Mapping Mechanisms of Emerging Antibiotic Resistance Using Hospital-Wide Pathogen Surveillance and Whole-Genome Analysis

Antibiotics represent one of the greatest advancements in modern medicine. Their clinical use has significantly decreased human morbidity and mortality through prevention and treatment of infectious diseases. The overuse of antibiotics in healthcare, agriculture and manufacturing, however, have led to the rapid rise of antibiotic resistant bacteria. Bacteria are adapting to the widespread antibiotic usage by acquiring single and structural mutations that confer enhanced survival and drug resistance. The limited therapeutic options for treatment of infections are a global health and economic burden. New therapies, increased surveillance of antibiotic resistance rates and consumption, reduced incidence of infection, and research into the emergence of resistance, are all required for a sustainable solution to tackling antibiotic resistance. Critically, a deeper understanding of how resistance emerges during antibiotic treatment is needed. Our current understanding is based on in vitro studies or focused on broad bacterial population changes over time. There is an urgent need to understand evolutionary dynamics of how bacteria acquire these genetic resistance determinants in vivo. In this dissertation, I present studies that leveraged bacterial pathogen surveillance and whole-genome analysis to characterize the emergence and spread of antibiotic resistance at Mount Sinai Hospital. I first review seminal studies that have shaped our understanding of antibiotic resistance and how resistance emerges in bacteria. In Chapters 2, 3 and 4, I identified and characterized single nucleotide and structural genetic changes associated with varying antibiotic susceptibilities. I applied an unbiased screen of bacteremia cases for changing antibiotic susceptibilities during the course of infection. I demonstrated how heteroresistance is prevalent and underlies emerging resistance. In Chapter 5, I used genomic surveillance of bacteremia cases, equipment tracking data, and comparative transcriptomics to reveal how resistant bacteria transmitted between patients in a hospital outbreak. In Chapter 6, I leveraged electronic healthcare records in order to characterize how antibiotic resistance rates and consumption is changing at Mount Sinai Hospital. Finally, I conclude with the implications of these findings, and discuss future directions of research to better understand heteroresistance and emerging resistance within host