What is the initial step in a Clostridioides difficile (C-diff) workup?

C. difficile Workup: Initial Step

The initial step in a C. difficile workup is to confirm the patient has clinically significant diarrhea (≥3 unformed stools in 24 hours that take the shape of the container) with no obvious alternative explanation, then test ONLY unformed stool using a multistep diagnostic algorithm rather than any single test alone. 1, 2

Patient Selection Criteria (Critical First Step)

Before ordering any laboratory test, verify the following clinical criteria are met:

• Diarrhea definition: ≥3 unformed/loose stools in 24 hours with no laxative use within the preceding 48 hours 1, 2
• Stool consistency: Only test liquid or soft stools that conform to the shape of the container—reject formed stool specimens as these lead to false positives and unnecessary treatment 1, 3
• Clinical context: Recent antibiotic exposure, hospitalization within past 3 months, or hospital stay >72 hours increases suspicion 1
• Exclude alternative causes: Rule out laxative use, other enteropathogens, and non-infectious causes of diarrhea 1

Common pitfall: Testing asymptomatic patients or those with formed stools dramatically increases false-positive rates, leading to overdiagnosis of colonization rather than true infection. 1, 2

Recommended Diagnostic Algorithm

Use a multistep testing approach rather than NAAT/PCR alone, as single-step NAAT cannot distinguish active infection from asymptomatic colonization (which occurs in 44-55% of PCR-positive patients). 1, 2

Preferred Two-Step Algorithm:

1. First step: Glutamate dehydrogenase (GDH) enzyme immunoassay as initial screening test 1, 2, 3

   • High sensitivity (89-93%) for detecting C. difficile presence 1
   • If GDH negative → Report as negative (high NPV of 99.8%) 1, 4

2. Second step for GDH-positive specimens: Toxin A/B enzyme immunoassay (EIA) 1, 2

   • If toxin positive → Confirms active infection requiring treatment 2
   • If toxin negative → Proceed to third step

3. Third step for discordant results (GDH+/Toxin-): NAAT/PCR for arbitration 1, 2, 3

   • This approach provides results for 85-92% of samples same-day, with only 8-15% requiring the third step 1, 2

Alternative Algorithm (If Institutional Criteria Exist):

If your institution has pre-agreed criteria for appropriate stool submission, NAAT alone OR the multistep algorithm above may be used to maximize sensitivity. 1, 2

Clinical Interpretation Framework

Toxin-positive patients (GDH+/Toxin+):

• Represent true infection requiring antimicrobial treatment 2
• Have significantly worse outcomes: 7.6% complication rate, 8.4% mortality, longer diarrhea duration 2

PCR-positive but toxin-negative patients (GDH+/Toxin-/NAAT+):

• May represent colonization rather than active infection 2
• Have minimal complications: 0% complication rate in largest studies, 0.6% mortality 2
• Consider "excretors" who pose infection control risk but may not require treatment 2
• Clinical assessment crucial to rule out alternative diarrhea causes 2

Special Circumstances

Patients with ileus unable to produce stool:

• Perirectal swabs tested by PCR provide acceptable alternative 1, 3
• Performance: 95.7% sensitivity, 100% specificity, 100% PPV, 99.1% NPV 1, 3
• Use same multistep algorithms as for stool specimens 3

Severe illness presentation (high fever, significant leukocytosis, rising creatinine):

• Consider empiric treatment with oral vancomycin 125 mg four times daily while awaiting results 2
• Do not delay treatment for confirmatory testing in severely ill patients 2

Critical Testing Pitfalls to Avoid

• Never repeat testing within 7 days during the same diarrheal episode—this has only 2% diagnostic yield and increases false positives 1, 2, 5
• Never test infants ≤12 months due to high asymptomatic carriage rates 2
• Never perform test of cure after treatment, as >60% remain positive despite clinical resolution 2
• Never use NAAT alone in endemic settings without pre-agreed institutional criteria—low PPV leads to overdiagnosis of colonization 1, 2

Supporting Laboratory Tests

Beyond C. difficile testing, assess disease severity with:

• White blood cell count (leukocytosis suggests severe disease) 1
• Serum creatinine (rising levels indicate severity) 1, 2
• Serum lactate (elevated in severe cases) 1