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, treat with oral vancomycin 125 mg four times daily for 10-14 days or fidaxomicin 200 mg twice daily for 10 days; for second and subsequent recurrences, use either vancomycin tapered/pulsed regimen or proceed directly to fecal microbiota transplantation (FMT), which achieves 87-92% clinical resolution. 1, 2, 3

First Recurrence Management

• Treat the first recurrence identically to the initial episode unless disease has progressed from non-severe to severe. 4, 1, 3

• Oral vancomycin 125 mg four times daily for 10-14 days is the preferred first-line option, with moderate quality evidence supporting its superiority over metronidazole for sustained response. 1, 2, 3

• Fidaxomicin 200 mg twice daily for 10 days is an excellent alternative, particularly for patients at high risk for subsequent recurrence (elderly, multiple comorbidities), as it reduces recurrence rates to 19.7% compared to 35.5% with standard vancomycin. 2, 3

• Do not use metronidazole for recurrent CDI due to lower sustained response rates and cumulative neurotoxicity risk with prolonged use. 2, 3

Second and Subsequent Recurrences

Vancomycin Tapered/Pulsed Regimen

• For patients with multiple recurrences, vancomycin tapered and pulsed regimen is the most evidence-supported antibiotic approach: vancomycin 125 mg every 6 hours for 10-14 days, then 125 mg every 12 hours for 7 days, then 125 mg every 24 hours for 7 days, then 125 mg every 48-72 hours for 2-8 weeks. 4, 2, 3

• This prolonged taper strategy allows for gradual microbiome recovery while suppressing C. difficile spores. 4

Fecal Microbiota Transplantation (FMT)

• FMT should be offered after at least 2 recurrences in patients who have failed appropriate antibiotic treatments, with strong recommendation and moderate to high quality evidence. 4, 1, 2, 3

• FMT demonstrates superior outcomes with clinical resolution rates of 87-92% compared to 40-50% with antibiotics alone. 2, 3

• Administer oral vancomycin 125 mg four times daily for 4-10 days as a lead-in before FMT. 2

• FMT can be delivered via colonoscopy (preferentially to cecum or terminal ileum), nasojejunal tube, or capsulized formulation with similar efficacy. 4, 2

• A minimum washout period of 24 hours between the last antibiotic dose and FMT is required to minimize deleterious effects on the transplanted microbiota. 4

• Bowel lavage with polyethylene glycol preparation should be considered prior to FMT. 4

Adjunctive Therapy for High-Risk Patients

• Consider adding bezlotoxumab (monoclonal antibody against C. difficile toxin B) 10 mg/kg as a single intravenous infusion over 60 minutes to standard antibiotic therapy for patients at high risk of recurrence, particularly those with severe CDI presentation. 3, 5

• Bezlotoxumab is FDA-approved to reduce recurrence in adults and pediatric patients ≥1 year receiving antibacterial treatment for CDI. 5

• Bezlotoxumab is not an antibacterial drug and must be used in conjunction with antibiotic treatment for CDI. 5

Critical Supportive Measures

• Discontinue all inciting antibiotics immediately if clinically possible, as continued antibiotic use is the strongest predictor of treatment failure and recurrence. 1, 2, 3

• If continued antibiotics are necessary, switch to agents less associated with CDI (parenteral aminoglycosides, sulfonamides, macrolides, tetracyclines/tigecycline) and avoid high-risk antibiotics (clindamycin, third-generation cephalosporins, penicillins, fluoroquinolones). 2

• Discontinue proton pump inhibitors if not absolutely required, as they are associated with increased CDI recurrence risk. 2, 3

• Do not use antimotility agents (loperamide, opiates), especially in the acute setting, as they can worsen outcomes and precipitate toxic megacolon. 1, 3

• Implement strict handwashing with soap and water (alcohol does not inactivate C. difficile spores) and isolate patients until resolution of diarrhea (formed stool for at least 48 hours). 1

Monitoring for Severe or Fulminant Disease

• Watch for warning signs requiring escalation: WBC ≥15,000-25,000 cells/mL or rising, serum lactate ≥5.0 mmol/L, ileus, toxic megacolon, peritoneal signs, or hemodynamic instability. 1, 2, 3

• If severe features develop during recurrent CDI treatment, add IV metronidazole 500 mg every 8 hours to oral vancomycin and consider higher vancomycin doses (up to 500 mg four times daily). 4, 2

• For patients unable to take oral medications, use IV metronidazole 500 mg every 8 hours PLUS vancomycin 500 mg via nasogastric tube four times daily and/or vancomycin 500 mg retention enema in 100 mL normal saline every 4-12 hours. 4, 3

• Obtain prompt surgical consultation if perforation, toxic megacolon, severe ileus, lactate >5.0 mmol/L, or systemic inflammation with deteriorating clinical condition despite antibiotic therapy develops. 1, 3

Common Pitfalls to Avoid

• Do not perform "test of cure" after CDI treatment, as C. difficile can persist asymptomatically and testing does not predict clinical outcomes. 4

• Do not use intravenous vancomycin for CDI, as it is not excreted into the colon and has no efficacy against CDI. 3

• Do not delay FMT in multiply recurrent cases waiting for additional antibiotic courses, as each recurrence increases risk of subsequent recurrence and FMT has superior efficacy. 4, 2, 3