Do data support the use of oral vancomycin prophylaxis for primary prevention of Clostridium difficile infection CDI in high-risk patients?

Background
Systemic antibiotic therapy (SAT) represents the top inciting factor of primary and recurrent Clostridium difficile infections (CDIs).¹ Hospitalization and immunosuppression are additional important contributors to CDI risk. Among the many strategies aimed to prevent CDI in high-risk patients, oral vancomycin prophylaxis (OVP) is a therapeutic approach that clinicians have applied when the development of CDI is a concern. A frequently asked question (FAQ) was published in February 2022 summarizing updated data for the use of OVP for secondary prevention of CDI (available here).² Secondary prevention of CDI includes the administration of OVP to patients with a history of CDI.¹ Conversely, primary prevention of CDI is defined as the use of OVP in patients with no prior history of CDI. The previous FAQ did not discuss OVP for primary prevention of CDI, an area with more limited published literature.² Therefore, the focus of the following summary is on guidelines and primary literature that addresses OVP for primary prophylaxis of CDI.

Guideline updates
In 2021, several reputable medical societies updated their guidelines for CDI management.^3-6 However, only the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) specifically makes a recommendation concerning primary OVP, stating, “Routine prophylaxis with anti-CDI antibiotics when on systemic antibiotic treatment is not recommended.”³ This recommendation was graded as a “Good Practice Statement,” which indicates that the recommendation is not supported by evidence, but guidance was deemed necessary by the committee. Guidelines from other organizations acknowledge the potential benefit of primary OVP in selected high-risk patients, including in patients receiving SAT, and those who are post-hematopoietic stem cell transplant (HCT) or solid organ transplant (SOT).^4-6

Literature review
Evidence describing the use of OVP for primary prophylaxis of CDI is summarized in Table 1. Tariq and colleagues published a meta-analysis of studies published through January 2020 which reported on a subgroup of 4 retrospective cohort studies and 1 randomized, open-label study (n=1352) that evaluated OVP for primary CDI prevention.⁷ The dosing and duration of OVP was variable across these studies, including 125 mg once, twice, or 4 times daily. Results for this subgroup showed a non-significant trend toward a decrease in the risk of CDI in patients who received primary OVP (OR, 0.18; 95% CI, 0.03 to 1.09; p=0.06). Maraolo et al published another meta-analysis of data through September 2021 that included a subgroup analysis of 3 retrospective cohort studies and 1 randomized, open-label study that evaluated OVP for primary CDI prevention (n=1125); all of these data overlapped with the Tariq et al MA but one retrospective cohort study was not included.¹ In this MA, the results were on the borderline of statistical significance, demonstrating that OVP may be an efficacious option for the primary prevention of CDI (OR, 0.02; 95% CI, 0.00 to 0.18). The use of OVP was not associated with a higher risk of vancomycin-resistant enterococci (VRE) infections in either analysis.

Johnson et al performed the only randomized, open-label trial of OVP for the prevention of healthcare facility-onset CDI (HCFO-CDI) in high-risk adult patients receiving SAT during hospitalization.⁸ Data from this trial was included in the meta-analyses summarized above. Patients who were at least 60 years of age, had been hospitalized for more than 72 hours and less than or equal to 30 days prior to the index hospitalization, and had received SAT during that prior hospitalization were considered at high risk for HCFO-CDI. Patients who were randomized to receive OVP received therapy as an oral solution 125 mg once daily throughout SAT and 5 days thereafter. Results demonstrated that no events of HCFO-CDI were reported in the OVP group compared with 6 (12%) in the no-prophylaxis group (p=0.03). Colonization with VRE did not occur in either group. Only 1 patient reported mild gastrointestinal side effects to OVP.

Lastly, a single-center retrospective chart review by Altemeier and Konrardy was the first to assess the efficacy of OVP in allogenic hematopoietic cell transplant (alloHCT) recipients.⁹  In this study, OVP was provided at a dose of 125 mg twice daily starting on the day of inpatient admission for alloHCT and continued until discharge. Results demonstrated that 11% of patients developed CDI in the control group versus 2% of patients in the OVP group (p=0.018). There were similar rates of VRE infections (n=12 with no prophylaxis vs. n=11 with prophylaxis) and graft-versus-host disease (GVHD) grades 2 to 4 (36% with no prophylaxis vs. 38% with prophylaxis; p=0.77) in both treatment arms.

