Journal Article

Carbapenem-resistant Enterobacterales (CRE) acquisition and molecular characterization following colistin monotherapy and colistin-meropenem combination therapy: findings from the AIDA randomized trial

Neuberger, Ami, Kaplan, Ella, Dishon Benattar, Yael, Stern, Anat, Bernardo, Mariano, Carmeli, Yehuda, Skiada, Anna, Lurie-Weinberger, Mor, Friberg, Lena, Amar Ben Dalak, Maayan, Daikos, George, Lellouche, Jonathan, Nutman, Amir, Temkin, Elizabeth, Theuretzbacher, Ursula, Iossa, Domenico, Daitch, Vered, Paul, Mical, Pavleas, Ioannis, Durante-Mangoni, Emanuele, Eliakim-Raz, Noa, Leibovici, Leonard

2025

Overview

Background Colistin-carbapenem combination therapy is frequently used for carbapenem-resistant Gram-negative infections, but its impact on subsequent acquisition of carbapenem-resistant Enterobacterales (CRE) requires further investigation. We evaluated the incidence of CRE acquisition and performed molecular characterization of recovered isolates following treatment with colistin–meropenem versus colistin monotherapy. Methods This analysis addressed a pre-specified secondary aim of the AIDA multicenter randomized controlled trial, which compared colistin monotherapy to colistin–meropenem combination therapy for carbapenem-resistant Gram-negative infections at six hospitals in Israel, Greece, and Italy. Rectal swabs were obtained at enrollment and weekly until day 28 or discharge. Swabs were processed centrally by plating onto MacConkey agar supplemented with imipenem to selectively isolate CRE. Recovered colonies were identified using MALDI-TOF mass spectrometry, and meropenem minimum inhibitory concentrations (MICs) were determined by broth microdilution. Clinical cultures were obtained as indicated and processed locally, and CRE isolates were sent to the central laboratory for confirmation and characterization. Whole-genome sequencing was used to determine sequence types and resistance genes. Patients were excluded if they had CRE detected at baseline, either by rectal culture or as the index clinical isolate, or if no follow-up rectal cultures were available. Results Among 197 eligible patients (99 colistin; 98 colistin–meropenem), CRE acquisition occurred in 6 (3.0%): 1/99 (1.0%, 95% CI 0.03–5.5%) in the monotherapy arm and 5/98 (5.1%, 95% CI 1.7–11.5%) in the combination arm ( p  = 0.12). Two patients in the combination arm developed clinical infections caused by CRE (bacteremia and pneumonia); none occurred in the monotherapy arm. Carbapenemase genes were detected in four of the six acquired CRE isolates: one in the monotherapy arm ( bla VIM ) and three in the combination arm (all bla KPC ). Identified species included Klebsiella pneumoniae and Escherichia coli belonging to established and emerging high-risk, multidrug-resistant clones. Conclusions Patients treated with colistin-meropenem had a higher, though not statistically significant, rate of CRE acquisition. Early detection of high-risk CRE clones highlights the need to weigh potential unintended consequences when selecting combination regimens for multidrug-resistant infections. Trial Registration AIDA trial was registered with ClinicalTrials.gov, number NCT01732250 (submitted 19-11-2012).

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Aged / Anti-Bacterial Agents - pharmacology / Anti-Bacterial Agents - therapeutic use / Antibiotics / Antimicrobial resistance / Biomedical and Life Sciences / Biomedicine / Carbapenem-resistant Enterobacterales (CRE) / Carbapenem-Resistant Enterobacteriaceae - drug effects / Carbapenem-Resistant Enterobacteriaceae - genetics / Carbapenem-Resistant Enterobacteriaceae - isolation & purification / Carbapenemase-producing Enterobacterales (CPE) / Carbapenems - pharmacology / Catheters / Clinical trials / Colistin / Colistin - pharmacology / Colistin - therapeutic use / Colonization / Combination therapy / Combination treatment / Comparative analysis / CRE acquisition / Drug Resistance / Drug resistance in microorganisms / Drug Resistance, Multiple, Bacterial / Drug Therapy, Combination / E coli / Enrollments / Enterobacteriaceae Infections - drug therapy / Enterobacteriaceae Infections - epidemiology / Enterobacteriaceae Infections - microbiology / Female / Genes / Genetic aspects / Greece - epidemiology / Hemodialysis / Hemodynamics / Hospital patients / Humans / Infection / Infections / Infectious Diseases / Israel - epidemiology / Italy - epidemiology / Male / Mass spectrometry / Medical Microbiology / Meropenem / Meropenem - pharmacology / Meropenem - therapeutic use / Microbial Sensitivity Tests / Middle Aged / Mortality / Ventilation / Ventilators / Whole-genome sequencing