Colistin Monotherapy versus Combination Therapy for Carbapenem-Resistant Organisms

Keith S Kaye, Dror Marchaim, Visanu Thamlikitkul, Yehuda Carmeli, Cheng-Hsun Chiu, George Daikos, Sorabh Dhar, Emanuele Durante-Mangoni, Achilles Gikas, Anastasia Kotanidou, Mical Paul, Emmanuelle Roilides, Michael Rybak, Michael Samarkos, Matthew Sims, Dora Tancheva, Sotirios Tsiodras, Daniel Kett, Gopi Patel, David Calfee, Leonard Leibovici, Laura Power, Sylvia Munoz-Price, Kurt Stevenson, Laura Susick, Katie Latack, Jolene Daniel, Christine Chiou, George W Divine, Varduhi Ghazyaran, Jason M Pogue, Keith S Kaye, Dror Marchaim, Visanu Thamlikitkul, Yehuda Carmeli, Cheng-Hsun Chiu, George Daikos, Sorabh Dhar, Emanuele Durante-Mangoni, Achilles Gikas, Anastasia Kotanidou, Mical Paul, Emmanuelle Roilides, Michael Rybak, Michael Samarkos, Matthew Sims, Dora Tancheva, Sotirios Tsiodras, Daniel Kett, Gopi Patel, David Calfee, Leonard Leibovici, Laura Power, Sylvia Munoz-Price, Kurt Stevenson, Laura Susick, Katie Latack, Jolene Daniel, Christine Chiou, George W Divine, Varduhi Ghazyaran, Jason M Pogue

Abstract

Background: Pneumonia and bloodstream infections (BSI) due to extensively drug-resistant (XDR) Acinetobacter baumannii, XDR Pseudomonas aeruginosa, and carbapenem-resistant Enterobacterales (CRE) are associated with high mortality rates, and therapeutic options remain limited. This trial assessed whether combination therapy with colistin and meropenem was superior to colistin monotherapy for the treatment of these infections.

Methods: The OVERCOME (Colistin Monotherapy versus Combination Therapy) trial was an international, randomized, double-blind, placebo-controlled trial. We randomly assigned participants to receive colistin (5 mg/kg once followed by 1.67 mg/kg every 8 hours) in combination with either meropenem (1000 mg every 8 hours) or matching placebo for the treatment of pneumonia and/or BSI caused by XDR A. baumannii, XDR P. aeruginosa, or CRE. The primary outcome was 28-day mortality, and secondary outcomes included clinical failure and microbiologic cure.

Results: Between 2012 and 2020, a total of 464 participants were randomly assigned to treatment, and 423 eligible patients comprised the modified intention-to-treat population. A. baumannii was the predominant trial pathogen (78%) and pneumonia the most common index infection (70%). Most patients were in the intensive care unit at the time of enrollment (69%). There was no difference in mortality (43 vs. 37%; P=0.17), clinical failure (65 vs. 58%; difference, 6.8 percentage points; 95% confidence interval [CI], -3.1 to 16.6), microbiologic cure (65 vs. 60%; difference, 4.8 percentage points; 95% CI, -5.6 to 15.2), or adverse events (acute kidney injury, 52 vs. 49% [P=0.55]; hypersensitivity reaction, 1 vs. 3% [P=0.22]; and neurotoxicity, 5 vs. 2% [P=0.29]) between patients receiving monotherapy and combination therapy, respectively.

Conclusions: Combination therapy with colistin and meropenem was not superior to colistin monotherapy for the treatment of pneumonia or BSI caused by these pathogens. (Funded by the National Institute of Allergy and Infectious Diseases, Division of Microbiology and Infectious Diseases protocol 10-0065; ClinicalTrials.gov number, NCT01597973.).

Figures

Figure 1.. Consolidated Standards of Reporting Trials…
Figure 1.. Consolidated Standards of Reporting Trials Flow Diagram for Enrollment in the OVERCOME Trial.
*Includes four patients who received colistin in combination with imipenem. mITT denotes modified intention-to-treat; and OVERCOME, Colistin Monotherapy versus Combination Therapy.
Figure 2.
Figure 2.
Kaplan–Meier Survival Curves for Trial Patients Treated with Combination Therapy (Colistin plus Meropenem) and Monotherapy (Colistin plus Placebo).

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Source: PubMed

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