Clostridioides difficile infection (CDI) is common among patients undergoing hematopoietic stem cell transplantation (HSCT). Oral vancomycin prophylaxis may effectively prevent CDI in certain populations. We investigated the effectiveness of oral vancomycin primary prophylaxis in preventing CDI in HSCT patients.

We searched six databases from inception to March 21, 2025, for studies comparing the incidence of CDI in HSCT patients who received oral vancomycin primary prophylaxis versus those who did not. We built a Bayesian random-effects model for meta-analysis. The primary outcome was the incidence of CDI. Secondary outcomes included incidence of positive vancomycin-resistant Enterococcus cultures, blood stream infections, graft-vs-host disease, and length of hospital stay. We also assessed for heterogeneity and publication bias using Robust Bayesian Meta-Analyses.

Six studies met inclusion criteria with a total of 1,236 patients. Four of the studies were of fair to good quality. Oral vancomycin primary prophylaxis reduced the incidence of CDI during hospitalization (OR 0.31; 95%CrI 0.16–0.59). Studies were weakly heterogeneous but had strong publication bias. Oral vancomycin primary prophylaxis reduced the odds of CDI by 12% after accounting for publication bias (OR 0.88; 95%CrI 0.32–1.16), although this reduction was not statistically significant. Secondary outcomes were similar in both groups.

Oral vancomycin primary prophylaxis prevented CDI in HSCT patients without significantly affecting secondary outcomes. However, after controlling for publication bias, these findings were no longer significant. Further studies are needed to provide stronger evidence for or against this intervention, assess long-term safety, and assess potential effects on antimicrobial resistance.