Emergence of ceftazidime-avibactam resistance in clinical Klebsiella pneumoniae during therapy.

Abstract

Background: The emergence of ceftazidime-avibactam resistance in Klebsiella pneumoniae poses a significant public health threat, driven by mutations in the bla . This study investigates the evolution of KPC variants (KPC-33, KPC-84, KPC-190) during therapy, highlighting their impact on resistance profiles and treatment challenges. Understanding these mechanisms is critical for guiding clinical interventions.

Methods: Four K. pneumoniae strains were isolated from a patient undergoing ceftazidime-avibactam therapy. Antimicrobial susceptibility testing and bioinformatics tools were used to characterize genetic mutations and their phenotypic effects. Whole genome sequencing, cloning, and enzymatic kinetic assays were performed to analyze resistance mechanisms.

Results: The study identified mutations in the Ω-loop and 240-loop of KPC-2, leading to reduced avibactam affinity and increased ceftazidime hydrolysis. KPC-33 restored carbapenem susceptibility, while KPC-84 and KPC-190 conferred dual resistance. Enzymatic assays confirmed altered kinetic parameters, correlating with clinical resistance patterns.

Conclusions: KPC variants exhibit complex evolutionary pathways under antibiotic pressure, complicating treatment. Enhanced surveillance and optimized dosing regimens, including higher avibactam concentrations, are recommended to mitigate resistance. This study underscores the need for global monitoring of KPC variants to inform therapeutic strategies.