Project Summary Clostridioides difficile (CD) is a ubiquitous, spore-former and the most prevalent healthcare- associated infection. While infections are often triggered by antibiotics, particularly in immunocompromised individuals, we know little about the factors and risks for triggering symptomatic CD infection (CDI). The overarching objective of Dr. Cersosimo’s research is to understand the dynamics of CDI in at-risk patient populations and optimize testing strategies for toxin C. difficile carriage to enable surveillance in broad clinical settings. The proposed research uses advanced genomic-epidemiologic analyses to enhance our understanding of CDI epidemiology in at-risk inpatients, identifies associations among C. difficile genomic and antibiotic resistance profiles, and optimizes current hospital CD surveillance programs for deployment to a diverse range of healthcare institutions. Aim 1 applies molecular epidemiologic strategies to identify patient and strain-specific risks for the development of CDI. Subaim 1a defines the dynamics of infection risk in oncology and ICU wards with genomic-epidemiologic analyses of CD in patients and using patient co-variate data obtained from the electronic health record. Subaim 1b defines genomic and phenotypic drivers of strain antibiotic resistance and their contribution to asymptomatic carriage and progression to CDI in inpatient oncology wards versus other ICU settings. Aim 2 optimizes tools for CD surveillance through the a) development of a more rapid and accessible clinical diagnostics assay for the identification of toxin positive CD and b) generation of informative data that demonstrates antibiotic triggers of CD carriage to inform population-based CDI preventative strategies in collaborations with clinical infection control and infectious disease pharmacy teams. Dr. Cersosimo brings a One Health background per her previous training in animal gut health, clinical diagnostics, and food science. Her prior experiences and training goals will: 1) optimize bioinformatic and statistical approaches in the analysis of C. difficile genomic data, 2) advance her understanding of microbiology, infectious diseases, epidemiology through hands-on learning in the healthcare setting, 3) develop strategies to generate, analyze, and interpret high-dimensional genomic and phenotypic antibiotic resistance data to inform strain genomic landscapes and associated hospital-focused antibiograms for C. difficile, and 4) improve her professional and leadership skills to progress as an independent investigator studying questions in infectious disease genomics and epidemiology from a One Health perspective. Her appointments at Brigham and Women’s Hospital and Harvard Medical School provide access to state-of-the-art clinical, laboratory, and computational resources and an internationally renowned mentoring committee with expertise in C. difficile epidemiology, antibiotic stewardship, genomics, and hospital infection surve...