Tellapragada Chaitanya, Dunleavy Chantel, Jonsson Patrik, Giske Christian G
Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.
Department of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden.
J Antimicrob Chemother. 2025 Apr 2;80(4):1137-1140. doi: 10.1093/jac/dkaf045.
We aimed to investigate the in vitro activity and genetic determinants of decreased susceptibility (DS; MIC > 4 mg/L) to cefepime/zidebactam of carbapenemase-producing Escherichia coli.
Clinical isolates (N = 150) of carbapenemase-producing E. coli (CP-EC) belonging to seven distinct STs, isolated at a university clinical microbiology laboratory during 2019-2023 in Stockholm, Sweden were included. MICs for cefepime/zidebactam were determined using the broth microdilution method and interpreted using the tentative EUCAST clinical breakpoints (Susceptible; MIC < 4 mg/L; based on cefepime breakpoint). Whole genome sequences of the isolates were analysed with an emphasis on identifying alterations in PBPs 2 and 3.
Of the 150 isolates, 145 (96.6%) isolates had MICs <4 mg/L indicating susceptibility and 5 (3.3%) had MICs >4 mg/L. MICs for zidebactam alone among the five isolates with DS to cefepime/zidebactam were ≥8 mg/L. WGS analysis revealed that these five isolates were NDM-5 producers and belonged to ST405 (n = 1), ST410 (n = 2) and ST648 (n = 2). Presence of four-amino-acid inserts (YRIK/YRIN) in PBP3 was observed in 80/150 (53.3%) isolates, and mutations leading to alterations in PBP2 were observed in 41/150 (27.3%) isolates. Presence of other β-lactamases (CTX-M group) and/or cephalosporinases (blaCMY) did not have an impact on the susceptibility to cefepime/zidebactam. Three of the five isolates with DS had a V522I substitution in PBP2.
Our results indicate that DS to cefepime/zidebactam among clinical isolates of E. coli could arise due to targeted mutations in PBP2.
我们旨在研究产碳青霉烯酶大肠埃希菌对头孢吡肟/齐他美汀敏感性降低（DS；MIC＞4mg/L）的体外活性及遗传决定因素。
纳入2019年至2023年期间在瑞典斯德哥尔摩一所大学临床微生物实验室分离出的属于7个不同序列型（STs）的产碳青霉烯酶大肠埃希菌（CP-EC）临床分离株（N = 150株）。采用肉汤微量稀释法测定头孢吡肟/齐他美汀的MIC，并根据暂定的欧盟CAST临床断点（敏感；MIC＜4mg/L；基于头孢吡肟断点）进行判读。对分离株的全基因组序列进行分析，重点是鉴定青霉素结合蛋白（PBPs）2和3的改变。
150株分离株中，145株（96.6%）的MIC＜4mg/L，表明敏感，5株（3.3%）的MIC＞4mg/L。在对头孢吡肟/齐他美汀敏感性降低的5株分离株中，单独齐他美汀的MIC≥8mg/L。全基因组测序分析显示，这5株分离株均产NDM-5，分别属于ST405（n = 1）、ST410（n = 2）和ST648（n = 2）。在150株分离株中有80株（53.3%）观察到PBP3中存在四氨基酸插入（YRIK/YRIN），在41株（27.3%）分离株中观察到导致PBP2改变的突变。其他β-内酰胺酶（CTX-M组）和/或头孢菌素酶（blaCMY）的存在对头孢吡肟/齐他美汀的敏感性没有影响。5株敏感性降低的分离株中有3株PBP2发生了V522I替换。
我们的结果表明，大肠埃希菌临床分离株对头孢吡肟/齐他美汀敏感性降低可能是由于PBP2的靶向突变所致。
