Emerging resistance to novel β-lactam β-lactamase inhibitor combinations in Klebsiella pneumoniae bearing KPC variants

Abstract

Objective: Klebsiella pneumoniae carbapenemase (KPC) variants, predominantly KPC-2 and KPC-3, are sig- nificant global resistance mechanisms, conferring resistance to many β-lactams, including carbapenems, while remaining susceptible to ceftazidime-avibactam (CZA). Recently, new KPC variants have developed resistance to CZA through mutations, insertions, or deletions in regions such as the -loop, 240-loop (237–243 aa), and 270-loop (266–275 aa). This study investigated collateral resistance to cefiderocol (FDC) and cefepime/zidebactam (FPZ) in isolates with these mutations. Methods: Fifteen clinical KPC-producing Klebsiella spp. isolates representing 15 distinct variants were analysed. Antimicrobial susceptibility testing determined the MICs for CZA, carbapenems, FDC, FPZ, and other antibiotics. Synergy between CZA and FDC was assessed. Whole-genome sequencing (WGS) was used to identify resistance-related mutations. Results: CZA resistance was confirmed in 12/15 variants. Collateral resistance to FDC occurred in eight isolates, with five exhibiting spontaneous resistant subpopulations. Six FDC-resistant strains had muta- tions in the 270-loop (266–275 aa). FPZ resistance was seen in three KPC variants, especially those with mutations in the 270-loop, though many -loop and 240-loop (237–243 aa) mutants remained suscepti- ble. WGS of FDC-resistant subpopulations revealed additional mutations in ompC, rpoC, dksA , and cirA . Conclusions: Emerging CZA-resistant KPC variants often exhibit collateral FDC resistance, with FPZ seen less frequently. Mutations in blaKPC , cirA , and other genes contribute to resistance. Understanding these emerging resistant patterns linked with new KPC variants is crucial to inform therapeutic decisions, as emerging resistance may limit last-line treatment options in clinical settings.