What is the recommended dose of metronidazole (Flagyl) for treating Clostridioides difficile (C. difficile) infection?

Metronidazole Dosing for C. difficile Infection

Metronidazole 500 mg orally three times daily for 10 days should only be used for non-severe C. difficile infection when vancomycin or fidaxomicin is unavailable, as it is inferior to vancomycin with cure rates of 84% versus 97% overall. 1, 2

First-Line Therapy Recommendations

Vancomycin and fidaxomicin are now preferred over metronidazole for initial CDI treatment:

• Vancomycin 125 mg orally four times daily for 10 days OR fidaxomicin 200 mg twice daily for 10 days are the recommended first-line therapies for non-severe CDI 1, 2
• Metronidazole has been relegated to second-line status and should only be used when vancomycin or fidaxomicin cannot be obtained due to access or cost barriers 1, 3
• The inferior efficacy of metronidazole was demonstrated in randomized controlled trials showing cure rates of only 76% versus 97% for vancomycin in severe disease 2, 4

Disease Severity-Based Dosing Algorithm

For mild-to-moderate CDI:

• Metronidazole 500 mg orally three times daily for 10 days (only if vancomycin/fidaxomicin unavailable) 5, 1
• Treatment duration may be extended to 14 days in patients with delayed response 5, 1

For severe CDI:

• Vancomycin 125 mg orally four times daily for 10-14 days is required 5, 1
• Metronidazole should NOT be used as monotherapy for severe disease 3

For fulminant/complicated CDI:

• Vancomycin 500 mg orally four times daily PLUS intravenous metronidazole 500 mg every 8 hours 5, 1
• Consider adding vancomycin per rectum (500 mg in 500 mL saline as enema) four times daily if ileus is present 5

Critical Limitations and Safety Warnings

Metronidazole should be avoided in recurrent CDI:

• For first recurrence, repeat the initial therapy regimen if metronidazole was used initially 5, 6
• For second or subsequent recurrences, metronidazole must NOT be used due to risk of cumulative and potentially irreversible neurotoxicity 1, 2, 6
• Switch to vancomycin tapered/pulsed regimens for multiple recurrences 1, 6

Common pitfalls to avoid:

• Do not perform "test of cure" after CDI treatment—testing should only be done in symptomatic patients 5, 1
• Metronidazole causes metallic taste and gastrointestinal side effects 1, 3
• Prolonged or repeated courses increase neurotoxicity and hepatotoxicity risk 2, 6

Comparative Efficacy Data

The evidence strongly favors vancomycin over metronidazole:

• In mild CDI: metronidazole achieved 90% cure versus 98% with vancomycin (not statistically significant) 4
• In severe CDI: metronidazole achieved only 76% cure versus 97% with vancomycin (P=0.02) 4
• Overall pooled analysis showed metronidazole 72.7% cure versus vancomycin 81.1% cure (P=0.02) 7