What is the recommended treatment for a patient who is positive for Clostridioides difficile (C. difficile) toxin and not antigen, indicating an active C. difficile infection?

Treatment for C. difficile Toxin-Positive, Antigen-Negative Patient

Treat this patient with oral vancomycin 125 mg four times daily for 10 days, as toxin positivity indicates active C. difficile infection requiring antibiotic therapy regardless of antigen status. 1, 2, 3

Diagnostic Interpretation

• Toxin positivity is the critical determinant for treatment decisions, as it indicates active toxin production and true infection rather than colonization. 1

• Patients who are toxin-positive have significantly higher rates of complications (39% vs 3%), mortality (16.6% vs 9.7%), and recurrence compared to those who are PCR-positive but toxin-negative. 1

• The presence of toxins A and B correlates more strongly with disease severity and clinical outcomes than PCR or antigen positivity alone. 1

Treatment Algorithm Based on Disease Severity

Assess Disease Severity First

Non-severe CDI (most common presentation):

• Stool frequency < 4 times daily
• White blood cell count < 15 × 10^9/L
• No signs of severe colitis 2

Severe CDI indicators:

• Fever, rigors, hemodynamic instability
• Signs of peritonitis or ileus
• Marked leukocytosis (WBC ≥ 15 × 10^9/L)
• Rising serum creatinine or elevated lactate
• Pseudomembranous colitis on endoscopy 2

Treatment Recommendations

For non-severe CDI:

• Oral vancomycin 125 mg four times daily for 10 days is the preferred first-line treatment. 2, 3
• Alternative: Oral metronidazole 500 mg three times daily for 10 days (though vancomycin is now generally preferred). 4, 2

For severe CDI:

• Oral vancomycin 125 mg four times daily for 10 days (doses up to 500 mg have been used in fulminant cases, though evidence is limited). 4, 2, 3
• Fidaxomicin 200 mg twice daily for 10 days is an alternative that may reduce recurrence risk, particularly in elderly patients with multiple comorbidities or those receiving concomitant antibiotics. 4

Critical Management Steps

Discontinue inciting antibiotics immediately if possible, as continued antibiotic use significantly increases the risk of CDI recurrence. 4, 1

Implement contact precautions with soap and water handwashing (not alcohol-based sanitizers, which do not kill C. difficile spores). 4

Avoid antimotility agents (such as loperamide) and opiates, as these can prevent toxin clearance and worsen infection. 2

Consider discontinuing proton pump inhibitors if not medically necessary, as they are associated with increased CDI risk. 4, 2

Special Considerations and Pitfalls

• Do not repeat testing within 7 days during the same diarrheal episode, as this has only 2% diagnostic yield and increases false-positive results. 1, 5

• Do not perform test of cure, as >60% of patients remain C. difficile-positive even after successful treatment. 1

• Monitor renal function in patients >65 years of age, as oral vancomycin can cause nephrotoxicity even though systemic absorption is typically minimal. 3

• Patients with inflammatory bowel disorders or severe colitis may have significant systemic absorption of oral vancomycin and require serum concentration monitoring. 3

Recurrent or Refractory Disease

For second or subsequent recurrence:

• Vancomycin 125 mg four times daily orally for at least 10 days, OR
• Fidaxomicin 200 mg twice daily for 10 days 2

For multiple recurrences after appropriate antibiotic treatment:

• Fecal microbiota transplantation (FMT) is an effective option. 4

For fulminant colitis not responding to medical therapy:

• Early surgical consultation is warranted
• Consider total colectomy or diverting loop ileostomy with colonic lavage 4, 2

Adjunctive therapy with bezlotoxumab (monoclonal antibody against toxin B) may prevent recurrences in high-risk patients, including those with the 027 epidemic strain, immunocompromised patients, or those with severe CDI. 4