A genomic investigation into gastrointestinal antimicrobial resistance and clinical infection in patients undergoing transplantation

Abstract

Globally, antimicrobial-resistant bloodstream infections (AMR-BSIs) claim 1.5 million lives annually. High-resolution sequencing data allows us to derive novel insights into AMR-BSIs. Immunosuppressed patients have a disrupted gut microbiome; therefore, transplant recipients provide an ideal reservoir for populations of opportunistic AMR pathogens to flourish. Specifically, clinical infections caused by enteric AMR bacteria that translocate across the intestinal epithelium pose a significant barrier to the improvement of transplant outcomes worldwide. My thesis re-examines the significant body of research that encompasses gut-origin sepsis and contextualises it within the ongoing AMR crisis. I combined whole-genome and metagenomic sequencing approaches to 1) characterise BSI-associated AMR; 2) study the phenomenon of bacterial translocation in two distinct cohorts of transplant recipients – Small Bowel Transplantation and Haematopoietic Stem Cell Transplantation; and 3) illustrate the longitudinal evolution of AMR in these transplant cohorts. Using genomic data, I developed high-throughput screening strategies to aid in the monitoring and mitigation of post-transplant infectious complications caused by gut-residing pathogens. Enteric E. coli, Klebsiella spp. and Enterococcus spp. were identified as significant contributors to the cumulative burdens of BSI and AMR. These organisms also showed evidence of translocation and temporally diversified transplant recipients’ gut resistomes. Investigating these resistomes revealed patterns in paired AMR gene co-localisation, suggesting links with mobile genetic elements and potential for transmission via horizontal gene transfer (HGT). In summary, improved surveillance of HGT can bolster efforts to ensure judicious use of existing antimicrobials and optimise treatment regimens to minimise inadvertent selection for resistance among patients undergoing transplantation.