What is the recommended workup and treatment for a patient with a history of antibiotic use, suspected of having Clostridium (C.) difficile infection, presenting with diarrhea, abdominal pain, and fever?

Workup for Suspected Clostridioides difficile Infection

For a patient with diarrhea, abdominal pain, fever, and recent antibiotic use, immediately test a single diarrheal stool specimen using nucleic acid amplification testing (NAAT) or a two-step algorithm starting with glutamate dehydrogenase (GDH) followed by toxin A/B enzyme immunoassay (EIA). 1

Clinical Criteria for Testing

Test only patients with:

• ≥3 unformed stools in 24 hours (stool that takes the shape of the container) 1
• Recent antibiotic use within the preceding 8-12 weeks 1
• Healthcare-associated diarrhea (onset >72 hours after hospital admission) 1, 2
• Accompanying symptoms: abdominal pain, fever, or leukocytosis 1

Critical caveat: Never test formed stool, as this results in false positives detecting asymptomatic colonization rather than active infection 1

Diagnostic Testing Algorithm

First-Line Testing Options (Choose One Approach):

Option 1: NAAT as Single Test

• NAAT for C. difficile toxin genes is highly sensitive and specific 1
• Warning: NAAT alone may increase detection of asymptomatic colonization, so reserve for patients with high clinical suspicion or use in two-step algorithms 1

Option 2: Two-Step Algorithm (Preferred by Most Guidelines)

1. Screen with GDH EIA (high sensitivity but cannot differentiate toxigenic from non-toxigenic strains) 1, 3
2. If GDH positive: Follow with toxin A/B EIA 1
3. If GDH positive but toxin negative: Consider reflex NAAT to detect toxigenic strains 1

Never use toxin A/B EIA alone due to relatively low sensitivity (60-90%), which can miss true infections 1, 2

Specimen Collection

Standard approach:

• Submit one diarrheal stool specimen 1
• Multiple specimens do not increase diagnostic yield 1
• Transport to laboratory within 2 hours 1

Special circumstance - Ileus or toxic megacolon:

• If patient cannot produce stool due to ileus, perirectal swabs provide an acceptable alternative (sensitivity 95.7%, specificity 100%) 1
• This is critical for severe CDI cases where stool production is impaired 1

Additional Workup Based on Severity

Laboratory Assessment

• Complete blood count: Look for leukocytosis (≥15,000 cells/mm³ indicates severe disease; ≥30,000 cells/mm³ warrants urgent evaluation even without diarrhea) 1
• Serum creatinine: Elevated levels (>1.5 mg/dL) indicate severe disease 1
• Serum lactate: Useful for defining severity 1
• Albumin: Hypoalbuminemia is often overlooked but clinically significant 2

Imaging (When Indicated)

Obtain CT imaging if:

• Signs of ileus or peritonitis are present 1
• Suspected toxic megacolon 1
• Severe abdominal distension 1

Endoscopy considerations:

• Less sensitive than stool toxin assays 2
• Reserve for cases requiring immediate diagnosis or when differential diagnosis includes other conditions 2
• Pseudomembranes on sigmoidoscopy/colonoscopy are nearly diagnostic 1
• Limitation: Isolated right-sided disease can be missed on sigmoidoscopy 1

Testing Pitfalls to Avoid

1. Never test asymptomatic patients - C. difficile colonizes healthy individuals, leading to unnecessary treatment 1
2. Do not send repeat specimens if first test is negative unless diarrhea persists, then submit 1-2 additional specimens 1
3. Do not test for "test of cure" - post-treatment testing is not indicated 1
4. Avoid testing patients on laxatives - ensure no alternative explanation for diarrhea 1

Risk Stratification Context

High-risk features requiring urgent evaluation:

• Advanced age (>65 years) 1
• Recent hospitalization 1, 2
• Multiple antibiotic exposures (hazard ratio increases from 2.5 for 2 antibiotics to 9.6 for ≥5 antibiotics) 4
• Proton pump inhibitor use (discontinue if no clear indication) 4, 5
• High-risk antibiotics: clindamycin, third-generation cephalosporins, fluoroquinolones, penicillins 5

Immediate Management Considerations During Workup

While awaiting test results:

• Discontinue inciting antibiotics immediately if clinically feasible 4, 5
• If continued antibiotics needed, switch to agents less associated with CDI (aminoglycosides, sulfonamides, tetracyclines) 5
• Discontinue proton pump inhibitors unless clear indication exists 4, 5
• Implement contact precautions and strict handwashing (alcohol-based sanitizers do not kill C. difficile spores) 1