# In Vitro Evaluation of Colistin–Meropenem Activity Against XDR and PDR Carbapenemase-Producing Klebsiella pneumoniae and Acinetobacter baumannii

## TL;DR

This study tests the effectiveness of combining colistin and meropenem against highly drug-resistant bacteria, finding it can reduce antibiotic doses and toxicity.

## Contribution

The study provides new evidence on synergy and dose optimization of colistin-meropenem against XDR/PDR bacteria.

## Key findings

- The colistin-meropenem combination showed synergy in 35.5% of Klebsiella and 40.7% of Acinetobacter isolates.
- Time-kill assays confirmed bactericidal activity at higher concentrations, suggesting dose-dependent efficacy.
- Genes blaNDM and blaOxa-48 were associated with reduced synergy in the combination therapy.

## Abstract

Carbapenem-resistant Klebsiella pneumoniae (CRKP) and Acinetobacter baumannii (CRAB) pose significant therapeutic challenges due to their high resistance and global spread. Combination therapy with colistin (COL) and meropenem (MEM) was used to enhance antimicrobial activity. This study evaluated the COL-MEM combination against CRKP and CRAB isolates with a high resistance profile. A total of 58 carbapenem-resistant clinical isolates (31 CRKP and 27 CRAB), including extensively resistant and pandrug-resistant strains, were collected over a period of 12 months. Synergy between COL and MEM was assessed by microdilution checkerboard (MCB) and time-kill (TKA) assays. Carbapenemase genes were detected using molecular methods. The results showed that the COL-MEM combination yielded synergy (35.5% and 40.7%, respectively) and additive effects (35.5% and 37.0%, respectively), while no antagonism was observed. TKA confirmed bactericidal activity, especially at doubled MCB-detected concentrations, indicating dose-dependent activity. The significant reduction in the minimum inhibitory concentration in the combination indicated its potential for dose optimization, minimizing COL-associated toxicities. Genotypic profiling showed that the expression of blaNDM and blaOxa-48 can reduce synergy. These findings, obtained with isolates of high resistance, support the efficacy of this combination therapy and could reduce the dose-related side effects of COL. However, they also highlight genotype-specific variations and COL resistance mechanisms as limiting variables.