In a concerning development for infectious disease management, researchers have identified the emergence of ceftazidime-avibactam resistance in Klebsiella pneumoniae during the course of therapy, driven by novel mutations in KPC enzymes. These findings raise important clinical implications for managing carbapenem-resistant Enterobacteriaceae in hospitalized patients.
The study focused on a single patient undergoing treatment with ceftazidime-avibactam, from whom four sequential K. pneumoniae strains were isolated. Through antimicrobial susceptibility testing and whole genome sequencing, investigators documented the evolution of key KPC variants—specifically KPC-33, KPC-84, and KPC-190—that altered the bacteria’s resistance profile.
The underlying mechanism was traced to mutations in critical structural regions of the KPC-2 β-lactamase enzyme, namely the Ω-loop and 240-loop. These mutations reduced avibactam binding affinity and simultaneously increased the bacteria’s ability to hydrolyze ceftazidime, leading to significant therapeutic resistance. KPC-33 interestingly restored susceptibility to carbapenems, while KPC-84 and KPC-190 conferred dual resistance to both carbapenems and ceftazidime-avibactam.
Enzyme kinetic assays confirmed that these mutations significantly altered the catalytic properties of the enzymes, correlating with observed clinical resistance. The researchers emphasize that these adaptive shifts illustrate the complex evolutionary pathways of KPC variants under antibiotic pressure.
These findings highlight the necessity for enhanced genomic surveillance, as well as a reassessment of therapeutic strategies, potentially including increased avibactam dosing, to stay ahead of resistance trends. The rapid evolution of resistance even during treatment underscores the urgent need for continuous monitoring and tailored antimicrobial stewardship programs.
This study adds to the growing body of evidence that resistance can evolve dynamically in response to selective pressure, and supports a proactive approach in the clinical management of multidrug-resistant Gram-negative infections.
Reference:
Shen S et al. Emergence of ceftazidime-avibactam resistance in clinical Klebsiella pneumoniae during therapy. Eur J Clin Microbiol Infect Dis. 2025. doi: 10.1007/s10096-025-05180-y.
