Multidrug-resistant organisms (MDROs) lead to adverse patient outcomes, including increased mortality, morbidity, and length of hospitalization. The CDC recently outlined three primary strategies to prevent the transmission of MDROs, including antimicrobial stewardship, surveillance, and infection prevention. Many of our current strategies, however, are either insufficient or have not been adequately proven with rigorous scientific studies. The overall objective of this proposal is to identify potential strategies to decrease MDRO transmission and acquisition. To do so, we will complete a series of 6 unique studies to complete 5 specific aims (SA). These studies will 1) identify novel strategies for feeding back MDRO and antimicrobial utilization data to prescribers (SA 1); 2) examine the impact of antimicrobial therapy on the cutaneous microbiome (SA 2); 3) identify effective disinfectants against human papilloma virus (SA 3); 4) identify the best method(s) to identify environmental contamination (SA 4); and 5) identify candidate enhanced strategies for daily/continuous room disinfection (SA 5). We will achieve our objective and complete our specific aims using the strengths of a unique, innovative, and previously successful collaboration between investigators at Duke University, including the Duke Infection Control Outreach Network, and the University of North Carolina. We will capitalize on programmatic strengths in both institutions: expertise in antimicrobial stewardship, healthcare epidemiology, and environmental disinfection; unique research networks and infrastructure; and proven success with research involving multiple institutions. In addition, we are proposing 3 additional projects in collaboration with other CDC Prevention Epicenters Programs to 1) develop and test the efficacy of an opt-out protocol for antimicrobial de-escalation among patients with sepsis; 2) evaluate antimicrobial therapy as a risk factor for surgical site infection and determine the impact of standard interventions on the cutaneous microbiome of surgical patients; and 3) determine if the use of ertapenem for surgical prophylaxis increases the risk of C. difficile and/or MDR infection. All projects proposed in this application represent early stage translational research (T0-T2) that will help expedite identification and development of practices that effectively prevent healthcare-associated infections and MDROs. These studies exemplify our ongoing collaboration between scientists with T0 microbiome and microbiology expertise and researchers with T1-T2 expertise within our Epicenter. The contribution of these studies will be significant because they will lead to new strategies to prevent healthcare-associated infections and the transmission of MDROs, thereby improving the health and safety of the US population.