What is the first-line treatment for Clostridioides (C.) difficile infection?

First-Line Treatment for Clostridioides difficile Infection

Vancomycin 125 mg orally four times daily for 10 days is the preferred first-line treatment for both non-severe and severe C. difficile infection, with fidaxomicin 200 mg orally twice daily for 10 days as an equally acceptable alternative that offers lower recurrence rates. 1

Treatment Algorithm by Disease Severity

Non-Severe CDI

• Vancomycin 125 mg orally four times daily for 10 days is the current standard of care 1
• Fidaxomicin 200 mg orally twice daily for 10 days is an equally acceptable first-line option with superior recurrence prevention (13.3% vs 24.0% with vancomycin) 1
• Metronidazole is no longer recommended as first-line therapy for initial CDI due to vancomycin's superior clinical cure rates and metronidazole's cumulative neurotoxicity risk 1, 2, 3, 4

Severe CDI

• Vancomycin 125 mg orally four times daily for 10 days is the definitive treatment 1, 2
• Patients treated with vancomycin have lower all-cause 30-day mortality compared to metronidazole 2
• Metronidazole should not be used for severe CDI under any circumstances 1

Severe CDI is defined by: temperature >38.5°C, white blood cell count >15,000 cells/mL, serum creatinine >1.5 mg/dL, albumin <2.5 mg/dL, or 10 or more bowel movements within 24 hours 1, 2

When to Choose Fidaxomicin Over Vancomycin

Fidaxomicin should be strongly considered for patients at high risk of recurrence, including:

• Age >65 years 1
• Ongoing antibiotic use for other infections 1
• Proton pump inhibitor use 1
• Concern for vancomycin-resistant Enterococci (VRE) acquisition, as fidaxomicin causes VRE in only 7% vs 31% with vancomycin 1

Critical Management Steps

• Immediately discontinue the inciting antibiotic if clinically feasible, as this significantly influences recurrence risk 1
• Never use IV vancomycin for CDI treatment – it is not excreted into the colon and is completely ineffective 1
• Do not perform a "test of cure" after completing CDI treatment 1, 2

When Oral Therapy Is Not Possible

For patients unable to take oral medications with severe CDI:

• Metronidazole 500 mg IV three times daily PLUS 1
• Vancomycin 500 mg via nasogastric tube four times daily AND/OR 1
• Vancomycin 500 mg retention enema in 100 mL normal saline every 4-12 hours 1

Common Pitfalls to Avoid

• Do not use metronidazole for initial CDI treatment – older 2009 guidelines recommended this for non-severe disease 5, but current evidence demonstrates vancomycin's superiority and metronidazole's neurotoxicity risk with prolonged use 1, 2
• Do not confuse disease severity – the same vancomycin dose (125 mg four times daily) is used for both non-severe and severe CDI; higher doses provide no additional benefit 1
• Do not delay treatment while awaiting test results if clinical suspicion is high, as severe CDI can progress rapidly to fulminant disease with hypotension, shock, ileus, or toxic megacolon 2, 4