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Update: Is oral vancomycin prophylaxis (OVP) beneficial for secondary prevention of Clostridioides difficile infection (CDI)?


While Clostridioides difficile infections (CDIs) have been steadily decreasing in the United States for the past several years, 113,415 cases of community-onset and hospital-onset infections across 3,653 general acute care hospitals were reported to the Centers for Disease Control and Prevention’s National Healthcare Safety Network in 2020.1 A frequently asked question (FAQ) was published in November 2020 summarizing data for the use of oral vancomycin prophylaxis (OVP) for secondary prevention of CDI (available here).2 At the time the 2020 FAQ was published, the author found that certain populations may benefit from OVP for secondary prevention of CDI. However, the literature was mostly of low quality (eg, retrospective cohorts). Available guidelines at the time likewise did not specifically make a recommendation for or against the use of OVP for secondary prophylaxis, but suggested factors that might influence the decision to administer secondary prophylaxis and provided suggestions for dosing regimens.3

Since the publication of this FAQ, several new guidelines for CDI management have been published.4-7 This update will focus on recommendations from newer guidelines, as well as newer primary literature that addresses the question. Of note, data for the use of OVP for primary prophylaxis of CDI will be discussed in a future FAQ.

Guideline updates

In 2021, several reputable medical societies updated their guidelines for CDI management.4-7 Recommendations for secondary OVP are summarized in Table 1. Briefly, guidelines published in 2021 are generally in agreement that OVP may provide some benefit for high-risk patients requiring subsequent antibiotic therapy.4,5,7 The American College of Gastroenterology guideline identifies high-risk groups as patients who are 65 years of age or older, those with significant immunocompromise, and hospitalization for severe CDI within the past 3 months.4 This guideline graded their recommendation for secondary OVP in these groups as conditional and based on low quality of evidence. The European Society of Clinical Microbiology and Infectious Diseases identifies high-risk patients as those with a history of recurrent CDIs that were triggered by systemic antibiotics, and recommends consideration of secondary OVP in these patients based on expert opinion.6 The American Society of Colon and Rectal Surgeons and Infectious Diseases Society of America do not provide formal recommendations for or against the use of secondary OVP, but relevant statements from their 2021 guidelines are provided in Table 1.5,7

Table 1. Recommendations for the use of OVP for CDI.3-7
Society (year)Recommendation
American College of Gastroenterology (2021)4“[OVP] may be considered during subsequent systemic antibiotic use in patients with a history of CDI who are at high risk of recurrence to prevent further recurrence.”
American Society of Colon and Rectal Surgeons (2021)5No formal recommendation provided.
Authors state: “Prophylactic use of antibiotics to prevent CDI lacks sufficient supporting data, although some studies evaluating high-risk patients suggest possible benefit.”
European Society of Clinical Microbiology and Infectious Diseases (2021)6“Routine prophylaxis with anti-CDI antibiotics when on systemic antibiotic treatment is not recommended.”

“In very selected patients with a history of multiple recurrent CDI precipitated by systemic antibiotic use, prophylaxis with microbiota sparing anti-CDI antibiotics may be warranted, after carefully balancing the risk and benefits, and after consultation with an Infectious Diseases or Clinical Microbiology specialist.”
Infectious Diseases Society of America (2021)7No formal recommendation provided.
The 2017 version of the guideline notes the following:3“If the decision is to institute CDI prevention agents, it may be prudent to administer low doses of vancomycin or fidaxomicin (eg, 125 mg or 200 mg, respectively, once daily) while systemic antibiotics are administered. Factors that might influence the decision to administer secondary prophylaxis include length of time from previous CDI treatment, and patient characteristics (number of previous CDI episodes, severity of previous episodes, and underlying frailty of the patient).”
Abbreviations: CDI=Clostridioides difficile infection; OVP=oral vancomycin prophylaxis.

