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

Treatment of Recurrent Clostridioides difficile Infection

For first recurrence of C. difficile infection, use oral vancomycin 125 mg four times daily for 10 days, particularly if metronidazole was used initially, or fidaxomicin 200 mg twice daily for 10 days to reduce subsequent recurrence risk. 1, 2

First Recurrence Management

Vancomycin is the preferred agent for first recurrence, especially when metronidazole was used for the initial episode. 1 The standard regimen is 125 mg orally four times daily for 10 days. 1, 2

Fidaxomicin offers superior recurrence prevention compared to standard vancomycin courses. In a randomized substudy of patients with first recurrence, subsequent second recurrence occurred in 19.7% with fidaxomicin versus 35.5% with vancomycin (P = 0.045). 1 The dose is 200 mg orally twice daily for 10 days. 1, 3

Metronidazole should not be used for recurrent CDI due to lower sustained response rates (67.6% vs 83.3% for vancomycin) and cumulative neurotoxicity risk with prolonged use. 1, 3

Second and Subsequent Recurrences

For multiple recurrences, use vancomycin in a tapered and pulsed regimen as the primary antibiotic strategy. 1, 3 The recommended schedule is:

• 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

This approach aims to suppress C. difficile vegetative forms while allowing microbiota restoration. 1 In one case series, tapered regimens resulted in 31% recurrence versus 44.8% overall, and pulsed courses showed 14.3% recurrence, though patient numbers were small. 1

Alternative regimen: Vancomycin followed by rifaximin. After completing standard vancomycin therapy, rifaximin 400 mg three times daily for 20 days reduced recurrence to 15% versus 31% with placebo, though this did not reach statistical significance (P = 0.11). 1

Fecal Microbiota Transplantation

FMT is strongly recommended for patients with multiple recurrences who have failed appropriate antibiotic treatments. 1, 2 Clinical resolution rates range from 87-92% across studies. 3, 4 This represents the most effective intervention for multiply recurrent disease. 1, 4

Two FDA-approved standardized microbiome therapies are now available as alternatives to traditional FMT:

• SER-109 (oral bacterial spores): Reduced recurrence to 12% versus 40% with placebo in the ECOSPOR III trial 4
• RBX2660: Demonstrated 70.6% efficacy versus 57.5% in the PUNCH CD3 trial 4

Adjunctive Prevention Strategy

Bezlotoxumab (10 mg/kg IV single dose) can be administered during antibiotic treatment to reduce recurrence risk in high-risk patients. 5 This monoclonal antibody against C. difficile toxin B is specifically indicated to prevent recurrence, not to treat active infection. 5

Critical Supportive Measures

Discontinue the inciting antibiotic immediately if clinically feasible, as continued antibiotic exposure is a major risk factor for recurrence. 1, 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

Discontinue proton pump inhibitors when possible, as continued PPI use increases recurrence risk. 1

Common Pitfalls to Avoid

Do not use metronidazole for any recurrence. Despite older guidelines suggesting it for first recurrence, current evidence shows inferior outcomes and neurotoxicity concerns with prolonged use. 1, 3

Do not use fidaxomicin for fulminant or complicated disease. Evidence is limited to non-severe cases, and post-approval data suggest less efficacy in patients with ≥2 recurrences. 1

Do not extend standard antibiotic courses empirically for patients requiring subsequent antibiotics after CDI treatment completion, as retrospective data show no benefit. 1

Do not rely on probiotics alone. While some data support Saccharomyces boulardii as adjunctive therapy, no probiotic has demonstrated significant reproducible efficacy in controlled trials for preventing recurrence. 1, 3

Treatment Algorithm Summary

• First recurrence: Vancomycin 125 mg QID × 10 days OR fidaxomicin 200 mg BID × 10 days 1, 2, 3
• Second recurrence: Vancomycin tapered/pulsed regimen OR fidaxomicin 1, 3
• Third or subsequent recurrence: FMT or standardized microbiome therapy (SER-109, RBX2660) 1, 2, 4
• High-risk patients: Consider bezlotoxumab during antibiotic treatment 5, 4