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OBJECTIVES: Secondary oral vancomycin prophylaxis (OVP) has been used in adults with a history of Clostridioides difficile infection (CDI) while receiving systemic antibiotics to prevent CDI recurrence. However, this practice has not been studied in pediatric patients. The objective of this study was to assess the utility of secondary OVP in pediatric patients with previous CDI who received subsequent antibiotic exposure. METHODS: A multicampus, retrospective cohort evaluation was conducted among patients aged #18 years with any history of clinical CDI and receiving systemic antibiotics in a subsequent encounter from 2013--2019. Patients who received concomitant OVP with antibiotics were compared with unexposed patients. The primary outcome was CDI recurrence within 8 weeks after antibiotic exposure. Infection with vancomycin-resistant enterococci and risk factors for CDI recurrence were assessed. RESULTS: A total of 148 patients were screened, of which 30 and 44 patients received OVP and no OVP, respectively. Patients who received OVP had greater antibiotic use and hospital lengths of stay. The incidence of CDI recurrence within 8 weeks of antibiotic exposure was significantly lower in patients who received OVP (3% vs 25%; P 5 .02) despite this group having notably more risk factors for recurrence. There were no vancomycin-resistant enterococci infections in any patients within either group. After adjustment in a multivariable analysis, secondary OVP was associated with less risk of recurrence (odds ratio, 0.10; 95% confidence interval, 0.01--0.86; P 5 .04). CONCLUSIONS: Secondary OVP while receiving systemic antibiotics reduces the risk of recurrent CDI in pediatric patients with a history of CDI. [ABSTRACT FROM AUTHOR]