What is the empirical treatment for a typical adult patient with suspected Clostridioides difficile (C. difficile) infection?

Empirical Treatment for C. difficile Infection

For suspected C. difficile infection in adults, start oral vancomycin 125 mg four times daily or fidaxomicin 200 mg twice daily for 10 days empirically only when substantial delay in laboratory confirmation is expected or for fulminant disease. 1

When to Initiate Empirical Therapy

Empirical treatment should be reserved for specific clinical scenarios and is not routinely recommended:

• Start empirically when substantial delay in laboratory confirmation is expected 1
• Start empirically for fulminant CDI (severe systemic toxicity, shock, ileus, or megacolon) 1
• Avoid empirical therapy in mild cases where testing results will be available promptly 1

The key principle is that empirical therapy should be avoided except in cases of strong suspicion of severe CDI 2. Do not delay corticosteroid treatment in other conditions (like inflammatory bowel disease) pending C. difficile results, but do send stool tests 1.

First-Line Empirical Regimens

For Initial Episode (Non-Severe to Severe Disease)

Preferred options (strong recommendation, high quality evidence):

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

These two agents are recommended over metronidazole for initial episodes 1. The 2018 IDSA/SHEA guidelines represent a major shift from prior recommendations that favored metronidazole for mild disease 1.

For Fulminant CDI

Vancomycin 500 mg orally four times daily (strong recommendation, moderate quality evidence) 1

Plus, if ileus is present:

• Vancomycin 500 mg in 100 mL normal saline per rectum every 6 hours as retention enema (weak recommendation, low quality evidence) 1
• Intravenous metronidazole should be administered together 1

Fulminant CDI is defined by hypotension, shock, ileus, or megacolon 1. Intravenous vancomycin alone is ineffective because it is not excreted into the colon 3, 4.

Why Metronidazole Is No Longer First-Line

Metronidazole should only be used in settings where access to vancomycin or fidaxomicin is limited (weak recommendation, high quality evidence) 1:

• Use only for nonsevere initial episodes 1
• Dosage: 500 mg orally three times daily for 10 days 1
• Avoid repeated or prolonged courses due to risk of cumulative and potentially irreversible neurotoxicity 1
• Clinical success rates are lower than vancomycin 1
• Longer time to symptomatic improvement compared to vancomycin 1

The evidence shows metronidazole has inferior outcomes, with only 71% of patients responding within 6 days after emergence of epidemic strains 1.

Critical Concurrent Management

Discontinue Inciting Antibiotics

Stop the causative antibiotic as soon as possible (strong recommendation, moderate quality evidence) 1. This influences risk of recurrence and is a cornerstone of treatment 4, 5.

Severity Assessment Criteria

Classify disease severity to guide treatment intensity 1:

Non-severe CDI:

• White blood cell count ≤15,000 cells/mL AND
• Serum creatinine <1.5 mg/dL 1

Severe CDI:

• White blood cell count >15,000 cells/mL OR
• Serum creatinine ≥1.5 mg/dL 1

Fulminant CDI:

• Hypotension or shock
• Ileus or toxic megacolon
• Peritoneal signs
• Serum lactate >5.0 mmol/L 4

Special Considerations for NPO Patients

If the patient cannot take oral medications 3:

• Vancomycin 500 mg IV every 8 hours
• PLUS vancomycin 250-500 mg in 100-500 mL saline rectally 2-4 times daily 3
• PLUS intravenous metronidazole for severe/fulminant cases 1, 3

There is no intravenous formulation of fidaxomicin available 3.

Common Pitfalls to Avoid

• Testing asymptomatic patients: Only test patients with ≥3 unformed stools in 24 hours 6. Testing colonized patients leads to unnecessary treatment 1, 2
• Delaying treatment in fulminant disease: Do not wait for test results when clinical suspicion is high and patient is critically ill 1
• Using IV vancomycin alone: It does not reach the colon and is ineffective 3, 4
• Continuing PPIs unnecessarily: Discontinue if not essential, though insufficient evidence exists for mandatory discontinuation 1
• Using antimotility agents: Loperamide and opiates worsen outcomes 4
• Performing "test of cure": Not recommended as patients shed spores for weeks after successful treatment 1, 2

Monitoring Response

• Assess clinical and biochemical response after 3 days of therapy 1
• If no improvement by day 3, consider rescue therapy or surgical consultation 1
• Approximately 20% of patients experience recurrence regardless of initial treatment 6