Discussion
Two meta-analyses, an open-label randomized trial, and a newer retrospective chart review have evaluated primary OVP.^1,7-9 In both meta-analyses, there was moderate heterogeneity with respect to included study designs, at-risk populations, type and duration of SAT, dosage and duration of OVP, and the follow-up time.^1,7 Furthermore, all but 1 study in both analyses were retrospective cohorts. Retrospective data does not allow the determination of causality and is subject to numerous biases, notably selection and information bias. The only randomized, open-label study by Johnson et al (2020) revealed that OVP 125 mg daily protects against HCFO-CDI during hospitalization in targeted older adults (≥60 years) who are hospitalized ≤30 days prior to the index hospitalization, and who received SAT during the prior hospitalization.⁸

The disruption of gut microbiota and VRE infection are concerns with vancomycin use. The incidence of VRE infection was not significantly increased with OVP in 2 meta-analyses.^1,7 However, assessment of VRE infection may not be the best measure of the potential negative impact of vancomycin on microbiota.¹ Instead, the rate of VRE colonization would be a more clinically useful evaluation because this measure may have implications on future antibiotic therapies. Johnson et al did not detect any cases of VRE colonization in either treatment arm while the difference between treatment arms was not significant in alloHCT recipients.^8,9

Conclusion
Newer guidelines and available literature suggest that certain populations may benefit from primary OVP for CDI, including patients receiving SAT and those who are immunocompromised following HCT or SOT. Data from recent meta-analyses found that there is variability in OVP dosing regimens, ranging from 125 mg 1 to 4 times daily; the duration of therapy ranges from 7 days to 29 days or for the duration of hospitalization in alloHCT patients. More research is necessary to fully quantify the benefits of primary OVP, establish an optimal dosing regimen, and address issues surrounding cost-effectiveness. The potential risks of OVP also require further exploration, particularly whether or not the disruption of the gut microbiota increases the risk of VRE colonization or infection or recurrent CDI following completion of OVP.

References

1. Maraolo AE, Mazzitelli M, Zappulo E, et al. Oral vancomycin prophylaxis for primary and secondary prevention of Clostridioides difficile infection in patients treated with systemic antibiotic therapy: a systematic review, meta-analysis and trial sequential analysis. Antibiotics (Basel). 2022;11(2):183. doi: 10.3390/antibiotics11020183.
2. Sarna K. Update: Is oral vancomycin prophylaxis (OVP) beneficial for secondary prevention of Clostridioides difficile infection (CDI)? University of Illinois Drug Information Group. February 2022. Accessed April 05, 2022. https://dig.pharmacy.uic.edu/faqs/2022-2/february-2022-faqs/update-is-oral-vancomycin-prophylaxis-ovp-beneficial-for-secondary-prevention-of-clostridioides-difficile-infection-cdi/
3. 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
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 difficile. Dis Colon Rectum. 2021;64(6):650-668. doi:10.1097/DCR.0000000000002047
6. 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. doi: 10.1093/cid/cix1085
7. Tariq R, Laguio-Vila M, Tahir MW, Orenstein R, Pardi DS, Khanna S. Efficacy of oral vancomycin prophylaxis for prevention of Clostridioides difficile infection: a systematic review and meta-analysis. Therap Adv Gastroenterol. Published 2021 Feb 23. doi:10.1177/1756284821994046
8. Johnson SW, Brown SV, Priest DH. Effectiveness of oral vancomycin for prevention of healthcare facility-onset Clostridioides difficile infection in targeted patients during systemic antibiotic exposure. Clin Infect Dis. 2020;71(5):1133-1139. doi: 10.1093/cid/ciz966
9. Altemeier OJ, Konrardy KT. Oral vancomycin for Clostridioides difficile prophylaxis in allogenic hematopoietic cell transplant. Transpl Infect Dis. 2022;24(2):e13790. doi: 10.1111/tid.13790

Prepared by:
Duyen Bui
PharmD Candidate Class of 2022
University of Illinois at Chicago College of Pharmacy

Edited by:
Katherine Sarna, PharmD, BCPS

May 2022

The information presented is current as of April 11, 2022. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.