What is the best course of treatment for a patient with Clostridioides difficile (C. difficile) infection, considering their past medical history and recent antibiotic use?

Treatment of Clostridioides difficile Infection

For initial C. difficile infection, fidaxomicin 200 mg twice daily for 10 days is the preferred treatment over vancomycin, though vancomycin 125 mg four times daily for 10 days remains an acceptable alternative; metronidazole should only be used when neither fidaxomicin nor vancomycin are available. 1

Initial Episode Treatment Based on Disease Severity

Non-Severe Disease

Non-severe CDI is defined as white blood cell count ≤15,000 cells/μL AND serum creatinine <1.5 mg/dL AND stool frequency <4 times daily. 2

• First-line treatment options include:

  • Fidaxomicin 200 mg orally twice daily for 10 days (preferred due to lower recurrence rates) 1, 2
  • Oral vancomycin 125 mg four times daily for 10 days (acceptable alternative) 2

• Metronidazole 500 mg three times daily for 10 days should only be used when vancomycin or fidaxomicin are unavailable, as vancomycin demonstrates a 97% cure rate versus 76% for metronidazole in severe disease 2

Severe Disease

Severe CDI is defined as white blood cell count ≥15,000 cells/μL OR serum creatinine ≥1.5 mg/dL, with additional markers including marked leukocytosis, elevated creatinine (>50% above baseline), or decreased albumin (<30 g/L). 2

• Treatment options include:

  • Oral vancomycin 125 mg four times daily for 10 days 2
  • Fidaxomicin 200 mg twice daily for 10 days 2

• Metronidazole should NOT be used for severe disease 2

Fulminant Disease

Fulminant CDI is characterized by hypotension or shock, ileus, megacolon, hemodynamic instability, or signs of peritonitis. 2

• Treatment regimen:
  • High-dose oral vancomycin 500 mg four times daily PLUS intravenous metronidazole 500 mg every 8 hours 3, 2
  • If ileus is present, add rectal vancomycin 500 mg in 100 mL normal saline every 4-12 hours 3, 2

Recurrent CDI Treatment

For first recurrence, fidaxomicin 200 mg twice daily for 10 days is preferred over standard vancomycin due to lower recurrence rates. 1

• Alternative options for first recurrence:

  • Vancomycin in a tapered and pulsed regimen 1
  • Standard course of vancomycin 1

• For multiple recurrences, options include:

  • Fidaxomicin (standard or extended-pulsed regimen) 1
  • Vancomycin in a tapered and pulsed regimen 1
  • Vancomycin followed by rifaximin 1
  • Fecal microbiota transplantation 1

• Consider bezlotoxumab 10 mg/kg IV once as adjunctive therapy for patients with recurrent CDI within the last 6 months who are at high risk of recurrence 1, 2

Treatment Failure Management

Treatment failure is defined as absence of clinical response when stool frequency does not decrease or consistency does not improve after 3 days, or when new signs of severe colitis develop. 3

• Assess clinical response by 72 hours and escalate therapy immediately if no improvement is seen 3, 2

• Escalation algorithm:

  • Escalate to high-dose oral vancomycin 500 mg four times daily 3
  • Add intravenous metronidazole 500 mg every 8 hours as combination therapy 3
  • If ileus is present, add rectal vancomycin enemas 500 mg in 100 mL normal saline every 4-12 hours 3

Surgical Intervention Criteria

Colectomy should be performed urgently in cases of perforation of the colon, systemic inflammation with deteriorating clinical condition, toxic megacolon, or severe ileus. 3

• Serum lactate exceeding 5.0 mmol/L is a critical marker indicating the need for surgery 3
• Do not delay surgical consultation when clinical deterioration continues despite maximal medical therapy, as early surgery saves lives 3

Critical Management Principles

Discontinue Inciting Factors

• Discontinue all inciting antibiotics immediately if clinically feasible, as continued use of antibiotics for infections other than CDI is significantly associated with increased risk of CDI recurrence 1, 3, 2
• If continued antibiotic therapy is required, use agents less frequently implicated with CDI including parenteral aminoglycosides, sulfonamides, macrolides, vancomycin, or tetracycline/tigecycline 1

Avoid Harmful Agents

• Antiperistaltic agents and opiates must be avoided completely, as they worsen outcomes by promoting toxin retention and increase the risk of toxic megacolon 3, 2
• Avoid repeated or prolonged courses of metronidazole due to risk of cumulative and potentially irreversible neurotoxicity, particularly concerning in elderly patients 1, 3, 2

Empirical Therapy Considerations

• Empirical therapy for CDI should be avoided unless there is strong suspicion for CDI 1
• If a patient has strong suspicion for severe CDI, empirical therapy should be considered while awaiting test results 1

Common Pitfalls to Avoid

• Never continue metronidazole monotherapy for severe or resistant disease, as vancomycin has a higher cure rate 3
• Never use metronidazole as first-line therapy for initial CDI, as it is no longer recommended due to inferior efficacy 2
• Treatment response may require 3-5 days, with stool frequency decreasing or consistency improving after 3 days without new signs of severe colitis developing 2