GDH-Positive, Toxin A/B-Negative Results: Further Testing Required Before Treatment Decision
A patient with positive C. difficile GDH antigen and negative toxin A/B should NOT be treated immediately but requires confirmatory testing with either NAAT (PCR) or toxigenic culture, as this discordant result represents an indeterminate state that could indicate either non-toxigenic colonization (~20% of C. difficile strains) or true toxigenic infection with toxin levels below the EIA detection threshold. 1
The Diagnostic Dilemma of GDH+/Toxin-Negative Results
The core issue is that GDH cannot differentiate between toxigenic and non-toxigenic C. difficile strains 1. When you encounter this discordant pattern:
- Approximately 63% of GDH+/toxin-negative specimens harbor toxigenic C. difficile when subjected to culture and confirmatory testing 2
- The remaining ~37% represent either non-toxigenic colonization or false-positive GDH results 2
- This means treatment without confirmation would result in unnecessary antibiotics in over one-third of cases 1
The Three-Step Algorithm: What Guidelines Recommend
European guidelines explicitly state that GDH-positive but toxin-negative samples require testing with a reference method as a third step 1. The recommended approach:
Step 1: GDH Screening (Already Done - Positive)
- High sensitivity (89-93%) but cannot confirm infection alone 1, 3
- Negative predictive value of 100% in most studies 3
Step 2: Toxin A/B EIA (Already Done - Negative)
- Your result shows no detectable toxin by EIA 1
- However, toxin EIA has suboptimal sensitivity (32-98%), missing many true cases 1
Step 3: Confirmatory Testing (Required Now)
You must perform ONE of the following:
- NAAT/PCR for toxin genes (tcdB): Sensitivity 80-100%, specificity 87-99% 1, 4
- Toxigenic culture with cytotoxicity assay: Gold standard but slower (24-48 hours) 1
Clinical Context Matters for Interpretation
While awaiting confirmatory results, assess clinical probability:
High suspicion for true CDI (consider empiric treatment while testing): 1, 5
- ≥3 unformed stools in 24 hours
- Recent antibiotic exposure (within 8 weeks)
- Hospitalization or healthcare facility exposure
- Fever, leukocytosis, abdominal pain
- Elevated creatinine or lactate
Lower suspicion (await results before treating): 5
- Formed stool (should not have been tested)
- No recent antibiotic exposure
- Chronic diarrhea without acute change
- Alternative diagnosis more likely
Performance Data Supporting This Approach
The two-step algorithm (GDH → toxin EIA) followed by confirmatory testing achieves:
- Sensitivity: 94% 4
- Specificity: 99% 4
- Negative predictive value: 99% 4
- Results available within 4 hours for 92% of specimens 6
In contrast, stopping at toxin EIA alone misses 61% of true CDI cases (sensitivity only 39%) 4.
Critical Pitfalls to Avoid
- Never treat based on GDH alone - this leads to overtreatment of non-toxigenic colonization 1
- Do not assume toxin-negative means no infection - toxin EIA has poor sensitivity 1, 4
- Do not test asymptomatic patients or formed stool - this generates false positives requiring unnecessary workup 1, 5
- Avoid repeat testing within 7 days unless clinical status changes significantly 7
If NAAT/PCR is Positive
- Treat as CDI if clinically symptomatic with ≥3 unformed stools 1, 5
- Recognize this confirms presence of toxigenic strain 7