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已发表论文
由 blaKPC-71 和铁载体气单胞菌素缺失驱动的 ST11-KL64 型高毒力肺炎克雷伯菌中头孢他啶-阿维巴坦耐药性的可逆进化
Authors Yang Z, Xu S, Xiao Z, Xu D, Tao Q
Received 15 September 2025
Accepted for publication 21 November 2025
Published 6 December 2025 Volume 2025:18 Pages 6407—6420
DOI https://doi.org/10.2147/IDR.S565339
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Hazrat Bilal
Zhuoyuan Yang,1 Si Xu,2,3 Zhiyou Xiao,2,3 Derong Xu,2,3 Qiaozhen Tao1
1Department of Psychosomatic Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330000, People’s Republic of China; 2Jiangxi Institute of Translational Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330000, People’s Republic of China; 3Jiangxi Key Laboratory of Drug Target Discovery and Validation, Jiangxi Medical College, Nanchang University, Jiangxi, 330000, People’s Republic of China
Correspondence: Qiaozhen Tao, Email ndyfy05436@ncu.edu.cn
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 blaKPC genes located on a conserved IncFII/IncR-type plasmid containing an intact ISKpn27-blaKPC-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 blaKPC mutations and plasmid remodeling, highlighting the risk of resistance cycling during CZA treatment and the need for genomic surveillance in managing CRKP infections.
Keywords: Klebsiella pneumoniae, ST11-KL64, KPC-71, virulence, resistance
1Department of Psychosomatic Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330000, People’s Republic of China; 2Jiangxi Institute of Translational Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330000, People’s Republic of China; 3Jiangxi Key Laboratory of Drug Target Discovery and Validation, Jiangxi Medical College, Nanchang University, Jiangxi, 330000, People’s Republic of China
Correspondence: Qiaozhen Tao, Email ndyfy05436@ncu.edu.cn
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 blaKPC genes located on a conserved IncFII/IncR-type plasmid containing an intact ISKpn27-blaKPC-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 blaKPC mutations and plasmid remodeling, highlighting the risk of resistance cycling during CZA treatment and the need for genomic surveillance in managing CRKP infections.
Keywords: Klebsiella pneumoniae, ST11-KL64, KPC-71, virulence, resistance