Genomic epidemiology reveals geographical clustering of multidrug-resistant <i>Escherichia coli</i> sequence type (ST)131 associated with bacteraemia in Wales, United Kingdom

2. Abstract Increasing resistance to third-generation cephalosporins (3GCs) threatens public health, as these antimicrobials are prescribed as empirical therapies for systemic infections caused by Gram-negative bacteria. Resistance to 3GCs in urinary tract infections (UTIs) and bacteraemia is associated with the globally disseminated, multidrug-resistant, uropathogenic Escherichia coli sequence type (ST)131. This study combines the epidemiology of E . coli blood culture surveillance with whole-genome sequencing (WGS) to investigate ST131 associated with bacteraemia in Wales between 2013 and 2014. This population-based prospective genomic analysis investigated temporal, geographic, and genomic risk factors. To identify spatial clusters and lineage diversity, we contextualised 142 genomes collected from twenty hospitals, against a global ST131 population ( n =181). All three major ST131 clades are represented across Wales, with clade C/ H 30 predominant ( n =102/142, 71.8%). Consistent with global findings, Welsh strains of clade C/ H 30 contain β -lactamase genes from the bla CTX-M-1 group ( n =65/102, 63.7%), which confers resistance to 3GCs. In Wales, the majority of clade C/ H 30 strains belonged to sub-clade C2/ H 30Rx ( n =88/151, 58.3%), whereas sub-clade C1/ H 30R strains were less common ( n =14/67, 20.9%). A sub-lineage unique to Wales was identified within the C2/ H 30Rx sub-clade (named GB-WLS.C2/ H 30Rx) and is defined by six non-recombinogenic single-nucleotide polymorphisms (SNPs), including a missense variant in febE (ferric enterobactin transport protein) and fryC (fructose-like permease IIC component), and the loss of the capsular biosynthesis genes encoding the K5 antigen. Bayesian analysis predicted that GB-WLS.C2/ H 30Rx diverged from a common ancestor (CA) most closely related to a Canadian strain between 1998 and 1999. Further, our analysis suggests a descendent of GB-WLS.C2/ H 30Rx arrived through an introduction to North Wales circa 2002, spread and persists in the geographic region, causing a cluster of cases (CA emerged circa 2009) with a maximum pair-wise distance of 30 non-recombinogenic SNPs. This limited genomic diversity likely depicts local transmission within the community in North Wales. This investigation emphasises the value of genomic epidemiology, allowing detection of suspected transmission clusters and the spread of genetically similar/identical strains in local areas. These analyses will enable targeted and timely public health interventions. 3. Impact statement Uropathogenic Escherichia coli (UPEC) is a leading cause of bacteraemia, resulting in substantial mortality and morbidity, with rates of E. coli bacteraemia (ECB) becoming a particular concern in Wales(1). Previous genomic and multilocus sequence typing (MLST) studies have identified that ECB cases are disproportionately caused by specific groups [sequence types (ST)] of related E. coli . Previous work reports ST131 as a globally disseminated lineage associated with bacteraemia and antimicrobial resistance (AMR). Despite widespread study of ECB, the temporal and geographic patterns of key ECB clones remain an important area of study. Moreover, by gaining a detailed understanding of the population structure of key ECB clones, it should be possible to develop and improve public health measures to reduce the risk of ECB and act to combat the rise of AMR. Using whole-genome sequencing, we describe the temporal and spatial relationship of a collection of E. coli ST131 bacteraemia cases sampled across Wales. High-resolution analyses of genetic variants identified a local (North Wales) cluster of strains within the highly antimicrobial-resistant sub-clade C2/ H 30Rx, which are characterised by resistance to nitrofurantoin and the loss of the K5 capsule. Notably, AMR stewardship guidelines in Wales recently changed to include nitrofurantoin as a first-line treatment for uncomplicated UTIs. This local cluster likely represents environmentally-mediated community transmission, environmentally mediated, from the strain’s common ancestor that existed circa 2009, highlighting the need for national genomic surveillance, close to real-time, to track and understand the evolution of AMR in communities. 4. Data summary The study sequences are available in the National Center for Biotechnology Information (NCBI) under BioProject accession number PRJNA729115. Raw Illumina sequence read data have been deposited to the NCBI sequence read archive [SRA ( https://www.ncbi.nlm.nih.gov/sra )] under the accession numbers SRR14519411 to SRR14519567. A complete list of SRA accession numbers is available in Table S1 (available in the online version of this article). The high-quality draft assemblies have been deposited to GenBank under the accession numbers JAHBGJ000000000 to JAHBMG000000000, and JAHBRR000000000 to JAHBRT000000000. The programs used to analyse raw sequence reads for polymorphism discovery and whole-genome sequencing based phylogenetic reconstruction are available as described in the materials and methods. The authors confirm all supporting data, code, and protocols have been provided within the article or through supplementary data files.

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