Shen Siquan, Deng Xiren, Guo Lu, Yang Li, Yu Hua, Hu Fupin, Huang Xiangning
Institute of Antibiotics, Huashan Hospital, Fudan University, 12 M. Wulumuqi Road, Shanghai, 200040, China.
Key Laboratory of Clinical Pharmacology of Antibiotics, Ministry of Health, Shanghai, China.
Eur J Clin Microbiol Infect Dis. 2025 Jun 14. doi: 10.1007/s10096-025-05180-y.
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.
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.
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.
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.
肺炎克雷伯菌中头孢他啶-阿维巴坦耐药性的出现构成了重大的公共卫生威胁，这是由bla基因突变驱动的。本研究调查了治疗期间KPC变体（KPC-33、KPC-84、KPC-190）的演变，强调了它们对耐药谱的影响和治疗挑战。了解这些机制对于指导临床干预至关重要。
从一名接受头孢他啶-阿维巴坦治疗的患者中分离出四株肺炎克雷伯菌菌株。使用抗菌药物敏感性测试和生物信息学工具来表征基因突变及其表型效应。进行全基因组测序、克隆和酶动力学分析以分析耐药机制。
该研究确定了KPC-2的Ω环和240环中的突变，导致阿维巴坦亲和力降低和头孢他啶水解增加。KPC-33恢复了对碳青霉烯类药物的敏感性，而KPC-84和KPC-190则赋予双重耐药性。酶分析证实了动力学参数的改变，这与临床耐药模式相关。
KPC变体在抗生素压力下表现出复杂的进化途径，使治疗复杂化。建议加强监测并优化给药方案，包括提高阿维巴坦浓度，以减轻耐药性。本研究强调了对KPC变体进行全球监测以指导治疗策略的必要性。
