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

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.

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.

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.

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.

AIDA trial was registered with ClinicalTrials.gov, number NCT01732250 (submitted 19-11-2012).