MDRO Carriage, Transmission, Sequelae, and Prevention in Nursing Homes - Abstract Overview: MDRO Carriage, Transmission, Sequelae, and Prevention in Nursing Homes This P01 Program proposal will address critically important questions surrounding the expanding problem of multidrug-resistant organisms (MDROs) in nursing homes (NH). Of the 1.4 million residents residing annually in 15,000 U.S. NHs, more than half (65%) are estimated to harbor MDROs. These MDROs not only impact medically vulnerable residents in NHs, but they can spread to surrounding hospitals and long-term care facilities, causing significant morbidity and mortality. Despite growing evidence that NHs are major reservoirs of MDROs, investments to address MDROs in this health sector are lacking. Little is known about sources or drivers of MDRO transmission, and identification of effective interventions is needed. This program integrates expertise in infectious diseases, epidemiology, microbiology, pathogen genomics, human microbiome, statistics, systems science, health economics, and agent-based models to conduct an unprecedented set of studies on five MDROs in NHs – methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococcus (VRE), extended-spectrum beta-lactamase producers (ESBLs), carbapenem-resistant Enterobacterales (CRE) and the newly-emerged resistant fungus, Candida auris. By leveraging previous and newly-conducted studies, this program will provide one of the largest compilations of MDRO isolates from NH residents and environmental fomites. A total of 16,000 MDRO isolates and 3,000 metagenomic samples from 50 NHs will be studied using epidemiology, genomics, and simulation modeling as distinct and synergistic vantage points to elucidate 1) best sampling methods for MDRO carriage and co- carriage, 2) key sources and drivers of MDRO transmission, 3) major risk factors associated with carriage, infection, and hospitalization, and 4) high-yield interventions to inform infection prevention policies to mitigate adverse health outcomes due to MDROs in NHs.