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

Antibiotic Treatment for Confirmed C. difficile Infection

For initial nonsevere C. difficile infection, oral vancomycin 125 mg four times daily for 10 days or fidaxomicin 200 mg twice daily for 10 days are the preferred first-line treatments, with metronidazole no longer recommended as first-line therapy. 1, 2, 3

Initial Episode: Nonsevere CDI

Nonsevere disease is defined by white blood cell count ≤15,000 cells/μL and serum creatinine <1.5 mg/dL. 1

First-Line Options:

• Oral vancomycin 125 mg four times daily for 10 days is the preferred treatment, demonstrating superior clinical outcomes compared to metronidazole 1, 4, 2
• Fidaxomicin 200 mg twice daily for 10 days is an equally acceptable first-line option, particularly for patients at high risk for recurrence (elderly, multiple comorbidities) 1, 4, 3
• Extended fidaxomicin regimen (200 mg twice daily for 5 days, then once every other day for 20 days) may be considered for high-risk patients 1

Alternative Only When Above Unavailable:

• Metronidazole 500 mg three times daily for 10-14 days should only be used if vancomycin and fidaxomicin are unavailable, due to inferior outcomes and cumulative neurotoxicity risk with prolonged use 1, 4

Initial Episode: Severe/Fulminant CDI

Severe disease is characterized by white blood cell count >15,000 cells/μL, serum creatinine ≥1.5 mg/dL, or other clinical markers of severity. 1

Fulminant disease includes hypotension/shock, ileus, or megacolon. 1

Treatment for Severe CDI:

• Oral vancomycin 125 mg four times daily for 10 days remains the standard approach 1, 4
• Vancomycin is superior to metronidazole in severe disease with high-quality evidence 4

Treatment for Fulminant CDI:

• Oral vancomycin 500 mg four times daily (higher dose) by mouth or nasogastric tube 1, 4
• Add intravenous metronidazole 500 mg every 8 hours in conjunction with oral vancomycin, particularly if ileus is present 1, 4
• Consider rectal vancomycin instillation (500 mg in 100 mL normal saline every 4-12 hours) if ileus prevents oral administration 1
• Early surgical consultation is critical; colectomy should be performed before severe deterioration (ideally before serum lactate exceeds 5.0 mmol/L) 1

First Recurrence

For first recurrence, fidaxomicin or tapered/pulsed vancomycin regimens are preferred over standard vancomycin courses. 1, 4

Preferred Options:

• Fidaxomicin 200 mg twice daily for 10 days, which demonstrates lower recurrence rates compared to vancomycin 1, 4
• Extended fidaxomicin regimen (200 mg twice daily for 5 days, then once every other day for 20 days) 1
• Tapered and pulsed vancomycin regimen: 125 mg four times daily for 10-14 days, then 125 mg twice daily for 7 days, then 125 mg once daily for 7 days, then 125 mg every 2-3 days for 2-8 weeks 1, 4

Alternative:

• Standard vancomycin 125 mg four times daily for 10 days if metronidazole was used for the initial episode 1

Adjunctive Therapy:

• Bezlotoxumab 10 mg/kg intravenously once during antibiotic administration may be considered for patients at high risk for recurrence (age >65, immunocompromised, severe CDI on presentation), though data with fidaxomicin are limited and caution is advised in congestive heart failure 1

Multiple Recurrences (Second or Subsequent)

After two or more recurrences, fecal microbiota transplantation becomes the most effective option, with 87-92% clinical resolution rates. 1, 4

Treatment Options:

• Fecal microbiota transplantation (FMT) is strongly recommended after failure of appropriate antibiotic treatments for at least 2 recurrences (3 total CDI episodes), with strong recommendation and moderate quality evidence 1, 4
• Fidaxomicin using standard or extended regimens 1
• Tapered and pulsed vancomycin regimen as described above 1, 4
• Vancomycin 125 mg four times daily for 10 days followed by rifaximin 400 mg three times daily for 20 days 1

Essential Supportive Measures

Discontinue the inciting antibiotic immediately if clinically possible, as this is critical for treatment success. 1, 4

Additional Measures:

• Switch to lower-risk antibiotics if continued antimicrobial therapy is necessary: parenteral aminoglycosides, sulfonamides, macrolides, or tetracyclines are preferred 5, 6, 4
• Avoid high-risk antibiotics: clindamycin, third-generation cephalosporins, fluoroquinolones, and penicillins are strongly associated with CDI 6
• Discontinue proton pump inhibitors if not absolutely required, as they increase CDI risk and recurrence 5, 6, 4
• Avoid antiperistaltic agents and opiates, which can worsen disease 1

Pediatric Considerations

For children with initial nonsevere CDI, either metronidazole or vancomycin is recommended. 1

Dosing:

• Metronidazole 7.5 mg/kg/dose three or four times daily (maximum 500 mg per dose) for 10 days 1
• Vancomycin 10 mg/kg/dose four times daily (maximum 125 mg per dose) for 10 days 1

Severe/Fulminant Pediatric CDI:

• Vancomycin 10 mg/kg/dose four times daily (maximum 500 mg per dose) for 10 days, with or without intravenous metronidazole 1

Critical Pitfalls to Avoid

• Never use intravenous vancomycin for CDI treatment—it is not excreted into the colon and has no effect on CDI 5, 2
• Do not use metronidazole for recurrent CDI due to lower sustained response rates and neurotoxicity concerns 4, 7
• Monitor for systemic absorption in patients with inflammatory bowel disorders or renal insufficiency, as oral vancomycin can achieve clinically significant serum concentrations 2
• Watch for nephrotoxicity in patients >65 years receiving oral vancomycin; monitor renal function during and after treatment 2
• Consider treatment extension to 14 days if delayed response occurs, particularly with metronidazole 1