# Activity of cefepime/enmetazobactam against highly multidrug-resistant bacterial isolates recovered from war-associated wounds in Ukraine

## TL;DR

This study tests the effectiveness of cefepime/enmetazobactam against drug-resistant bacteria from war wounds in Ukraine, showing improved but limited success.

## Contribution

The study evaluates cefepime/enmetazobactam against highly resistant war-wound isolates, revealing genotype-phenotype correlations and resistance mechanisms.

## Key findings

- Cefepime/enmetazobactam reduced resistance in Enterobacterales and P. mirabilis compared to cefepime alone.
- Resistance in K. pneumoniae and A. baumannii remained high due to specific genetic factors like OmpK36 and OXA-type carbapenemases.
- Permeability defects and non-target β-lactamases limited the effectiveness of the combination therapy.

## Abstract

Escalating resistance among Gram-negative pathogens limits β-lactam options. Cefepime/enmetazobactam combines a fourth-generation cephalosporin with a class A β-lactamase inhibitor. We evaluated its activity against multidrug, extensive and pandrug-resistant war-wound isolates from Ukraine.

We tested 215 clinical samples (2022–2023) isolated from wounded patients in Ukraine by broth microdilution. Paired comparisons of cefepime monotherapy versus cefepime/enmetazobactam was done to evaluate enmetazobactam. Whole-genome sequencing (n = 83) identified β-lactamases, sequence types and outer-membrane protein alterations.

Across Enterobacterales, resistance decreased from 60.5% (26/43) with cefepime to 27.9% (12/43) with the cefepime/enmetazobactam combination. In K. pneumoniae, resistance declined from 92.6% (75/81) to 74% (60/81) and in P. mirabilis, from 88.9% (8/9) to 11.1% (1/9), respectively. P. aeruginosa showed a modest change [77.8% (23/36) to 58.3% (32/36)], while A. baumannii remained non-susceptible to both cefepime and cefepime/enmetazobactam with the rates of 91.3% (42/46) to 82.6% (36/46), respectively. Genotype–phenotype correlation revealed that in K. pneumoniae, reduced activity was associated with OmpK36 loop-3 insertions, OmpK35 loss and metallo-β-lactamases, whereas selected sequence types lacking these changes were more susceptible. In A. baumannii, OXA-type carbapenemases and blaADC beta-lactamases predominated; isolates lacking type VI secretion, omp33-36 and adhesin genes (ata/bap) demonstrated relatively higher susceptibility to cefepime/enmetazobactam.

Cefepime/enmetazobactam improved susceptibility relative to cefepime, most notably in Enterobacterales, but activity was constrained by permeability defects and non-target β-lactamases. Combination therapy with agents that does not get hydrolysed by MBLs and integrated β-lactamase detection with practical permeability indicators may optimize the clinical use of this combination in high-resistance settings.