Is oral vancomycin prophylaxis (OVP) beneficial for secondary prevention of Clostridioides difficile infection (CDI)?
Background
Clostridioides difficile, formerly known as Clostridium difficile, is known for causing diarrhea and colitis, especially after the use of systemic antibiotics.1 Per the Centers for Disease Control and Prevention (CDC), C. difficile infections (CDIs) are most prevalent in patients who are ≥65 years of age and receiving medical care and antibiotics, hospitalized or in nursing homes for extended periods, immunosuppressed, or have a history of CDI. The Antibiotic Resistance Threats in the United States report published by the CDC estimates that 223,900 cases of CDI in hospitalized patients and 12,800 CDI-related deaths occurred in 2017.2 Health care costs attributable to CDI are nearly 1 billion dollars. Interestingly, infection control and antimicrobial stewardship efforts have substantially decreased CDI cases since 2012.
Recurrent CDI is defined as the new onset of symptoms (diarrhea, megacolon, or severe ileus) along with the presence of C. difficile toxin using an enzyme immunoassay (EIA) or nucleic acid amplification test (NAAT), after having a positive EIA or NAAT within the last 2 to 8 weeks.3 It is estimated that roughly 15% to 30% of patients initially responding to therapy subsequently develop recurrent CDI, and the rates of second recurrence are even higher (upwards of 40%).4 These statistics highlight the need for effective strategies to not only appropriately treat active CDI but prevent future episodes.
Guidelines
Oral vancomycin prophylaxis (OVP) is a proposed method for primary and secondary prevention of CDI. The use of OVP for secondary prevention is the focus of this review. Secondary prevention has been studied in a variety of patient populations, but primarily in hospitalized patients receiving systemic antibiotics and immunosuppressed transplant patients. Despite available data in this arena, a consensus regarding the effectiveness of OVP as secondary prevention is lacking. Guidelines from the Infectious Diseases Society of America (IDSA) for the management of CDI were last updated in 2017. At that time, no recommendation for OVP was provided due to insufficient data.3 However, if CDI prevention agents were deemed necessary, the authors recommended low doses of vancomycin or fidaxomicin (eg, 125 mg or 200 mg, respectively, once daily) while systemic antibiotics are administered.
Relevant literature published since these guidelines is summarized in the following sections.
Newer data for OVP
A 2020 systematic review and meta-analysis published by Babar et al. summarizes available literature through March 2019 on the use of OVP in both primary and secondary prevention of CDI.5 Authors identified 9 trials, 6 of which were retrospective cohort studies specifically looking at OVP for secondary prevention. Results of the meta-analysis demonstrated that CDI recurrence was significantly reduced in patients receiving OVP for secondary prevention (odds ratio [OR], 0.36; 95% confidence interval [CI], 0.20 to 0.65; I2=55%). These results represent study data from adult patients with a history of CDI given systemic antibiotics (4 studies) and recipients of hematopoietic stem cell transplant and renal transplant (1 study each). Oral vancomycin dosing varied among the secondary prevention studies, but typically ranged from 125 to 250 mg 2 to 4 times daily. Meta-regression analysis identified total daily dose of OVP as the only covariate having a significant correlation with odds for CDI. This finding suggests that lower dose OVP may be more beneficial compared to higher dose OVP due to less disruption of the gastrointestinal microbiome. Lastly, the duration of OVP also varied among studies, ranging from 7 to 19 days or for the duration of systemic antibiotics. Carignan et al. was the only included study to specifically examine the impact of duration of treatment, finding that OVP is more effective when given for a duration ≥50% of the duration of systemic antibiotic treatment.6
