What is the treatment for Clostridium difficile infection?

Treatment of Clostridioides difficile Infection

For initial CDI episodes, use vancomycin 125 mg orally four times daily for 10 days as first-line therapy regardless of severity, or fidaxomicin 200 mg twice daily for 10 days as an alternative, particularly for patients at high risk of recurrence. 1

This represents a significant evolution from older guidelines that stratified initial treatment by severity—current evidence supports vancomycin or fidaxomicin as superior first-line agents for both non-severe and severe disease. 1, 2

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Disease Severity Classification

Before initiating treatment, classify disease severity to guide management intensity:

Non-severe CDI: 1, 3

• Stool frequency <4 times daily
• White blood cell count ≤15,000 cells/μL
• Serum creatinine <1.5 mg/dL
• No signs of severe colitis

Severe CDI: 1, 2

• Temperature >38.5°C
• Hemodynamic instability
• Leukocyte count >15×10⁹/L
• Serum creatinine rise >50% above baseline
• Elevated serum lactate
• Pseudomembranous colitis on endoscopy
• Colonic wall thickening on imaging

Fulminant CDI: 2

• Hypotension or shock
• Ileus or megacolon
• Signs of peritonitis

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Initial Episode Treatment Algorithm

For Patients Who Can Take Oral Therapy:

First-line options: 1, 4

• Vancomycin 125 mg orally four times daily for 10 days (preferred for both non-severe and severe CDI)
• Fidaxomicin 200 mg orally twice daily for 10 days (alternative, especially for high recurrence risk)

Less preferred alternative for non-severe CDI only: 1, 3

• Metronidazole 500 mg orally three times daily for 10 days (relegated to alternative status due to vancomycin's superior efficacy)

For Fulminant CDI:

Combination therapy is mandatory: 2

• Vancomycin 500 mg orally four times daily (note the higher dose)
• PLUS metronidazole 500 mg IV every 8 hours
• PLUS rectal vancomycin 500 mg in 100 mL normal saline every 4-12 hours as retention enema if ileus is present 5, 2

When Oral Therapy Is Impossible:

Non-severe disease: 5, 3

• Metronidazole 500 mg IV three times daily for 10 days

Severe disease: 5, 3

• Metronidazole 500 mg IV three times daily
• PLUS intracolonic vancomycin 500 mg in 100 mL normal saline every 4-12 hours
• AND/OR vancomycin 500 mg four times daily by nasogastric tube

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Recurrent CDI Treatment

First Recurrence:

Treat based on severity, similar to initial episode, but consider: 1

• Fidaxomicin 200 mg twice daily for 10 days (preferred to reduce subsequent recurrence)
• OR vancomycin in a tapered and pulsed regimen
• Consider adding bezlotoxumab 10 mg/kg IV as a single dose for patients at high risk of recurrence (age ≥65 years, history of CDI in past 6 months, immunocompromised, severe CDI, or ribotype 027) 1, 6

Second and Subsequent Recurrences:

Vancomycin tapered and pulsed regimen: 5, 1, 3

• Vancomycin 125 mg orally four times daily for at least 10 days
• Followed by tapering doses (e.g., 125 mg twice daily for 1 week, then once daily for 1 week, then every 2-3 days for 2-8 weeks)

For multiple recurrences after appropriate antibiotic treatment: 1

• Consider fecal microbiota transplantation

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Surgical Management

Colectomy should be performed urgently for: 5, 2, 3

• Perforation of the colon
• Systemic inflammation and deteriorating clinical condition not responding to antibiotic therapy
• Toxic megacolon
• Severe ileus
• Serum lactate >5.0 mmol/L (operate before reaching this threshold when possible)

Mortality following colectomy in advanced disease is high, so earlier surgical intervention is recommended when clinical deterioration is evident despite medical therapy. 5

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Critical Adjunctive Measures

Always implement these supportive strategies: 5, 1, 2, 3

• Discontinue the inciting antibiotic immediately if possible (mild CDI may resolve with antibiotic cessation alone under close observation)
• If continued antibiotic therapy is required for another infection, choose agents less associated with CDI (fidaxomicin demonstrates superior efficacy when concomitant antibiotics are necessary) 7
• Discontinue unnecessary proton pump inhibitors 1
• Avoid antiperistaltic agents and opiates (these worsen outcomes by promoting toxin retention and increasing risk of toxic megacolon) 2, 3
• Hand hygiene with soap and water is mandatory (alcohol-based sanitizers are ineffective against C. difficile spores) 1
• Isolate patients promptly 5

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Common Pitfalls and Caveats

Metronidazole limitations: 1, 2

• Using metronidazole for severe CDI has higher failure rates
• The 2021 guidelines represent a significant shift, relegating metronidazole to alternative status

Concomitant antibiotic use: 7

• CA use during CDI treatment is associated with lower cure rates (84.4% vs 92.6%) and extended time to resolution (97 vs 54 hours)
• When CAs are necessary, fidaxomicin achieves 90.0% cure rate versus 79.4% for vancomycin
• CA use during follow-up increases recurrence risk (24.8% vs 17.7%)

Bezlotoxumab considerations: 6

• Does NOT treat CDI—only reduces recurrence risk
• Must be given with standard antibiotic therapy
• Use caution in patients with history of congestive heart failure (higher rate of heart failure and death observed)
• Single IV dose of 10 mg/kg given over 1 hour

Treatment duration: 1

• May need extension beyond 10 days in patients with delayed response to therapy
• Clinical cure rates equalize by 3 weeks post-treatment even if initial response differs

Teicoplanin alternative: 5, 3

• Teicoplanin 100 mg twice daily can replace oral vancomycin if available (primarily used in Europe)