Outcomes of Staphylococcal Periprosthetic Joint Infections Treated With Rifampin and the Potential Role of Rifabutin as a Substitute When High-risk Drug-drug Interactions Exist

Background This study evaluated outcomes of patients meeting Infectious Disease Society of America guidelines for rifampin therapy in treating staphylococcal periprosthetic joint infection (PJI) and explored the role of rifabutin as a substitute when rifampin was contraindicated due to drug-drug interaction (DDI). Materials and Methods An institutional database at a tertiary referral center was queried for patients who had staphylococcal PJI and underwent debridement and implant retention procedure (DAIR) or one-stage revision from January 1, 2013, to April 30, 2023. Patients were stratified by rifampin treatment, and their rates of successful PJI treatment were compared. Rifampin and rifabutin DDIs were collected for all patients and compared. Results Of 935 total patients screened, 87 patients with a mean follow-up time of 4.4 years met IDSA guidelines for rifampin therapy. Of the 35 patients who completed rifampin therapy, 71.4% were successfully treated. Logistic regression analysis showed that those who did not initiate rifampin therapy were less likely to have successful treatment (odds ratio: 0.76 [0.60 to 0.97]; P =0.031). Cox-proportional hazard regression showed that those who did not initiate rifampin therapy were at higher risk of requiring revision for infection (hazard ratio: 2.22 [1.06 to 4.68]; P =0.035). Of the 87 patients in this study, 18.4% had a DDI that contraindicated rifampin; however, only 3.4% had a DDI that contraindicated rifabutin. Conclusion This study supports that rifampin as combination therapy with DAIR or one-stage revision in staphylococcal PJI leads to better outcomes; however, its implementation is limited by DDIs. [ Orthopedics . 2025;48(4):239–247.]