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

Abstract

Background Escalating resistance among Gram-negative pathogens limits beta-lactam options. Cefepime/enmetazobactam combines a fourth-generation cephalosporin with a class A beta-lactamase inhibitor. We evaluated its activity against multidrug, extensive and pandrug-resistant war-wound isolates from Ukraine.Materials and methods 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 beta-lactamases, sequence types and outer-membrane protein alterations.Results 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-beta-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.Conclusions Cefepime/enmetazobactam improved susceptibility relative to cefepime, most notably in Enterobacterales, but activity was constrained by permeability defects and non-target beta-lactamases. Combination therapy with agents that does not get hydrolysed by MBLs and integrated beta-lactamase detection with practical permeability indicators may optimize the clinical use of this combination in high-resistance settings.