First-Line Treatment for Clostridioides difficile Infection
Oral vancomycin 125 mg four times daily for 10 days or fidaxomicin 200 mg twice daily for 10 days is the first-line treatment for any initial episode of C. difficile infection, regardless of disease severity. 1, 2
Preferred First-Line Regimens
Vancomycin 125 mg orally four times daily for 10 days is a guideline-recommended first-line option with strong evidence for all initial CDI episodes. 1, 2, 3
Fidaxomicin 200 mg orally twice daily for 10 days is equally effective as first-line therapy and is preferred when cost is not limiting because it significantly reduces recurrence rates (15% vs 25-31% with vancomycin). 1, 2
Both agents are recommended for non-severe AND severe disease—the same standard doses apply regardless of severity classification. 1, 2
When Metronidazole May Be Used
Metronidazole 500 mg orally three times daily for 10 days should only be used when vancomycin and fidaxomicin are unavailable and the disease is non-severe. 1, 2, 4
Metronidazole is no longer a first-line option because it has inferior cure rates compared to vancomycin (84% vs 97% overall; 76% vs 97% in severe disease). 4
Repeated courses of metronidazole beyond 14 days must be avoided due to cumulative and potentially irreversible neurotoxicity. 5, 1, 4
Critical Initial Management Steps
Immediately discontinue the inciting antibiotic that precipitated the infection—this is the single most important modifiable factor to reduce recurrence and treatment failure. 1, 2
Start empiric therapy without waiting for test results if clinical suspicion is high and the patient is critically ill. 5
Severity-Specific Dosing
Non-Severe CDI (WBC ≤15,000/µL AND creatinine <1.5 mg/dL)
- Use the standard first-line regimen: vancomycin 125 mg four times daily or fidaxomicin 200 mg twice daily. 1, 2
Severe CDI (WBC ≥15,000/µL OR creatinine ≥1.5 mg/dL)
- The same standard vancomycin dose (125 mg four times daily) is recommended—higher doses provide no additional benefit for non-fulminant severe disease. 1, 2, 6
Fulminant CDI (hypotension/shock, ileus, or megacolon)
- High-dose oral vancomycin 500 mg four times daily (via mouth or nasogastric tube). 1, 2
- Add intravenous metronidazole 500 mg every 8 hours to ensure adequate colonic drug levels when oral delivery is compromised. 1, 2
- Add vancomycin retention enema 500 mg in 100 mL normal saline every 6 hours if ileus is present. 1, 2
Treatment Duration
A standard 10-day course is recommended for all initial episodes, with possible extension to 14 days if clinical response is delayed, particularly after escalation from metronidazole to vancomycin. 1, 2
Clinical response is expected within 3-5 days after starting therapy. 5, 1
Common Pitfalls to Avoid
Never use intravenous vancomycin alone for CDI—it does not achieve therapeutic colonic concentrations and is completely ineffective. 1, 2, 3
Do not use higher vancomycin doses (>500 mg/day) for non-fulminant disease—the standard 125 mg dose already exceeds the MIC90 for C. difficile by several orders of magnitude. 2, 6
Avoid antiperistaltic agents (loperamide, diphenoxylate) and opioid analgesics in active CDI, as they worsen outcomes and increase complications. 1, 2
Do not perform a "test of cure" after treatment completion—clinical improvement is the appropriate endpoint. 5, 1
Failing to discontinue the inciting antibiotic dramatically increases recurrence risk and is the most common preventable cause of treatment failure. 1, 2