How should I diagnose and treat an adult who develops ≥ three watery stools in 24 hours after recent antibiotic exposure or hospitalization, suspecting Clostridioides difficile infection, including initial therapy, management of severe disease, recurrence, and infection control?

Clostridioides difficile Infection: Diagnosis and Management

For an adult with ≥3 watery stools in 24 hours after recent antibiotic exposure or hospitalization, test stool for C. difficile toxin using a two-step algorithm (GDH plus toxin or NAAT plus toxin), and if positive, initiate oral vancomycin 125 mg four times daily for 10 days as first-line therapy. 1, 2, 3

Diagnostic Approach

When to Suspect CDI

• Suspect C. difficile in any patient with ≥3 unformed stools in 24 hours who has received antibiotics or chemotherapy in the previous 4-6 weeks, or who developed diarrhea after hospitalization. 1, 2

• Recent antibiotic exposure is the strongest risk factor—one-third of colonized patients develop symptomatic infection within 2 weeks of antibiotic therapy. 1, 2

• Consider CDI even in patients with severe leukocytosis (≥30,000 cells/mm³) without diarrhea, abdominal pain, or recent antibiotic use. 1

• Importantly, CDI can present without diarrhea—suspect it in patients with rapid abdominal distention, constipation, or ileus, especially with multi-organ failure. 4 This atypical presentation can progress to toxic megacolon and carries high mortality.

Testing Algorithm

Only test patients with clinically significant diarrhea—do not test asymptomatic patients or those with formed stools, as this detects colonization rather than infection. 1, 5

Use a two-step testing algorithm: 1, 2, 5

• First step: GDH screening or NAAT (high sensitivity: 91-100%)
• Second step: Toxin confirmation (higher specificity: 98-99%)
• This approach balances sensitivity and specificity while avoiding false positives from asymptomatic colonization

Do not use toxin EIA alone—insufficient sensitivity (70-80%). 1, 5

Submit a single diarrheal stool specimen for testing. 1 If the first test is negative but fever, abdominal pain, and diarrhea persist despite discontinuing antibiotics, submit 1-2 additional specimens. 1

Do not perform repeat testing within 7 days during the same diarrheal episode. 1

Do not perform "test of cure"—patients may shed C. difficile spores for up to 6 weeks after successful treatment. 1, 5

Additional Diagnostic Considerations

• For severe illness with negative C. difficile toxin, obtain stool cultures for invasive enteropathogens (Campylobacter, Salmonella, Shigella, E. coli O157:H7). 1

• In patients with signs of ileus or peritonitis, transfer to hospital for urgent CT imaging. 1

• Endoscopy is less useful than toxin assays and can miss isolated right-sided disease. 1

Initial Treatment

First-Line Therapy

Oral vancomycin 125 mg four times daily for 10 days is first-line therapy for initial episodes, with clinical success rates of approximately 81%. 2, 3, 6

Discontinue the causative antibiotic if clinically feasible—continued antibiotic use significantly increases recurrence risk. 2, 5

Metronidazole is no longer recommended as first-line therapy for adults. 7, 8

Severe Disease Management

Define severe CDI as: 3, 6

• ≥10 unformed bowel movements per day, OR
• WBC ≥15,000 cells/mm³, OR
• Serum creatinine >1.5 times baseline

For severe CDI, use oral vancomycin 125 mg four times daily for 10 days. 5, 3

Fulminant disease (hypotension, septic shock, ileus, toxic megacolon) requires: 6, 4, 7

• Urgent surgical consultation with low threshold for total colectomy
• Aggressive supportive care including fluid resuscitation and electrolyte monitoring
• Consider vancomycin 500 mg four times daily orally PLUS metronidazole 500 mg IV every 8 hours
• If ileus present, consider vancomycin enemas (500 mg in 100 mL saline every 6 hours)

Monitor for complications: 5, 4

• Dehydration and electrolyte disturbances (especially hypokalemia and hypomagnesemia)
• Acute kidney injury
• Toxic megacolon
• Multi-organ failure

Critical Pitfall: Antimotility Agents

Antiperistaltic agents like loperamide are absolutely contraindicated in CDI—they worsen disease severity, mask symptoms, and precipitate toxic megacolon. 2 The mechanism involves trapping C. difficile toxins against the colonic wall, allowing deeper tissue damage while hiding clinical warning signs.

If symptomatic management is needed, use opioids or octreotide as alternatives. 2

Recurrent CDI

Recurrence occurs in 18-25% of patients within 4 weeks after successful initial treatment. 3, 6

For first recurrence: 6, 8

• Oral vancomycin 125 mg four times daily for 10 days, OR
• Fidaxomicin 200 mg twice daily for 10 days (superior sustained response rates: 70-72% vs. 57% with vancomycin) 6

For multiple recurrences (≥3 episodes): 5, 8, 9

• Fecal microbiota transplantation (FMT) is highly effective with success rates of approximately 90% 5
• FMT should be considered after appropriate antibiotic therapy for at least 3 episodes

Post-infectious irritable bowel syndrome can occur in 4.3% of patients more than 3 months after infection—distinguish this from true recurrence before retreating. 1, 5

Infection Control Measures

Handwashing with soap and water is mandatory—alcohol-based sanitizers do not inactivate C. difficile spores. 1, 2 Mechanical removal through friction and running water is the only effective hand hygiene method.

Implement contact precautions: 1, 2, 5

• Private room or cohort patients with CDI
• Gloves and gowns for all patient contact
• Continue precautions until diarrhea resolves

Environmental cleaning with sporicidal agents (bleach-based products) is essential. 1

Antibiotic stewardship is the key prevention strategy to decrease CDI rates. 8, 9

Common Pitfalls to Avoid

• Testing asymptomatic patients or those on laxatives—this detects colonization, not infection 1, 5
• Using toxin EIA alone—suboptimal sensitivity misses cases 1, 5
• Prescribing antimotility agents—can precipitate toxic megacolon 2
• Assuming CDI always presents with diarrhea—ileus and constipation presentations exist 4
• Continuing the causative antibiotic—dramatically increases recurrence risk 2, 5
• Using metronidazole as first-line therapy—no longer recommended due to resistance concerns 7, 8
• Performing test of cure—patients shed spores for weeks after successful treatment 1, 5
• Using alcohol-based hand sanitizers alone—ineffective against spores 1, 2