Following the publication of the above meta-analysis, 2 additional retrospective, observational studies were published in 2020 (Table 1).7,8 Both studies examined OVP for prevention of breakthrough or recurrent CDI in hospitalized adults. Connor et al. (N=82) looked at several prophylaxis strategies in addition to OVP (doses ranging from 125 to 250 mg 1 to 4 times daily), including metronidazole monotherapy and combination therapy with metronidazole and vancomycin.7 This study specifically examined patients in the intensive care unit, and found a CDI recurrence (defined as diarrhea or loose stool in presence of confirmed C. difficile toxin, empiric use of CDI treatment, or direct visual evidence of pseudomembranous colitis) rate of 5.9% with OVP; there was no statistically significant difference between treatment groups for the primary outcome. The second study by Zacharioudakis et al. specifically studied oral vancomycin 125 mg twice daily in hospitalized patients receiving antibiotics who have a history of CDI. Results demonstrated the effectiveness of OVP for reducing breakthrough CDI (defined as CDI during OVP), CDI recurrence (defined as CDI 1 month after initiation of OVP), and CDI-associated hospitalization, although lacking any comparator group.8
| Table 1. Newer evidence for oral vancomycin for secondary prevention of CDI.7,8 | |||
|---|---|---|---|
| Study design and duration | Population | Interventions | Key Results |
| Connor7 2020 MC, retrospective observational study Follow-up: 90 days | N=82 (average age ~58 years) Inclusion: ICU admitted patients for ≥72 hours History of CDI within 1 year Receiving broad-spectrum antibiotics ≥48 hours Exclusion: Treatment for known or suspected CDI Death within 72 hours of broad-spectrum antibiotics | OVP: 125 to 250 mg every 6 to 24 hours (most common regimen was 125 mg every 12 hours) (n=17) Oral or IV metronidazole: 250 to 500 mg every 6 to 12 hours (n=20) Combination OVP 125 mg every 6 to 12 hours plus IV or oral metronidazole 500 mg every 8 hours (n=7) | CDI recurrence occurred in 21.1%, 14.3%, 5.9%, and 0% of the control, combination, OVP, and metronidazole treatment groups, respectively |
| Zacharioudakis8 2020 MC, retrospective study Average duration of OVP treatment: 8.4 days | N=264 (average age 65.9 years) Inclusion: Hospitalized patients >18 years Previous history of CDI Receiving systemic antibiotics Exclusion: Receiving vancomycin for treatment of CDI Previous diagnosis of CDI within 14 days First dose administered >24 hours after first dose of systemic antibiotics Last dose administered >24 hours prior to end of systemic antibiotic course | OVP: 125 mg twice daily for duration of antimicrobial therapy | Breakthrough CDI (CDI occurrence during OVP) occurred in 17 patients Recurrent CDI (CDI 1 month after initiation OVP) occurred in 22 patients Of the 102 patients with a history of CDI in preceding 3 months, 4 patients had breakthrough CDI and 9 had recurrent CDI 70 patients were re-admitted in the 30-days following discharge, but only 2 re-admissions were for CDI VRE was isolated from urine or superficial wound cultures at 3- and 6-month follow up in 23 and 26 patients, respectively; the increase in VRE colonization following OVP was statistically significant at both time points |
| Abbreviations: CDI=Clostridioides difficile infection; CI=confidence interval; ICU=intensive care unit; IV=intravenous; MC=multicenter; OVP=oral vancomycin prophylaxis; VRE=vancomycin resistant enterococci. | |||
Cost-effectiveness
Given that the common goal of decreasing CDI recurrence is to reduce associated hospitalizations, an important consideration for OVP is whether or not therapy is cost-effective. While there are limited data regarding this issue, 1 abstract has been published examining cost-effectiveness of OVP.9 Namn et al. utilized Marokov Chain Monte Carlo simulations in a cohort representing hospitalized patients with a history of CDI receiving systemic antibiotics to assess the financial implications of OVP for secondary prevention. In the 500 simulations analyzed in the study, OVP resulted in a significantly greater cost compared to no oral vancomycin at $12,045.67 (95% CI, $11,880.80 to $12,210.53) versus $8,135.48 (95% CI, $8,047.37 to $8,223.58), respectively (p<0.000001). Additionally, OVP was associated with a nearly 2.45 increased risk of mortality, largely driven by risks of developing resistant organisms, namely VRE.
