What is the preferred treatment for Clostridium difficile (C. difficile)?

Treatment of Clostridium difficile Infection

The preferred treatment for Clostridium difficile infection depends on disease severity, with oral vancomycin 125 mg four times daily for 10 days now recommended as first-line therapy for both non-severe and severe cases, replacing metronidazole as the primary treatment option. 1

Disease Severity Classification

Disease severity guides treatment selection:

• Non-severe CDI: Stool frequency <4 times daily; no signs of severe colitis 1
• Severe CDI: Presence of one or more of the following 1:
  • Temperature >38.5°C
  • Hemodynamic instability
  • Leukocyte count >15×10⁹/L
  • Serum creatinine rise >50% above baseline
  • Elevated serum lactate
  • Evidence of pseudomembranous colitis on endoscopy
  • Colonic wall thickening on imaging

First-Line Treatment Recommendations

For Initial Episode (Oral Therapy Possible):

• Non-severe CDI:

  • Vancomycin 125 mg four times daily orally for 10 days 1
  • Alternative: Metronidazole 500 mg three times daily orally for 10 days (less preferred) 1

• Severe CDI:

  • Vancomycin 125 mg four times daily orally for 10 days 1
  • Alternative: Fidaxomicin 200 mg twice daily orally for 10 days (especially for patients at high risk of recurrence) 1, 2

When Oral Therapy Not Possible:

• Non-severe CDI:

  • Metronidazole 500 mg three times daily intravenously for 10 days 1

• Severe CDI:

  • Metronidazole 500 mg three times daily intravenously for 10 days PLUS
  • Intracolonic vancomycin 500 mg in 100 mL normal saline every 4-12 hours and/or
  • Vancomycin 500 mg four times daily via nasogastric tube 1

Special Considerations

Mild CDI Induced by Antibiotics

• Consider discontinuing the inciting antibiotic and observe clinical response
• Monitor closely for deterioration and initiate antibiotic therapy immediately if condition worsens 1
• Avoid antiperistaltic agents and opiates 1

Concomitant Antibiotic Use

• Discontinue offending antibiotics if possible 1
• If continued antibiotic therapy is required, consider agents less associated with CDI (aminoglycosides, sulfonamides, macrolides) 1
• Be aware that concomitant antibiotic use increases treatment failure rates with metronidazole 3

Treatment of Recurrent CDI

First Recurrence:

• Treat as a first episode based on severity 1
• Consider fidaxomicin 200 mg twice daily for 10 days 1, 2
• Alternative: Vancomycin in a tapered and pulsed regimen 1

Second or Subsequent Recurrences:

• Vancomycin 125 mg four times daily orally for at least 10 days, followed by tapered and pulsed regimen 1
• Consider fidaxomicin 200 mg twice daily for 10 days 1, 2
• Fecal microbiota transplantation (FMT) for multiple recurrences that have failed appropriate antibiotic treatments 1, 4

Surgical Management

Consider colectomy in the following situations:

• Perforation of the colon
• Systemic inflammation and deteriorating clinical condition not responding to antibiotic therapy
• Toxic megacolon or severe ileus
• Perform surgery before serum lactate exceeds 5.0 mmol/L 1

Common Pitfalls and Caveats

• Metronidazole limitations: Increasing treatment failures have been reported with metronidazole, particularly in severe cases 4, 3
• Proton pump inhibitors: Consider discontinuing unnecessary PPIs in patients at high risk for CDI 1
• Hand hygiene: Alcohol-based hand sanitizers are ineffective against C. difficile spores; handwashing with soap and water is required 1
• Treatment duration: Consider extending treatment beyond 10 days in patients with delayed response to therapy 1
• Recurrence risk: Approximately 20% of patients develop recurrent disease despite appropriate initial therapy 5, 6

Emerging Therapies

• Bezlotoxumab: A human monoclonal antibody that may prevent CDI recurrence by blocking C. difficile toxin B 1
• Fecal microbiota transplantation: Highly effective for multiple recurrent CDI 1, 4