Diagnostic Testing for Clostridioides difficile Infection
Use a multistep testing algorithm rather than any single test alone, with nucleic acid amplification testing (NAAT) either as part of a two-step approach or to arbitrate discordant results between glutamate dehydrogenase (GDH) and toxin enzyme immunoassay (EIA). 1
Patient Selection for Testing
Only test patients with ≥3 unformed stools in 24 hours who have not received laxatives and have no obvious alternative explanation for diarrhea. 1, 2
- Testing formed stool leads to false positives and unnecessary treatment 1
- Clinical context matters: recent antibiotic exposure and hospitalization increase pretest probability 1, 2
- Never test infants ≤12 months due to high asymptomatic colonization rates 2
- Do not test asymptomatic patients except for epidemiological studies 1, 3
Recommended Testing Algorithms
When Institutional Criteria for Stool Submission Exist:
Use NAAT alone OR a multistep algorithm (GDH plus toxin; GDH plus toxin arbitrated by NAAT; or NAAT plus toxin). 1, 2
When No Pre-Agreed Institutional Criteria Exist:
Use a stool toxin test as part of a multistep algorithm rather than NAAT alone to avoid detecting asymptomatic colonization. 1, 2
The preferred approach is:
- Screen with GDH EIA first (high sensitivity, detects all C. difficile strains) 2
- If GDH positive, perform toxin A/B EIA (choose assays with sensitivity in the upper range of published literature) 1
- If GDH positive but toxin negative, arbitrate with NAAT 1, 2
This three-step algorithm provides results for 85-92% of samples on the day of receipt 2
Understanding Test Characteristics
NAAT (PCR) Testing:
- Sensitivity: 93-94%, but cannot distinguish active infection from colonization 2
- Approximately 44-55% of NAAT-positive patients are toxin-negative, representing colonization rather than true infection 2
- Should not be used as standalone test in endemic settings due to low positive predictive value 2
Toxin EIA Testing:
- Sensitivity: 32-98%, Specificity: 84-100% 1
- Not recommended alone due to low sensitivity 1
- Positive toxin results correlate with worse outcomes: 7.6% complication rate, 8.4% mortality 2
- Toxin-negative/NAAT-positive patients have minimal complications: 0% complication rate, 0.6% mortality 2
GDH Testing:
- Sensitive but does not differentiate toxigenic from non-toxigenic strains 1
- Must be paired with confirmatory testing 1
- About 20% of C. difficile strains are non-toxigenic 1
Critical Testing Pitfalls to Avoid
Never repeat testing within 7 days during the same diarrheal episode—diagnostic yield is only 2% and increases false positives. 1, 3
- Never perform "test of cure"—>60% of successfully treated patients remain positive 3
- Do not test patients with ileus who cannot produce stool; consider perirectal swabs instead (sensitivity 95.7%, specificity 100%) 1
- Repeat testing only justified during epidemic situations or with very high ongoing clinical suspicion 1
Clinical Decision-Making Based on Results
For Toxin-Positive Patients:
- These represent true infections requiring treatment 2
- Significantly higher complication rates and longer diarrhea duration 2
- Treat with oral vancomycin 125 mg four times daily for 10 days 4 or fidaxomicin 5
For NAAT-Positive/Toxin-Negative Patients:
- Consider these "excretors" who pose infection control risk but generally do not require treatment 2
- Evaluate for alternative causes of diarrhea 2
- If severe illness present (high fever, WBC ≥15,000/mm³, rising creatinine, severe diarrhea), consider empiric treatment with oral vancomycin 125 mg four times daily while awaiting confirmatory results 2
For Persistent Symptoms After Treatment:
- Do not repeat testing—consider alternative diagnoses 3
- Post-infectious irritable bowel syndrome occurs in up to 25% of cases 3
- Evaluate for complications of severe/fulminant CDI requiring additional interventions 3
- Consider inflammatory bowel disease flare 3