What is the recommended treatment for an adult with an initial episode of Clostridioides difficile colitis, including severe disease and recurrent episodes?

Treatment of Clostridioides difficile Colitis

For any initial episode of C. difficile infection, oral fidaxomicin 200 mg twice daily for 10 days is the preferred first-line therapy, regardless of disease severity. 1

Initial Episode Treatment Algorithm

Preferred First-Line Regimen

• Fidaxomicin 200 mg orally twice daily for 10 days is the top recommendation from IDSA/SHEA guidelines because it achieves similar cure rates to vancomycin (88% vs 86-87%) but significantly reduces recurrence risk (13-17% vs 24-27%). 1, 2, 3
• Fidaxomicin demonstrates superior sustained cure rates (approximately 77%) compared to vancomycin (63-68%), meaning fewer patients require additional treatment courses. 2

Acceptable Alternative

• Oral vancomycin 125 mg four times daily for 10 days remains an acceptable alternative when fidaxomicin is unavailable or cost-prohibitive, with clinical cure rates of 81-92%. 1, 2
• The standard 125 mg dose is appropriate for both non-severe and severe disease; higher doses provide no additional benefit in non-fulminant cases. 2, 4

Last-Resort Option (Resource-Limited Settings Only)

• Metronidazole 500 mg orally three times daily for 10 days should be used only when fidaxomicin and vancomycin are unavailable, and only for non-severe CDI (WBC ≤15,000 cells/µL and creatinine <1.5 mg/dL). 1, 2
• Metronidazole is inferior to vancomycin in severe CDI, achieving only 76% cure rates versus 97% with vancomycin. 2, 5
• Never use repeated metronidazole courses due to cumulative, potentially irreversible neurotoxicity risk. 2, 4

Fulminant/Life-Threatening CDI (Medical Emergency)

Defining Fulminant Disease

• Fulminant CDI is identified by hypotension or shock, ileus, or megacolon—any one of these constitutes a medical emergency requiring immediate escalation. 1, 2

Fulminant Treatment Regimen

• High-dose oral vancomycin 500 mg four times daily (via mouth or nasogastric tube) PLUS intravenous metronidazole 500 mg every 8 hours. 1, 2, 4
• If ileus is present, add vancomycin retention enema 500 mg in 100 mL normal saline every 4-12 hours rectally. 1, 2
• This combination ensures adequate colonic drug levels when oral delivery is compromised by ileus. 2, 4

Critical Pitfall to Avoid

• Never use intravenous vancomycin alone for CDI—it is not excreted into the colon and has zero efficacy against luminal infection. 2

Surgical Consultation

• Obtain immediate surgical consultation for total abdominal colectomy with ileostomy if perforation occurs, systemic inflammation fails to respond to antibiotics within 2-5 days, or toxic megacolon develops. 2
• Surgery should be performed early, ideally before serum lactate exceeds 5.0 mmol/L. 2

First Recurrence Treatment

If Initial Episode Was Treated With Metronidazole

• Oral vancomycin 125 mg four times daily for 10 days. 1, 2, 4

If Initial Episode Was Treated With Standard Vancomycin

• Fidaxomicin 200 mg orally twice daily for 10 days is the preferred option, reducing second recurrence risk from 35.5% (vancomycin) to 19.7%. 1, 6
• Alternative: Tapered-and-pulsed vancomycin regimen over 6-11 weeks total:
  • 125 mg four times daily for 10-14 days
  • Then 125 mg twice daily for 7 days
  • Then 125 mg once daily for 7 days
  • Then 125 mg every 2-3 days for 2-8 weeks 1, 2, 4
• The pulse phase (every 2-3 days dosing) is essential—it suppresses C. difficile while allowing normal gut flora to recover. 2
• Maintain the 125 mg dose throughout; do not escalate to 500 mg, which is reserved only for fulminant disease. 2, 4

Adjunctive Therapy for High-Risk Patients

• Bezlotoxumab 10 mg/kg intravenously as a single dose during antibiotic therapy can reduce recurrence risk in patients >65 years, immunocompromised, or with severe initial disease. 1, 2
• FDA warning: Reserve bezlotoxumab for patients with congestive heart failure only when benefit outweighs risk. 1, 2

Second and Subsequent Recurrences

Treatment Hierarchy

1. Fidaxomicin 200 mg twice daily for 10 days (standard or extended-pulsed regimen: 5 days twice daily, then once every other day for 20 days). 1, 2
2. Tapered-and-pulsed vancomycin (same regimen as first recurrence). 1, 2
3. Sequential vancomycin-rifaximin: vancomycin 125 mg four times daily for 10 days followed immediately by rifaximin 400 mg three times daily for 20 days. 1, 2

Fecal Microbiota Transplantation (FMT)

• FMT is strongly recommended after at least two recurrences (i.e., three total CDI episodes) that have failed appropriate antibiotic therapy. 1, 2
• FMT achieves resolution rates of 70-92% compared to 23-40% with antibiotics alone. 2
• The IDSA/SHEA panel opinion is that appropriate antibiotic treatments for at least 2 recurrences should be tried before offering FMT. 1

Essential Management Principles

Antibiotic Stewardship

• Discontinue the inciting antibiotic immediately—this is the single most important modifiable factor to reduce recurrence and treatment failure. 2, 4, 7

Medications to Avoid

• Never use antiperistaltic agents (loperamide, diphenoxylate) or opioid analgesics in active CDI—they worsen outcomes and increase complications. 2, 4

Monitoring Treatment Response

• Clinical response typically requires 3-5 days after starting therapy; evaluate daily for stool frequency, consistency, and clinical parameters. 2
• Do not perform a "test of cure" after completing therapy—clinical improvement is the appropriate endpoint. 2, 4

Treatment Duration

• A standard 10-day course is appropriate for all initial episodes and most recurrences. 1, 4
• Extension to 14 days may be considered only when clinical response is delayed, particularly after escalation from metronidazole to vancomycin. 2, 4

Common Pitfalls to Avoid

• Do not use metronidazole for severe CDI—cure rates are significantly lower (66% vs 79% for vancomycin). 2
• Do not forget rectal vancomycin in fulminant CDI with ileus—oral therapy alone may not reach the colon. 4
• Do not omit the pulse phase of tapered vancomycin—stopping after the daily taper eliminates the critical 2-8 week intermittent dosing component. 2
• Do not delay surgical consultation in fulminant CDI—operate before the patient becomes critically ill with lactate >5.0 mmol/L. 2