Division of Infectious Diseases

#PharmToExamTable: Treatment of Clostridioides difficile infection in adults: What is the evidence supporting a tapered vancomycin regimen?

This is a continuation of this month’s #PharmToExamTable question about C. difficile treatment, answered by Andre Wilt, PharmD 2020 Graduate of UNMC College of Pharmacy, who is now a pharmacy manager at PharmScript

(Reviewed by Scott Bergman PharmD and Andrew Watkins PharmD)

In the last blog post published on September 8, 2020, we reviewed the The Infectious Disease Society of America (IDSA) recommendations for diagnosis and treatment of non-severe Clostridioides difficile infection (CDI), severe CDI, fulminant CDI, and recurrent CDI. In this post, we evaluate the evidence to support the recommendation for use of a tapered oral vancomycin regimen for recurrent CDI.

The first evidence for an oral vancomycin tapered regimen was reported by Tedesco et. al in a 1985 observational report.6-7 This retrospective case series included 22 patients with 17 having a baseline of ≥3 CDI relapses. The patients were subject to an oral vancomycin regimen similar to the one eventually recommended in the IDSA guidelines consisting of 125 mg twice daily for 7 days, 125 mg once daily for 7 days, 125 mg once every 2 days for 7 days, then 125 mg every 3 days for 14 days. All patients were diarrhea-free within 72 hours of completion and relapse free at a mean of 6 months.

The second report of evidence for a tapered vancomycin regimen was published by McFarland et. al in 2002. This retrospective case series studied 163 patients with 29 and 7 cases attributed to tapered and pulsed oral vancomycin regimens, respectively. The study population had a mean baseline of 3.2 prior CDI episodes. Patients were subject to receive low, medium or high doses of either metronidazole or oral vancomycin. Patients with treatment failure were subject to a subsequent tapered or a pulsed regimen with the same antibiotic. Statistically fewer recurrences occurred in the oral vancomycin tapered [9/29 (31%), p = 0.01] and pulsed [1/7 (14.3%), p = 0.02] regimens compared to medium dose (1-2 g/day) oral vancomycin alone [10/14 (71.4%)]. Additionally, fewer occurrences occurred in the tapered and pulsed regimens compared to the low dose (<1 g/day) oral vancomycin regimen [26/48 (54.2%)] and high dose (≥2 g/day) oral vancomycin regimen [9/21 (42.9%)].

Additional evidence for tapered oral vancomycin regimens from observational studies were reported by Bakken in 2014 and Sirbu et. al in 2017. The prospective case series from Bakken studied 25 patients using a tapered and pulse vancomycin or metronidazole regimen in addition to lifeway kifer, a fermented dairy product containing probiotics. The study population had a mean baseline of 4 CDI relapses. The 21 patients subject to an oral vancomycin taper and pulse planned over 8 weeks had a regimen consisting of: 125 mg every 6 hours for 14 days, 375 mg every 72 hours for 14 days, 250 mg every 72 hours for 14 days, then 125 mg every 72 hours for 14 days. Of the patients receiving vancomycin, 17 (81.0%) were cured and remained diarrhea-free at least 9 months after intervention.

The retrospective case series from Sirbu et. al studied 100 patients using two different tapered and pulsed oral vancomycin regimens. The study population had a mean baseline of 3.15 prior CDI episodes. Both study groups were subject to oral vancomycin four times daily for 10-14 days followed by tapering to twice daily dosing for 7 days, once daily dosing for 7 days, then every other day dosing for at least 2 weeks. One treatment group was subject to additional dosing every 3 days for at least 2 weeks. Patients who received dosing every other day plus additional dosing every 3 days had higher cure rates [52/64 (81.1%)] compared to patients who only received every other day dosing [22/36 (61.1.%)]. There was a higher cure rate in patients with ≤2 prior CDI episodes [56/71 (81.1%)] compared to those with >2 prior CDI episodes [18/29 (62.1%)].

Evidence in a randomized controlled trial for tapered oral vancomycin was reported by Hota et. al. This prospective, open-label study evaluated 30 patients subject to treatment with vancomycin plus either a taper and pulse or a fecal transplant. The study population had a baseline of ≥2 prior CDI episodes. Both study groups were initially treated with oral vancomycin 125 mg four times daily for 14 days. One group received a fecal transplant enema 48 hours after discontinuing vancomycin, while the other group was given a vancomycin taper and pulse regimen consisting of: 125 mg twice daily for 7 days, 125 mg once daily for 7 days, 125 mg every other day for 7 days, then 125 mg every 3 days for 7 days. The primary outcome was recurrence of symptomatic, laboratory-confirmed CDI within 120 days of the intervention. More patients experienced CDI recurrence in the fecal transplant group [9/16 (56.2%)] than in the vancomycin taper group [5/12 (41.7%)], which correlated to a 43.8% and 58.3% resolution in symptoms, respectively.

The current data from four observational studies and an open-label clinical trial supports recurrent CDI success rates ranging from 58-100% when using oral vancomycin tapered and pulsed regimens. Dosing regimens from these studies were adopted in the IDSA guidelines for recurrent CDI. However, for recurrent CDI episodes, the IDSA classifies the strength of vancomycin tapered and pulsed regimens as weak with a low quality of evidence. These recommendations were based on the limitations of data being primarily from observational studies and small sample sizes of patients. In the future, more randomized controlled trials with larger sample sizes should be conducted to compare with the evidence presented in the previous studies. Overall, evidence supports the use of vancomycin taper regimens in recurrent CDI.

References
1. Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L, eds. Pharmacotherapy: A Pathophysiological Approach, 10th ed. New York, NY: McGraw-Hill; 2017.
2. Lamont JT, Kelly CP, Bakken JS (2018). Clostridioides (formerly Clostridium) difficile infection in adults: Clinical manifestations and diagnosis. UpToDate. Retrieved March 22, 2020.
3. Lamont JT, Kelly CP, Bakken JS (2020). Clostridioides (formerly Clostridium) difficile infection in adults: Treatment and prevention. UpToDate. Retrieved March 22, 2020.
4. 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):1-48.
5. Tedesco FJ, Gordon D, Fortson WC. Approach to patients with multiple relapses of antibiotic-associated pseudomembranous colitis. Am J Gastroenterol. 1985;80(11):867-868.
6. McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: Treatment Strategies for 163 Cases of Recurrent Clostridium difficile Disease. Am J Gastroenterol. 2002;97(7):1769-1775.
7. Murphy MM, Patatanian E, Gales MA. Extended duration vancomycin in recurrent Clostridium difficile infection: a systematic review. Ther Adv Infectious Dis. 2018;5(6):111-119.
8. Bakken JS. Staggered and Tapered Antibiotic Withdrawal with Administration of Kefir for Recurrent Clostridium difficile Infection. Clin Infect Dis. 2014;59(6):858-861.
9. Sirbu BD, Soriano MM, Manzo C, et al. Vancomycin Taper and Pulse Regimen with Careful Follow-up for Patients with Recurrent Clostridium difficile Infection. Clin Infect Dis. 2017;65(8):1396-1399.
10. Hota SS, Sales V, Tomlinson G, et al. Oral vancomycin Followed by Fecal Transplantation Versus Tapering Oral Vancomycin Treatment for Recurrent Clostridium difficile Infection: an Open-label, Randomized Controlled trial. Clin Infect Dis. 2017;64(3):265-271.

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