What is the recommended treatment regimen for a confirmed Clostridioides difficile infection in an adult, including first‑episode, severe, and fulminant presentations?

Treatment of Clostridioides difficile Infection

First-Line Therapy for Initial Episodes (All Severity Levels)

Oral vancomycin 125 mg four times daily for 10 days OR fidaxomicin 200 mg twice daily for 10 days is the recommended first-line treatment for any initial C. difficile infection, regardless of severity. 1, 2

• Metronidazole is no longer a first-line agent and should only be used when vancomycin or fidaxomicin are unavailable 1, 2, 3
• If metronidazole must be used, the dose is 500 mg orally three times daily for 10 days 1, 3
• Avoid repeated courses of metronidazole due to cumulative and potentially irreversible neurotoxicity 1, 2, 3
• Discontinue the inciting antibiotic as soon as clinically feasible to reduce recurrence risk 2

Dosing Clarification for Non-Fulminant Disease

• The standard vancomycin dose of 125 mg four times daily is equally effective as higher doses (500 mg four times daily) for non-severe and severe (but non-fulminant) CDI 2, 4, 5, 6
• Higher doses (>500 mg/day) have not demonstrated additional benefit in non-fulminant disease and are not recommended 2, 4, 5
• Treatment duration may be extended to 14 days if clinical response is delayed, particularly in patients initially treated with metronidazole 1, 2

Severity-Specific Management

Severe CDI (WBC ≥15,000/µL or creatinine >1.5 mg/dL)

• Use the same standard dose: oral vancomycin 125 mg four times daily for 10 days 1, 2
• Do not escalate to higher doses unless fulminant features develop 2, 5

Fulminant CDI (Hypotension/Shock, Ileus, or Megacolon)

This is a medical emergency requiring aggressive multi-route therapy: 1, 2, 7

• High-dose oral vancomycin 500 mg four times daily (via mouth or nasogastric tube) 1, 2
• Add rectal vancomycin 500 mg in 100 mL normal saline every 6 hours as a retention enema when ileus is present 1, 2
• Add IV metronidazole 500 mg every 8 hours concurrently to ensure adequate colonic drug levels when oral delivery is compromised 1, 2, 8
• Early surgical consultation is critical; consider subtotal colectomy if medical therapy fails within 24-48 hours 7

Management of First Recurrence

The treatment strategy depends on what was used for the initial episode: 1, 2

• If metronidazole was used initially: Give oral vancomycin 125 mg four times daily for 10 days 1, 2

• If standard vancomycin was used initially: Use a tapered-and-pulsed vancomycin regimen 1, 2:

  • 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
  • (Total duration: 6-11 weeks)

• Alternative option: Fidaxomicin 200 mg twice daily for 10 days 1, 2

• Adjunctive therapy: Consider bezlotoxumab 10 mg/kg IV (single dose) during antibiotic treatment to reduce recurrence risk, but use cautiously in patients with congestive heart failure 2

Management of Second or Subsequent Recurrences

Multiple effective options exist for multiply recurrent CDI: 1, 2

• Option A: Continue tapered-and-pulsed vancomycin regimen (as described above for first recurrence) 1, 2

• Option B: Oral vancomycin 125 mg four times daily for 10 days followed by rifaximin 400 mg three times daily for 20 days (30 days total sequential therapy) 1, 2

• Option C: Fidaxomicin 200 mg twice daily for 10 days 1, 2

• Option D: Fecal microbiota transplantation (FMT) after failure of at least two appropriate antibiotic treatments (i.e., after three total CDI episodes) 1, 2, 7

Critical Pitfalls to Avoid

• Do not use metronidazole as first-line therapy when vancomycin or fidaxomicin is available; cure rates are inferior (76% vs 97% in severe disease) 2, 3
• Do not use high-dose vancomycin (500 mg four times daily) for non-fulminant disease; it offers no additional benefit and increases cost 2, 4, 5, 6
• Do not give repeated courses of metronidazole beyond 14 days due to neurotoxicity risk 1, 2, 3
• Do not delay empiric therapy in fulminant presentations while awaiting laboratory confirmation 2
• Do not forget rectal vancomycin in fulminant CDI with ileus; oral therapy alone may not reach the colon 1, 2

Pediatric Considerations

For children with initial non-severe CDI 1:

• Metronidazole 7.5 mg/kg/dose three or four times daily (max 500 mg/dose) for 10 days, OR
• Vancomycin 10 mg/kg/dose four times daily (max 125 mg/dose) for 10 days

For severe/fulminant pediatric CDI 1:

• Vancomycin 10 mg/kg/dose four times daily (max 500 mg/dose) with or without IV metronidazole 10 mg/kg/dose three times daily (max 500 mg/dose)