IntroductionVancomycin is frequently used for prolonged courses in treating osteoarticular infections despite a high rate of adverse drug events (ADE). The objective of this study was to evaluate the safety and effectiveness of transitioning to oral therapy compared to continuing parenteral vancomycin in patients with orthopedic infections.MethodsWe conducted a single‐center, retrospective cohort study of patients with orthopedic infections discharged on parenteral vancomycin with a planned duration of at least four weeks. We compared rates of ADE while on vancomycin to rates of ADE after switching to an oral regimen. As a secondary analysis, we compared unplanned hospital readmission within 60 days and treatment failure at one year between patients who were transitioned to oral antibiotics within four weeks of vancomycin initiation and those that were not.ResultsTwo hundred twenty‐eight patients met inclusion criteria. Vancomycin was associated with significantly greater toxicity compared to oral regimens. Fifty‐one patients had an adverse event while on vancomycin (5.87 ADE per 1000 patient‐days) while 9 patients had an adverse event on oral therapy (1.49 ADE per 1000 patient‐days) (Rate difference 4.39 per 1000 patient days, 95% CI: 2.52 to 6.26 events per 1000 patient‐days). In proportional hazards analysis, transition to an oral antibiotic regimen was independently associated with a lower rate of ADE (aHR 0.12, 95% CI: 0.02‐0.86). Forty‐one patients (18%) were transitioned to oral therapy within four weeks; these patients did not have an increased rate of unplanned readmission (12.2% vs 17.1%) or treatment failure (17.1% vs 21.9%).ConclusionsPatients transitioned to oral therapy within 4 weeks of discharge had significantly fewer adverse events and similar incidences of one‐year treatment failure compared to patients maintained on parenteral vancomycin. Substituting oral antibiotics for parenteral vancomycin is a potential strategy to minimize vancomycin toxicity during the treatment of orthopedic infections.