Discussion
The studies outlined in Table 1 and those included in the Barbar et al. meta-analysis, though showing promise regarding the use of OVP for secondary prevention of CDI, come with several limitations.5,7,8 The currently available literature in this arena is all retrospective, thus lacking the ability to demonstrate causality between OVP and prevention of CDI recurrence. Additionally, there is no consensus regarding OVP dosing, albeit, vancomycin 125 mg twice daily was the most commonly used dose across studies. One of the major concerns related to the use of OVP is the risk of developing multi-drug resistant organisms, namely vancomycin-resistant Enterococcus spp. (VRE). Zacharioudakis et al. included an assessment of VRE colonization within their study, finding that patients treated with OVP were at a significantly higher risk of VRE colonization.8 Additionally, the cost-effectiveness analysis by Namn et al. identified a higher risk of mortality in their simulations with OVP, driven primarily by the development of VRE.9 The risk of VRE colonization associated morbidity and mortality likely drove the increased costs shown within the OVP simulations. Both the risk of VRE colonization and the financial considerations of OVP require further evaluation to determine if benefits truly outweigh the clinical and financial risks associated with OVP.
Overall, larger prospective studies are necessary to further establish the benefits of OVP in secondary prevention of CDI and to and identify the length of time from previous CDI treatment and high-risk populations that are most likely to benefit (number and severity of previous CDI episodes, etc). Future studies should also elucidate differences in dosing regimens to determine an optimal dose, frequency, and duration.
Conclusion
Despite the current lack of consensus guideline recommendations on the utility of OVP for secondary prevention of CDI, the available literature suggests certain populations may benefit from therapy. Although available studies have largely not differentiated which patients specifically are at highest risk for recurrent CDI, hospitalized patients with a history of CDI and receiving systemic antibiotics are the key population with supporting evidence. The most commonly studied OVP dosing regimen is 125 mg twice daily, albeit doses ranging from 125 to 250 mg 1 to 4 times daily have been studied. More research is necessary to fully quantify the benefits of OVP, identify patients most likely to benefit, establish an effective dosing regimen, and address issues surrounding cost-effectiveness and potentials risks of treatment.
References
- Clostridioides difficile– Healthcare-associated Infections. Centers for Disease Control and Prevention. November 23, 2019. Accessed November 30, 2020. https://www.cdc.gov/hai/organisms/cdiff/cdiff_infect.html
- Antibiotic Resistance Threats in the United States Report (2019). Center for Disease Control and Prevention. December 2019. Accessed November 30, 2020. https://www.cdc.gov/DrugResistance/Biggest-Threats.html
- 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. https://doi.org/10.1093/cid/cix1085
- Song JH, Kim YS. Recurrent Clostridium difficle infection: risk factors, treatment, and prevention. Gut Liver. 2019;13(1):16-24. doi: 10.5009/gnl18071
- Babar S, El Kurdi B, El Iskandarani M, et al. Oral vancomycin prophylaxis for the prevention of Clostridium difficile infection: A systematic review and meta-analysis. Infect Control Hosp Epidemiol. 2020 Jun 29:1-8. doi: 10.1017/ice.2020.277
- Carignan A, Poulin S, Martin P,et al. Efficacy of secondary prevention with vancomycin for preventing recurrent Clostridium difficile infections. Am J Gastroenterol 2016;111(12):1834–1840. doi:10.1038/ajg.2016.417
- Connor K, Conn K. Analysis of the impact of secondary prevention on Clostridioides difficile recurrence in critically ill adults. SAGE Open Med. 2020;8:2050312120930898. doi:10.1177/2050312120930898
- Zacharioudakis IM, Zervou FN, Dubrovskaya Y, Phillips MS. Oral vancomycin prophylaxis against recurrent Clostridioides difficile infection: efficacy and side effects in two hospitals. Infect Control Hosp Epidemiol. 2020;41(8):908-913. doi:10.1017/ice.2020.176
- Namn Y, Penmetcha A, Desal D. Cost-effective analysis of prophylactic oral vancomycin use to prevent recurrent clostridium difficile infections in hospitalized patients. Am J Gstroenterol. 2019;114:S112-113. doi:10.14309/01.ajg.0000590268.74639.c8
Prepared by:
Caleb Rux, PharmD
PGY1 Pharmacy Practice Resident
September 2020
Edited by:
Katherine Sarna, PharmD, BCPS
November 2020
The information presented is current as of September 18, 2020. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.