Servicio de Microbiología and Instituto de Investigación Biomédica A Coruña (INIBIC), Complexo Hospitalario Universitario A Coruña, A Coruña, Spain.
Laboratorio de Referencia para tipado molecular y detección de mecanismos de resistencia a antimicrobianos de Andalucía (PIRASOA). Unidad de Gestión Clínica de Microbiología y Enfermedades Infecciosas, Hospital Universitario Virgen Macarena, Sevilla. Instituto de Biomedicina de Sevilla (IBIS), CSIC, Universidad de Sevilla, Spain; CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain.
Int J Antimicrob Agents. 2024 May;63(5):107150. doi: 10.1016/j.ijantimicag.2024.107150. Epub 2024 Mar 19.
To analyse the impact of the most clinically relevant β-lactamases and their interplay with low outer membrane permeability on the activity of cefiderocol, ceftazidime/avibactam, aztreonam/avibactam, cefepime/enmetazobactam, cefepime/taniborbactam, cefepime/zidebactam, imipenem/relebactam, meropenem/vaborbactam, meropenem/xeruborbactam and meropenem/nacubactam against recombinant Escherichia coli strains.
We constructed 82 E. coli laboratory transformants expressing the main β-lactamases circulating in Enterobacterales (70 expressing single β-lactamase and 12 producing double carbapenemase) under high (E. coli TG1) and low (E. coli HB4) permeability conditions. Antimicrobial susceptibility testing was determined by reference broth microdilution.
Aztreonam/avibactam, cefepime/zidebactam, cefiderocol, meropenem/xeruborbactam and meropenem/nacubactam were active against all E. coli TG1 transformants. Imipenem/relebactam, meropenem/vaborbactam, cefepime/taniborbactam and cefepime/enmetazobactam were also highly active, but unstable against most of MBL-producing transformants. Combination of β-lactamases with porin deficiency (E. coli HB4) did not significantly affect the activity of aztreonam/avibactam, cefepime/zidebactam, cefiderocol or meropenem/nacubactam, but limited the effectiveness of the rest of carbapenem- and cefepime-based combinations. Double-carbapenemase production resulted in the loss of activity of most of the compounds tested, an effect particularly evident for those E. coli HB4 transformants in which MBLs were present.
Our findings highlight the promising activity that cefiderocol and new β-lactam/β-lactamase inhibitors have against recombinant E. coli strains expressing widespread β-lactamases, including when these are combined with low permeability or other enzymes. Aztreonam/avibactam, cefiderocol, cefepime/zidebactam and meropenem/nacubactam will help to mitigate to some extent the urgency of new compounds able to resist MBL action, although NDM enzymes represent a growing challenge against which drug development efforts are still needed.
分析最具临床相关性的β-内酰胺酶及其与低外膜通透性的相互作用对头孢地尔、头孢他啶/阿维巴坦、氨曲南/阿维巴坦、头孢吡肟/恩美曲巴坦、头孢吡肟/替加环素、头孢吡肟/唑巴坦、亚胺培南/雷利巴坦、美罗培南/沃巴坦、美罗培南/克卢巴坦和美罗培南/那卢巴坦对重组大肠埃希菌的活性的影响。
我们构建了 82 株大肠埃希菌实验室转化株，在高通透性（大肠埃希菌 TG1）和低通透性（大肠埃希菌 HB4）条件下表达肠杆菌科中循环的主要β-内酰胺酶（70 株表达单一β-内酰胺酶，12 株产生双重碳青霉烯酶）。通过参考肉汤微量稀释法测定抗菌药物敏感性。
氨曲南/阿维巴坦、头孢吡肟/唑巴坦、头孢地尔、美罗培南/克卢巴坦和美罗培南/那卢巴坦对所有大肠埃希菌 TG1 转化株均具有活性。亚胺培南/雷利巴坦、美罗培南/沃巴坦、头孢吡肟/替加环素和头孢吡肟/恩美曲巴坦也具有高度活性，但对大多数产 MBL 转化株不稳定。β-内酰胺酶与孔蛋白缺陷（大肠埃希菌 HB4）的组合并没有显著影响氨曲南/阿维巴坦、头孢吡肟/唑巴坦、头孢地尔或美罗培南/那卢巴坦的活性，但限制了其余基于碳青霉烯类和头孢吡肟类的组合的有效性。双重碳青霉烯酶的产生导致大多数测试化合物的活性丧失，这一效应在那些存在 MBL 的大肠埃希菌 HB4 转化株中尤为明显。
我们的研究结果突出了头孢地尔和新型β-内酰胺/β-内酰胺酶抑制剂对表达广泛的β-内酰胺酶的重组大肠埃希菌菌株具有的有前景的活性，包括在这些菌株与低通透性或其他酶结合时。氨曲南/阿维巴坦、头孢地尔、头孢吡肟/唑巴坦和美罗培南/那卢巴坦将在一定程度上有助于缓解对能够抵抗 MBL 作用的新化合物的迫切需求，尽管 NDM 酶是一个日益严峻的挑战，但仍需要为此类药物的开发做出努力。
