What diagnostic test should be requested for a patient suspected of having Clostridium difficile infection?

Diagnostic Testing for Clostridium difficile Infection

Primary Recommendation

Request a multi-step diagnostic algorithm rather than a single test: either GDH screening followed by toxin A/B EIA confirmation, or NAAT followed by toxin EIA confirmation, performed only on unformed stool specimens from patients with ≥3 loose stools in 24 hours. 1, 2

When to Test

• Only test unformed (liquid/loose) stool specimens from symptomatic patients with ≥3 unformed stools in 24 hours with no obvious alternative explanation 1, 3
• Testing formed stool results in false positives and unnecessary antibiotic therapy 1, 3
• Clinical context supporting testing includes: recent antibiotic exposure, hospitalization, fever, abdominal pain, and leukocytosis 1, 3
• Do not exclude testing based on lack of traditional risk factors - community-acquired CDI occurs in 25-26% of cases without healthcare exposure or recent antibiotics 3

Recommended Testing Algorithms

Two-Step Approach (Preferred)

The most recent guidelines strongly recommend multi-step algorithms over single tests to balance sensitivity and specificity: 2, 3

1. Option 1: GDH screening → Toxin A/B EIA confirmation

   • GDH is highly sensitive but cannot differentiate toxigenic from non-toxigenic strains 1
   • Positive GDH results require toxin confirmation 1
   • This approach has 94% sensitivity, 99% specificity, 94% PPV, and 99% NPV 4

2. Option 2: NAAT screening → Toxin EIA confirmation

   • NAAT alone has excellent sensitivity (~95%) but may detect asymptomatic colonization 1, 5
   • Without pre-agreed institutional criteria for stool submission, toxin testing should arbitrate positive NAAT results 2
   • This prevents overdiagnosis and unnecessary treatment 5

3. Option 3: GDH → Toxin EIA → NAAT for discordant results

   • Three-step algorithm for maximum accuracy 2

Single Test Approaches (Not Recommended as Sole Method)

• Toxin A/B EIA alone is NOT recommended due to low sensitivity (32-98%, often 39-60%) resulting in significant false negatives 1, 4
• NAAT alone should only be used in patients with high clinical suspicion for CDI or when institutional pre-agreed criteria for testing are established 1
• The widespread use of NAAT as sole diagnostic method has led to overdiagnosis by identifying colonized patients rather than true infection 5

Special Circumstances

Patients with Ileus Unable to Produce Stool

• Request PCR testing of perirectal swabs as an acceptable alternative 1, 2
• Perirectal swabs demonstrate 95.7% sensitivity, 100% specificity, 100% PPV, and 99.1% NPV compared to stool testing 1, 2
• Use the same multi-step algorithms recommended for stool specimens when testing perirectal swabs 2

Tests to Avoid or Use Selectively

• Cell culture cytotoxicity assay (CCA): Reference standard but time-consuming (24-48 hours), requires specialized facilities, not practical for routine use 1
• Toxigenic culture: Slow turnaround time, may detect colonization (7% of asymptomatic hospitalized patients), reserved for epidemiological typing and strain characterization 1
• Repeat testing after initial negative: Only useful in selected cases with ongoing high clinical suspicion during epidemic situations 1

Critical Pitfalls to Avoid

• Never test formed stool - this generates false positives from colonization 1, 3
• Do not use toxin EIA as the sole test - sensitivity is inadequate (39-60%) and will miss significant cases 1, 4
• Avoid NAAT alone without confirmatory testing unless institutional criteria ensure appropriate patient selection - this leads to overdiagnosis, unnecessary treatment, and antimicrobial resistance 2, 5
• Do not test asymptomatic patients or test of cure - up to 7% of hospitalized patients are colonized without disease 1

Interpretation Considerations

• Positive predictive value of all tests depends heavily on disease prevalence - at 5% prevalence, PPV ranges from 0.28-0.77, but improves to 0.71-1.00 at 50% prevalence 1
• Clinical correlation is essential: interpret results in context of diarrhea severity, fever, abdominal pain, leukocytosis, creatinine, and serum lactate 1, 3
• NAAT positivity may represent colonization rather than active infection, which is why toxin confirmation improves clinical specificity 3, 5