What is the recommended treatment approach for a symptomatic patient with a negative Clostridioides difficile (C. diff) toxin test and a positive C. diff antigen test?

Management of Symptomatic Patient with Negative C. difficile Toxin and Positive C. difficile Antigen

Do not treat based on antigen positivity alone—use a nucleic acid amplification test (NAAT/PCR) to arbitrate the discordant result, then base treatment on clinical severity and the NAAT result, not the antigen alone. 1

Understanding the Discordant Result

A positive C. difficile antigen (GDH) with negative toxin represents an indeterminate result that requires further testing, not immediate treatment. 1

• GDH (antigen) positivity indicates the presence of C. difficile bacteria but does not confirm toxin production or active disease. 1
• Toxin negativity suggests either colonization without active infection or low toxin levels below the assay's detection threshold. 2, 1
• The three-step algorithm (GDH + toxin, arbitrated by NAAT when discordant) provides definitive results for 85-92% of samples on the day of receipt. 1

Immediate Diagnostic Step

Perform NAAT/PCR testing immediately to arbitrate this discordant result before making treatment decisions. 1

• The Infectious Diseases Society of America recommends using a multistep algorithm (GDH plus toxin, arbitrated by NAAT) rather than toxin testing alone. 2
• Do not repeat the toxin test within 7 days—the diagnostic yield is only 2% and increases false-positive results. 1
• Repeat testing should only be considered in epidemic situations or if symptoms worsen significantly. 1

Clinical Interpretation Based on NAAT Result

If NAAT is Positive (Toxin Negative/PCR Positive):

This likely represents colonization rather than active infection—patients in this category have outcomes similar to those without C. difficile. 2, 1

• Complication rate: 0% 1
• Mortality rate: 0.6% 1
• These patients had similar demographics, comorbidities, and clinical parameters to toxin-negative/PCR-negative patients. 2
• Treatment should be based on clinical severity, not the PCR result alone. 1

If NAAT is Also Negative:

Do not treat for C. difficile infection—investigate alternative causes of diarrhea. 1

• Consider celiac disease, protozoal infections (especially Giardia if symptoms persist beyond 7 days), inflammatory bowel disease, or medication-related diarrhea. 2, 1
• Evaluate for other enteric pathogens if colitis symptoms are present: Campylobacter jejuni, Salmonella, Shigella, and E. coli O157:H7. 2

Clinical Criteria That Justify Empirical Treatment (Regardless of Test Results)

Treat empirically if the patient has severe or fulminant disease while awaiting NAAT results. 2, 1

Severe Disease Indicators:

• White blood cell count ≥15,000 cells/mL 1, 3
• Serum creatinine >1.5 mg/dL 1, 3
• Fever >38.5°C with rigors 3
• Hemodynamic instability or septic shock 3
• Signs of peritonitis or ileus 3
• Elevated serum lactate 3
• Pseudomembranous colitis on endoscopy 3
• Colonic distension or wall thickening on imaging 3

Additional Clinical Factors Supporting Treatment:

• ≥3 unformed stools in 24 hours that conform to the shape of the container 1
• Recent antibiotic exposure (strong risk factor for true CDI) 1
• Substantial delay in laboratory confirmation (>48 hours) 1

Treatment Recommendations If Severe Disease Present

For severe/fulminant disease, initiate oral vancomycin 125 mg four times daily immediately while awaiting confirmatory testing. 1, 3

• For fulminant CDI with ileus, increase vancomycin to 500 mg four times daily orally PLUS vancomycin 500 mg in 100 mL normal saline every 6 hours as a retention enema. 1, 3
• Fidaxomicin 200 mg twice daily for 10 days is an alternative for severe disease. 3
• Discontinue the causative antibiotic immediately if clinically feasible—continued antibiotic use significantly increases CDI recurrence risk. 1, 3, 4
• If ongoing antibiotic therapy is required, switch to agents less frequently associated with CDI: parenteral aminoglycosides, sulfonamides, macrolides, vancomycin, or tetracycline/tigecycline. 2, 4

Management If Non-Severe Disease

For non-severe disease with toxin-negative/PCR-positive results, withhold CDI-specific treatment and observe clinically. 2, 1

• These patients have complication and mortality rates similar to patients without C. difficile. 2, 1
• Focus on supportive care and discontinuing unnecessary antibiotics and proton pump inhibitors. 1, 3
• Monitor for clinical deterioration that would warrant treatment. 1

Additional Diagnostic Considerations

Flexible sigmoidoscopy may be helpful when there is high clinical suspicion despite negative stool assays. 2

• Endoscopy should be used sparingly and is most useful when stool tests are negative but clinical suspicion remains high. 2
• Colonoscopy may be hazardous in fulminant colitis due to increased perforation risk. 2
• CT imaging showing colonic wall thickness >4 mm with nodularity, accordion sign, peri-colonic stranding, or unexplained ascites supports the diagnosis. 2

Critical Pitfalls to Avoid

• Never use parenteral vancomycin for CDI—it is not excreted into the colon and is ineffective. 3
• Avoid antimotility agents and opiates—they may precipitate toxic megacolon. 3
• Do not perform "test of cure" after treatment—clinical improvement is the primary measure of success. 3
• Do not treat asymptomatic carriers—treatment is indicated only for symptomatic patients. 5
• Discontinue unnecessary proton pump inhibitors—they increase CDI risk and recurrence. 1, 4