What is the recommended treatment for an initial episode of Clostridioides difficile infection, including management of severe disease (white‑cell count >15,000/µL or serum creatinine >1.5× baseline) and recurrences?

Treatment of Clostridioides difficile Infection

For an initial episode of C. difficile infection, use oral vancomycin 125 mg four times daily for 10 days or fidaxomicin 200 mg twice daily for 10 days, regardless of whether the disease is classified as non-severe or severe. 1

Initial Management Steps

• Discontinue the inciting antibiotic immediately if clinically feasible, as this reduces recurrence risk 1
• Start empiric treatment without waiting for laboratory confirmation in fulminant cases or when significant diagnostic delays are expected 1

Initial Episode Treatment by Severity

Non-Severe Disease (WBC ≤15,000/µL AND creatinine <1.5 mg/dL)

• Preferred: Vancomycin 125 mg orally four times daily for 10 days OR fidaxomicin 200 mg twice daily for 10 days 1, 2
• Alternative (only if vancomycin/fidaxomicin unavailable): Metronidazole 500 mg orally three times daily for 10 days 1
  • Metronidazole should be avoided as first-line therapy when vancomycin or fidaxomicin is accessible, as it has inferior cure rates (approximately 76% vs 97% for vancomycin) 2
  • Avoid repeated courses of metronidazole due to cumulative and potentially irreversible neurotoxicity 1

Severe Disease (WBC ≥15,000/µL OR creatinine >1.5 mg/dL)

• Same regimen as non-severe disease: Vancomycin 125 mg orally four times daily for 10 days OR fidaxomicin 200 mg twice daily for 10 days 1, 2
• The 2021 IDSA/SHEA guidelines emphasize that severity does not change the initial dosing regimen—both non-severe and severe cases receive the same 125 mg four times daily vancomycin dose 1, 2
• Do not use higher vancomycin doses (>500 mg/day) for severe non-fulminant disease, as research shows no benefit in cure rates, time to cure, or complications compared to standard dosing 3, 4
• Consider extending treatment to 14 days if clinical response is delayed, particularly in patients initially treated with metronidazole 1, 2

Fulminant Disease (Hypotension/shock, ileus, or megacolon)

• High-dose oral vancomycin 500 mg four times daily by mouth or nasogastric tube 1, 2
• Add rectal vancomycin 500 mg in 100 mL normal saline every 6 hours as a retention enema if ileus is present 1, 2
• Add IV metronidazole 500 mg every 8 hours concurrently with oral/rectal vancomycin, particularly when ileus limits oral drug delivery 1, 2
• This triple-therapy approach ensures adequate colonic drug concentrations when intestinal motility is compromised 2

Recurrent C. difficile Infection

First Recurrence

• If metronidazole was used initially: Vancomycin 125 mg four times daily for 10 days 1
• If standard vancomycin was used initially: Use a prolonged tapered-and-pulsed vancomycin regimen 1, 2
  • Example: 125 mg four times daily for 10–14 days, then twice daily for 7 days, then once daily for 7 days, then every 2–3 days for 2–8 weeks (total duration 6–11 weeks) 1, 2
• Alternative: Fidaxomicin 200 mg twice daily for 10 days (or extended regimen: twice daily for 5 days, then once every other day for 20 days) 1
• Consider bezlotoxumab 10 mg/kg IV once during antibiotic treatment to reduce recurrence risk, though data with fidaxomicin are limited and caution is needed in congestive heart failure 1

Second or Subsequent Recurrence

• Option 1: Tapered-and-pulsed vancomycin regimen (as described above) 1, 2
• Option 2: Vancomycin 125 mg four times daily for 10 days followed by rifaximin 400 mg three times daily for 20 days 1, 2
• Option 3: Fidaxomicin 200 mg twice daily for 10 days (or extended regimen) 1
• Option 4: Fecal microbiota transplantation after failure of at least two recurrences (i.e., after three total CDI episodes) 1, 2
  • A 2025 randomized trial showed FMT may be considered even for primary CDI, with 66.7% achieving cure without recurrence versus 61.2% with vancomycin, though this represents emerging evidence not yet incorporated into guidelines 5

Key Clinical Pitfalls

• Do not escalate vancomycin dose to 500 mg four times daily for severe non-fulminant disease—reserve this high dose exclusively for fulminant CDI 2, 3, 4
• Pulse dosing regimens (every 2–3 days) do not facilitate C. difficile clearance between doses when vancomycin levels drop; they are used to prevent recurrence, not to eradicate colonization 6
• Metronidazole is no longer first-line therapy even for non-severe disease when vancomycin or fidaxomicin is available 1, 2
• Fidaxomicin is preferred over vancomycin in the 2021 guidelines when resources permit, as it reduces recurrence rates 1
• Bezlotoxumab carries an FDA warning to reserve use in congestive heart failure patients only when benefits outweigh risks 1

Treatment Duration

• Standard duration is 10 days for all initial episodes and most recurrences 1, 7
• Clinical trials used 10-day courses, achieving 81% cure rates in FDA registration trials 7
• Median time to diarrhea resolution is 4–5 days in clinical trials, with slightly longer times (6 days) in patients over 65 years 7
• Recurrence occurs in 18–25% of patients within 4 weeks after successful treatment 7