Staphylococcus aureus causes ~30-50% of surgical site infections (SSIs). We previously reviewed published studies and current practices to identify ways to decrease S. aureus SSI rates. On the basis of our review, we developed an evidence-based bundle: 1) screening for S. aureus, 2) decolonization of carriers, and 3) prophylaxis with cefazolin and vancomycin for methicillin-resistant S. aureus carriers. The bundle efficacy is being tested in the AHRQ-funded STOP SSI Study among patients undergoing cardiac operations (CO), total hip (THA), or total knee (TKA) arthroplasties at 20 Hospital Corporation of America (HCA) hospitals. However, no one has compared the effectiveness of the whole bundle or of bundle elements with no bundle. Moreover, the STOP SSI Study did not evaluate facilitators and barriers to implementation of the bundle. These gaps in our knowledge may discourage surgeons or hospitals from implementing the bundle. Our goal is to decrease S. aureus SSIs. Thus, we propose to extend the current STOP SSI Study at the 20 HCA hospitals and to expand the study to additional hospitals and surgical populations so that we can accomplish 4 aims: 1) Assess the comparative effectiveness (CE) of implementing the full bundle, implementing parts of the bundle, and not implementing the bundle for preventing S. aureus SSIs among patients undergoing CO, THA, TKA, spine operations (SO), or craniotomy/craniectomy (CRANI); 2) Identify facilitators and barriers to bundle implementation at the hospital, surgical service, and patient level; 3) Create a toolkit that hospitals can use to facilitate bundle implementation; 4) Determine whether the bundle increases the number of mupirocin-resistant or CHG-resistant S. aureus isolates. Aim 1 involves 3 tasks: 1) Continue the quasi-experimental (QE) STOP SSI Study at 20 HCA hospitals; 2) Add hospitals and surgical populations: the Iowa City Veterans Affairs Medical Center (ICVAMC; THA, TKA), the University of Iowa Hospitals and Clinics (UIHC; CO, THA, TKA, SO, CRANI), and Covenant Hospital (CH; SO, CRANI); 3) Repeat the time series analysis from the QE study on the expanded dataset and conduct a CE study assessing the effectiveness of the full bundle, elements of the bundle, decolonization only, and no bundle elements. HCA, UIHC, ICVAMC, 9 additional VAMCs, and CH will be the CE intervention group; 8 Duke-affiliated hospitals, which do not use the bundle, will be the no bundle group. Aim 2 includes 2 tasks (UI, ICVAMC, CH, Johns Hopkins Hospital, Johns Hopkins-affiliated hospitals) to help us identify factors that facilitate or inhibit bundle implementation by healthcare workers and by patients: 1) Interview healthcare workers; 2) Survey patients. The toolkit created for Aim 3 will provide practical tools to help staff at other hospitals implement the bundle as easily as possible. Because mupirocin or CHG resistance could limit future use of these agents, Aim 4 will help us ensure that the bundle does not increase the number of S. aureus resistant to these agents.