Next Best Step for Indeterminate C. Diff Test Result
When a C. difficile test returns as indeterminate (typically GDH positive/toxin negative), perform a nucleic acid amplification test (NAAT/PCR) to arbitrate the discordant result. 1, 2
Understanding the Indeterminate Result
An indeterminate result most commonly occurs in multi-step testing algorithms when:
- GDH (glutamate dehydrogenase) is positive - indicating C. difficile organism is present 2
- Toxin A/B enzyme immunoassay (EIA) is negative - indicating no detectable toxin 1
This discordant pattern requires arbitration because it cannot distinguish between colonization and active infection 1, 2.
Immediate Action: Arbitration Testing
Perform NAAT/PCR testing on the same specimen to resolve the discordant result 1, 2. This three-step algorithm (GDH + toxin, arbitrated by NAAT when discordant) provides definitive results for approximately 85-92% of samples 1, 2.
Clinical Decision-Making Based on Results
If NAAT Positive AND Toxin Positive:
- Treat immediately - these patients have true infection with significantly worse outcomes 1, 2
- Complication rate: 7.6%, mortality: 8.4%, longer duration of diarrhea 1, 2
- First-line treatment: Oral vancomycin 125 mg four times daily for 10 days OR fidaxomicin 200 mg twice daily for 10 days 1
If NAAT Positive BUT Toxin Negative:
- Generally do NOT treat - these patients represent colonization, not active infection 1, 2
- Complication rate: 0%, mortality: 0.6%, outcomes similar to patients without C. difficile 1, 2
- Consider alternative causes of diarrhea 2
- Exception: Treat if severe clinical illness is present (see below) 1
When to Treat Empirically While Awaiting Results
Consider empirical treatment with oral vancomycin 125 mg four times daily if ANY of the following are present 1, 3:
- Severe disease markers: WBC ≥15,000 cells/mL, serum creatinine >1.5 mg/dL, high fever 1, 3
- Fulminant disease: Hypotension, shock, ileus, megacolon 1
- Significant clinical symptoms: ≥3 unformed stools in 24 hours conforming to container shape 1, 2
- Recent antibiotic exposure - strong risk factor for true CDI 1, 2
- Substantial laboratory delay (>48 hours for results) 1
Critical Pitfalls to Avoid
Do NOT Repeat Testing Within 7 Days
Avoid repeat testing during the same diarrheal episode - diagnostic yield is only 2% and increases false-positive results 4, 2. The negative predictive value of highly sensitive tests exceeds 99% 4.
Exception for repeat testing: Only consider if 4:
- Clinical symptoms worsen significantly 4
- Epidemic setting with high CDI acquisition rates 4
- Recurrence after successful treatment and symptom resolution 4
Do NOT Test Asymptomatic Patients
Never test for test-of-cure - >60% of successfully treated patients remain C. difficile positive 4, 2.
Do NOT Test Infants ≤12 Months
Colonization rates exceed 40% in this age group, making testing unreliable 4, 2.
Supportive Management
Regardless of treatment decision 1, 5:
- Discontinue the offending antibiotic as quickly as possible 1, 5
- Stop unnecessary proton pump inhibitors to reduce recurrence risk 1, 2
- Implement contact precautions for infection control 3
If Multiple Tests Remain Negative
For patients with persistent diarrhea and multiple negative C. difficile tests, investigate alternative causes 1: