What is the recommended treatment for an adult with a first recurrence of Clostridioides difficile infection after successful initial therapy?

Treatment of First Recurrence of Clostridioides difficile Infection

For an adult with a first recurrence of CDI after successful initial therapy, fidaxomicin 200 mg orally twice daily for 10 days is the preferred treatment over vancomycin, based on the 2021 IDSA/SHEA focused update guidelines. 1, 2

Primary Treatment Options (in Order of Preference)

First Choice: Fidaxomicin

• Fidaxomicin 200 mg orally twice daily for 10 days is now the preferred agent for first recurrence, demonstrating superior sustained response rates compared to vancomycin (relative risk 1.27; 95% CI: 1.05–1.54) at 30 days after end of therapy 1
• Fidaxomicin reduces subsequent recurrence from 35.5% with vancomycin to 19.7% (P = 0.045) in patients with first recurrence 1
• This represents a conditional recommendation with moderate-quality evidence from the 2021 IDSA/SHEA guidelines 1, 2

Second Choice: Vancomycin Tapered and Pulsed Regimen

• If fidaxomicin is unavailable or cost-prohibitive, use oral vancomycin in a tapered and pulsed regimen rather than a standard 10-day course 1
• The specific regimen: vancomycin 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
• This approach allows suppression of C. difficile vegetative forms while permitting restoration of normal gut microbiota 1

Third Choice: Standard Vancomycin Course

• If metronidazole was used for the initial episode, treat the first recurrence with a standard 10-day course of vancomycin 125 mg four times daily 1
• This is a weak recommendation with low-quality evidence 1

Adjunctive Therapy to Consider

Bezlotoxumab

• Consider adding bezlotoxumab 10 mg/kg IV as a single infusion for patients with a first recurrence, particularly those at high risk for subsequent recurrence 2
• This monoclonal antibody against C. difficile toxin B is recommended as adjunctive therapy by IDSA/SHEA guidelines 2

What NOT to Do: Critical Pitfalls

• Never use metronidazole for treatment of recurrent CDI – it has lower initial and sustained response rates compared to vancomycin and carries risk of cumulative neurotoxicity with repeated courses 1
• Do not use a standard 10-day vancomycin course if vancomycin was already used for the initial episode – the tapered and pulsed regimen is preferred in this scenario 1
• Avoid IV vancomycin alone – it does not achieve therapeutic colonic concentrations 2, 3
• Do not perform test-of-cure after treatment completion – PCR can remain positive for weeks due to colonization 4

Clinical Decision Algorithm

Step 1: Determine what was used for initial episode

• If metronidazole was used initially → Standard vancomycin 125 mg four times daily × 10 days OR fidaxomicin 200 mg twice daily × 10 days 1
• If vancomycin was used initially → Vancomycin tapered/pulsed regimen OR fidaxomicin 200 mg twice daily × 10 days 1

Step 2: Assess resource availability

• If fidaxomicin is available → Use fidaxomicin as first-line (preferred option regardless of initial therapy) 1, 2
• If fidaxomicin is unavailable → Use vancomycin per algorithm above 1

Step 3: Consider adjunctive therapy

• Assess risk factors for subsequent recurrence (advanced age, continued antibiotic use, immunosuppression) 1
• If high-risk features present → Add bezlotoxumab 10 mg/kg IV × 1 dose 2

Important Nuances in the Evidence

The 2021 IDSA/SHEA focused update represents an evolution from the 2018 guidelines 1. While the 2018 guidelines listed fidaxomicin and vancomycin as equivalent options for first recurrence (with choice based on what was used initially), the 2021 update now conditionally recommends fidaxomicin over vancomycin based on pooled analysis of three RCTs showing improved sustained response 1. However, this is a conditional recommendation acknowledging that vancomycin remains an acceptable alternative when resources are limited 1, 2.

The evidence shows fidaxomicin achieves similar initial cure rates but significantly better sustained response, meaning fewer patients experience a second recurrence 1. An ad hoc subgroup analysis demonstrated that for patients with exactly one prior recurrence, the relative risk for sustained response with fidaxomicin was 1.23 (95% CI: 1.01–1.49) 1.

When to Escalate Beyond First Recurrence Treatment

• If the patient experiences a second recurrence (≥2 total recurrences), escalate to more aggressive strategies: extended-pulsed fidaxomicin, vancomycin followed by rifaximin, or fecal microbiota transplantation 1, 2
• Fecal microbiota transplantation is strongly recommended after at least two recurrences that have failed appropriate antibiotic treatments, with cure rates of 87–94% 2