What is the recommended treatment for an adult inpatient with a laboratory‑confirmed Clostridioides difficile infection?

Treatment of Clostridioides difficile Infection in Hospitalized Adults

Oral vancomycin 125 mg four times daily for 10 days or fidaxomicin 200 mg twice daily for 10 days is the first-line treatment for any initial episode of CDI in hospitalized adults, regardless of disease severity. 1, 2, 3

Initial Episode Management

Discontinue the Inciting Antibiotic

• Stop the causative antibiotic immediately as this is the single most important modifiable factor to reduce recurrence risk and treatment failure. 1, 2, 3

First-Line Antimicrobial Therapy (All Severity Levels)

Preferred regimens (equal efficacy for initial cure):

• Vancomycin 125 mg orally four times daily for 10 days 1, 2, 3
• Fidaxomicin 200 mg orally twice daily for 10 days 1, 2, 3

Key advantages of fidaxomicin:

• Significantly lower recurrence rates (15% vs. 25-31% with vancomycin), making it the preferred agent when cost is not prohibitive. 2, 4

Metronidazole is no longer first-line:

• Use metronidazole 500 mg orally three times daily for 10 days only when vancomycin and fidaxomicin are unavailable, and only for non-severe disease. 1, 2, 3
• Never use repeated courses of metronidazole due to cumulative, potentially irreversible neurotoxicity risk. 1, 2

Severity Classification

Non-severe CDI:

• White blood cell count ≤ 15,000 cells/µL and serum creatinine < 1.5 mg/dL 1, 2, 5
• Treat with standard vancomycin 125 mg four times daily or fidaxomicin 200 mg twice daily 2, 3

Severe CDI:

• White blood cell count ≥ 15,000 cells/µL or serum creatinine ≥ 1.5 mg/dL 1, 2, 5
• Use the same standard dose: vancomycin 125 mg four times daily for 10 days—higher doses provide no additional benefit for non-fulminant severe disease. 2, 5, 6

Fulminant CDI (medical emergency):

• Hypotension/shock, ileus, or megacolon 1, 2, 3
• High-dose vancomycin 500 mg orally (or via nasogastric tube) four times daily 1, 2, 5
• Add intravenous metronidazole 500 mg every 8 hours concurrently to ensure adequate colonic drug levels when oral delivery is compromised 1, 2, 5
• Add vancomycin retention enema 500 mg in 100 mL normal saline every 6 hours if ileus is present 1, 2

Treatment Duration

• Standard duration is 10 days for all initial episodes. 1, 2, 3
• Consider extending to 14 days if clinical response is delayed, particularly in patients initially treated with metronidazole who required escalation to vancomycin. 2, 3

First Recurrence Management

Treatment depends on initial therapy:

If metronidazole was used initially:

• Give vancomycin 125 mg orally four times daily for 10 days 2, 3

If standard vancomycin was used initially:

• Employ a prolonged tapered-and-pulsed vancomycin regimen: 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, followed by 125 mg every 2-3 days for 2-8 weeks (total duration 6-11 weeks). 2, 3

Alternative option:

• Fidaxomicin 200 mg twice daily for 10 days 2, 3

Adjunctive therapy:

• Consider bezlotoxumab 10 mg/kg IV as a single dose during antibiotic treatment to reduce recurrence risk, but use cautiously in patients with congestive heart failure. 2

Second or Subsequent Recurrences

Treatment options (in order of preference):

• Continue tapered-and-pulsed vancomycin regimen as described above 2, 3
• Sequential therapy: vancomycin 125 mg four times daily for 10 days followed by rifaximin 400 mg three times daily for 20 days 2, 3
• Fidaxomicin 200 mg twice daily for 10 days 2, 3
• Fecal microbiota transplantation (FMT) after failure of at least two appropriate antibiotic courses (i.e., after three total CDI episodes) 2, 3

Critical Pitfalls to Avoid

• Never use intravenous vancomycin alone for CDI—it does not reach therapeutic colonic concentrations. 3
• Avoid antiperistaltic agents (loperamide, diphenoxylate) and opiates in patients with active CDI, as they worsen outcomes and increase complications. 1, 5
• Do not perform a "test of cure" after treatment completion—clinical response (expected within 3-5 days) is the appropriate endpoint. 3
• Do not use high-dose vancomycin (500 mg four times daily) for non-fulminant disease—the standard 125 mg dose achieves fecal concentrations thousands of times higher than the MIC90 for C. difficile. 2, 5, 7
• Failing to discontinue the inciting antibiotic dramatically increases recurrence risk and is the most common preventable cause of treatment failure. 2, 3