What is the recommended treatment for Clostridioides difficile infection (CDI)?

Treatment of Clostridioides difficile Infection (CDI)

Fidaxomicin 200 mg twice daily for 10 days is the preferred first-line treatment for initial CDI episodes in adults, with vancomycin 125 mg four times daily for 10 days as an acceptable alternative. 1, 2

Treatment Based on Clinical Presentation

Initial CDI Episode

• First-line: Fidaxomicin 200 mg twice daily for 10 days 1, 2
• Alternative: Vancomycin 125 mg four times daily by mouth for 10 days 1, 2
• Alternative for non-severe CDI (if above agents unavailable): Metronidazole 500 mg three times daily by mouth for 10-14 days 1
  • Non-severe CDI defined as: WBC ≤15,000 cells/μL and serum creatinine <1.5 mg/dL

First CDI Recurrence

• Preferred options:
  • Fidaxomicin 200 mg twice daily for 10 days, OR
  • Fidaxomicin 200 mg twice daily for 5 days followed by once every other day for 20 days 1, 2
• Alternatives:
  • Vancomycin in tapered and pulsed regimen (e.g., 125 mg 4 times daily for 10-14 days, then 2 times daily for 7 days, then once daily for 7 days, then every 2-3 days for 2-8 weeks) 1
  • Vancomycin 125 mg four times daily for 10 days (especially if metronidazole was used for initial episode) 1, 2
• Adjunctive treatment: Bezlotoxumab 10 mg/kg IV once during antibiotic treatment (use with caution in patients with heart failure) 1, 3

Second or Subsequent CDI Recurrence

• Fidaxomicin 200 mg twice daily for 10 days, OR twice daily for 5 days followed by once every other day for 20 days 1
• Vancomycin in tapered and pulsed regimen 1, 2
• Vancomycin 125 mg four times daily for 10 days followed by rifaximin 400 mg three times daily for 20 days 1
• Fecal microbiota transplantation (FMT) after failure of appropriate antibiotic treatments for at least 2 recurrences 1, 2
  • Important safety consideration: FDA safety alerts have documented transmission of pathogenic E. coli and potential transmission of SARS-CoV-2 through FMT 1

Fulminant CDI

• Vancomycin 500 mg four times daily by mouth or nasogastric tube 1, 2
• If ileus present: Add rectal instillation of vancomycin 500 mg in 100 mL normal saline every 6 hours as retention enema 2
• Add IV metronidazole 500 mg every 8 hours 1, 2
• Early surgical consultation for possible colectomy in cases with perforation, severe systemic inflammation, toxic megacolon, or severe ileus 2

Evidence Supporting Recommendations

Fidaxomicin has demonstrated superiority over vancomycin in preventing CDI recurrence. A 2024 study showed fidaxomicin was associated with a 63% reduction in the risk of treatment failure, 30-day relapse, or CDI-related death compared to vancomycin 4. This confirms findings from earlier studies showing fidaxomicin reduced recurrence rates compared to vancomycin (19.7% vs 35.5%) 5.

A 2022 meta-analysis of 14 studies with 3,944 patients found fidaxomicin was associated with a 31% reduction in recurrence risk compared to vancomycin across multiple clinical scenarios, including initial CDI, first recurrent CDI, and both non-severe and severe CDI 6.

Important Clinical Considerations

• Discontinue the inciting antibiotic as soon as possible to reduce recurrence risk 2
• Avoid antiperistaltic agents and opiates as they may mask symptoms and worsen disease 2
• Monitor treatment response: Expect decreased stool frequency and improved consistency within 3 days of starting treatment 2
• For pediatric patients ≥6 months: Fidaxomicin is FDA-approved 7, with vancomycin 10 mg/kg/dose (max 125 mg) four times daily for 10 days as an alternative 2
• Bezlotoxumab is indicated as adjunctive therapy to reduce CDI recurrence in high-risk patients ≥1 year of age, but is not an antibacterial drug and should only be used with antibacterial treatment 3

Common Pitfalls to Avoid

1. Using metronidazole as first-line therapy for severe CDI - this is no longer recommended due to lower efficacy 1, 2
2. Failure to recognize fulminant CDI requiring urgent intervention and possible surgical consultation
3. Overuse of FMT before trying appropriate antibiotic regimens for recurrent CDI
4. Not screening FMT donors properly for transmissible pathogens per FDA recommendations 1
5. Inadequate duration of therapy - ensure full 10-day course of treatment is completed

Fidaxomicin's persistent presence in the gut for >20 days after treatment (compared to ~4 days for vancomycin and metronidazole) may contribute to its superior efficacy in preventing recurrence 8.