Literature review

Since November 2020, newer literature evaluating the efficacy of secondary OVP in patients receiving subsequent antibiotic therapy has been published (Table 2). Tariq et al published a meta-analysis of 10 retrospective cohort studies published through January 2020.8 The dosing and duration of OVP was variable across studies. Nonetheless, results demonstrated that patients who received OVP had an estimated 66% reduction in the risk of recurrent CDI, with consistent results observed in a subgroup of hospitalized patients. Another subgroup analysis identified a reduced risk CDI with OVP when using data from 7 studies with a follow up of more than 60 days (16.4% vs 21.9%; odds ratio [OR], 0.41; 95% CI, 0.22 to 0.77). Interestingly, an analysis of data from 3 high-quality studies found a higher rate of CDI recurrence in the OVP versus control group (22.6% vs 17.6%), but the between-group difference in risk did not reach statistical significance (OR, 0.58; 95% CI, 0.24 to 1.38).

Two additional studies became available after the date of the literature search in the aforementioned meta-analysis.9,10 Pisipati et al performed a single center randomized trial of adult patients receiving OVP at a dose of 125 mg once or twice daily or no prophylaxis.10 There was a zero rate of CDI recurrence and vancomycin-resistant enterococci (VRE) infection in all study groups, which precluded analysis of most prespecified efficacy and safety outcomes. The rate of all-cause mortality in the overall study population was 10.1%, with approximately equal occurrence in the treatment and control groups. Lastly, a multicenter retrospective cohort study by Bao et al assessed the efficacy of OVP in children at least 1 year of age. Results demonstrated a statistically significant reduction in the incidence of CDI recurrence within 8 weeks after antibiotic exposure in the group that received OVP. Ten of the 11 children who experienced recurrence had nonsevere disease. The median time to CDI recurrence was 19 days in the OVP group and 6 days in the control group (p=0.67). Receipt of OVP remained protective against CDI recurrence in a multivariable logistic regression analysis that controlled for recent hospitalization, duration of antibiotics, and previous high-risk antibiotic use (OR, 0.10; 95% CI, 0.01 to 0.86).

Table 2. Studies describing secondary OVP for CDI prevention in patients receiving subsequent antibiotics.8,9,10
Study design and durationPopulationInterventionsCDI recurrence, OVP vs control
VRE infection, OVP vs control
Tariq et al (2021)8
MA of 10 R studies
Follow up: 30 days to 1 year
Adults with a history of CDIOVP 125 mg once to four times daily or 250 mg twice to four times daily; duration ranged from 2.5 to 19 days (n=713)
Control (n=8545)
Hospitalized patients and solid organ and hematopoietic stem cell transplant patients:13.5% vs 21.9%; OR 0.34; 95% CI, 0.20 to 0.59
Hospitalized patients only: OR, 0.35; 95% CI, 0.19 to 0.63
4% vs 4.7%; OR, 1.11; 95% CI, 0.35 to 3.49
Clinical studies 
Bao et al (2021)9
Follow up: 8 weeks
Children 1 to 17 years of age with a history of CDIOVP 10 mg/kg (up to 125 mg per dose) twice daily until 5 days after the completion of antibiotics (n=30)
Control (n=44)
3% vs 25%; p=0.02No cases in either group
Pisipati et al (2020)*10
Follow up: 12 weeks
Adults with a history of CDI
OVP 125 mg once daily (n=36) or twice daily (n=36) until the completion of antibiotics
Control (n=36)
No cases in either groupNo cases in either group
Abbreviations: CDI=Clostridioides difficile infection; MA=meta-analysis; MC=multicenter; OR=odds ratio; OVP=oral vancomycin prophylaxis; R=retrospective; RCT=randomized controlled trial; SC=single center; VRE=vancomycin resistant enterococci.
*Abstract only publication.


