Infection and drug resistance · 2025
Reversible Evolution of Ceftazidime-Avibactam Resistance Driven by bla KPC-71 and Aerobactin Loss in ST11-KL64 Hypervirulent Klebsiella Pneumoniae.
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Yang Zhuoyuan, Xu Si, Xiao Zhiyou, Xu Derong, Tao Qiaozhen
Аннотация
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 production, siderophore activity, serum survival, and attenuated virulence in G. mellonella, which associated with the loss of the iucABCD/iutA locus on an IncHI1B-type virulence plasmid. Functional validation confirmed that KPC-71 expression alone conferred high-level CZA resistance while modulating susceptibility to other β-lactams.
CONCLUSION: This study provides the first clinical evidence of the reversible in vivo evolution of an insertional KPC-71 variant under antibiotic pressure. The findings reveal a dynamic balance between resistance and virulence mediated by bla KPC mutations and plasmid remodeling, highlighting the risk of resistance cycling during CZA treatment and the need for genomic surveillance in managing CRKP infections.
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 production, siderophore activity, serum survival, and attenuated virulence in G. mellonella, which associated with the loss of the iucABCD/iutA locus on an IncHI1B-type virulence plasmid. Functional validation confirmed that KPC-71 expression alone conferred high-level CZA resistance while modulating susceptibility to other β-lactams.
CONCLUSION: This study provides the first clinical evidence of the reversible in vivo evolution of an insertional KPC-71 variant under antibiotic pressure. The findings reveal a dynamic balance between resistance and virulence mediated by bla KPC mutations and plasmid remodeling, highlighting the risk of resistance cycling during CZA treatment and the need for genomic surveillance in managing CRKP infections.