Temporal dynamics of genetically heterogeneous extended-spectrum cephalosporin-resistant bloodstream infections.

Extended-spectrum cephalosporin-resistant (ESC-R-) is an urgent public health threat with sequence type clonal complex 131 (STc131), phylogroup B2 strains being particularly concerning as the dominant cause of ESC-R- infections. To address the paucity of recent ESC-R- molecular epidemiology data in the United States, we used whole-genome sequencing (WGS) to fully characterize a large cohort of invasive ESC-R- at a tertiary care cancer center in Houston, Texas, collected from 2016 to 2020. During the study time frame, there were 1,154 index bloodstream infections (BSIs) of which 389 (33.7%) were ESC-R-. Using time series analyses, we identified a temporal dynamic of ESC-R- distinct from ESC-susceptible (ESC-S-), with cases peaking in the last 6 months of the calendar year. WGS of 297 ESC-R- strains revealed that while STc131 strains accounted for ~45% of total BSIs, the proportion of STc131 strains remained stable across the study time frame with infection peaks driven by genetically heterogeneous ESC-R- clonal complexes. variants accounted for most β-lactamases conferring the ESC-R phenotype (89%; 220/248 index ESC-R), and amplification of genes was widely detected in ESC-R- strains, particularly in carbapenem non-susceptible, recurrent BSI strains. was significantly enriched within phylogroup A strains, and we identified plasmid-to-chromosome transmission occurring across non-B2 strains. Our data provide important information regarding the current molecular epidemiology of invasive ESC-R- infections at a large tertiary care cancer center and provide novel insights into the genetic basis of observed temporal variability for these clinically important pathogens. IMPORTANCE Given that is the leading cause of worldwide ESC-R infections, we sought to assess the current molecular epidemiology of ESC-R- using a WGS analysis of many BSIs over a 5-year period. We identified fluctuating temporal dynamics of ESC-R- infections, which have also recently been identified in other geographical regions such as Israel. Our WGS data allowed us to visualize the stable nature of STc131 over the study period and demonstrate a limited but genetically diverse group of ESC-R- clonal complexes are detected during infection peaks. Additionally, we provide a widespread assessment of β-lactamase gene copy number in ESC-R- infections and delineate mechanisms by which such amplifications are achieved in a diverse array of ESC-R- strains. These data suggest that serious ESC-R- infections are driven by a diverse array of strains in our cohort and impacted by environmental factors suggesting that community-based monitoring could inform novel preventative measures.