Reversible Evolution of Ceftazidime-Avibactam Resistance Driven by blaKPC-71 and Aerobactin Loss in ST11-KL64 Hypervirulent Klebsiella Pneumoniae
Abstract
Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a major global health threat, and the emergence of ceftazidime-avibactam (CZA)-resistant KPC variants presents an increasing clinical challenge. This study aimed to investigate the in vivo evolution and phenotypic difference of a KPC-2 variant, KPC-71, during CZA therapy. Methods: Seven CRKP isolates were sequentially collected from a single hospitalized patient over a 147-day period. Whole-genome sequencing, phylogenetic analysis, plasmid profiling, antimicrobial susceptibility testing, and virulence assays (including Galleria mellonella infection, siderophore production, and serum resistance) were performed to characterize the evolutionary dynamics and biological consequences of KPC-71. Results: KPC-71 emerged repeatedly during CZA treatment, replacing KPC-2 and conferring high-level CZA resistance while reducing carbapenem MICs. Withdrawal of CZA resulted in reversion to KPC-2, restoring carbapenem resistance and CZA susceptibility, indicating a reversible resistance trade-off. Phylogenetic analysis revealed clonal expansion of the KPC-71-producing sublineage. Plasmid analysis identified bla KPC genes located on a conserved IncFII/IncR-type plasmid containing an intact ISKpn27- bla KPC -ISKpn6 transposon, while progressive remodeling of an IncFII(pCRY) plasmid in CRKP103 led to chromosomal integration of multiple resistance genes. Notably, the final isolate, CRKP103, exhibited markedly reduced capsule…
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