孔蛋白缺乏对可乐定与β-内酰胺/β-内酰胺酶抑制剂联用抗产 ESBL 和碳青霉烯酶肺炎克雷伯菌协同作用潜力的影响。

IF 4.1 2区 医学 Q2 MICROBIOLOGY
Antimicrobial Agents and Chemotherapy Pub Date : 2024-11-06 Epub Date: 2024-10-04 DOI:10.1128/aac.00762-24
Lisa Allander, Karin Vickberg, Elin Fermér, Thomas Söderhäll, Linus Sandegren, Pernilla Lagerbäck, Thomas Tängdén
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引用次数: 0

摘要

体外试验显示,可乐定与β-内酰胺/β-内酰胺酶抑制剂(BLBLIs)的组合对产β-内酰胺酶菌株有协同作用。然而,数据有限且相互矛盾,这可能归因于所研究菌株之间的差异。本研究调查了孔蛋白 OmpK35 和 OmpK36 的缺失是否会影响可乐定与头孢唑肟-阿维巴坦或美罗培南-阿维巴坦联用对产β-内酰胺酶肺炎克雷伯菌的协同作用潜力。通过将 blaCTX-M-15、blaKPC-2 和 blaOXA-48 染色体导入肺炎克雷伯菌 ATCC 35657,构建了转基因菌株,其中主要的孔蛋白编码基因(ompK35 和 ompK36)要么保持完整,要么被敲除。通过延时显微镜筛选和静态时间杀伤实验,评估了可乐定与头孢他啶-阿维巴坦或美罗培南-阿维巴坦联合使用的体外活性。在产β-内酰胺酶菌株中删除孔蛋白后,β-内酰胺酶和 BLBLIs 的 MICs 增加了 2 到 128 倍。阿维菌素的活性与浓度有关,在失去孔蛋白的菌株中,要达到类似的β-内酰胺酶抑制效果,需要4-16倍的高浓度。在筛选过程中,观察到秋水仙素和头孢他啶-阿维巴坦对 CTX-M-15 产菌株的协同作用,以及秋水仙素和美罗培南-阿维巴坦对 KPC-2 和 OXA-48 产菌株的协同作用。在时间致死实验中,联合用药的效果并不明显,很少发现协同作用。在 OmpK35 和 OmpK36 的缺失与秋水仙碱和 BLBLIs 的组合效果之间没有发现明显的关联,这表明还有其他因素决定了此类组合的协同潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Impact of porin deficiency on the synergistic potential of colistin in combination with β-lactam/β-lactamase inhibitors against ESBL- and carbapenemase-producing Klebsiella pneumoniae.

Combinations of colistin and β-lactam/β-lactamase inhibitors (BLBLIs) have shown in vitro synergy against β-lactamase-producing strains. However, data are limited and conflicting, potentially attributed to variations among the examined strains. This study investigated whether loss of porins OmpK35 and OmpK36 impacts the synergistic potential of colistin in combination with ceftazidime-avibactam or meropenem-avibactam against β-lactamase-producing Klebsiella pneumoniae. Genetically modified strains were constructed by introducing blaCTX-M-15, blaKPC-2, and blaOXA-48 chromosomally into K. pneumoniae ATCC 35657, in which the major porin-encoding genes (ompK35, ompK36) were either intact or knocked out. The in vitro activity of colistin in combination with ceftazidime-avibactam or meropenem-avibactam was evaluated by time-lapse microscopy screening and in static time-kill experiments. The deletion of porins in the β-lactamase-producing strains resulted in 2- to 128-fold increases in MICs for the β-lactams and BLBLIs. The activity of avibactam was concentration-dependent, and 4- to 16-fold higher concentrations were required to achieve similar inhibition of the β-lactamases in strains with porin loss. In the screening, synergy was observed for colistin and ceftazidime-avibactam against the CTX-M-15-producing strains and colistin and meropenem-avibactam against the KPC-2- and OXA-48-producing strains. The combination effects were less pronounced in the time-kill experiments, where synergy was rarely detected. No apparent associations were found between the loss of OmpK35 and OmpK36 and combination effects with colistin and BLBLIs, indicating that additional factors determine the synergistic potential of such combinations.

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来源期刊
CiteScore
10.00
自引率
8.20%
发文量
762
审稿时长
3 months
期刊介绍: Antimicrobial Agents and Chemotherapy (AAC) features interdisciplinary studies that build our understanding of the underlying mechanisms and therapeutic applications of antimicrobial and antiparasitic agents and chemotherapy.
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