Clostridioides difficile (C. diff) infection (CDI)

Criteria & Principles

General Principles of Clostridioides difficile Treatment

• Evaluate use of laxatives and other causes for diarrhea when considering testing and diagnosis for C. difficile infection.

• Discontinue antibiotics and proton-pump inhibitors (such as pantoprazole) as soon as clinically appropriate.

• If possible, avoid use of anti-peristaltic agents, e.g. loperamide, as they may obscure symptoms and precipitate toxic megacolon. Use of cholestyramine is not recommended as it may bind anti-C. difficile therapies.

• Response assessment should be based on resolution of signs/symptoms and NOT repeated PCR testing. Do not test for “cure”.

• ID consultation is recommended for management of fulminant or recurrent infection.

• Preferred vancomycin preparation is the commercial oral capsules. Oral solution is reserved for those who cannot swallow capsules or who require administration via tube.

• Oral administration of vancomycin is NOT systemically absorbed and should NOT replace IV vancomycin for treatment of concomitant systemic Gram positive infections. Vancomycin IV should NOT be used to treat C. difficile infection.

Cost & Access Considerations

• Access to fidaxomicin in the outpatient setting may be cost-prohibitive. Patient’s ability to pay for complete course of therapy in the outpatient setting must be assessed at the time of starting fidaxomicin. Information about workflow can be found on the Fidaxomicin page.
• Fecal microbiota transplantation (FMT) access is subject to availability. Discuss patient eligibility with Gastroenterology (GI) or Infectious Diseases (ID) consultants.
• Merck discontinued production of bezlotoxumab as of 1/31/25. DUHS has purchased extra doses; however, supply will be limited and likely depleted in 2025-2026.

Treatment

Severity

All Severity

Occurrence / Severity	Recommendations
First Occurrence	Vancomycin 125 mg PO QID x 10 days OR Fidaxomicin* 200 mg PO BID x 10 days Fidaxomicin should be considered for patients at increased risk of CDI recurrence (list not all-inclusive): Age > 65 yaers old Moderate-severe immune compromise Concomitant moderate-high risk systemic antibiotic use anticipated for ≥ 4 days during CDI treatment **If access to vancomycin and fidaxomicin is limited: Consider using metronidazole 500mg PO TID x 10 days
Recurrent Episode	If vancomycin was used for the initial episode:     Vancomycin in tapered and pulsed regimenA    OR    Fidaxomicin* 200 mg PO BID for 10 days If fidaxomicin was used for the initial episode: Vancomycin in tapered and pulsed regimenA If metronidazole was used for the initial episode: Vancomycin 125 mg PO QID x 10 days OR fidaxomicin* 200 mg PO BID x 10 days
Second or Subsequent Recurrent Episode	Fidaxomicin* 200 mg BID x 10 days OR Vancomycin in tapered and pulsed regimenA NOTE: If considering fecal microbiota transplantation (FMT) for the prevention of recurrent CDI, consider placing an E-communication to Infectoius Disease or Gastroenterology
Fulminant Disease	Vancomycin 500 mg PO QID (If vancomycin unable to be given PO, use enteral tube) AND Metronidazole 500 mg IV Q8H If ileus is present: Consider adding vancomycin enema 500 mg/100 mL of normal saline q6h For patients with fulminant CDI refractory to standard therapy: Recommend GI and ID consult. Consider fecal microbiota rectal suspension [REBYOTA]B If FMT is performed for the treatment of fulminant CDI: Anti-CDI antibiotics should be continued until pseudomembranes are no longer detected on colonoscopy and the patient has clinically improved following FMT (i.e., improvement in CDI-related symptoms, WBC, and CRP) The optimal choice of anti-CDI antibitic after FMT for fulminant CDI remains unknown; however, fidaxomicin may be preferred as vancomycin is more disruptive to the newly transplanted microbiota
C. difficile Prophylaxis: Agents for Use and Recommendations
BezlotoxumabC	Bezlotoxumab 10 mg/kg IV x 1 dose as adjunctive therapy with active CDI treatment for patients at increased risk for CDI recurrence (i.e., age >65 years, immunocompromised, severe CDI, and/or NAP1 strain) NOTE: Merck discontinued production of bezlotoxumab as of 1/31/25. DUHS has purchased extra doses, but supply will likely be depleted in 2025-2026.
Oral vancomycin prophylaxis (OVP)	Dose: vancomycin 125 mg PO daily for secondary prophylaxis in select patients Duration: while receiving high-risk systemic antibiotics PLUS 5 days after antibiotic cessation Evidence for efficacy of oral vancomycin prophylaxis (OVP) remains limited and largely observational. Some studies have found benefit with OVP; however, this is not consistent across studies. Additionally, one case series found OVY may not reduce CDI incidence but rather just delays disease onset. One meta-analysis suggests no benefit when used as primary prophylaxis. Refer to the oral vancomycin page or the attached document for a detailed summary of available evidence. Clinicians may consider OVP for secondary prophylaxis in select individuals at high risk of recurrence For example, history of recurrent or severe CDI within the past 6 months AND concomitant use of high-risk systemic antibiotics such as fluoroquinolones, clindamycin, or 3rd/4th generation cephalosporins History of fecal microbiota therapy in the last 12 months Oral vancomycin prophylaxis is NOT recommended for ANY of the following patient populations: Low-risk systemic antibiotic use (e.g., tetracyclines, macrolides, penicillin alone, amoxicillin alone, nitrofurantoin) Abscence of recurrent CDI episode in the past 6 months (e.g., primary prophylaxis) Metronidazole-containing systemic antibiotic regimens, due to anti-CDI activity of metronidazole

