Comparative activity of established versus new-generation β-lactams against AmpC-hyperproducing clinical isolates of Enterobacter cloacae complex and Klebsiella aerogenes : a multicentre study

Abstract Background Antimicrobial resistance among Enterobacter cloacae complex and Klebsiella aerogenes is a growing clinical challenge, often driven by AmpC β-lactamase hyperproduction. This phenotype limits therapeutic options to cefepime or carbapenems. Objectives To assess the in vitro activity of conventional β-lactams, such as cefepime, piperacillin/tazobactam or carbapenems, and new-generation agents, including ceftazidime/avibactam, cefepime/taniborbactam, imipenem/relebactam, meropenem/vaborbactam, and cefiderocol, against AmpC-hyperproducing E. cloacae complex and K. aerogenes. Methods A total of 314 clinical isolates (200 E. cloacae complex and 114 K. aerogenes) recovered between March and December 2024, from eight Spanish centres were tested by broth microdilution (EUCAST). AmpC hyperproduction was confirmed phenotypically and carbapenemase was screened phenotypically/molecularly. WGS was performed for (i) 84 E. cloacae complex isolates, and (ii) six isolates with reduced susceptibility to at least one novel agent. Results High resistance rates were observed for piperacillin/tazobactam (up to 82.4%) and cefepime (up to 20.5%), whereas carbapenems showed variable activity. New-generation agents exhibited excellent activity, with susceptibility rates ≥99% in both species. Resistance to at least one new agent was found in only six isolates. In the WGS-analysed E. cloacae complex subset, Enterobacter hormaechei predominated (75%) with high STs and blaACT allele diversity. In the six reduced-susceptibility isolates, no carbapenemase or explanatory acquired β-lactamase was found. Conclusions Our findings underscore the need to take this phenotype into account in clinical practice and confirm the limited activity of conventional β-lactams against AmpC-hyperproducing E. cloacae complex and K. aerogenes, and support the use of newer agents as effective alternatives.