resistance Development Following Colistin-Meropenem Combination Therapy Versus Colistin Monotherapy in Patients With Infections Caused by Carbapenem-Resistant Organisms

Abstract

Background We evaluated whether carbapenem-colistin combination therapy reduces the emergence of colistin resistance, compared to colistin monotherapy, when given to patients with infections due to carbapenem-resistant Gram-negative organisms. Methods This is a pre-planned analysis of a secondary outcome from a randomized, controlled trial comparing colistin monotherapy with colistin-meropenem combination for the treatment of severe infections caused by carbapenem-resistant, colistin-susceptible Gram-negative bacteria. We evaluated rectal swabs taken on Day 7 or later for the presence of new colistin-resistant (ColR) isolates. We evaluated the emergence of any ColR isolate and the emergence of ColR Enterobacteriaceae (ColR-E). Results Data were available for 214 patients for the primary analysis; emergent ColR organisms were detected in 22 (10.3%). No difference was observed between patients randomized to treatment with colistin monotherapy (10/106, 9.4%) versus patients randomized to colistin-meropenem combination therapy (12/108, 11.1%; P = .669). ColR-E organisms were detected in 18/249 (7.2%) patients available for analysis. No difference was observed between the 2 treatment arms (colistin monotherapy 6/128 [4.7%] vs combination therapy 12/121 [9.9%]; P = .111). Enterobacteriaceae, as the index isolate, was found to be associated with development of ColR-E (hazard ratio, 3.875; 95% confidence interval, 1.475–10.184; P = .006). Conclusions Carbapenem-colistin combination therapy did not reduce the incidence of colistin resistance emergence in patients with infections due to carbapenem-resistant organisms. Further studies are necessary to elucidate the development of colistin resistance and methods for its prevention.

Contemporary Perspective on the Treatment of Acinetobacter baumannii Infections: Insights from the Society of Infectious Diseases Pharmacists

“…The synergistic activity often manifests through prevention of bacterial regrowth, which occurs commonly in vitro against single agents, particularly colistin. The impact of the colistin–carbapenem combinations on the delay in the emergence of resistance remains to be elucidated given conflicting reports of both clinical successes and failures [ 61 , 66 ]. Decreased susceptibility to colistin may inhibit in vitro synergy and prompt clinicians to explore alternative therapies, including three-drug combinations [ 62 ].…”

Re: ‘Colistin plus meropenem for carbapenem-resistant gram-negative infections: in vitro synergism is not associated with better clinical outcomes’—Author's reply

“…This was examined as a secondary outcome in the AIDA trial. We found no difference in the emergence of colistin resistance between individuals randomized to colistin monotherapy (9.4%) versus colistin-meropenem combination therapy (11.1%) (p 0.67) [2].…”

Disease Severity Is an Independent Risk Factor of Mortality and Outcomes in Critically Ill Patients With Carbapenem-resistant Klebsiella Pneumoniae Bloodstream Infections: a 5-year Retrospective Analysis

“…A recent retrospective cohort study found that combination therapies, mostly polymyxin B plus amikacin, had signi cantly lower 30-day mortality rates than monotherapies (37.5% vs. 64.75%, p = 0.01) in 82 patients with CRKP-BSIs (28). However, reports still emerge of inadequate dosages, treatment failures, adverse effects, and heterogeneous resistance during polymyxin B treatment (29).…”