What is the treatment for recurrent Clostridioides (C.) difficile infection?

Treatment of Recurrent Clostridioides difficile Infection

For first recurrence of C. difficile infection, treat with oral vancomycin 125 mg four times daily for 10-14 days or fidaxomicin 200 mg twice daily for 10 days; for multiple recurrences (≥2 episodes), use either a tapered/pulsed vancomycin regimen or proceed directly to fecal microbiota transplantation, which achieves 87-94% cure rates. 1, 2, 3

First Recurrence Management

Oral vancomycin is the preferred treatment for first recurrence, particularly if metronidazole was used initially. 1, 3 The standard regimen is 125 mg four times daily for 10-14 days. 1, 2, 3

Fidaxomicin 200 mg twice daily for 10 days is an excellent alternative that demonstrates superior outcomes in preventing subsequent recurrences compared to vancomycin (19.7% vs 35.5% second recurrence rate). 1, 4 This makes fidaxomicin particularly valuable for patients at high risk for further recurrences, including elderly patients, those with multiple comorbidities, or those requiring ongoing antibiotic therapy. 3, 4

Metronidazole should NOT be used for recurrent CDI due to lower sustained response rates and risk of cumulative neurotoxicity with repeated courses. 1, 3

Multiple Recurrences (≥2 Episodes)

For patients with two or more recurrences, you have two evidence-based options:

Option 1: Tapered and Pulsed Vancomycin Regimen

Use vancomycin in a prolonged tapered/pulsed schedule: 125 mg four times daily for 10-14 days, then 125 mg twice daily for 7 days, then 125 mg once daily for 7 days, then 125 mg every 2-3 days for 2-8 weeks. 1, 3 This extended regimen allows C. difficile vegetative forms to be suppressed while permitting restoration of normal gut microbiota. 1

Important caveat: No randomized controlled trials have validated this approach specifically for second or subsequent recurrences—the evidence is based on uncontrolled case series and expert consensus. 1, 3

Option 2: Fecal Microbiota Transplantation (FMT)

FMT is highly effective and should be strongly considered after multiple recurrences. 1 The evidence is compelling:

• Clinical resolution rates of 87-94% across multiple studies and systematic reviews 1
• The landmark van Nood trial (stopped early for efficacy) showed 81% sustained cure with FMT versus only 27% with vancomycin alone 1
• Success after single treatment in 89% of patients in a systematic review of 317 patients 1

FMT carries a strong recommendation from IDSA/SHEA guidelines for patients with multiple recurrences who have failed appropriate antibiotic treatments. 1, 2

Route of administration: Colonic delivery (via colonoscopy) achieves the highest success rates (80-100%), though nasoduodenal administration also shows good efficacy (77-94%). 1

Safety profile: Generally well-tolerated with most common adverse events being transient abdominal discomfort and diarrhea. 1 However, serious adverse events are possible, particularly in immunocompromised patients. 1

Standardized Microbiome Therapies (FDA-Approved Alternatives to FMT)

Two standardized microbiome restoration products are now FDA-approved and provide alternatives to traditional FMT:

• SER-109 (oral bacterial spores): Reduced recurrence to 12% versus 40% with placebo in the ECOSPOR III trial 5
• RBX2660: Demonstrated 70.6% efficacy versus 57.5% in the PUNCH CD3 trial 5

These offer advantages of standardization and potentially improved safety compared to donor-dependent FMT. 5

Adjunctive Therapy: Bezlotoxumab

Bezlotoxumab (10 mg/kg IV single dose) reduces recurrence risk and should be considered as an adjunct to antibiotic therapy in high-risk patients. 4, 6

Key efficacy data: In the MODIFY trials, bezlotoxumab reduced recurrence rates from 26-28% (placebo) to 15-17% (bezlotoxumab). 7

Optimal candidates for bezlotoxumab include:

• Patients with CDI due to epidemic 027 strain 4
• Immunocompromised patients 4
• Severe CDI presentation 4
• History of prior recurrence 7

Administration: Give as a single IV infusion during antibiotic treatment for CDI. 6 It is NOT an antibiotic and does not treat active infection—only prevents recurrence. 6

Essential Supportive Measures

Discontinue the inciting antibiotic immediately if clinically feasible, as continued antibiotic exposure is a major risk factor for recurrence. 2, 3

If ongoing antibiotics are necessary, switch to lower-risk agents (aminoglycosides, sulfonamides, macrolides, tetracyclines) and avoid high-risk antibiotics (clindamycin, third-generation cephalosporins, fluoroquinolones). 3

Consider secondary prophylaxis with low-dose vancomycin (125 mg once daily) or fidaxomicin (200 mg once daily) during subsequent systemic antibiotic courses, particularly for patients with prior recurrent CDI episodes. 1

Discontinue proton pump inhibitors when possible, as they are associated with increased recurrence risk. 1, 3

Common Pitfalls to Avoid

Do not use metronidazole for recurrent CDI—this is a critical error given inferior outcomes and neurotoxicity concerns. 1, 3, 4

Do not delay FMT in patients with multiple recurrences—the evidence strongly supports early use rather than exhausting multiple antibiotic courses. 1, 2

Do not use antimotility agents (loperamide, opiates) as they can precipitate toxic megacolon. 2

Do not perform "test of cure" stool testing after treatment completion, as patients may remain colonized without active infection. 1

Do not rely on alcohol-based hand sanitizers—C. difficile spores are alcohol-resistant; soap and water handwashing is essential. 2