^A Tapered and pulsed vancomycin regimen example: 125 mg PO QID x 10-14 days, then BID x 7 days, then daily x 7 days, then every 2 or 3 days for 2-8 weeks

^B Fecal microbiota rectal suspension [REBYOTA] is nonformulary at DUH Raleigh Campus and therefore restricted to GI or ID consult PLUS 2nd level pharmacy admin approval. Prior to use, REBYOTA must be thawed for ~24 hours.

^C Bezlotoxumab is restricted to outpatient use ONLY at DUH Raleigh Campus; therefore, for inpatient use, bezlotoxumab is nonformulary and restricted to GI or ID consult PLUS 2nd level pharmacy admin approval.

* The patient’s ability to pay to complete the course of therapy in the outpatient setting must be assessed at the time of starting therapy (see Fidaxomicin page for additional information). Fidaxomicin should not be used for fulminant disease.

References

1. 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. Clinical Infectious Diseases. 2021;73(5):e1029-e1044.  

2. 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.

3. Rao K, Zhao Q, Bell J, et al. An Open-Label, Randomized Trial Comparing Fidaxomicin with Oral Vancomycin for the Treatment of Clostridioides difficile infection in Hospitalized Patients Receiving Concomitant Antibiotics for Concurrent Infections. Clin Infect Dis 2023; 78(2):277-282.

4. Mullane KM, Miller MA, Weiss K, et al. Efficacy of Fidaxomicin Versus Vancomycin as Therapy for Clostridium difficile Infection in Individuals Taking Concomitant Antibiotics for Other Concurrent Infections. Clin Infect Dis 2011;53(5):440-447.

5. Fitzpatrick F, Safdar N, Prehn J, Tschudin-Sutter S. How can patients with Clostridioides difficile infection on concomitant antibiotic treatment be best managed? Lancet Infect Dis 2022;22(11):e336-e340.

6. Alsoubani M, Chow JK, Rodday AM, et al. Comparative Effectiveness of Fidaxomicin vs Vancomycin in Populations with Immunocompromising Conditions for the Treatment of Clostridioides difficile Infection: A Single-Center Study. Open Forum Infect Dis 2024;11(1):ofad622.

7. Tariq R, Laguio-Vila M, Tahir MW, et al. Efficacy of oral vancomycin prophylaxis for prevention of Clostridioides difficile infection: A systematic review and meta-analysis. Therap Adv Gastroenterol 2021;14:1-11.