What is the treatment for recurrent Clostridioides difficile (C. diff) 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% resolution rates. 1, 2

First Recurrence Management

• Oral vancomycin 125 mg four times daily for 10-14 days is the preferred treatment if metronidazole was used initially, or if the initial episode was treated with vancomycin 1, 2, 3

• Fidaxomicin 200 mg twice daily for 10 days is an excellent alternative that demonstrates superior outcomes, with recurrence rates of 19.7% compared to 35.5% with standard vancomycin in first recurrence cases 1, 4

• Avoid metronidazole for any recurrent episode due to lower sustained response rates and cumulative neurotoxicity risk with repeated or prolonged use 1, 3, 4

Multiple Recurrences (≥2 Episodes)

Tapered and Pulsed Vancomycin Regimen

For patients with second or subsequent recurrences who are not candidates for FMT, use the following vancomycin taper 1, 3:

• 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

This approach allows C. difficile vegetative forms to be suppressed while permitting gut microbiota restoration, though it reduces recurrence to only 14-31% based on limited case series data 1

Fecal Microbiota Transplantation (FMT)

FMT is the most effective treatment for multiple recurrences and should be strongly considered after ≥2 recurrences 1, 2, 4:

• Achieves 87-94% clinical resolution rates across multiple studies, far superior to antibiotic therapy alone 1
• The landmark van Nood trial demonstrated 81% resolution with FMT versus only 27% with vancomycin alone (P<0.001), leading to early trial termination 1
• Can be administered via colonoscopy (highest success rates 80-100%), nasogastric/nasoduodenal tube, or oral capsules 1
• Standardized microbiome products (SER-109, RBX2660) are now FDA-approved alternatives to traditional FMT, with SER-109 showing 12% recurrence versus 40% with placebo 5

Important Caveats About FMT

• Generally safe with most common adverse events being transient abdominal discomfort and diarrhea 1
• Serious caution in immunocompromised patients: One case report documented severe cardiac allograft vasculopathy and rejection following FMT in a pediatric heart transplant recipient 6
• The FDA considers FMT investigational, though enforcement discretion allows use for recurrent CDI 1

Adjunctive Therapies

Bezlotoxumab

• Bezlotoxumab 10 mg/kg as a single IV infusion during antibiotic treatment reduces recurrence risk by blocking C. difficile toxin B 4, 7
• Particularly beneficial for high-risk patients: those with 027 epidemic strain, immunocompromised status, severe CDI, or multiple prior recurrences 4, 7
• Must be given during active antibiotic treatment for CDI, not as monotherapy 7

Rifaximin

• Rifaximin 400 mg three times daily for 20 days immediately following vancomycin showed trend toward reduced recurrence (15% vs 31%, P=0.11) in one small RCT 1
• Use only as adjunctive therapy after standard treatment; avoid monotherapy due to resistance risk 1

Probiotics

• Evidence for probiotics remains weak and inconsistent for recurrent CDI 1, 3
• Contraindicated in immunocompromised or critically ill patients due to bacteremia/fungemia risk 1, 3
• Saccharomyces boulardii combined with high-dose vancomycin showed some benefit in limited data 3

Essential Supportive Measures

• Discontinue the inciting antibiotic immediately if clinically feasible, as continued antibiotic exposure is the strongest risk factor for recurrence 1, 2, 3
• If ongoing antibiotics are necessary, switch to lower-risk agents (aminoglycosides, sulfonamides, macrolides, tetracyclines) and avoid high-risk antibiotics (clindamycin, cephalosporins, fluoroquinolones, penicillins) 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 episodes 1
• Discontinue proton pump inhibitors when possible, as they increase recurrence risk 1, 3

Treatment Algorithm Summary

First recurrence → Vancomycin 125 mg QID × 10-14 days OR Fidaxomicin 200 mg BID × 10 days (+ consider bezlotoxumab)

Second recurrence → Tapered/pulsed vancomycin regimen OR proceed to FMT (+ consider bezlotoxumab)

Third or subsequent recurrence → FMT is strongly recommended as the most effective option 1, 2, 4

Common Pitfalls to Avoid

• Never use metronidazole for recurrent CDI - it has inferior outcomes and neurotoxicity concerns with repeated use 1, 3, 4
• Do not perform "test of cure" after treatment completion, as asymptomatic colonization is common and does not require treatment 1
• Avoid antimotility agents (loperamide, opiates) during active infection as they can worsen outcomes 2
• Fidaxomicin efficacy appears lower in patients with ≥2 prior recurrences compared to first recurrence, so consider FMT earlier in multiply recurrent cases 1