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

Treatment of Clostridioides difficile Infection

First-Line Treatment for Initial Episode

For both non-severe and severe initial CDI episodes, use oral vancomycin 125 mg four times daily for 10 days OR fidaxomicin 200 mg twice daily for 10 days as first-line therapy. 1, 2

Disease Severity Classification

• Non-severe CDI: White blood cell count ≤15,000 cells/μL AND serum creatinine <1.5 mg/dL 1, 2
• Severe CDI: White blood cell count >15,000 cells/μL OR serum creatinine ≥1.5 mg/dL 1, 2
• Fulminant CDI: Hypotension or shock, ileus, or megacolon 1

Treatment Selection

• Preferred regimens for initial episode (regardless of severity):

  • Vancomycin 125 mg orally four times daily for 10 days 1, 2
  • Fidaxomicin 200 mg orally twice daily for 10 days 1, 2, 3

• Alternative only if above agents unavailable (non-severe CDI only): Metronidazole 500 mg three times daily orally for 10-14 days 1

The 2021 IDSA/SHEA guidelines represent a significant shift from older recommendations, as metronidazole is now relegated to alternative status only when vancomycin and fidaxomicin are unavailable. 1 This change reflects concerns about lower cure rates and neurotoxicity risk with metronidazole. 2

Important Dosing Considerations

Higher vancomycin doses (500 mg four times daily) provide no clinical benefit over standard dosing (125 mg four times daily) for severe CDI. 2, 4 Research demonstrates that even 125 mg four times daily achieves fecal concentrations 3 orders of magnitude higher than the MIC90 against C. difficile. 5

Treatment for First Recurrence

For first CDI recurrence, use fidaxomicin 200 mg twice daily for 10 days (standard or extended regimen) as preferred therapy. 1, 2

Recurrence Treatment Options

• Preferred: Fidaxomicin 200 mg twice daily for 10 days, OR twice daily for 5 days followed by once every other day for 20 days 1

• Alternative: Vancomycin in tapered and pulsed regimen (e.g., 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) 1, 2

• Alternative: Standard vancomycin 125 mg four times daily for 10 days (particularly if metronidazole was used for initial episode) 1, 2

• Adjunctive therapy: Consider bezlotoxumab 10 mg/kg IV once during antibiotic administration for patients at high risk of recurrence (age >65, immunocompromised, severe CDI) 1

  • Caution: Use bezlotoxumab cautiously in patients with congestive heart failure 1

Treatment for Second or Subsequent Recurrence

For multiple recurrences, use vancomycin in tapered/pulsed regimen, fidaxomicin extended regimen, vancomycin followed by rifaximin, or fecal microbiota transplantation after at least 2 recurrences. 1, 2

Multiple Recurrence Options

• Fidaxomicin 200 mg twice daily for 10 days OR extended regimen 1
• Vancomycin tapered and pulsed regimen 1
• Vancomycin 125 mg four times daily for 10 days followed by rifaximin 400 mg three times daily for 20 days 1, 2
• Fecal microbiota transplantation after appropriate antibiotic treatments for at least 2 recurrences (i.e., 3 total CDI episodes) 1, 2
• Bezlotoxumab 10 mg/kg IV once as adjunctive therapy 1

Fulminant CDI Management

For fulminant CDI, use high-dose vancomycin 500 mg four times daily orally or by nasogastric tube PLUS intravenous metronidazole 500 mg every 8 hours. 1, 2

Fulminant Disease Protocol

• Vancomycin 500 mg four times daily by mouth or nasogastric tube 1
• If ileus present: Add vancomycin retention enema (500 mg in 100 mL normal saline every 4-12 hours) 1
• Always add: IV metronidazole 500 mg every 8 hours, particularly if ileus present 1
• Early surgical consultation for patients with perforation, toxic megacolon, severe ileus, or deteriorating clinical condition despite antibiotics 1
• Consider colectomy before serum lactate exceeds 5.0 mmol/L 1

NPO Patients (Cannot Take Oral Medications)

For patients unable to take oral medications, use IV metronidazole 500 mg every 8 hours PLUS vancomycin retention enema 500 mg in 100 mL normal saline four times daily. 1, 6

NPO Treatment Approach

• IV metronidazole 500 mg every 8 hours 1, 6
• Vancomycin retention enema 250-500 mg in 100-500 mL saline 2-4 times daily 1, 6
• Transition to oral therapy (vancomycin or fidaxomicin) once patient can tolerate oral intake 6
• Note: IV vancomycin alone is ineffective as it is not excreted into the colon 6

Critical Management Principles

Essential Actions

• Discontinue inciting antibiotics as soon as medically feasible 1, 2
• Standard treatment duration: 10 days (may extend to 14 days if delayed response) 1, 2
• Avoid antiperistaltic agents and opiates 1
• Do NOT perform "test of cure" after treatment completion 2, 6

Common Pitfalls to Avoid

• Never use metronidazole for severe or recurrent CDI due to inferior cure rates 2
• Never use IV vancomycin alone for CDI treatment—it does not reach therapeutic colonic concentrations 6
• Avoid repeated metronidazole courses due to cumulative neurotoxicity risk 2, 6
• Do not delay empiric therapy when substantial laboratory confirmation delay is expected or for fulminant CDI 2
• Do not use higher vancomycin doses (>500 mg daily) for non-fulminant disease—no clinical benefit demonstrated 2, 4