Abstract

Background

Recent reports reveal the emergence of Escherichia coli isolates harbouring a novel resistance mechanism based on four-amino-acid inserts in PBP3. These organisms concomitantly expressed ESBLs or/and serine-/metallo-carbapenemases and were phenotypically detected by elevated aztreonam/avibactam MICs.

Objectives

The in vitro activities of the investigational antibiotic cefepime/zidebactam and approved antibiotics (ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/relebactam and others) were determined against E. coli isolates harbouring four-amino-acid inserts in PBP3.

Methods

Whole-genome sequenced E. coli isolates (n = 89) collected from a large tertiary care hospital in Southern India (n = 64) and from 12 tertiary care hospitals located across India (n = 25) during 2016–18, showing aztreonam/avibactam MICs ≥1 mg/L (≥4 times the aztreonam epidemiological cut-off) were included in this study. The MICs of antibiotics were determined using the reference broth microdilution method.

Results

Four-amino-acid inserts [YRIK (n = 30) and YRIN (n = 53)] were found in 83/89 isolates. Among 83 isolates, 65 carried carbapenemase genes [bla_NDM (n = 39), bla_OXA-48-like (n = 11) and bla_NDM + bla_OXA-48-like (n = 15)] and 18 isolates produced ESBLs/class C β-lactamases only. At least 16 unique STs were noted. Cefepime/zidebactam demonstrated potent activity, with all isolates inhibited at ≤1 mg/L. Comparator antibiotics including ceftazidime/avibactam and imipenem/relebactam showed limited activities.

Conclusions

E. coli isolates concurrently harbouring four-amino-acid inserts in PBP3 and NDM are an emerging therapeutic challenge. Assisted by the PBP2-binding action of zidebactam, the cefepime/zidebactam combination overcomes both target modification (PBP3 insert)- and carbapenemase (NDM)-mediated resistance mechanisms in E. coli.

中文翻译：

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头孢吡肟/齐达巴坦抗MDR大肠杆菌分离物的活性具有基于PBP3中四个氨基酸插入片段的新型耐药机制。

摘要

背景

最近的报道揭示了大肠杆菌分离物的出现，该菌株具有基于PBP3中四个氨基酸插入片段的新型耐药机制。这些生物体同时表达ESBLs或/和丝氨酸/金属-卡巴咪唑，并通过氨曲南/ avibactam MIC的升高进行了表型检测。

目标

针对在PBP3中带有四氨基酸插入片段的大肠杆菌分离株，确定了研究用抗生素头孢吡肟/齐达巴坦和已批准的抗生素（头孢他啶/阿维巴坦，头孢洛赞/他唑巴坦，亚胺培南/雷巴坦等）的体外活性。

方法

在2016-18年度期间，从印度南部一家大型三级医院（n =  64）和印度各地的12家三级医院（n =  25）收集的全基因组测序大肠杆菌分离株（n =  89）。这项研究包括≥1 mg / L avibactam MIC（≥4倍于氨曲南流行病学临界值）。使用参考肉汤微稀释法确定抗生素的MIC。

结果

在83/89个分离物中发现了四个氨基酸的插入片段[YRIK（n =  30）和YRIN（n =  53）]。在83个分离株中，有65个带有碳青霉烯酶基因[ bla _NDM（n =  39），bla _OXA-48-like（n =  11）和bla _NDM  +  bla _OXA-48-like（n =  15）]和18个分离株产生了ESBLs /仅C类β-内酰胺酶。至少记录了16个唯一的ST。头孢吡肟/齐达巴坦显示出强效活性，所有分离株的抑制均≤1mg / L。包括头孢他啶/ avibactam和亚胺培南/ relebactam的比较抗生素显示出有限的活性。

结论

同时在PBP3和NDM中带有四个氨基酸插入片段的大肠杆菌分离株是新兴的治疗挑战。通过zidebactam的PBP2结合动作的协助下，头孢吡肟/ zidebactam组合克服了这两个靶修饰（PBP3插入） -在碳青霉烯酶和（NDM）介导的耐药性机制的大肠杆菌。