Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Clinical Pharmacology of Antibiotics, Ministry of Health, Shanghai, China.
Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Clinical Pharmacology of Antibiotics, Ministry of Health, Shanghai, China.
Int J Antimicrob Agents. 2024 Aug;64(2):107228. doi: 10.1016/j.ijantimicag.2024.107228. Epub 2024 May 31.
The rapid dissemination of carbapenem-resistant Enterobacterales (CRE) especially carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a great threat to global public health. Ceftazidime-avibactam, a novel β-lactam/β-lactamase inhibitor combination, has been widely used due to its excellent antibacterial activity against KPC-producing K. pneumoniae. However, several resistance mechanisms have been reported since its use. Here, we conducted a series of in vitro experiments to reveal and demonstrate the dynamic evolution of ceftazidime-avibactam resistance including interspecies IncX3_NDM-5 plasmid transfer between Enterobacter cloacae and K. pneumoniae and bla mutation from bla to bla. Through the analysis of conjugation frequency and fitness cost, the IncX3_NDM-5 plasmid in this study showed strong transmissibility and stability in E. coli EC600 and clinical strain K. pneumoniae 5298 as recipient strain. With increasing ceftazidime-avibactam concentration, the conjugation frequency remained at 10-10, while the mutation frequency of K. pneumoniae 5298 was 10-10 at the same concentration. Further plasmid analysis (the IncX3_NDM plasmid from this study and other 658 plasmids from the NCBI database) revealed the diverse origin and genetic structure of bla carrying plasmids. E. coli (42.9%), China (43.9%), IncX3 (66.6%) are the most common strains, regions, and Inc types respectively. By analysing of genetic environment detected in IncX3 plasmids, the dominant structures (168/258, 65.1%) were identified: ISKox3-IS26-bla-IS5-ISAba125-Tn3000-Tn3. In additon, several structural variations were found in the core gene structure. In conclusion, the high fitness and transmissibility of the IncX3_NDM-5 plasmids were noteworthy. More importantly, the diverse ceftazidime-avibactam resistance mechanisms including bla tranfer and bla mutation highlighted the importance of the continuous monitoring of antimicrobial susceptibility and carbapenemases subtype during ceftazidime-avibactam treatment.
碳青霉烯类耐药肠杆菌科（CRE），尤其是碳青霉烯类耐药肺炎克雷伯菌（CRKP）的快速传播对全球公共健康构成了巨大威胁。头孢他啶-阿维巴坦作为一种新型的β-内酰胺/β-内酰胺酶抑制剂复合制剂，由于对产 KPC 肺炎克雷伯菌具有良好的抗菌活性而被广泛应用。然而，自其使用以来，已经报道了几种耐药机制。在这里，我们进行了一系列的体外实验，揭示并证明了头孢他啶-阿维巴坦耐药性的动态演变，包括肠杆菌属和肺炎克雷伯菌之间的种间 IncX3_NDM-5 质粒转移，以及 bla 从 bla 到 bla 的突变。通过接合频率和适应性代价的分析，本研究中的 IncX3_NDM-5 质粒在 E. coli EC600 和临床分离株肺炎克雷伯菌 5298 作为受体菌时表现出很强的可传递性和稳定性。随着头孢他啶-阿维巴坦浓度的增加，接合频率保持在 10-10，而在相同浓度下，肺炎克雷伯菌 5298 的突变频率为 10-10。进一步的质粒分析（本研究中的 IncX3_NDM 质粒和 NCBI 数据库中的其他 658 个质粒）揭示了携带 bla 的质粒的多样化起源和遗传结构。E. coli（42.9%）、中国（43.9%）、IncX3（66.6%）分别是最常见的菌株、地区和 Inc 类型。通过分析 IncX3 质粒中检测到的遗传环境，确定了优势结构（168/258，65.1%）：ISKox3-IS26-bla-IS5-ISAba125-Tn3000-Tn3。此外，在核心基因结构中还发现了几种结构变异。总之，IncX3_NDM-5 质粒的高适应性和可传递性值得关注。更重要的是，包括 bla 转移和 bla 突变在内的多种头孢他啶-阿维巴坦耐药机制强调了在头孢他啶-阿维巴坦治疗期间持续监测抗菌药物敏感性和碳青霉烯酶亚型的重要性。
