How to treat a patient with Clostridioides difficile (C. difficile) infection who tests positive for the C. difficile antigen but negative for toxin B?

Management of C. difficile Antigen-Positive, Toxin B-Negative Results

For patients who test positive for C. difficile antigen (GDH) but negative for toxin B, treatment should generally NOT be initiated, as these patients likely represent colonization rather than true infection and have significantly lower complication rates (3% vs 39%) compared to toxin-positive patients. 1

Diagnostic Interpretation

• Antigen-positive (GDH-positive) but toxin-negative results indicate the presence of C. difficile bacteria but not active toxin production, which correlates with colonization rather than disease. 1, 2

• Patients who are PCR/antigen-positive but toxin-negative have markedly better outcomes: 0-0.6% mortality compared to 8.4-16.6% in toxin-positive patients, with complication rates of 0-3% versus 7.6-39%. 1, 2

• These patients should be considered "excretors" who pose an infection control risk but generally do not require antimicrobial treatment. 1, 2

Clinical Assessment Algorithm

Evaluate for high-risk features that might warrant treatment despite negative toxin:

• Severe leukocytosis (WBC >15,000/μL) or rising serum creatinine levels 1, 3

• Significant clinical symptoms: ≥3 unformed stools in 24 hours that conform to container shape, fever, severe abdominal pain 1, 2

• Recent antibiotic exposure within the past 8 weeks 2

• Absence of alternative explanations for diarrhea 1

Management Approach Based on Risk Stratification

Low-Risk Patients (Most Common Scenario)

• Do NOT initiate antibiotic therapy for C. difficile 1

• Implement contact precautions to prevent transmission to other patients 1, 3

• Discontinue inciting antibiotics if clinically feasible 1

• Evaluate for alternative causes of diarrhea (laxatives, tube feeds, other medications, viral gastroenteritis) 1

• Do NOT repeat C. difficile testing within 7 days of the initial test, as this has only 2% diagnostic yield and increases false-positive results 2, 3

High-Risk Patients (Severe Clinical Features Present)

• Consider empiric treatment with oral vancomycin 125 mg four times daily for 10 days while awaiting additional confirmatory testing 1, 3

• Alternative: Oral fidaxomicin 200 mg twice daily for 10 days (particularly if concerned about recurrence risk) 4

• Request additional testing with cell cytotoxicity neutralization assay (CCNA) or repeat toxin EIA to confirm true infection 1, 3

Important Clinical Pitfalls

• Testing formed stool can result in false-positive results that lead to unnecessary antibiotic therapy—only test unformed, diarrheal stools 5

• Do not test asymptomatic patients, as up to 7% of hospitalized patients are colonized with C. difficile without disease 5, 2

• Avoid using NAAT/PCR alone without toxin testing, as this detects colonization in 44-55% of positive results 2

• Multi-step algorithms (GDH plus toxin, arbitrated by NAAT when discordant) provide better clinical correlation than single tests 2

Infection Control Measures

• Maintain contact precautions regardless of treatment decision 1, 3

• These patients can transmit C. difficile to others even without active infection 1

Follow-Up Considerations

• Do NOT perform test of cure, as >60% of successfully treated patients remain C. difficile-positive 1, 2

• Consider discontinuing proton pump inhibitors if not absolutely necessary 1, 2

• Implement antimicrobial stewardship to reduce recurrence risk 1, 2