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

Treatment of Recurrent Clostridioides difficile Infection

For first recurrence of C. difficile infection, use oral vancomycin 125 mg four times daily for 10-14 days or fidaxomicin 200 mg twice daily for 10 days, with fidaxomicin preferred if cost is not prohibitive due to lower subsequent recurrence rates. 1, 2, 3

First Recurrence Management

• Oral vancomycin 125 mg four times daily for 10-14 days is the standard approach, particularly if metronidazole was used for the initial episode 1, 2, 4
• Fidaxomicin 200 mg twice daily for 10 days demonstrates superior outcomes with 19.7% subsequent recurrence versus 35.5% with vancomycin in stratified studies 1, 5
• Metronidazole should be avoided for recurrent CDI due to lower sustained response rates and cumulative neurotoxicity risk with repeated courses 1, 3

The evidence strongly favors vancomycin or fidaxomicin over metronidazole for any recurrence. While both vancomycin and fidaxomicin achieve similar initial cure rates (87-88%), fidaxomicin's lower recurrence rate makes it the preferred choice when available 1.

Second and Subsequent Recurrences

For multiple recurrences (≥2), use either a tapered/pulsed vancomycin regimen OR proceed directly to fecal microbiota transplantation, which achieves 87-94% resolution rates. 1, 3

Tapered and Pulsed Vancomycin Regimen:

• Vancomycin 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, 6

This approach allows C. difficile vegetative forms to be suppressed while permitting gut microbiota restoration, though no randomized trials validate this specific regimen 1, 3.

Alternative for Multiple Recurrences:

• Vancomycin 125 mg four times daily for 10 days followed by rifaximin 400 mg three times daily for 20 days reduced recurrence to 15% versus 31% with placebo, though this difference did not reach statistical significance (p=0.11) 1

Fecal Microbiota Transplantation

FMT is strongly recommended after failure of appropriate antibiotic treatments for recurrent CDI, typically after ≥2 recurrences. 1, 2, 6

• Clinical resolution occurs in 87-94% of patients across multiple studies, with the highest success rates (80-100%) achieved via colonic administration 1
• The landmark van Nood trial demonstrated 81% sustained resolution with FMT versus 27% with vancomycin alone (p<0.001), leading to early trial termination 1
• Standardized microbiome therapies now offer FDA-approved alternatives: SER-109 achieved 12% recurrence versus 40% placebo, and RBX2660 demonstrated 70.6% efficacy 7

Important FMT Considerations:

• Most common adverse effects are abdominal discomfort and diarrhea 7
• Rare serious adverse events have been reported, including potential immune-mediated complications in transplant recipients 8
• Traditional FMT lacks standardization in preparation and administration; FDA-approved standardized products (SER-109, RBX2660) provide more controlled alternatives 7

Adjunctive Therapies

• Bezlotoxumab (monoclonal antibody against toxin B) reduces recurrence risk, particularly beneficial for patients with 027 epidemic strain, immunocompromised status, or severe CDI 6
• Probiotics (Saccharomyces boulardii, Lactobacillus) show promise but lack reproducible efficacy in controlled trials for preventing recurrence 1, 3
• Probiotics are contraindicated in immunocompromised patients due to bacteremia/fungemia risk 1, 3

Critical Supportive Measures

• Discontinue the inciting antibiotic immediately if clinically feasible 2, 3
• If continued 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 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 any recurrence - it has inferior outcomes and neurotoxicity concerns with prolonged use 1, 3
• Do not delay FMT consideration - waiting through multiple failed antibiotic courses increases morbidity when FMT has 87-94% success rates 1
• Do not use standard 10-14 day vancomycin courses for multiple recurrences - tapered/pulsed regimens or FMT are required 1, 3
• Avoid antimotility agents (loperamide, opiates) as they can worsen outcomes 2