Diagnosis and Management of Chronic Diarrhea with Indeterminate Clostridioides difficile Toxin Test Results

Diagnostic Approach for Indeterminate Results

The Infectious Diseases Society of America recommends not repeating the test within 7 days and basing the treatment decision on rigorous clinical evaluation, using a multi-step testing algorithm to arbitrate discordant results 1, 2
For an initial result of GDH positive/toxina negative (indeterminate), a nucleic acid amplification test (NAAT/PCR) should be performed to arbitrate the discordant result, although this specific recommendation is from Praxis Medical Insights, a similar approach is supported by other guidelines 3
The three-step algorithm (GDH + toxin, arbitrated by NAAT when discordant) provides results for approximately 85-92% of samples on the day of receipt, according to Praxis Medical Insights 3

Patients who are positive for both genetic testing (PCR) and toxin have significantly worse outcomes: complication rate of 7.6%, mortality of 8.4%, and longer duration of diarrhea, as reported by Praxis Medical Insights 3
Patients positive on genetic testing but negative for toxin have minimal outcomes: complication rate of 0%, mortality of 0.6%, and results similar to patients without C. difficile, according to Praxis Medical Insights 3
The presence of toxins correlates with true clinical disease that requires antimicrobial intervention, as stated by Praxis Medical Insights 3

The American College of Gastroenterology suggests that patients with ≥3 unformed stools in 24 hours that conform to the shape of the container should be considered for treatment 3
Recent exposure to antibiotics (a strong risk factor for true ICD) should also be considered for treatment, as recommended by Praxis Medical Insights 3
Severe disease present, such as high fever, significant leukocytosis (≥15,000 cells/mL), serum creatinine >1.5 mg/dL, or severe diarrhea, should be treated, according to Praxis Medical Insights 3, 4

The Infectious Diseases Society of America recommends not repeating tests unnecessarily within 7 days during the same episode of diarrhea - the diagnostic yield is only 2% and increases false-positive results 1, 2, 5
Repeat testing should only be considered in epidemic situations or in patients with high clinical suspicion whose symptoms worsen, as stated by the Infectious Diseases Society of America 1, 2

For severe/fulminant disease, consider empirical treatment with oral vancomycin 125 mg four times a day while awaiting toxin test results, as recommended by Praxis Medical Insights 3
Severe disease justifies treatment even before confirmatory test results are available, according to Praxis Medical Insights 3
If there is a substantial delay in laboratory confirmation (>48 hours) or for fulminant ICD, initiate empirical therapy, as suggested by Praxis Medical Insights 4

Vancomycin oral 125 mg four times a day for 10 days or fidaxomicina oral 200 mg twice a day for 10 days, as recommended by Praxis Medical Insights 4
For fulminant ICD, vancomycin oral 500 mg four times a day; if ileus is present, add vancomycin rectal 500 mg in 100 mL of normal saline every 6 hours as a retention enema, according to Praxis Medical Insights 4
Discontinue the causative antibiotic as quickly as possible to reduce the risk of ICD recurrence, as recommended by Praxis Medical Insights 4

In patients with multiple negative tests for C. difficile and persistent chronic diarrhea, consider evaluating other causes of chronic diarrhea, such as celiac disease, protozoal infections, or inflammatory bowel disease, as suggested by the European Society of Gastrointestinal Endoscopy 6
Consider discontinuing unnecessary proton pump inhibitors to reduce the risk of recurrence, as recommended by Praxis Medical Insights 3