新型β-内酰胺酶抑制剂复合制剂对碳青霉烯耐药肺炎克雷伯菌体外药物敏感性研究

doi:10.19871/j.cnki.xfcrbzz.2025.06.004

摘要/Abstract

摘要： 目的通过生物信息学分析与体外药物敏感性试验,系统阐明碳青霉烯耐药肺炎克雷伯菌（Carbapenem-resistant Klebsiella pneumoniae,CRKP）对多种新型β-内酰胺酶抑制剂复合制剂的敏感性,为临床抗感染治疗方案的优化提供科学依据。方法采用微量肉汤稀释法对2023年3月至8月期间贵州医科大学附属医院临床标本分离的146株CRKP进行体外药物敏感试验,评估瑞来巴坦、法硼巴坦、阿维巴坦和他尼硼巴坦联合用药方案的敏感性。同时完成146株CRKP的全基因组测序分析,运用Kleborate软件解析菌株的分子遗传学特征,并通过Snippy工具构建系统发育树。结果药物敏感试验显示,含新型β-内酰胺酶抑制剂的复合制剂（亚胺培南-瑞来巴坦、美罗培南-法硼巴坦、头孢他啶-阿维巴坦、氨曲南-阿维巴坦、头孢吡肟-他尼硼巴坦）较单药抗菌活性显著增强,最低抑菌浓度（minimal inhibit concentration,MIC）下降至单药的1/32或更低,所有复合制剂敏感度均>90.0%,其中氨曲南-阿维巴坦和头孢吡肟-他尼硼巴坦敏感度分别为100.0%和99.3%,抗菌效果最为突出。分子特征分析表明,ST11（84.2%）和KL64（79.4%）型菌株为优势流行株。碳青霉烯类耐药主要由bla_KPC-2基因型（90.4%）介导,同时外膜孔蛋白K35（91.8%）和外膜孔蛋白K36（84.3%）高频突变也发挥着重要作用。系统发育树分析显示多克隆传播特征,产OXA-232型碳青霉烯酶的菌株呈现聚集性分布,提示其可能具有特定的适应性优势。结论新型β-内酰胺酶抑制剂复合制剂对CRKP展现出显著的抗菌活性,但耐药菌株的出现提示需进一步探究耐药机制并加强流行病学监测。

关键词: 碳青霉烯耐药肺炎克雷伯菌, 新型β-内酰胺酶抑制剂, 体外药物敏感性

Abstract: Objective To systematically elucidate the susceptibility profiles of carbapenem-resistant Klebsiella pneumoniae (CRKP) to novel β-lactamase inhibitor combinations through integrated bioinformatics analysis and in vitro antimicrobial susceptibility testing, thereby providing scientific evidence for optimizing clinical anti-infective treatment strategies. Method Performed broth micr-dilution assays to evaluate the susceptibility of 146 CRKP clinical isolates (collected from March to August 2023) to relebactam-, vaborbactam-, avibactam-, and taniborbactam-based combination regimens. Whole-genome sequencing was conducted, and molecular characteristics were analyzed using Kleborate. Phylogenetic reconstruction was performed using Snippy. Result Antimicrobial susceptibility testing demonstrated that β-lactam/β-lactamase inhibitor combinations (imipenem-relebactam, meropenem-vaborbactam, ceftazidime-avibactam, aztreonam-avibactam, fcefepime-taniborbactam) exhibited significantly enhanced activity compared to monotherapies, with minimum inhibitory concentrations (MICs) decreased to 1/32 of the original value or lower, the susceptibility rates of all tested compound formulations exceeded 90%. Aztreonam-Avibactam (100%) and Fcefepime-Taniborbactam (99.3%) showed the highest efficacy. Molecular analysis revealed ST11 (84.2%) and KL64 (79.4%) as predominant sequence and capsular types, respectively. Carbapenem resistance was primarily mediated by bla_KPC-2 (90.4%), while high-frequency mutations in OmpK35 (91.8%) and OmpK36 (84.3%) also constituted the resistance mechanisms. Phylogenetic analysis indicated polyclonal transmission, with OXA-232-producing strains forming distinct clusters, suggesting potential adaptive advantages. Conclusion Novel β-lactamase inhibitor combinations demonstrated potent activity against CRKP isolates in our hospital. However, the emergence of resistant strains underscores the need for further investigation into resistance mechanisms and enhanced epidemiological surveillance.

Key words: Carbapenem-resistant Klebsiella pneumoniae, Novel β-lactamase inhibitors, In vitro antimicrobial susceptibility

中图分类号:

R378
R56

马克, 张宝芳, 徐伟, 张权. 新型β-内酰胺酶抑制剂复合制剂对碳青霉烯耐药肺炎克雷伯菌体外药物敏感性研究[J]. 新发传染病电子杂志, 2025, 10(6): 24-31.

Ma Ke, Zhang Baofang, Xu Wei, Zhang Quan. Activity of novel β-lactamase inhibitor combinations against carbapenem-resistant Klebsiella pneumoniae: an in vitro study[J]. Electronic Journal of Emerging Infectious Diseases, 2025, 10(6): 24-31.

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