How to treat a patient with positive C. difficile antigen and toxins but negative PCR?

Management of Patients with Positive C. difficile Antigen and Toxins but Negative PCR

Patients with positive C. difficile antigen and toxins but negative PCR should not receive antibiotic treatment as they likely represent colonization rather than active infection. 1

Understanding the Diagnostic Pattern

This unusual pattern (positive antigen + positive toxin + negative PCR) represents a diagnostic discrepancy that requires careful interpretation:

• GDH antigen: Indicates presence of C. difficile bacteria (both toxigenic and non-toxigenic strains)
• Positive toxin test: Suggests presence of toxins A/B in the stool
• Negative PCR: Indicates absence of toxin genes

Clinical Significance

The 2018 IDSA/SHEA guidelines provide important context for this scenario 1:

• Patients with positive toxin tests typically have worse clinical outcomes and higher mortality than those who are PCR-positive but toxin-negative
• Patients with positive toxin tests generally require treatment
• However, the negative PCR in this case contradicts the positive toxin result, suggesting a possible false positive toxin test

Recommended Approach

1. Verify test results and consider repeat testing:

   • Confirm that no laboratory error occurred
   • Consider repeating the PCR test, as it has higher sensitivity (86-94%) compared to toxin tests 1

2. Clinical assessment is crucial:

   • Evaluate for presence of significant diarrhea (≥3 loose stools in 24 hours)
   • Check for systemic symptoms (fever, leukocytosis)
   • Assess for alternative causes of diarrhea

3. Management decision:

   • If asymptomatic or mildly symptomatic: Observation without antibiotic treatment is appropriate
   • If severely symptomatic with no other explanation: Consider empiric treatment while awaiting repeat testing

Evidence Supporting Non-treatment

Recent evidence supports withholding antibiotics in patients with discordant test results:

• Polage et al. demonstrated that patients who were PCR-positive but toxin-negative had similar outcomes to those who tested negative by both methods 1
• A 2022 study showed that withholding antibiotics from PCR-positive/toxin-negative patients was non-inferior regarding mortality and diarrhea resolution 2

Potential Explanations for This Pattern

1. False positive toxin test: Toxin EIAs have variable specificity (84-97%) 1
2. False negative PCR: Less likely as PCR has high sensitivity (86-97%) 1
3. Laboratory error: Always consider this possibility with discordant results

Pitfalls to Avoid

• Overtreatment: Treating patients without true CDI exposes them to unnecessary antibiotics and potential side effects
• Misdiagnosis: Failing to consider alternative causes of diarrhea
• Isolation concerns: Even without treatment, patients may still require isolation precautions as they could be colonized with C. difficile

Follow-up Recommendations

• Monitor clinical symptoms closely
• If symptoms persist or worsen, reconsider diagnosis and treatment
• Consider alternative diagnoses for diarrhea (medication side effects, other pathogens, inflammatory bowel disease)

The discordant pattern of positive antigen and toxin with negative PCR is unusual and may represent a false positive toxin result. Given the higher reliability of PCR for detecting toxigenic C. difficile, and evidence that PCR-negative patients have better outcomes, observation without antibiotic treatment is the most appropriate approach in most cases.