Division of Infectious Diseases

#PharmToExamTable: Treatment of Clostridioides difficile infection in adults: Guideline review

This month’s #PharmToExamTable question was 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)

Clostridioides difficile infection (CDI) is the most common cause of infectious diarrhea in healthcare settings. The pathogenesis of CDI begins as an ingestion of toxigenic C. difficile spores which colonize the colonic microbiota (flora). Exposure to antibiotics, particularly clindamycin, fluoroquinolones, and cephalosporins leads to a disruption of the normal colonic microbiota. This disruption causes C. difficile overgrowth and production of exotoxin A and B, leading to manifestations of diarrhea and inflammation of the colon (colitis). CDI is defined as 3 or more unformed stools within 24 hours, during or after antibiotic use, that presents with diarrhea, fever, leukocytosis or abdominal pain. Diagnosis includes the presence of symptoms, a stool test positive for C. difficile toxins or detection of toxigenic C. difficile. CDI severity can range from mild to moderate (non-severe), severe and fulminant colitis (severe with complications). Common risk factors for CDI and recurrent episodes include antibiotic usage, advanced age and gastric acid suppression. The most important initial step in treatment is to discontinue offending antibiotic agents. However, after discontinuing the offending agents, treatment regimens for CDI include oral vancomycin, fidaxomicin, metronidazole and fecal microbiota transplantation specific to severity and recurrence.

Non-severe CDI is clinically defined as leukocytosis with a white blood cell (WBC) count of ≤15,000 cells/mL and an absolute serum creatinine level <1.5 mg/dL. The Infectious Disease Society of America (IDSA) recommends treatment of an initial non-severe CDI episode with either oral vancomycin 125 mg given four times daily for 10 days or fidaxomicin 200 mg given twice daily for 10 days. Alternatively, IDSA recommends treatment with oral metronidazole 500 mg three times daily for 10 days only if access to vancomycin or fidaxomicin is limited.

Severe CDI is clinically defined as leukocytosis with a WBC count of >15,000 cells/mL and an absolute serum creatinine level ≥1.5 mg/dL. For both non-severe and severe CDI, the serum creatinine values are based on absolute values and not in comparison to baseline values, as these are not always available. These criteria do not perform well in patients with chronic kidney disease and as a result further validation is needed. Similar to non-severe CDI, IDSA recommends treatment of an initial severe CDI episode with either oral vancomycin 125 mg given four times daily for 10 days or fidaxomicin 200 mg given twice daily for 10 days.

Fulminant CDI is clinically defined as the presence of hypotension or shock, ileus (intestinal obstruction/immobility) or toxic megacolon. The IDSA preferred regimen for an initial fulminant CDI episode is vancomycin 500 mg four times daily by mouth or nasogastric tube. Alternatively, rectal administration of vancomycin can be considered if ileus is present. Additionally, IDSA recommends the administration of intravenous metronidazole 500 mg three times daily with either oral or rectal vancomycin, especially with the presence of an ileus.

The IDSA guidelines reflect the use of a tapered and/or pulsed vancomycin regimen for the treatment of recurrent CDI. Tapered vancomycin regimens include dosing up to four times daily with a decrease in dosing frequency over several weeks. Pulsed vancomycin dosing regimens include a single dose given every 2-3 days for up to 2-8 weeks. The treatments can be performed in sequentially with a tapered regimen followed by pulsed dosing . The process of a tapered and/or pulsed vancomycin regimen is intended to target the elimination of C. difficile spores. The cycle of increasingly long antibiotic-free periods allows spores to germinate and the pulses of antibiotics eliminate newly germinated vegetative cells.

The IDSA recommends three separate treatment strategies for the first recurrent CDI episode. If metronidazole was used for the initial episode, treatment with the standard CDI regimen of oral vancomycin is recommended. Similarly, if vancomycin was used for the initial episode, treatment with the standard fidaxomicin regimen is recommended. If vancomycin was used for the initial episode, a prolonged taper and pulsed oral vancomycin regimen is recommended. The dosing regimen is as follows: oral vancomycin 125 mg four times daily for 10-14 days, oral vancomycin 125 mg two times daily for 7 days, oral vancomycin 125 mg once daily for 7 days, and then oral vancomycin 125 mg once every 2 or 3 days for 2-8 weeks.

The IDSA preferred treatment for two or more recurrent episodes is a fecal microbiota transplantation. Alternative treatments include again include a tapered and pulsed vancomycin regimen, or a course of vancomycin followed by a “chaser” of oral rifaximin or fidaxomicin.
Evidence for the treatment of CDI using a vancomycin tapered regimen was only studied for recurrent CDI in the primary literature. These included 4 observational studies and 1 clinical trial.

The next blog post will review the evidence to support using tapered oral vancomycin regimens for treatment of 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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