What are the treatment options for Clostridioides difficile (C. diff) infections?

Treatment of Clostridioides difficile Infection

For initial non-severe C. difficile infection, use oral vancomycin 125 mg four times daily for 10 days or fidaxomicin 200 mg twice daily for 10 days as first-line therapy; metronidazole is now relegated to situations where these preferred agents are unavailable. 1

Initial Episode Treatment

Non-Severe Disease

• Preferred regimens:
  • Oral vancomycin 125 mg four times daily for 10 days 1
  • Fidaxomicin 200 mg twice daily for 10 days 1, 2
• Alternative when preferred agents unavailable:
  • Metronidazole 500 mg three times daily for 10 days 1, 3
• Non-severe disease is defined as white blood cell count ≤15,000 cells/mL and serum creatinine <1.5 mg/dL 3

Severe Disease

• Vancomycin 125 mg orally four times daily for 10 days is the preferred treatment 1, 3
• Metronidazole is NOT recommended for severe CDI 3
• Severe disease indicators include WBC ≥15,000 cells/mL or serum creatinine >1.5 mg/dL 1, 3
• Additional severity markers: marked leucocytosis >15×10⁹/L, decreased albumin <30 g/L, rise in creatinine ≥133 μM or ≥1.5 times premorbid level 1

Fulminant/Complicated Disease

• Oral vancomycin 500 mg four times daily PLUS intravenous metronidazole 500 mg three times daily 1
• If oral therapy impossible: IV metronidazole 500 mg three times daily PLUS vancomycin 500 mg in 100 mL normal saline four times daily via retention enema or nasogastric tube 1
• Consider tigecycline 50 mg IV twice daily as salvage therapy for refractory cases 1
• Fulminant disease signs: hypotension, shock, ileus, megacolon, peritonitis 1, 3

Recurrent CDI Treatment

First Recurrence

• If metronidazole was used initially: Switch to vancomycin 125 mg four times daily for 10 days 1
• If standard vancomycin was used initially: Use tapered/pulsed vancomycin regimen (125 mg four times daily for 10-14 days, then twice daily for 1 week, once daily for 1 week, then every 2-3 days for 2-8 weeks) 1
• Alternative: Fidaxomicin 200 mg twice daily for 10 days 1, 2
• Do NOT use metronidazole for recurrent episodes 3

Second or Subsequent Recurrences

• Vancomycin tapered and pulsed regimen (as above) 1
• OR vancomycin 125 mg four times daily for 10 days followed by rifaximin 400 mg three times daily for 20 days 1
• OR fidaxomicin 200 mg twice daily for 10 days 1, 2
• Fecal microbiota transplantation is strongly recommended after failure of appropriate antibiotic treatments for at least 2 recurrences (i.e., 3 total CDI episodes) 1

Pediatric Dosing (≥6 months of age)

Non-Severe Disease

• Metronidazole 7.5 mg/kg/dose (maximum 500 mg) three or four times daily for 10 days 1, 3
• OR vancomycin 10 mg/kg/dose (maximum 125 mg) four times daily for 10 days 1

Severe/Fulminant Disease

• Vancomycin 10 mg/kg/dose (maximum 500 mg) four times daily for 10 days 1
• May add IV metronidazole 10 mg/kg/dose (maximum 500 mg) three times daily 1

Fidaxomicin Dosing (≥6 months, weight-based)

• 4 to <7 kg: 80 mg (2 mL) twice daily 2
• 7 to <9 kg: 120 mg (3 mL) twice daily 2
• 9 to <12.5 kg: 160 mg (4 mL) twice daily 2
• ≥12.5 kg: 200 mg (5 mL or one tablet) twice daily 2

Critical Management Principles

Essential Adjunctive Measures

• Discontinue the inciting antibiotic immediately 1, 3
• Avoid antiperistaltic agents and opiates 1, 3
• Narrow antibiotic spectrum when possible 1

Treatment Response Monitoring

• Expect decreased stool frequency or improved consistency after 3 days 1, 3
• Treatment failure = no response after 3 days 1, 3
• If metronidazole fails, switch to vancomycin 125 mg four times daily 3

Surgical Intervention

• Perform colectomy for: perforation, toxic megacolon, severe ileus not responding to antibiotics, deteriorating clinical condition 1
• Operate before serum lactate exceeds 5.0 mmol/L 1

Important Caveats

Metronidazole neurotoxicity warning: Avoid repeated or prolonged courses due to risk of cumulative and potentially irreversible neurotoxicity 3

Vancomycin dosing: Low-dose vancomycin (125 mg four times daily) is equally effective as high-dose (500 mg four times daily) for non-fulminant disease, with no difference in recurrence rates 4. Reserve higher doses for fulminant/complicated cases only 1, 5.

Fidaxomicin advantages: Associated with lower recurrence rates compared to vancomycin in clinical trials, though evidence for multiple recurrences is limited 1, 2

Treatment duration: Standard 10-day courses are recommended, though patients with delayed response (particularly on metronidazole) may benefit from extending to 14 days 1