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

Treatment of Clostridioides difficile Infection

For initial non-severe C. difficile infection, use oral vancomycin 125 mg four times daily for 10 days or fidaxomicin 200 mg twice daily for 10 days; metronidazole is no longer recommended as first-line therapy in adults. 1, 2

Initial Management Priorities

Discontinue the inciting antibiotic immediately if the infection was clearly induced by antibiotic use, as continued use significantly increases recurrence risk 1, 3. This is as important as antimicrobial therapy itself 4.

Avoid antiperistaltic agents (loperamide, diphenoxylate) and opiates as they can precipitate toxic megacolon and mask disease progression 4, 1, 2, 3.

Disease Severity Assessment

Classify disease severity before initiating treatment:

Non-Severe CDI

• Stool frequency <4 times daily 4, 3
• White blood cell count <15 × 10⁹/L 2, 3
• No signs of severe colitis 4

Severe CDI (any of the following)

• Leukocytosis (WBC >15 × 10⁹/L) 4, 1, 3
• Serum creatinine rise ≥50% above baseline or ≥133 μM (≥1.5 mg/dL) 4, 1
• Serum albumin <30 g/L 1
• Fever >38.5°C with rigors 4, 3
• Hemodynamic instability or septic shock 4, 3
• Signs of peritonitis (decreased bowel sounds, abdominal tenderness, rebound, guarding) 4, 3
• Ileus (vomiting, absent stool passage) 4, 3
• Elevated serum lactate 4, 3
• Pseudomembranous colitis on endoscopy 4, 3
• Colonic distension or wall thickening on imaging 4, 3

Fulminant CDI

• Hypotension, shock, ileus, or megacolon 4

Treatment Algorithm for Initial Episode

Non-Severe Disease (Oral Therapy Possible)

First-line: Oral vancomycin 125 mg four times daily for 10 days 4, 1, 2, 3

Alternative: Fidaxomicin 200 mg twice daily for 10 days (has fewer recurrences than vancomycin) 1, 5

Note: While older guidelines recommended metronidazole 500 mg three times daily for 10 days for non-severe disease 4, 3, current evidence shows metronidazole is no longer recommended as first-line therapy in adults due to reduced response rates and higher recurrence rates 1, 6. The 2020 Taiwan guideline still suggests metronidazole for first-line in non-severe pediatric cases due to VRE concerns 4, but this represents older thinking.

Severe Disease (Oral Therapy Possible)

First-line: Oral vancomycin 125 mg four times daily for 10 days 4, 1, 2, 3

Alternative: Fidaxomicin 200 mg twice daily for 10 days 1, 5

Severe Disease (Oral Therapy Impossible)

• IV metronidazole 500 mg three times daily for 10 days 4, 3
• PLUS intracolonic vancomycin 500 mg in 100 mL normal saline every 4-12 hours (retention enema) 4, 3
• AND/OR vancomycin 500 mg four times daily by nasogastric tube 4, 3

Critical pitfall: Never use IV vancomycin alone for CDI—it is not excreted into the colon and is completely ineffective 3.

Fulminant Disease in Children

• Oral vancomycin 10 mg/kg (maximum 125 mg) four times daily 4
• PLUS IV metronidazole 10 mg/kg/dose 4

Treatment of Recurrent CDI

First Recurrence

Treat the same as initial episode based on severity (vancomycin or fidaxomicin as first-line) 1, 2, 3.

Second and Subsequent Recurrences

First-line: Oral vancomycin 125 mg four times daily for at least 10 days 4, 1, 2, 3

Then consider vancomycin taper/pulse regimen: 4, 1

• Vancomycin 125 mg four times daily for 10-14 days
• Then 125 mg twice daily for 1 week
• Then 125 mg once daily for 1 week
• Then 125 mg every 2-3 days for 2-8 weeks

Alternative: Fidaxomicin 200 mg twice daily for 10 days 1, 2, 3, 5

Alternative: Teicoplanin 100 mg twice daily (if available) 4

Multiple Recurrences After Antibiotic Failure

Fecal microbiota transplantation (FMT) should be offered, with 70-90% success rates 4, 1, 3.

Adjunctive Therapies

Bezlotoxumab (monoclonal antibody against C. difficile toxin B) may prevent recurrences, particularly in high-risk patients with multiple recurrences 1.

Surgical Management

Urgent colectomy is indicated for: 4, 1, 2, 3

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

Timing is critical: Surgery should be performed early, before colitis becomes very severe, to improve outcomes 4, 3. Total colectomy has been traditional, but diverting loop ileostomy with colonic lavage is emerging as an alternative with potentially lower mortality 1.

Pediatric Considerations (6 Months to <18 Years)

Dosing by Weight for Oral Suspension 5

• 4 kg to <7 kg: 80 mg (2 mL) twice daily
• 7 kg to <9 kg: 120 mg (3 mL) twice daily
• 9 kg to <12.5 kg: 160 mg (4 mL) twice daily
• ≥12.5 kg: 200 mg (5 mL) twice daily or one 200 mg tablet twice daily

For severe CDI in children: Vancomycin is strongly recommended over metronidazole 4.

For fulminant CDI in children: Add IV metronidazole to oral vancomycin 4.

Critical Pitfalls to Avoid

• Do not use parenteral vancomycin for CDI—it does not reach the colon 3
• Do not repeat stool testing after treatment to assess response; clinical improvement is the measure of success 3
• Do not delay surgery in severe cases waiting for antibiotic response 3
• Do not use alcohol-based hand sanitizers for infection control—use soap and water, as alcohol does not kill C. difficile spores 1
• Do not assume all antibiotic-associated diarrhea is C. difficile—confirm diagnosis before treating 3

Infection Control

Hand hygiene with soap and water (not alcohol-based sanitizers) is essential to prevent transmission, as alcohol does not kill C. difficile spores 1.