ABSTRACT The Washington University (WU) / BJC Prevention Epicenter (PE) works collaboratively with CDC & other PEs to perform research & translate discoveries into novel strategies to prevent healthcare-associated infections (HAI) & antimicrobial resistance (AR). The WU/BJC PE is widely recognized for HAI & AR research & leadership. WU has outstanding research infrastructure. BJC is an integrated healthcare delivery system with 15 hospitals, long-term care facilities, & outpatient practices. BJC includes two academic hospitals, Barnes-Jewish & St. Louis Children’s Hospitals & 13 suburban & rural hospitals. We organized a research team with expertise in ID, epidemiology, informatics, microbiology, critical care, microbiome, & metabolism to study HAI & AR in diverse settings. We developed a high impact 5-yr proposal with novel strategies to: Evaluate & predict inappropriate antimicrobial use & AR regionally & nationally; Reduce surgical site infections; Test novel initiatives to improve outpatient antibiotic prescribing; Identify metagenomic & metabolite differences between hospital & community associated C. difficile; Reduce AR organism reservoirs in hospitals. To achieve these goals, we propose the following Specific Aims: Aim 1 A: Evaluate the use, effectiveness, and safety of antimicrobials in community-acquired pneumonia (CAP) with national administrative data. Aim 1 B: Develop aggregate antimicrobial resistance measures in sepsis caused by Gram-negative bacilli (GNB) using BJC electronic health record data. Aim 2: The impact of an existing Anesthesia Control Tower (ACT) intervention to improve intraoperative care on infectious outcomes. Aim 3 A: Stewardship initiative to limit post-discharge prophylactic antibiotic use after mastectomy. Aim 3 B: Improve antimicrobial stewardship practices in elderly patients with UTIs in assisted living facilities. Aim 4: Identify fecal microbiome and metabolite markers of community associated (CA) C. difficile colonization and infection (CDI). Aim 5: Define the prevalence of antibiotic resistant organisms (ARO) in the clinical ICU environment, relationship of ARO to ICU clinical culture isolates and measure the impact of an environmental hygiene intervention on ARO concentration in ICU sink drains, the surrounding environment and bioaerosols. We are also submitting 3 proposals to lead Small, Medium & Large Multicenter Collaborative Projects with Duke, U Penn, Hektoen / Rush, University of Maryland, and Iowa PEs as potential participants.