The Transmission and Evolution of Enteroccocus faecium Within the Hospital

Antibiotics are used for the treatment of bacterial infections. However, the increased use of antibiotics has coincided with a rapid increase in the prevalence of antibiotic-resistant bacteria, threatening the overall efficacy of antibiotics and posing significant public health challenges. In this thesis, I explore how two processes, resistance evolution and resistance transmission, shaped the prevalence of antibiotic-resistant bacteria within the hospital. Using isolates obtained and sequenced from a hospital surveillance program, I also aim to understand the factors that underlie these population dynamics. We focus our efforts on studying these processes in the nosocomial, opportunistic pathogen Enterococcus faecium, which is a leading cause of hospital acquired infections. In Chapter 1, we analyze the role of resistance evolution and transmission in the overall incidence of resistance infections in a hospital associated pathogen. Leveraging our unique dataset of sequenced surveillance isolates collected over 5 years, we describe and quantify using phylogenetic comparative analysis, the probability that resistance arose de novo or transmission in each daptomycin resistant blood stream infection in the hospital. We find strong molecular, phenotypic, and clinical evidence supporting the role of both resistance transmission and resistance evolution in new resistant infections. Chapters 2 and 3 detail the evolution of resistant isolates in vitro and in vivo. Despite the differences in these environments, analyzing bacterial evolution in these conditions can provide insight into the population dynamics of resistant bacteria in important settings: antibiotic free environments and the gut microbiome. In both settings, we observe the maintenance of resistance among certain classes of bacterial strains. Using laboratory evolution in antibiotic-free media, we find that transmitted daptomycin resistant strains of E. faecium generally maintained resistance throughout laboratory evolution. Diversity was minimal, with the founding strain comprising most of the evolved population. Similarly, in surveillance swabs obtained from serially sampled patients, deep sequencing revealed domination by single strains with minimal levels of diversity. Additional trends and features of the population dynamics in vitro are explored using the mathematical modelling of fitness and in vivo through population genetic models. Together, these projects highlight the dynamic nature of E. faecium. E. faecium has shown a remarkable ability to migrate between hosts and evolve resistance to antibiotics, consequently making it a problem endemic to hospitals worldwide. Our results here show possible reasons for this species’ success with possible implications for reducing its future health burden.