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In this review, we summarize the association of the gut microbiome and microbial perturbation with initial and recurrent CDI. Prevention of recurrent infection (CDI) is a challenge in clinical practice, particularly in patients who need systemic antimicrobial therapy. We aimed to evaluate the role of oral vancomycin prophylaxis (OVP) in prevention of primary or future CDI in patients on systemic antimicrobial therapy. A systematic search of MEDLINE, Embase, and Web of Science was performed from 2000 to January 2020.