Ten Years of Population-Level Genomic Escherichia coli and Klebsiella pneumoniae Serotype Surveillance Informs Vaccine Development for Invasive Infections

Abstract

Background: The incidence of bloodstream infections (BSIs) caused by Escherichia coli and Klebsiella pneumoniae is increasing, with substantial associated morbidity, mortality, and antimicrobial resistance. Unbiased serotyping studies to guide vaccine target selection are limited.

Methods: We conducted unselected, population-level genomic surveillance of bloodstream E. coli and Klebsiella pneumoniae isolates from 2008 to 2018 in Oxfordshire, United Kingdom. We supplemented this with an analysis of publicly available global sequencing data (n = 3678).

Results: We sequenced 3478 E. coli isolates (3278 passed quality control) and 556 K. pneumoniae isolates (535 [K-antigen] and 549 [O-antigen] passed quality control). The 4 most common E. coli O-antigens (O1/O2/O6/O25) were identified in 1499/3278 isolates; the incidence of these O-types increased over time (incidence rate ratio per year [IRRy] = 1.14, 95% confidence interval [CI]: 1.11-1.16). These O-types accounted for 616/1434 multidrug-resistant (MDR) and 173/256 extended-spectrum beta-lactamase (ESBL)-resistant isolates in Oxfordshire but only 19/90 carbapenem-resistant isolates across all studies. For Klebsiella pneumoniae, the most common O-antigens (O2v2/O1v1/O3b/O1v2) accounted for 410/549 isolates; the incidence of BSIs caused by these also increased annually (IRRy = 1.09; 95% CI: 1.05-1.12). These O-types accounted for 122/148 MDR and 106/123 ESBL isolates in Oxfordshire and 557/734 carbapenem-resistant isolates across all studies. Conversely we observed substantial capsular antigen diversity. Analysis of 3678 isolates from global studies demonstrated the generalizability of these findings. For E. coli, based on serotyping, the ExPEC4V and ExPEC10V vaccines under investigation would cover 46% and 72% of Oxfordshire isolates respectively, and 47% and 71% of MDR isolates.

Conclusions: O-antigen targeted vaccines may be useful in reducing the morbidity, mortality, and antimicrobial resistance associated with E. coli and K. pneumoniae BSIs.

Keywords: Enterobacteriaceae; antimicrobial resistance; bloodstream infection; vaccine; whole genome sequencing.

Figure 1.

Limited O-antigen diversity in Oxfordshire BSIs with broadly stable population structure over time. Proportion of (A) E. coli O-antigens, (B) Klebsiella spp. capsular antigens, and (C) Klebsiella spp. O-antigens observed in all isolates over the 10-year period. In panels D–F, red/green dashed lines denote the x-axis position of the 4/10 most prevalent O/K-types, and the blue dashed lines demonstrate the cumulative percentage of isolates that have these antigens, for (D) E. coli O-antigens, (E) Klebsiella spp. capsular (K) antigens, and (F) Klebsiella spp. O-antigens. Abbreviation: BSI, bloodstream infection.

Figure 2.

Left: Number of fully sensitive (to antibiotics shown in the righthand upset plot) E. coli BSI isolates by O-type. Right: Upset plot showing the number of E. coli isolates with phenotypic resistance to the antibiotics shown, stratified by O-antigen type (colors) and ordered by number of intersections. Horizontal bar plot shows the total number of isolates phenotypically resistance to each antibiotic in any combination. Abbreviation: BSI, bloodstream infection.

Figure 3.

Left: Number of K. pneumoniae BSI isolates either fully susceptible or resistant only to amoxicillin shown by O-antigen type. The jitter plot above shows the distribution of virulence scores, points are colored according to their O-antigen type. Right: Upset plot showing the number of K. pneumoniae isolates with resistance to the classes of antibiotics shown. Stacked bar plot shows the distribution of these by O-antigen type, and the jitter plots above demonstrate the corresponding distributions of virulence scores. Virulence score is as defined by Kleborate (see methods). Abbreviation: BSI, bloodstream infection.