Department of Biostatistics, University of Oslo, Oslo, Norway.
Institute of Microbiology and Infection, University of Birmingham, Birmingham, UK.
Lancet Microbe. 2021 Jul;2(7):e331-e341. doi: 10.1016/S2666-5247(21)00031-8. Epub 2021 May 10.
The clonal diversity underpinning trends in multidrug resistant Escherichia coli causing bloodstream infections remains uncertain. We aimed to determine the contribution of individual clones to resistance over time, using large-scale genomics-based molecular epidemiology.
This was a longitudinal, E coli population, genomic, cohort study that sampled isolates from 22 512 E coli bloodstream infections included in the Norwegian surveillance programme on resistant microbes (NORM) from 2002 to 2017. 15 of 22 laboratories were able to share their isolates, and the first 22·5% of isolates from each year were requested. We used whole genome sequencing to infer the population structure (PopPUNK), and we investigated the clade composition of the dominant multidrug resistant clonal complex (CC)131 using genetic markers previously reported for sequence type (ST)131, effective population size (BEAST), and presence of determinants of antimicrobial resistance (ARIBA, PointFinder, and ResFinder databases) over time. We compared these features between the 2002-10 and 2011-17 time periods. We also compared our results with those of a longitudinal study from the UK done between 2001 and 2011.
Of the 3500 isolates requested from the participating laboratories, 3397 (97·1%) were received, of which 3254 (95·8%) were successfully sequenced and included in the analysis. A significant increase in the number of multidrug resistant CC131 isolates from 71 (5·6%) of 1277 in 2002-10 to 207 (10·5%) of 1977 in 2011-17 (p<0·0001), was the largest clonal expansion. CC131 was the most common clone in extended-spectrum β-lactamase (ESBL)-positive isolates (75 [58·6%] of 128) and fluoroquinolone non-susceptible isolates (148 [39·2%] of 378). Within CC131, clade A increased in prevalence from 2002, whereas the global multidrug resistant clade C2 was not observed until 2007. Multiple de-novo acquisitions of both bla ESBL-encoding genes in clades A and C1 and gain of phenotypic fluoroquinolone non-susceptibility across the clade A phylogeny were observed. We estimated that exponential increases in the effective population sizes of clades A, C1, and C2 occurred in the mid-2000s, and in clade B a decade earlier. The rate of increase in the estimated effective population size of clade A (N=3147) was nearly ten-times that of C2 (N=345), with clade A over-represented in Norwegian CC131 isolates (75 [27·0%] of 278) compared with the UK study (8 [5·4%] of 147 isolates).
The early and sustained establishment of predominantly antimicrobial susceptible CC131 clade A isolates, relative to multidrug resistant clade C2 isolates, suggests that resistance is not necessary for clonal success. However, even in the low antibiotic use setting of Norway, resistance to important antimicrobial classes has rapidly been selected for in CC131 clade A isolates. This study shows the importance of genomic surveillance in uncovering the complex ecology underlying multidrug resistance dissemination and competition, which have implications for the design of strategies and interventions to control the spread of high-risk multidrug resistant clones.
Trond Mohn Foundation, European Research Council, Marie Skłodowska-Curie Actions, and the Wellcome Trust.
导致血流感染的多药耐药性大肠杆菌的克隆多样性基础仍不确定。我们旨在使用基于大规模基因组学的分子流行病学来确定随着时间的推移，个体克隆对耐药性的贡献。
这是一项纵向的大肠杆菌种群、基因组、队列研究，从 2002 年至 2017 年纳入挪威耐药微生物监测计划（NORM）的 22512 例大肠杆菌血流感染中采样分离株。15 个参与实验室能够共享其分离株，每年请求前 22.5%的分离株。我们使用全基因组测序推断种群结构（PopPUNK），并使用先前报道的用于序列型（ST）131 的遗传标记调查主导的多药耐药克隆复合体（CC）131 的分支组成，有效种群大小（BEAST）和抗菌药物耐药决定因素的存在（ARIBA、PointFinder 和 ResFinder 数据库）随时间的变化。我们比较了这两个时期的这些特征。我们还将我们的结果与英国在 2001 年至 2011 年进行的一项纵向研究进行了比较。
从参与实验室要求的 3500 株分离株中，收到了 3397 株（97.1%），其中 3254 株（95.8%）成功测序并纳入分析。2002-10 年耐药性 CC131 分离株的数量从 71 株（5.6%）增加到 2011-17 年的 207 株（10.5%）（p<0.0001），这是最大的克隆扩张。CC131 是产超广谱β-内酰胺酶（ESBL）阳性分离株（128 株中的 75 株，58.6%）和氟喹诺酮类药物不敏感分离株（378 株中的 148 株，39.2%）中最常见的克隆。在 CC131 内，从 2002 年开始，A 分支的流行率增加，而全球多药耐药性 C2 分支直到 2007 年才被观察到。在 A 分支的系统发育中，我们观察到了 A 分支和 C1 分支 bla ESBL 编码基因的多次从头获得以及表型氟喹诺酮类药物不敏感性的获得。我们估计，A、C1 和 C2 分支的有效种群数量在 2000 年代中期呈指数增长，而 B 分支则在十年前就出现了这种情况。A 分支（N=3147）的估计有效种群数量的增长率接近 C2 分支（N=345）的十倍，与英国研究相比，A 分支在挪威 CC131 分离株中过度表达（278 株中的 75 株，27.0%）（147 株分离株中的 8 株，5.4%）。
主要是抗菌药物敏感的 CC131 A 分支相对于多药耐药性 C2 分支的早期和持续建立，表明耐药性对于克隆的成功并非必要。然而，即使在挪威这种抗生素使用量较低的环境中，重要抗菌药物类别的耐药性也迅速在 CC131 A 分支中被选择。本研究表明，基因组监测在揭示多药耐药性传播和竞争的复杂生态方面的重要性，这对设计控制高危多药耐药克隆传播的策略和干预措施具有重要意义。
特隆·莫恩基金会、欧洲研究理事会、玛丽·居里行动和惠康信托基金会。
