What is the first line treatment for a third episode of Clostridioides difficile (C. diff) infection?

Treatment for Third Episode of C. difficile Infection

For a third episode of C. difficile infection (CDI), fidaxomicin 200 mg twice daily for 10 days, or an extended-pulsed regimen of fidaxomicin (200 mg twice daily for 5 days followed by once every other day for 20 days) is the recommended first-line treatment. 1

Treatment Algorithm for Third Episode CDI

First-line options (in order of preference):

1. Fidaxomicin regimens:

   • Standard: 200 mg twice daily for 10 days
   • Extended-pulsed: 200 mg twice daily for 5 days, then once every other day for 20 days 1

2. Vancomycin tapered and pulsed 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, 2

3. Vancomycin followed by rifaximin:

   • Vancomycin 125 mg four times daily for 10 days
   • Followed by rifaximin 400 mg three times daily for 20 days 1

For patients with multiple recurrences who have failed appropriate antibiotic treatments:

• Fecal microbiota transplantation (FMT) 1, 3

Evidence Supporting Recommendations

The 2021 IDSA/SHEA guidelines specifically address treatment for multiple CDI recurrences and recommend fidaxomicin as a preferred option for patients with recurrent CDI 1. The evidence shows that fidaxomicin increases sustained response of CDI 30 days after end of therapy compared with vancomycin (RR: 1.27; 95% CI: 1.05–1.54) 1.

For patients with multiple recurrences (≥2 recurrences, meaning a third episode), the guidelines recommend several options including fidaxomicin, vancomycin in a tapered and pulsed regimen, vancomycin followed by rifaximin, or fecal microbiota transplantation 1.

The extended-pulsed regimen of fidaxomicin has shown improved sustained responses with one of the lowest recurrence rates (2% compared to 17% with vancomycin at day 40) 1. This regimen may be particularly beneficial for patients with multiple recurrences.

Special Considerations

Severity Assessment

• Assess for severe or fulminant CDI, which may require different management:
  • Severe CDI: WBC ≥15,000 cells/mL OR serum creatinine >1.5 mg/dL
  • Fulminant CDI: Hypotension, shock, ileus, or megacolon 2

When to Consider FMT

• FMT should be considered after failure of appropriate antibiotic treatments for at least two recurrences (i.e., third episode) 1
• FMT has shown clinical cure rates between 70-90% in patients with recurrent CDI 3
• Lower gastrointestinal endoscopy delivery of FMT appears superior to other delivery methods 3

Avoid Metronidazole

• Metronidazole should not be used for recurrent CDI due to:
  • Lower response rates compared to vancomycin and fidaxomicin
  • Risk of cumulative neurotoxicity with repeated courses 1, 2

Supportive Measures

• Discontinue the inciting antibiotic whenever possible 2
• Avoid antiperistaltic agents and opiates 2
• Ensure adequate fluid and electrolyte replacement 1
• Consider albumin supplementation in patients with severe hypoalbuminemia (<2 g/dL) 1

By following this treatment algorithm for third episode CDI, clinicians can optimize outcomes and reduce the risk of further recurrences, which is associated with significant morbidity and mortality.