What is the initial treatment for a patient with Clostridioides (C.) difficile infection?

Treatment of Clostridioides difficile Infection

Oral vancomycin 125 mg four times daily for 10 days is the first-line treatment for initial C. difficile infection, regardless of severity, with fidaxomicin 200 mg twice daily for 10 days as an equally effective alternative that reduces recurrence risk. 1, 2

Initial Episode Treatment Algorithm

Non-Severe Disease

• Oral vancomycin 125 mg four times daily for 10 days is the cornerstone first-line therapy, having demonstrated superiority over metronidazole in clinical outcomes 1
• Fidaxomicin 200 mg orally twice daily for 10 days is an equally recommended alternative, particularly valuable for elderly patients or those with multiple comorbidities who face higher recurrence risk (15.4% vs 25.3% with vancomycin) 1, 3
• Metronidazole 500 mg three times daily for 10 days should only be considered when vancomycin or fidaxomicin are unavailable, and only for initial mild-moderate episodes—it is associated with longer time to symptom improvement and higher failure rates in patients >60 years, with fever, hypoalbuminemia, or ICU stay 2

Severe or Fulminant Disease

• Oral vancomycin 125 mg four times daily remains the foundation, though doses may be increased to 500 mg four times daily in fulminant cases 1, 2
• Add intravenous metronidazole 500 mg every 8 hours as adjunctive therapy when ileus is present or in fulminant disease, since IV vancomycin does not reach the colon 1, 2
• Add rectal vancomycin 500 mg in 100 mL normal saline every 6 hours as retention enema if ileus prevents oral medication from reaching the colon 4, 2
• Obtain immediate surgical consultation for patients with WBC ≥25,000 cells/mL, lactate ≥5 mmol/L, ileus, toxic megacolon, or peritoneal signs—early intervention reduces mortality 1, 2

Recurrent Infection Treatment

First Recurrence

• Use oral vancomycin 125 mg four times daily for 10-14 days if metronidazole was used initially 1
• Use tapered and pulsed vancomycin regimen if standard vancomycin was used for the initial episode: 125 mg four times daily for 10-14 days, then twice daily for 7 days, then once daily for 7 days, then every 2-3 days for 2-8 weeks 4, 1
• Fidaxomicin 200 mg twice daily for 10 days is the preferred option for first recurrence, demonstrating lower recurrence rates than vancomycin 4, 1

Multiple Recurrences (≥2 episodes)

• Fecal microbiota transplantation (FMT) is strongly recommended after failure of appropriate antibiotic treatments for at least two recurrences, with clinical resolution rates of 87-92% compared to 40-50% with antibiotics alone 5, 4, 1
• Administer oral vancomycin 125 mg four times daily for 4-10 days as lead-in therapy before FMT to reduce bacterial load 1
• FMT efficacy is highest with colonic instillation (80-100% success) compared to upper GI routes (77-94%), and may require 2-3 administrations for optimal response 5
• Bezlotoxumab (monoclonal antibody against C. difficile toxin B) reduces recurrent CDI and is particularly beneficial for patients with the 027 epidemic strain, immunocompromised status, or severe CDI presentation 4

Critical Supportive Measures

Antibiotic Management

• Discontinue the inciting antibiotic immediately—this is the single most important intervention beyond specific CDI treatment, as failure to stop offending antibiotics is associated with CDI recurrence 4, 1, 2
• If continued antibiotics are necessary for another infection, switch to lower-risk agents: parenteral aminoglycosides, sulfonamides, macrolides, or tetracyclines/tigecycline 1
• Avoid high-risk antibiotics: clindamycin, third-generation cephalosporins, penicillins, and fluoroquinolones are strongly associated with CDI development and recurrence 1

Supportive Care

• Provide intravenous fluid resuscitation, electrolyte replacement, and albumin supplementation for patients with severe CDI 4
• Avoid antimotility agents such as loperamide and opiates, especially in the acute setting, as they may worsen outcomes 2

Common Pitfalls to Avoid

• Never use IV vancomycin for CDI treatment—it is not excreted into the colon and has no efficacy against CDI; oral vancomycin must be used 1
• Do not use metronidazole as monotherapy for severe disease or any recurrent episode—it has inferior outcomes and risk of cumulative, potentially irreversible neurotoxicity with repeated or prolonged courses 4, 1, 2
• Do not delay surgical consultation in fulminant disease—mortality increases significantly with delayed intervention 1
• Assess disease severity before selecting treatment: severe CDI is characterized by WBC ≥15,000 cells/mL, serum creatinine >1.5 mg/dL, fever, rigors, hemodynamic instability, and signs of peritonitis or ileus 2

Secondary Prophylaxis Considerations

• For patients requiring continued systemic antibiotics after CDI treatment, consider low-dose vancomycin 125 mg once daily or fidaxomicin 200 mg once daily while systemic antibiotics are administered 5
• Factors influencing this decision include time from previous CDI treatment, number of previous episodes, severity of previous episodes, and underlying patient frailty 5