What are the diagnostic criteria and treatment options for Clostridioides difficile (C. difficile) infection?

Diagnostic Criteria and Treatment of Clostridioides difficile Infection

Diagnostic Criteria

Diagnosis of CDI requires BOTH clinical symptoms (≥3 unformed stools in 24 hours) AND laboratory confirmation via a positive stool test for toxigenic C. difficile or its toxins, or colonoscopic/histopathologic evidence of pseudomembranous colitis. 1

Clinical Requirements

• Diarrhea: Three or more unformed stools within 24 hours 1
• Additional symptoms: Abdominal pain, cramping, bloating, or signs of ileus/toxic megacolon 2
• Risk factors: Recent antibiotic exposure, hospitalization, advanced age, proton pump inhibitor use 1, 2
• Critical caveat: Testing should ONLY be performed on symptomatic patients with diarrhea—never test asymptomatic patients or those with formed stools, as this detects colonization rather than infection 1, 2

Laboratory Testing Algorithm

The optimal diagnostic approach is a two-step algorithm combining high-sensitivity screening with high-specificity confirmation. 1, 2

Two-Step Algorithm (Recommended):

1. Screen first with either:

   • Glutamate dehydrogenase (GDH) enzyme immunoassay (sensitivity 90.8%) 1, 2, OR
   • Nucleic acid amplification test/PCR for toxin genes (sensitivity 91-92%) 1, 2

2. Confirm positive screens with:

   • Toxin A/B enzyme immunoassay to distinguish active infection from colonization 1, 2
   • This two-step approach achieves sensitivity of 91% and specificity of 98% 2

Single-Step NAAT (Alternative):

• NAAT alone has excellent sensitivity (80-100%) and specificity (87-99%) 1
• Major limitation: Cannot distinguish infection from asymptomatic colonization (up to 7% of hospitalized patients are colonized) 1
• Should be reserved for patients with high clinical suspicion for CDI 1

Tests NOT Recommended as Sole Diagnostic:

• Toxin A/B EIA alone: Fast and inexpensive but poor sensitivity (32-98%), misses many true cases 1, 3
• GDH alone: Sensitive but cannot differentiate toxigenic from non-toxigenic strains 1
• Test of cure: Never recommended—patients shed spores for up to 6 weeks after successful treatment 1, 2

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Treatment Strategy

Treatment must be stratified by disease severity and recurrence status—vancomycin and fidaxomicin are first-line agents, while metronidazole is no longer adequate for initial therapy. 1, 4

Initial Steps (All Patients):

• Discontinue precipitating antibiotics if clinically feasible 1, 2
• Isolate patient immediately to prevent transmission 2
• Monitor electrolytes (creatinine, lactate) to assess severity 1, 2

Mild-to-Moderate CDI (First Episode):

Option 1 (Preferred):

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

Option 2:

• Fidaxomicin 200 mg orally twice daily for 10 days (significantly more expensive but may reduce recurrence risk) 1, 5

Historical option (no longer recommended):

• Metronidazole 500 mg orally three times daily was previously used but is now considered inadequate 4

Severe CDI:

Vancomycin is mandatory for severe disease—metronidazole is insufficient. 1

• Vancomycin 125 mg orally four times daily for 10-14 days 1
• Clinical success rate approximately 81% 2
• Severity indicators: WBC >15,000, creatinine >1.5x baseline, hypotension, shock, ileus, megacolon 1

Severe-Complicated/Fulminant CDI:

Combination therapy is required for life-threatening disease. 1

• Vancomycin 500 mg orally or via nasogastric tube four times daily 1
• PLUS Vancomycin enema 500 mg in 500 mL saline four times daily (if ileus present) 1
• AND/OR Metronidazole 500 mg IV every 8 hours 1
• Surgical consultation for possible colectomy if deteriorating despite medical therapy 1

First Recurrence:

Repeat the initial therapy regimen used for the first episode. 1

• Vancomycin 125 mg orally four times daily for 10 days, OR 1
• Fidaxomicin 200 mg orally twice daily for 10 days (may reduce subsequent recurrence) 1, 5

Second or Multiple Recurrences:

Vancomycin tapered/pulsed regimen or fidaxomicin are preferred; fecal microbiota transplantation should be strongly considered. 1, 2

Option 1 (Vancomycin taper):

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

Option 2:

• Fidaxomicin 200 mg orally twice daily for 10 days 1, 5

Option 3 (Highly Effective):

• Fecal microbiota transplantation (FMT): Success rate approximately 90% for recurrent CDI 1, 2
• Should be considered after 2+ recurrences 1

Pediatric Dosing (6 Months to <18 Years):

Fidaxomicin is FDA-approved for pediatric patients ≥6 months. 5

• Weight ≥12.5 kg and able to swallow tablets: 200 mg orally twice daily for 10 days 5
• Weight-based oral suspension dosing: 5
  • 4 to <7 kg: 80 mg (2 mL) twice daily
  • 7 to <9 kg: 120 mg (3 mL) twice daily
  • 9 to <12.5 kg: 160 mg (4 mL) twice daily
  • ≥12.5 kg: 200 mg (5 mL) twice daily

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Critical Pitfalls to Avoid

• Testing asymptomatic patients or formed stools: Detects colonization, not infection—leads to unnecessary treatment 1, 2
• Using toxin EIA alone: Misses 20-50% of true cases due to poor sensitivity 1, 3
• Performing "test of cure": Patients shed spores for weeks after successful treatment; repeat testing is not indicated 1, 2
• Repeat testing during same diarrheal episode: Only useful in outbreak situations or very high clinical suspicion with initial negative test 1
• Continuing slow-release medications during active diarrhea: Rapid intestinal transit prevents adequate absorption 2
• Failing to monitor electrolytes in severe disease: Hypomagnesemia and hypokalemia increase risk of toxic megacolon 2
• Using metronidazole as first-line therapy: No longer recommended due to inferior outcomes compared to vancomycin 4