What is the treatment approach for an adult with diarrhea of uncertain cause, suspected to be Clostridioides difficile (C. diff)?

Management of Adult Diarrhea with Uncertain C. difficile Status

Test for C. difficile immediately in any adult with diarrhea (≥3 unformed stools in 24 hours) who has received antibiotics, is hospitalized, or has healthcare exposure, but do NOT delay empiric treatment if the clinical picture suggests severe disease. 1

Immediate Diagnostic Approach

Who Should Be Tested for C. difficile

• Test only symptomatic patients with diarrhea (≥3 unformed stools in 24 hours) who have risk factors including recent antibiotic use, healthcare exposure, older age, or immunosuppression 1
• Never test asymptomatic patients or perform "test of cure" after treatment, as up to 56% of treated patients shed C. difficile asymptomatically for up to 6 weeks 1
• Testing formed stool is inappropriate and should be avoided 1

Optimal Testing Strategy

• Use multistep algorithms combining PCR for toxin genes with toxin enzyme immunoassay (sensitivity 0.68-1.00, specificity 0.92-1.00) or single-step PCR on liquid stool for best diagnostic performance 1
• A positive nucleic acid amplification test (NAAT) alone in the appropriate clinical context is reasonable for diagnosis 1
• Stool culture is the most sensitive test but less specific than cytotoxicity assay 2

Critical Red Flags Requiring Immediate Action

Obtain complete blood count, metabolic panel, C-reactive protein, and blood cultures if fever is present to assess for severe disease 3

Signs of severe/fulminant C. difficile infection requiring urgent intervention include:

• Leukocytosis ≥15 × 10⁹ cells/L or leukocytosis with left shift 1, 3
• Creatinine ≥1.5 mg/dL 1
• Hypotension, shock, ileus, or megacolon 1, 4
• Abdominal pain with fever and marked leukocytosis 3

Empiric Treatment While Awaiting Test Results

When to Start Empiric C. difficile Treatment

Do NOT delay treatment while awaiting stool culture results if clinical suspicion is high 1

Start empiric treatment immediately if:

• Strong clinical suspicion (recent antibiotics + diarrhea + leukocytosis) 3
• Severe disease indicators present (see above) 1, 4
• Healthcare-associated diarrhea with systemic toxicity 1

Initial Empiric Antibiotic Selection

For mild-to-moderate suspected C. difficile: Start oral vancomycin 125 mg four times daily 5

• Metronidazole is no longer first-line for initial episodes but remains appropriate for mild disease when vancomycin is unavailable 1, 6
• For severe disease (WBC ≥15,000 or creatinine ≥1.5 mg/dL): Use oral vancomycin 125 mg four times daily 1, 5
• For fulminant disease: Use high-dose oral vancomycin 500 mg four times daily PLUS IV metronidazole 500 mg every 8 hours 4, 5

Critical Management Steps

• Discontinue the causative antibiotic immediately if clinically feasible 4
• Avoid antiperistaltic agents (loperamide, diphenoxylate) in suspected C. difficile as they may precipitate toxic megacolon 1, 7
• Provide supportive care with IV fluid resuscitation for dehydration 3, 8

If C. difficile Testing Returns Negative

Broaden Differential and Adjust Treatment

• Send comprehensive stool studies including bacterial culture (Salmonella, Shigella, Yersinia, Campylobacter), fecal lactoferrin or leukocytes, and consider parasitic testing 3, 8
• Consider CT abdomen/pelvis with contrast to evaluate for bowel wall thickening, complications, or alternative diagnoses 3
• Discontinue C. difficile-directed antibiotics if testing is negative and clinical picture does not support C. difficile 8

Alternative Diagnoses to Consider

• Viral gastroenteritis (most common cause of acute diarrhea) 7
• Other bacterial pathogens requiring specific treatment (Shigella, Campylobacter, Salmonella) 8
• Inflammatory bowel disease flare 1
• Medication-related diarrhea 9

If C. difficile Testing Returns Positive

Confirm Appropriate Treatment Duration

• Standard treatment duration is 10 days for initial episode 5
• Continue oral vancomycin 125 mg four times daily for non-severe disease 5
• For severe disease, continue vancomycin at appropriate dose based on severity 4, 5

Special Considerations

If patient has inflammatory bowel disease with acute severe colitis AND C. difficile is diagnosed: Treat with oral vancomycin 500 mg four times daily for 10 days AND continue corticosteroids 1

• Monitor for systemic absorption in patients with inflammatory intestinal mucosa or renal insufficiency, as clinically significant serum vancomycin concentrations can occur 5
• In patients >65 years, monitor renal function during and after treatment due to increased nephrotoxicity risk 5

Monitoring for Treatment Failure

If no improvement within 48-72 hours or clinical deterioration occurs:

• Obtain CT imaging to assess for complications (toxic megacolon, perforation, severe colitis) 3, 4
• Escalate to fulminant disease protocol if indicated 4
• Obtain urgent surgical consultation if peritonitis, perforation, or megacolon develops 3, 4

Common Pitfalls to Avoid

• Never test asymptomatic patients or use C. difficile testing as "test of cure" 1
• Never use antiperistaltic agents when C. difficile is suspected 1, 7
• Never delay empiric treatment in severely ill patients while awaiting test results 1, 4
• Never use metronidazole alone for severe C. difficile infection 1, 4
• Never continue empiric C. difficile treatment if testing is negative and alternative diagnosis is identified 8