Resistance to piperacillin/tazobactam (TZP) in Escherichia coli has predominantly been associated with mechanisms that confer resistance to third generation cephalosporins. Recent reports have identified E. coli strains with phenotypic resistance to piperacillin/tazobactam but susceptibility to third generation cephalosporins (TZP-R/3GC-S). In this study we sought to determine the genetic diversity of this phenotype in E. coli (n = 58) isolated between 2014-2017 at a single tertiary hospital in Liverpool, UK, as well as the associated resistance mechanisms. We compare our findings to a UK-wide collection of invasive E. coli isolates (n = 1509) with publicly available phenotypic and genotypic data. These data sets included the TZP-R/3GC-S phenotype (n = 68), a piperacillin/tazobactam and third generation cephalosporin-susceptible (TZP-S/3GC-S, n = 1271) phenotypes. The TZP-R/3GC-S phenotype was displayed in a broad range of sequence types which was mirrored in the same phenotype from the UK-wide collection, and the overall diversity of invasive E. coli isolates. The TZP-R/3GC-S isolates contained a diverse range of plasmids, indicating multiple acquisition events of TZP resistance mechanisms rather than clonal expansion of a particular plasmid or sequence type. The putative resistance mechanisms were equally diverse, including hyperproduction of TEM-1, either via strong promoters or gene amplification, carriage of inhibitor resistant β-lactamases, and an S133G b/a_CTX-M-15 mutation detected for the first time in clinical isolates. Several of these mechanisms were present at a lower abundance in the TZP-S/3GC-S isolates from the UK-wide collection, but without the associated phenotypic resistance to TZP. Our findings highlight the complexity of this cryptic phenotype and the need for continued phenotypic monitoring, as well as further investigation to improve detection and prediction of the TZP-R/3GC-S phenotype from genomic data.

中文翻译：

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哌拉西林/他唑巴坦耐药、头孢菌素敏感的大肠杆菌血流感染是由跨不同序列类型的多重耐药性获得驱动的

大肠杆菌对哌拉西林/他唑巴坦 (TZP) 的耐药性主要与赋予第三代头孢菌素耐药性的机制有关。最近的报告已经确定了对哌拉西林/他唑巴坦具有表型抗性但对第三代头孢菌素 (TZP-R/3GC-S) 易感的大肠杆菌菌株。在这项研究中，我们试图确定2014-2017 年间在英国利物浦一家三级医院分离的大肠杆菌（n = 58）中这种表型的遗传多样性，以及相关的耐药机制。我们将我们的发现与英国范围内的侵入性大肠杆菌分离株（n= 1509) 具有公开可用的表型和基因型数据。这些数据集包括 TZP-R/3GC-S 表型(n = 68)、哌拉西林/他唑巴坦和第三代头孢菌素敏感 (TZP-S/3GC-S, n = 1271) 表型。TZP-R/3GC-S 表型显示在广泛的序列类型中，这反映在英国范围内收集的相同表型中，以及侵入性大肠杆菌的整体多样性隔离。TZP-R/3GC-S 分离株含有多种质粒，表明 TZP 抗性机制的多个获取事件，而不是特定质粒或序列类型的克隆扩增。假定的抗性机制同样多样，包括 TEM-1 的过度生产，通过强启动子或基因扩增，携带抑制剂抗性 β-内酰胺酶和 S133G b/a _CTX-M-15首次在临床分离株中检测到突变。其中一些机制在英国范围内收集的 TZP-S/3GC-S 分离物中的丰度较低，但没有相关的 TZP 表型抗性。我们的研究结果强调了这种神秘表型的复杂性和持续监测表型的必要性，以及进一步研究以改进从基因组数据中检测和预测 TZP-R/3GC-S 表型的必要性。