Bacterial genotypic and patient risk factors for adverse outcomes in Escherichia coli bloodstream infections: a prospective molecular-epidemiological study
Authors: Jauneikaite Elita , Honeyford Kate , Blandy Oliver , Mosavie Mia , Pearson Max , Ramzan Farzan A. , Ellington Matthew J. , Parkhill Julian , Costelloe Céire E , Woodford Neil , Sriskandan Shiranee 
Published: June 2021

AbstractBackgroundEscherichia coli bloodstream infections have increased rapidly in the UK, for reasons that are unclear. The relevance of highly fit, or multi-drug resistant lineages such as ST131 to overall E. coli disease burden remains to be fully determined. We set out to characterise the prevalence of E. coli multi-locus sequence types (MLST) and determine if these were associated with adverse outcomes in an urban population of E. coli bacteraemia patients.MethodsWe undertook whole genome sequencing of E. coli blood isolates from all patients with diagnosed E. coli bacteraemia in north-west London from July 2015 to August 2016 and assigned multi-locus sequence types to all isolates. Isolate sequence types were linked to routinely collected antimicrobial susceptibility, patient demographic, and clinical outcome data to explore relationships between the E. coli sequence types, patient factors, and outcomes.FindingsA total of 551 E. coli genomes were available for analysis. More than half of these cases were caused by four E. coli sequence types: ST131 (21%), ST73 (15%), ST69 (9%) and ST95 (8%). E. coli genotype ST131-C2 was associated with non-susceptibility to quinolones and third-generation cephalosporins, and also to amoxicillin, augmentin, gentamicin and trimethoprim. An association between the ST131-C2 lineage and longer length-of-stay was detected, although multivariable regression modelling did not demonstrate an association between E. coli sequence type and mortality. However, a number of unexpected associations were identified, including gentamicin non-susceptibility, ethnicity, and sex that might influence mortality and length-of-stay, requiring further research.InterpretationAlthough E. coli sequence type was associated with antimicrobial non-susceptibility patterns and length-of-stay, we did not find that E. coli sequence type was associated with increased mortality. Where ST131 is prevalent, caution is required when pairing beta-lactam agents with gentamicin or using single agent aminoglycosides.FundingUK NIHR HPRU, Wellcome Trust, Rosetrees Trust, Stoneygate Trust.Research in contextEvidence before this studyE. coli is the leading cause of bacteraemia in adults, with consequent major impact on patient morbidity and mortality, as well as cost of care. Identification of microbial and patient factors that contribute to severity from E. coli bacteraemia could inform clinical guidelines and improve outcomes. We searched PubMed for articles published in English between 1st of Jan 1999 to 3rd of May 2021 using the following terms: (“Escherichia coli” OR “E. coli”) AND (“bacteraemia” OR “bloodstream infection”) AND (“genotype” OR “multi-locus sequence typing” OR “MLST”). We screened titles, abstracts, and bibliographies of relevant articles to identify reports that examine microbial factors that influence outcome. Previous studies have examined the association between a narrow range of E. coli lineages carrying specific antimicrobial resistance genes and prior antibiotic consumption, patient comorbidities, and mortality. Only two previous studies have examined the association of a wider range of E. coli sequence types (via MLST or whole genome sequencing) with clinical disease phenotype. We provide an integrated observational analysis of E. coli sequence types, patient demographic data, and disease outcomes.Added value of this studyWe provide whole genome sequences from an un-biased collection of 551 E. coli strains causing consecutive bloodstream infections (BSI) in a one-year period in London. The study confirms ST131 to be the single leading BSI-causing genotype, albeit accounting for just 21% of infections. Only half of these were from the so-called multi-drug resistant ST131-C2 lineage however, suggesting factors other than antimicrobial resistance alone contribute to fitness of ST131, and other currently dominant lineages. The study provides a valuable resource to link genome sequence to antimicrobial resistance phenotypes and evaluates the contribution of both bacterial sequence type and patient factors to disease outcome. E. coli ST131 subclade C2 was associated with non-susceptibility to multiple antibiotics as well as a longer length-of-stay, underlining a value in sequence-type surveillance, but we did not detect an association with mortality. Multi-variate analysis unexpectedly identified ethnicity as a potential contributor to 90-day mortality, mandating further investigation, while microbial gentamicin resistance was also linked to adverse outcome.Implications of all available evidenceE. coli bloodstream infections continue to rise in the UK, despite implemented strategies aimed at reducing E. coli invasive infections and antimicrobial resistance. Certain E. coli lineages are more likely to be multidrug-resistant or associated with specific infection types, however a more detailed understanding of changes in these pathogenic lineages over time in vulnerable populations is needed. Although multi-drug resistant lineages such as ST131-C2 contribute to prolonged length-of-stay, factors other than E. coli genotype may have a greater role to play in final outcome. While co-morbidities play a major role in mortality from E. coli bacteraemia, other demographic factors require attention. A more comprehensive analysis of associations between E. coli genotype, patient factors, antimicrobial resistance phenotypes and clinical outcomes could inform prescribing guidelines for both urinary tract and invasive E. coli infections. Such information will further serve as a potential driver for developing and implementing lineage-specific E. coli vaccines in the future.