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

Treatment of Clostridioides difficile Infection

Oral vancomycin 125 mg four times daily for 10 days is the recommended first-line treatment for initial C. difficile infection regardless of severity, with fidaxomicin 200 mg twice daily for 10 days as an equally effective alternative. 1, 2, 3

Initial Episode Treatment

Non-Severe CDI

For patients with stool frequency <4 times daily and no signs of severe colitis, the treatment options are:

• Vancomycin 125 mg orally four times daily for 10 days (preferred first-line) 1, 2
• Fidaxomicin 200 mg orally twice daily for 10 days (alternative first-line with lower recurrence rates) 1, 3
• Metronidazole 500 mg orally three times daily for 10 days (acceptable only for non-severe initial episodes, but increasingly disfavored due to treatment failures) 4, 1, 5

The shift away from metronidazole reflects growing concerns about resistance and inferior outcomes compared to vancomycin and fidaxomicin. 6, 7

Severe CDI

Severe disease is defined by: WBC >15 × 10⁹/L, serum albumin <30 g/L, serum creatinine ≥1.5 times baseline, temperature >38.5°C, or hemodynamic instability. 5

• Vancomycin 125 mg orally four times daily for 10 days (treatment of choice) 1, 2
• Fidaxomicin 200 mg orally twice daily for 10 days (effective alternative with lower recurrence rates) 1, 3

Fulminant CDI

For patients with hypotension, shock, ileus, toxic megacolon, or peritonitis:

• Vancomycin 500 mg orally four times daily PLUS metronidazole 500 mg intravenously three times daily 1, 2
• When oral administration is impossible: Vancomycin 500 mg in 100 mL normal saline via nasogastric tube or retention enema four times daily PLUS intravenous metronidazole 500 mg three times daily 4, 1
• Early surgical consultation is mandatory for patients with systemic toxicity 1
• Consider subtotal colectomy with end ileostomy for perforation, toxic megacolon, or progressive deterioration despite medical therapy 1

Recurrent CDI Treatment

First Recurrence

• Vancomycin 125 mg four times daily for 10 days (especially if metronidazole was used initially) 1, 5
• Fidaxomicin 200 mg twice daily for 10 days (preferred when vancomycin was used for the first episode due to lower recurrence rates) 1, 3
• Avoid metronidazole for recurrent episodes due to lower sustained response rates 1

Second and Subsequent Recurrences

• Vancomycin tapered and pulsed regimen: 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 4, 1
• Fecal microbiota transplantation (FMT) should be strongly considered for multiple recurrences 1, 5, 7
• Bezlotoxumab (monoclonal antibody against C. difficile toxin B) may prevent recurrences in high-risk patients 5, 7

Pediatric Dosing (≥6 months of age)

Non-Severe or First Recurrence

• Vancomycin 10 mg/kg/dose (max 125 mg) four times daily for 10 days 1, 2
• Metronidazole 7.5 mg/kg/dose (max 500 mg) four times daily for 10 days (alternative) 1
• For children weighing ≥12.5 kg who can swallow tablets: One 200 mg fidaxomicin tablet twice daily for 10 days 3

Severe or Fulminant Pediatric CDI

• Vancomycin 10 mg/kg/dose (max 500 mg) every 8 hours for 10 days, with or without IV metronidazole 1

Multiple Recurrences in Children

• Vancomycin extended regimen (same tapering schedule as adults, weight-adjusted) 1
• Consider FMT for multiple recurrences 1

Critical Adjunctive Measures

• Discontinue the inciting antibiotic immediately if clinically feasible 1, 5
• Avoid antiperistaltic agents and opiates as they may worsen colitis 4, 5
• Hand hygiene with soap and water (not alcohol-based sanitizers, which do not kill C. difficile spores) 1, 5
• Monitor renal function during and after treatment, especially in patients >65 years of age, as nephrotoxicity can occur with oral vancomycin 2

Important Caveats

• Parenteral vancomycin is NOT effective for CDI; oral administration is required 2
• Fidaxomicin has lower recurrence rates than vancomycin but comes at higher cost 1, 7
• Avoid repeated or prolonged metronidazole courses due to risk of cumulative and potentially irreversible neurotoxicity 1
• No follow-up stool testing is needed if symptoms resolve, as patients may remain colonized 5
• Monitor for treatment failure (absence of improvement after 3-5 days) and escalate therapy accordingly 5
• Serum vancomycin levels may be significant in patients with inflammatory intestinal mucosa or renal insufficiency, warranting monitoring in select cases 2