PROJECT SUMMARY Staphylococcus aureus is a common cause of bacterial infections in the United States, causing non-invasive skin and soft tissue infections as well as invasive infections, including sepsis, pneumonia and necrotizing fasciitis. In the Southwest US, the American Indian population is disproportionately affected by morbidity and mortality related to S. aureus infections. Existing strategies have not been sufficient to control S. aureus disease and new approaches are urgently needed. Through a partnership between the White Mountain Apache Tribe, the Whiteriver Service Unit of the Indian Health Service, and the Johns Hopkins Center for American Indian Health, the proposed research will design and evaluate a community-informed approach to education and S. aureus decolonization to prevent S. aureus disease in high-risk individuals. In Year 1, formative work will be completed to: 1) develop culturally tailored educational materials for prevention and early recognition of S. aureus infections; and 2) assess the acceptability and feasibility of decolonization regimens in a rural American Indian community. This will be accomplished through focus-group discussions and in-depth interviews with key stakeholders, including healthcare providers and patients. At the end of the formative work, we will have educational materials and a decolonization protocol tailored for American Indian communities to optimize acceptability, adherence, and sustainability. In Years 2 to 4, the educational materials and decolonization protocol will be evaluated in a randomized controlled trial to evaluate the efficacy of an intermittent compared to a one-time decolonization protocol in decreasing S. aureus colonization and preventing S. aureus infections. Adults at high risk for S. aureus infection attending the Whiteriver Service Unit (index participants; n=200) will be enrolled along with their household members (n=1000) and followed for 12 months. Index participants will be randomized in a ratio of 1:1 to either: 1) education plus intermittent decolonization (E+iD); or 2) education plus one-time decolonization (E+1D; control group). Index participants randomized to the E+1D group will receive educational materials and one administration of the decolonization protocol at the baseline visit only. Index participants randomized to the E+iD group will receive educational materials at the baseline visit and will be provided with six administrations of the decolonization protocol to be performed at the baseline visit and then every other month. Household members from groups will receive the E+1D intervention. The primary outcome will be colonization among index participants 6 months after randomization. Secondary outcomes will include: 1) prevalence of colonization among index participants at 12 months; and 2) incidence of S. aureus and all-cause infections among index participants at 6 and 12 months. If found to be efficacious, this intervention could be broadly used in hi...