Data describing the use of secondary OVP continues to be primarily retrospective.8,9 Similar to a previously described meta-analysis by Barber et al, the meta-analysis by Tariq et al found a significant reduction in CDI recurrence with secondary OVP.3,8,10 In this analysis, the risk of VRE was not significantly different for the OVP versus control group, although the analysis for this outcome was based on 3 studies, one of which included patients receiving OVP for primary prophylaxis. A randomized trial evaluating OVP in adults did not identify any cases of CDI or VRE in a 12 week follow up, limiting the usefulness of this data for clinical decision-making. Lastly, a retrospective study by Bao et al found a reduced risk of recurrent CDI in children who received OVP, and is noted to be the first study to assess secondary OVP in this population.


Newer guidelines and literature continue to suggest that certain populations may benefit from OVP for secondary prevention of CDI, and patients with a history of CDI and receiving systemic antibiotics are the key population with continued supporting evidence. Data from a recent meta-analysis identified that there is variability in OVP dosing regimens used in adults, ranging from 125 to 250 mg 1 to 4 times daily; the duration of therapy ranges from 2.5 days to 19 days or for the duration of antibiotic therapy. A single study in children found benefit with a dose of 10 mg/kg (up to 125 mg per dose) twice daily for the duration of antibiotic therapy and 5 days thereafter. More research is necessary to fully quantify the benefits of secondary OVP, establish an effective dosing regimen, and address issues surrounding cost-effectiveness and potentials risks of treatment.



  1. C.difficile infections. Centers for Disease Control and Prevention. Accessed December 31, 2021.
  2. Rux C. Is oral vancomycin prophylaxis (OVP) beneficial for secondary prevention of Clostridioides difficile infection (CDI)? University of Illinois Drug Information Group. November 2020. Accessed December 31, 2021.
  3. McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66(7):e1-e48.
  4. Kelly CR, Fischer M, Allegretti JR, et al. ACG clinical guidelines: prevention, diagnosis, and treatment of clostridioides difficile infections. Am J Gastroenterol. 2021;116(6):1124-1147. doi:10.14309/ajg.0000000000001278
  5. Poylin V, Hawkins AT, Bhama AR, et al. The American Society of Colon and Rectal Surgeons clinical practice guidelines for the management of Clostridioides difficileDis Colon Rectum. 2021;64(6):650-668. doi:10.1097/DCR.0000000000002047
  6. van Prehn J, Reigadas E, Vogelzang EH, et al. European Society of Clinical Microbiology and Infectious Diseases: 2021 update on the treatment guidance document for Clostridioides difficile infection in adults. Clin Microbiol Infect. 2021;27(suppl 2):S1-S21. doi:10.1016/j.cmi.2021.09.038
  7. Johnson S, Lavergne V, Skinner AM, et al. Clinical practice guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 Focused update guidelines on management of clostridioides difficile infection in adults. Clin Infect Dis. 2021;73(5):e1029-e1044. doi:10.1093/cid/ciab549
  8. Tariq R, Laguio-Vila M, Tahir MW, Orenstein R, Pardi DS, Khanna S. Efficacy of oral vancomycin prophylaxis for prevention of Clostridioides difficileinfection: a systematic review and meta-analysis. Therap Adv Gastroenterol. Published 2021 Feb 23. doi:10.1177/1756284821994046
  9. Bao H, Lighter J, Dubrovskaya Y, et al. Oral vancomycin as secondary prophylaxis for Clostridioides difficilePediatrics. 2021;148(2):e2020031807. doi:10.1542/peds.2020-031807
  10. Pisipati S. S0179 role of oral vancomycin prophylaxis in preventing recurrent Clostridioides difficile infection in hospitalized patients requiring antibiotics: a randomized controlled trial. Am J Gastroenterol. 2020;115(suppl 1):S68-S68. doi:10.14309/01.ajg.0000702764.15425.e8
  11. Babar S, El Kurdi B, El Iskandarani M, et al. Oral vancomycin prophylaxis for the prevention of Clostridium difficileinfection: A systematic review and meta-analysis. Infect Control Hosp Epidemiol. 2020;41(11):1302-1309. doi:10.1017/ice.2020.277

Prepared by:
Katherine Sarna, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

February 2022

The information presented is current as of December 31, 2021. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.