What is the best diagnostic approach for a suspected Clostridioides (C.) difficile infection in an adult patient with a history of antibiotic use, presenting with diarrhea, abdominal pain, and fever?

Diagnostic Approach for Suspected C. difficile Infection

For an adult patient with diarrhea, abdominal pain, fever, and recent antibiotic use, use a two-step diagnostic algorithm starting with glutamate dehydrogenase (GDH) enzyme immunoassay followed by toxin A/B EIA if GDH is positive, or alternatively use nucleic acid amplification testing (NAAT) followed by toxin confirmation. 1, 2, 3

Clinical Criteria Before Testing

Only test patients who meet ALL of the following criteria:

• ≥3 unformed stools in 24 hours that conform to the container shape 1, 2, 4
• Recent antibiotic exposure within the preceding 8-12 weeks (or chemotherapy within 4-6 weeks) 2, 3
• Accompanying symptoms such as abdominal pain, fever, or leukocytosis 2

Do NOT test formed stools - this detects asymptomatic colonization rather than active infection and leads to false positives 2

Recommended Testing Algorithms

Primary Approach: Two-Step Algorithm

The preferred diagnostic strategy balances sensitivity and specificity: 1, 2, 3

1. First step: GDH enzyme immunoassay (screening test)
2. If GDH positive: Toxin A/B EIA
3. If GDH positive but toxin negative: Consider NAAT for arbitration in high clinical suspicion cases

This approach increases positive predictive value compared to single-step testing and avoids overdiagnosis of colonization 1

Alternative Approach: NAAT-Based Testing

NAAT alone is highly sensitive but may detect asymptomatic colonization (up to 7% of hospitalized patients), so it should be reserved for patients with high clinical suspicion or used with toxin confirmation 1, 2, 5

Stand-alone toxin EIA is NOT recommended due to insufficient sensitivity 3

Specimen Collection

• Submit only ONE diarrheal stool specimen - multiple specimens do not increase diagnostic yield (only ~2% additional detection) 1, 2, 5
• Transport to laboratory within 2 hours 1, 2
• Do NOT perform repeat testing within 7 days during the same diarrheal episode 1, 5

Severity Assessment

Obtain the following laboratory tests to stratify severity: 2

• Complete blood count: Leukocytosis ≥15,000 cells/mm³ indicates severe disease 2
• Serum creatinine: Elevated levels suggest severe infection 2, 5
• Serum lactate: Useful for defining severity 2

Imaging Considerations

Obtain CT imaging of abdomen/pelvis if: 2

• Signs of ileus or peritoneal irritation are present
• Suspected toxic megacolon
• Severe abdominal pain with leukocytosis but no diarrhea (some patients present with ileus rather than diarrhea) 1

Consider endoscopy when immediate diagnosis is required or differential diagnosis includes other conditions 2

High-Risk Features Requiring Urgent Evaluation

The following factors increase risk and warrant expedited testing: 2, 3

• Advanced age (>65 years)
• Recent hospitalization or healthcare-associated diarrhea
• Multiple antibiotic exposures
• Proton pump inhibitor use
• Immunocompromised status

Management While Awaiting Results

For patients with strong clinical suspicion of SEVERE C. difficile infection, consider empirical therapy while awaiting test results 5

Immediately discontinue the inciting antibiotic if clinically feasible - continued antibiotic use significantly increases recurrence risk 3, 5

If antibiotics must be continued for another infection, switch to agents less frequently associated with C. difficile infection 5

Critical Pitfalls to Avoid

• Never use antiperistaltic agents (loperamide) - they are absolutely contraindicated as they worsen disease severity, mask symptoms, and precipitate toxic megacolon by trapping toxins against the colonic wall 3
• Do not test asymptomatic patients - this only detects colonization 1
• Avoid testing patients on laxatives or those with alternative explanations for diarrhea 5, 4
• Do not use alcohol-based hand sanitizers - only soap and water with mechanical friction removes C. difficile spores 3