What is the treatment for Clostridium difficile (C. diff) infection?

Treatment of Clostridioides difficile Infection

Treatment selection for C. difficile infection depends primarily on disease severity: oral vancomycin 125 mg four times daily for 10 days is the preferred first-line therapy for severe disease, while oral metronidazole 500 mg three times daily for 10 days remains an option for non-severe cases, though vancomycin is increasingly preferred for all initial episodes. 1, 2, 3

Disease Severity Classification

Accurate severity assessment is critical for appropriate treatment selection:

Non-severe CDI is characterized by:

• Stool frequency <4 times daily 1, 2
• Absence of severe colitis markers 1

Severe CDI is defined by the presence of one or more of the following markers:

• Fever >38.5°C (core body temperature) 1, 3
• Leukocyte count >15 × 10⁹/L 1, 3
• Serum creatinine rise >50% above baseline 1, 3
• Elevated serum lactate 1, 3
• Hemodynamic instability or signs of septic shock 1, 3
• Signs of peritonitis (decreased bowel sounds, abdominal tenderness, rebound tenderness, guarding) 1
• Signs of ileus (vomiting, absent passage of stool) 1
• Pseudomembranous colitis on endoscopy 1, 3
• Colonic wall thickening or distension on imaging 1, 3

Initial Episode Treatment Algorithm

For Oral Therapy (Patient Can Swallow)

Non-severe disease:

• Metronidazole 500 mg orally three times daily for 10 days 1, 2
• Alternative: Vancomycin 125 mg orally four times daily for 10 days 3
• Alternative: Fidaxomicin 200 mg orally twice daily for 10 days 3, 4

Severe disease:

• Vancomycin 125 mg orally four times daily for 10 days (preferred) 1, 2
• Alternative: Fidaxomicin 200 mg orally twice daily for 10 days (especially for high recurrence risk) 3, 4

When Oral Therapy is Impossible (Ileus, Severe Vomiting)

Non-severe disease:

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

Severe disease (fulminant):

• Vancomycin 500 mg orally four times daily PLUS 3
• Metronidazole 500 mg intravenously every 8 hours PLUS 1, 3
• Consider intracolonic vancomycin 500 mg in 100 mL normal saline every 4-12 hours as retention enema 1, 3
• Consider vancomycin 500 mg four times daily via nasogastric tube 1

Critical Management Principles

Discontinue offending antibiotics immediately when possible, as this alone may resolve mild cases in approximately 25% of patients 1, 5, 6

Avoid antiperistaltic agents and opiates as they can worsen colitis and increase complications 1

Monitor for treatment response within 72 hours: expect decreased stool frequency or improved consistency after 3 days 2

Treatment failure is defined as absence of improvement in stool frequency or consistency after 3 days of appropriate therapy 2

Recurrent CDI Management

Approximately 20-25% of patients will experience at least one recurrence 2, 7

First recurrence:

• Treat as initial episode based on severity 1, 3, 8
• If disease has progressed from non-severe to severe, escalate therapy accordingly 1

Second recurrence and beyond:

• Vancomycin 125 mg orally four times daily for at least 10 days 1
• Followed by tapered/pulsed regimen: 1, 3
  • 125 mg twice daily for 7 days
  • 125 mg once daily for 7 days
  • 125 mg every 2-3 days for 2-8 weeks 8
• Alternative: Fidaxomicin 200 mg twice daily for 10 days 3, 4
• Consider fecal microbiota transplantation for multiple recurrences after antibiotic failure 3, 9

Critical caveat: Avoid metronidazole for second and subsequent recurrences due to potential neurotoxicity and hepatotoxicity with prolonged use 8

Surgical Intervention Criteria

Colectomy should be performed urgently in the following situations:

• Colonic perforation 1
• Toxic megacolon 1
• Severe ileus 1
• Systemic inflammation with deteriorating clinical condition despite appropriate antibiotic therapy 1

Timing is critical: Surgery should be performed before serum lactate exceeds 5.0 mmol/L, as mortality increases dramatically with advanced disease 1

Warning signs requiring surgical consultation:

• Rising WBC count ≥25,000 2
• Lactate ≥5 mmol/L 2
• Hemodynamic instability despite resuscitation 1

Common Pitfalls and Caveats

Fluoroquinolones significantly increase risk of worsening C. difficile infection and should be avoided if alternative antibiotics are available 2

Do not use metronidazole for severe CDI as it has higher failure rates compared to vancomycin 3

Proton pump inhibitors should be discontinued if not medically necessary, as they may increase CDI risk 3

Hand hygiene requires soap and water, not alcohol-based sanitizers, as alcohol is ineffective against C. difficile spores 3

Complete the full 10-day course even if symptoms improve early, as premature discontinuation increases recurrence risk and antibiotic resistance 4

Teicoplanin 100 mg twice daily may be substituted for oral vancomycin if available 1

Monitoring Requirements

Daily assessment should include:

• Physical examination for abdominal tenderness and peritoneal signs 5
• Stool frequency and character documentation 5
• Laboratory monitoring every 24-48 hours: complete blood count, inflammatory markers, electrolytes, renal function 5
• Fluid and electrolyte replacement for dehydration 5