What is the recommended treatment for an adult with a confirmed first episode of Clostridioides difficile infection?

Treatment of Clostridioides difficile Infection

For a confirmed first episode of C. difficile infection in an adult, prescribe oral vancomycin 125 mg four times daily for 10 days OR fidaxomicin 200 mg twice daily for 10 days, regardless of disease severity. 1, 2, 3

First-Line Antibiotic Therapy

Standard Regimen (All Severity Levels)

• Oral vancomycin 125 mg four times daily for 10 days is the established first-line treatment for any initial CDI episode, with strong evidence supporting equal efficacy across non-severe, severe, and fulminant disease when dosed appropriately. 1, 2, 4

• Fidaxomicin 200 mg twice daily for 10 days is equally effective for initial cure and carries a significant advantage: recurrence rates of 15% versus 25–31% with vancomycin. 1, 5

• Both agents are FDA-approved and guideline-endorsed with strong recommendations based on high-quality evidence. 1, 2, 3, 4, 6

When Preferred Agents Are Unavailable

• Metronidazole 500 mg orally three times daily for 10 days may be used only for non-severe CDI when vancomycin and fidaxomicin cannot be obtained. 1, 2, 3

• Metronidazole is no longer first-line therapy because cure rates in severe disease are inferior (≈76% vs ≈97% for vancomycin), and repeated courses carry risk of cumulative, potentially irreversible neurotoxicity. 1, 2, 3

Severity Classification and Dosing Adjustments

Non-Severe CDI

• Defined by white blood cell count ≤15,000 cells/µL AND serum creatinine <1.5 mg/dL. 1, 2, 3

• Use the standard vancomycin 125 mg four times daily or fidaxomicin 200 mg twice daily regimen. 1, 2

Severe CDI (Non-Fulminant)

• Defined by white blood cell count ≥15,000 cells/µL OR serum creatinine ≥1.5 mg/dL. 1, 2, 3

• The same standard dose—vancomycin 125 mg four times daily—is appropriate; do NOT escalate to 500 mg doses for severe non-fulminant disease. 1, 2, 3

• Higher vancomycin doses (>500 mg/day) have not demonstrated additional benefit in non-fulminant severe CDI. 2, 7

Fulminant CDI (Medical Emergency)

• Defined by hypotension/shock, ileus, or megacolon. 1, 2, 3

• High-dose oral vancomycin 500 mg four times daily (via mouth or nasogastric tube if unable to take orally). 1, 2, 3

• Add intravenous metronidazole 500 mg every 8 hours concurrently to ensure adequate colonic drug levels when oral delivery is compromised. 1, 2, 3

• Add rectal vancomycin 500 mg in 100 mL normal saline every 6 hours as a retention enema when ileus is present. 1, 2, 3

Critical Non-Antibiotic Management

Discontinue the Inciting Antibiotic

• Immediately stop the causative antibiotic as soon as clinically feasible—this is the single most important modifiable factor to reduce recurrence risk and treatment failure. 1, 2, 3

• Continuing the inciting antibiotic dramatically increases recurrence rates and is identified as the most common preventable cause of treatment failure. 1

Proton Pump Inhibitor Stewardship

• Discontinue PPIs only when they are not required for another indication; current evidence does not mandate PPI cessation solely to prevent CDI recurrence. 1

Avoid Antiperistaltic Agents

• Do not use loperamide, diphenoxylate, or opiates in patients with active CDI—these agents worsen outcomes and increase complications including toxic megacolon. 3

Treatment Duration and Monitoring

• The standard treatment duration is 10 days for all initial episodes. 1, 2, 3, 4

• Extension to 14 days may be considered for patients with delayed clinical response, especially those initially treated with metronidazole and later switched to vancomycin. 1, 2

• Clinical response is expected within 3–5 days after starting therapy. 1

• Do not perform a "test of cure" after treatment completion—stool testing remains positive for weeks and does not guide management. 1

Special Populations

Pediatric Patients (≥6 months to <18 years)

• Vancomycin 10 mg/kg/dose orally four times daily (maximum 125 mg per dose) for 10 days. 1, 4

• Fidaxomicin is FDA-approved for pediatric patients ≥6 months with weight-based dosing. 1, 6

Patients Unable to Take Oral Medications

• For NPO patients or those with ileus: intravenous metronidazole 500 mg every 8 hours plus vancomycin retention enema 500 mg in 100 mL normal saline four times daily, with transition to oral therapy once oral intake is possible. 1

Elderly Patients (>65 Years)

• Monitor renal function during and after treatment because nephrotoxicity risk is increased in this population, even in those with normal baseline renal function. 4

• Clinically significant serum vancomycin concentrations can occur with oral dosing in patients with inflammatory intestinal mucosa; consider monitoring serum levels in patients with renal insufficiency or colitis. 4

Common Pitfalls to Avoid

• Do not use intravenous vancomycin alone for CDI—parenteral vancomycin does not reach the colonic lumen and is ineffective for CDI. 1, 4

• Do not escalate vancomycin to 500 mg four times daily for severe non-fulminant disease—reserve this dose exclusively for fulminant CDI with ileus. 1, 2, 3

• Do not give repeated metronidazole courses beyond 14 days due to cumulative neurotoxicity risk. 1, 2

• Do not forget to add rectal vancomycin in fulminant CDI with ileus—oral therapy alone may not reach the colon. 1, 2

• Approximately 20% of patients experience recurrence after initial treatment, with higher risk in elderly patients, those with continued antibiotic use, and those with multiple prior episodes. 1