What is the treatment for Clostridioides difficile (C. diff) infection?

Treatment of Clostridioides difficile Infection

For initial C. difficile infection, use oral vancomycin 125 mg four times daily for 10 days or fidaxomicin 200 mg twice daily for 10 days—metronidazole is no longer first-line therapy due to inferior efficacy. 1, 2

Initial Episode Treatment Algorithm

Non-Severe Disease

Non-severe CDI is defined as: white blood cell count ≤15,000 cells/μL AND serum creatinine <1.5 mg/dL AND stool frequency <4 times daily. 3, 2

First-line options:

• Oral vancomycin 125 mg four times daily for 10 days (strong recommendation, high quality evidence) 2
• Fidaxomicin 200 mg twice daily for 10 days (strong recommendation, high quality evidence) 2, 4

Metronidazole 500 mg three times daily for 10 days should only be used when vancomycin or fidaxomicin are unavailable, and only for non-severe disease. 2 Metronidazole is relegated to alternative status due to vancomycin's superior efficacy, with vancomycin demonstrating a 97% cure rate versus 76% for metronidazole in severe disease. 2

Severe Disease

Severe CDI is defined as: white blood cell count ≥15,000 cells/μL OR serum creatinine ≥1.5 mg/dL. 2 Additional markers include marked leukocytosis, elevated creatinine (>50% above baseline), or decreased albumin (<30 g/L). 2

Treatment:

• Oral vancomycin 125 mg four times daily for 10 days (strong recommendation, high quality evidence) 3, 2
• Fidaxomicin is also appropriate 2
• Do NOT use metronidazole for severe disease 2

Fulminant Disease

Fulminant CDI is characterized by: hypotension or shock, ileus, megacolon, hemodynamic instability, or signs of peritonitis. 1

Treatment regimen:

• High-dose oral vancomycin 500 mg four times daily PLUS intravenous metronidazole 500 mg every 8 hours 1
• If ileus is present, add rectal vancomycin 500 mg in 100 mL normal saline every 4-12 hours 3, 1
• Consider vancomycin 500 mg four times daily via nasogastric tube if oral route compromised 3

Surgical intervention: Colectomy should be performed urgently for colonic perforation, systemic inflammation not responding to antibiotics, toxic megacolon, severe ileus, or serum lactate >5.0 mmol/L. 3, 1

Recurrent CDI Treatment

First Recurrence

Treatment options:

• Fidaxomicin 200 mg twice daily for 10 days (preferred due to lower recurrence rates) 2
• Vancomycin tapered/pulsed regimen 2
• Consider bezlotoxumab 10 mg/kg IV once as adjunctive therapy for patients at high risk of recurrence 2

Second and Subsequent Recurrences

Treatment:

• Vancomycin 125 mg four times daily for at least 10 days 3
• Consider taper/pulse strategy: decreasing daily dose by 125 mg every 3 days, or pulse dosing of 125 mg every 3 days for 3 weeks 3
• Fecal microbiota transplantation (FMT) is recommended for multiple recurrent CDI after appropriate antibiotic therapy for at least three episodes 5, 6

Critical Management Principles

What to Avoid

• Antiperistaltic agents and opiates must be avoided—they worsen outcomes by promoting toxin retention and increasing risk of toxic megacolon. 3, 2
• Avoid repeated or prolonged courses of metronidazole due to risk of cumulative and potentially irreversible neurotoxicity, particularly concerning in elderly patients. 2

Supportive Measures

• Discontinue inciting antibiotics immediately if clinically feasible. 2 Mild CDI (stool frequency <4 times daily, no signs of severe colitis) clearly induced by antibiotics may be treated by stopping the inducing antibiotic alone, with close observation. 3
• Assess clinical response by 72 hours—if no improvement, escalate therapy rather than continuing ineffective treatment. 2
• Treatment response may require 3-5 days; stool frequency should decrease or consistency improve after 3 days without new signs of severe colitis developing. 3, 2

Testing Considerations

• Do not perform "test of cure" after completing CDI treatment—testing should only be performed in symptomatic patients. 2
• Use enzyme immunoassays for glutamate dehydrogenase and toxins A and B, or nucleic acid amplification testing for diagnosis. 5

Pediatric Considerations

For pediatric patients aged 6 months to less than 18 years, fidaxomicin is FDA-approved with weight-based dosing. 4 Tablets (200 mg twice daily for 10 days) are appropriate for children weighing at least 12.5 kg who can swallow tablets; otherwise, oral suspension is available with weight-based dosing from 80 mg to 200 mg twice daily. 4