What is the recommended treatment for a patient with recurrent diarrhea and a history of Clostridioides difficile (C. diff) infection?

Treatment of Recurrent C. difficile Infection

For patients with recurrent C. difficile infection, fecal microbiota-based therapy should be administered after completion of standard antibiotic treatment, typically after the second recurrence (third episode), as this approach achieves 87-92% clinical resolution compared to 40-50% with antibiotics alone. 1

Initial Management of First Recurrence

• Treat the first recurrence with oral vancomycin 125 mg four times daily for 14 days or fidaxomicin 200 mg twice daily for 10 days, with fidaxomicin demonstrating lower subsequent recurrence rates. 2, 3
• Metronidazole should be avoided for recurrent CDI due to inferior sustained response rates and cumulative neurotoxicity risk. 2, 4
• Discontinue all inciting antibiotics immediately if clinically feasible, as continued antibiotic exposure significantly increases treatment failure and recurrence risk. 2, 3

Management of Multiple Recurrences (Second and Beyond)

Antibiotic-Based Approach

If fecal microbiota-based therapy is not immediately available or appropriate, use a vancomycin tapered and pulsed regimen: 1, 2

• Vancomycin 125 mg every 6 hours × 10-14 days
• Then 125 mg every 12 hours × 7 days
• Then 125 mg every 24 hours × 7 days
• Then 125 mg every 48-72 hours × 2-8 weeks 2

This represents the most evidence-supported antibiotic strategy for multiple recurrences, though no randomized controlled trials exist specifically for second or subsequent recurrences. 2

Fecal Microbiota-Based Therapy (Preferred)

The AGA recommends fecal microbiota-based therapies for immunocompetent adults with recurrent CDI upon completion of standard antibiotic treatment. 1

Timing and Patient Selection

• Consider after the second recurrence (third episode) or earlier in select high-risk patients who have recovered from severe/fulminant CDI or have significant comorbidities. 1
• British guidelines support offering FMT after at least two recurrences, or after one recurrence in patients with risk factors for further episodes. 1
• FMT demonstrates 81-92% sustained resolution rates across multiple studies, significantly superior to antibiotic therapy alone. 1, 2

Administration Protocol

• Complete a standard course of anti-CDI antibiotics first—FMT is for prevention of recurrence, not acute treatment. 1
• Use suppressive vancomycin to bridge until FMT administration if there is a delay. 1
• Stop CDI antibiotics 1-3 days before FMT: 1 day if bowel purge is given, 3 days if no purge. 1
• FMT can be delivered via colonoscopy, nasojejunal tube, or FDA-approved oral formulations (fecal microbiota live-jslm or fecal microbiota spores live-brpk) with similar efficacy. 1

Important Considerations

• Exercise caution in patients requiring frequent or long-term antibiotic prophylaxis, as ongoing antibiotics may diminish FMT efficacy. 1
• The 2024 AGA guideline provides conditional recommendation with low certainty evidence, reflecting the balance of high efficacy against limited long-term safety data. 1

Critical Supportive Measures

• Discontinue proton pump inhibitors if not absolutely required, as they are associated with increased CDI recurrence risk. 2, 3
• If additional antibiotics are necessary for other infections, switch to agents less associated with CDI: parenteral aminoglycosides, sulfonamides, macrolides, or tetracyclines. 2
• Avoid high-risk antibiotics including clindamycin, third-generation cephalosporins, penicillins, and fluoroquinolones. 2
• Never use antimotility agents (loperamide, opiates) as they can worsen outcomes and precipitate toxic megacolon. 3

Monitoring for Severe Disease

Watch for warning signs requiring escalation: 2

• WBC ≥25,000 or rising
• Lactate ≥5 mmol/L
• Ileus or toxic megacolon
• Peritoneal signs
• Serum creatinine >1.5 mg/dL or rising

If severe features develop during recurrent infection, add IV metronidazole 500 mg every 8 hours to oral vancomycin and obtain urgent surgical consultation. 2

Common Pitfalls

• Do not test for cure—testing asymptomatic patients after treatment is not recommended, as PCR can remain positive for weeks despite clinical resolution. 1
• Recurrent diarrhea after CDI treatment may represent alternative diagnoses (post-infectious IBS, medication side effects, other enteric pathogens) rather than true CDI recurrence, especially if symptoms are atypical or unresponsive to vancomycin. 1
• A positive nucleic acid amplification test alone requires clinical correlation—acute-onset diarrhea (≥3 unformed stools in 24 hours) with improvement on CDI-directed antibiotics is essential for diagnosis. 1
• Patients over 65 years have increased risk of nephrotoxicity with oral vancomycin, particularly with prolonged courses; monitor renal function during and after treatment. 5