What is the best treatment approach for a patient with recurrent Clostridioides difficile (C. diff) infection?

Treatment of Recurrent Clostridioides difficile Infection

For recurrent C. difficile infection, fecal microbiota-based therapy should be offered after at least 2 recurrences (third episode), achieving 87-92% clinical resolution compared to 40-50% with antibiotics alone. 1

First Recurrence Management

For the first recurrence, fidaxomicin (standard or extended-pulsed regimen) is preferred over vancomycin, demonstrating superior sustained clinical response at 30 days (RR: 1.27; 95% CI: 1.05–1.54) with significantly lower subsequent recurrence rates (19.7% vs 35.5%, P = .045). 2

Alternative acceptable options for first recurrence include: 2

• Vancomycin tapered and pulsed regimen: 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 1
• Standard 10-14 day course of vancomycin 125 mg four times daily (particularly if metronidazole was used initially) 2

The rationale for preferring fidaxomicin is its ability to achieve high fecal concentrations while sparing the normal microbiota, resulting in fewer recurrences despite similar initial clinical cure rates. 2 However, cost remains a significant barrier, with average wholesale price of $4,871 per 20-tablet package, though patient-assistance programs are available. 2

Multiple Recurrences (≥2 Recurrences)

After the second recurrence (third episode), fecal microbiota-based therapy becomes the preferred treatment, with the American Gastroenterological Association recommending it for immunocompetent adults upon completion of standard antibiotic treatment. 1 This achieves sustained resolution rates of 81-92% across multiple studies. 1

If fecal microbiota-based therapy is not immediately available, alternative options include: 2

• Vancomycin tapered and pulsed regimen (as detailed above) 1
• Fidaxomicin extended-pulsed regimen 2
• Vancomycin standard course followed by rifaximin 400 mg three times daily for 20 days 2

Fecal microbiota-based therapy can be delivered via colonoscopy, nasojejunal tube, or FDA-approved oral formulations with similar efficacy. 1

Adjunctive Therapy: Bezlotoxumab

Consider adding bezlotoxumab 10 mg/kg as a single IV infusion during or shortly after completion of antibiotic therapy for patients at high risk of recurrence. 3, 4 This monoclonal antibody against C. difficile toxin B reduced recurrence rates from 26-28% to 16-17% in phase 3 trials. 3

High-risk factors warranting bezlotoxumab include: 4

• Age ≥65 years
• History of CDI in the past 6 months
• Immunocompromised state
• Severe CDI at presentation (Zar score ≥21)
• Infection with hypervirulent strain (ribotypes 027,078, or 244)

Important limitation: Bezlotoxumab is not an antibacterial drug and does not treat CDI—it only reduces recurrence risk and must be used in conjunction with appropriate antibiotic therapy. 4

Critical Supportive Measures

Immediately discontinue all modifiable risk factors: 1, 5

• Stop all non-essential antibiotics, particularly high-risk agents (clindamycin, third-generation cephalosporins, fluoroquinolones, penicillins) 1
• Discontinue proton pump inhibitors unless absolutely required, as they increase recurrence risk 1, 5
• Never use antimotility agents (loperamide, opiates) as they can precipitate toxic megacolon 1

Monitoring for Severe/Fulminant Disease

Watch for warning signs requiring immediate escalation: 1, 5

• WBC ≥15,000-25,000 cells/mL or rising
• Serum lactate ≥5.0 mmol/L
• Serum creatinine >1.5 mg/dL or rising
• Ileus or toxic megacolon
• Peritoneal signs

If fulminant disease develops, escalate to high-dose oral vancomycin 500 mg four times daily PLUS intravenous metronidazole 500 mg every 8 hours, add vancomycin retention enemas if ileus present, and obtain immediate surgical consultation. 3

Common Pitfalls to Avoid

• Do not test for cure: PCR can remain positive for weeks despite clinical resolution, and testing asymptomatic patients after treatment is not recommended 1
• Do not use metronidazole for recurrent CDI: Initial and sustained response rates are lower than vancomycin, and prolonged use risks cumulative neurotoxicity 2
• Do not use fidaxomicin for fulminant disease: No data support its efficacy in complicated or fulminant CDI 3
• Consider alternative diagnoses: Recurrent diarrhea after treatment may represent post-infectious irritable bowel syndrome, medication side effects, or other conditions rather than true CDI recurrence 1
• Recognize that ongoing antibiotics may diminish FMT efficacy: Carefully consider timing if patient requires continued antimicrobial therapy 5