Emergence and Dissemination of Antimicrobial Resistance in Escherichia Coli Causing Bloodstream Infections: A Nationwide Longitudinal Microbial Population Genomic Cohort Study in Norway between 2002-2017

Background: The clonal diversity underpinning trends in multi-drug resistant (MDR) E. coli causing bloodstream infections (BSI) remain uncertain. We determine these from the largest longitudinal E. coli population genomic study conducted to date. Methods: E. coli from BSI collected by the Norwegian surveillance program on resistant microbes were randomly sampled between 2002-2017. The 3254 isolates, representing ~7% of annual cases and all health regions, were whole-genome sequenced. Findings: The equilibrium of major clones was disrupted by the increase of MDR clonal complex (CC)131 and its component clades. CC131 was the dominant contributor to increases in ESBL prevalence and fluoroquinolone resistance. Clade A increased from 2002, whilst the global MDR clade C2 was not observed until 2007. Frequent de novo acquisition of both blaCTX-M ESBL genes in clades A and C1, and of fluoroquinolone resistance in clade A were observed. We estimated exponential increases in the effective population sizes of clades A, C1 and C2 occurring in the mid-2000’s, and in clade B a decade earlier. The rate of increase in clade A was nearly ten-fold that of C2, with clade A over-represented in Norway compared to a UK study by Kallonen et al. Interpretation: Despite Norway's low antimicrobial use, multiple clades of CC131 rapidly established themselves, with non-C2 clades acquiring resistance to important antimicrobial classes. This suggests that antimicrobial resistance is a consequence of, rather than a determinant of success. This study demonstrates the importance of genomic surveillance in uncovering complex ecology underlying MDR dissemination and competition, within clones of priority pathogens. Funding: This work was supported by a Trond Mohn Foundation AMR grant TMS2019TMT04 (R.G., A.P., J.C., O.S., P.J.) and ERC grant 742158 (J.C.). Declaration of Interests: The authors report no conflicts of interest. Ethics Approval Statement: Data in NORM are disidentified. Ethical approval was not required after evaluation by the Regional Ethical Committee (REC North ref: 93528).