What is the recommended treatment for Clostridioides difficile infection?

Treatment of Clostridioides difficile Infection

Oral vancomycin 125 mg four times daily for 10 days is the first-line treatment for both non-severe and severe initial C. difficile infection. 1, 2, 3

Disease Severity Classification

Before initiating treatment, classify disease severity using these specific criteria:

• Non-severe CDI: Stool frequency <4 times daily, WBC ≤15,000/μL, serum creatinine <1.5 mg/dL, and absence of severe systemic signs 1, 2
• Severe CDI: Any of the following: fever >38.5°C with rigors, hemodynamic instability or septic shock, WBC >15,000/μL, serum creatinine ≥1.5 mg/dL or rise >50% above baseline, elevated serum lactate, pseudomembranous colitis on endoscopy, or colonic wall thickening/distension on imaging 1, 2, 3
• Fulminant CDI: Hypotension, shock, ileus, toxic megacolon, or serum lactate >5.0 mmol/L 1, 3

First-Line Treatment Algorithm for Initial Episode

Non-Severe Disease (Oral Therapy Possible)

• Preferred: Oral vancomycin 125 mg four times daily for 10 days 1, 2, 3
• Alternative (less preferred): Metronidazole 500 mg orally three times daily for 10 days 1, 3
• Alternative (high recurrence risk): Fidaxomicin 200 mg orally twice daily for 10 days 3, 4

The shift away from metronidazole as first-line reflects concerns about resistance and higher failure rates in severe disease. 5, 6 While older guidelines favored metronidazole for cost reasons, current evidence strongly supports vancomycin or fidaxomicin as superior options. 2, 3

Severe Disease (Oral Therapy Possible)

• Preferred: Oral vancomycin 125 mg four times daily for 10 days 1, 2, 3
• Alternative: Fidaxomicin 200 mg orally twice daily for 10 days 3

Fulminant Disease

• Combination therapy: Oral vancomycin 500 mg (not 125 mg) four times daily PLUS intravenous metronidazole 500 mg every 8 hours 1, 3
• If ileus present: Add rectal vancomycin 500 mg in 100 mL normal saline every 4-12 hours as retention enema AND/OR vancomycin 500 mg via nasogastric tube four times daily 1, 2, 3

When Oral Therapy Is Impossible (Non-Severe)

• Metronidazole 500 mg intravenously three times daily for 10 days 1

Treatment of Recurrent CDI

First Recurrence

• Treat based on severity using the same algorithm as initial episode: vancomycin 125 mg four times daily for 10 days OR fidaxomicin 200 mg twice daily for 10 days 1, 2, 3

Second and Subsequent Recurrences

• Preferred: Oral vancomycin tapered-pulse regimen: 125 mg four times daily for ≥10 days, then decrease daily dose by 125 mg every 3 days, followed by pulse dosing (125 mg every 3 days for 3 weeks) 1, 2, 3
• Alternative: Fidaxomicin 200 mg orally twice daily for 10 days 1, 3
• For multiple recurrences failing antibiotics: Fecal microbiota transplantation (FMT) with 70-90% success rates 1, 3, 6

Bezlotoxumab (monoclonal antibody against C. difficile toxin B) may be considered as adjunctive therapy in patients with multiple risk factors for recurrence. 6

Surgical Intervention Criteria

Urgent colectomy is indicated for:

• Colonic perforation 1, 2, 3
• Toxic megacolon 1, 2, 3
• Severe ileus 1, 2, 3
• Systemic inflammation with deteriorating clinical condition despite maximal antibiotic therapy 1, 2, 3
• Serum lactate >5.0 mmol/L 1, 3

Do not delay surgical consultation when clinical deterioration continues despite antibiotics—early surgery improves survival. 2 Surgery should be performed before lactate exceeds 5.0 mmol/L. 1, 3

Critical Management Principles

Immediate Actions

• Discontinue the inciting antibiotic immediately if clinically feasible—this alone resolves symptoms in approximately 25% of mild cases 2
• If continued antibiotic therapy is required, switch to agents with lower CDI risk (parenteral aminoglycosides, sulfonamides, macrolides, vancomycin, tetracyclines/tigecycline) 1

Medications to Avoid

• Never use antiperistaltic agents (loperamide, diphenoxylate) or opioid analgesics—they promote toxin retention and precipitate toxic megacolon 1, 2
• Never use parenteral vancomycin for CDI—it is not excreted into the colon and is completely ineffective 1
• Avoid prolonged or repeated metronidazole courses due to cumulative, potentially irreversible neurotoxicity risk 1, 2

Monitoring and Follow-Up

• Do not repeat stool toxin testing after treatment to assess response—clinical improvement is the primary endpoint 1, 2
• Treatment duration may need extension beyond 10 days in patients with delayed response 3

Infection Control

• Hand hygiene with soap and water is required—alcohol-based hand sanitizers are ineffective against C. difficile spores 3
• Discontinue unnecessary proton pump inhibitors in high-risk patients 3

Common Pitfalls to Avoid

• Using metronidazole for severe CDI has higher failure rates and is no longer recommended 3, 5
• Delaying surgery in fulminant cases while waiting for antibiotic response worsens outcomes 1, 2
• Assuming all antibiotic-associated diarrhea is C. difficile—confirm diagnosis with stool toxin testing before treating 1
• Using the 125 mg vancomycin dose in fulminant disease—increase to 500 mg four times daily 1, 3