Treatment of Recurrent Clostridioides difficile Infection
For first recurrence of C. difficile infection, use oral fidaxomicin 200 mg twice daily for 10 days as the preferred treatment, or alternatively use oral vancomycin in a tapered and pulsed regimen if vancomycin was used initially. 1
First Recurrence Treatment Options
The treatment approach differs based on what antibiotic was used for the initial episode:
If metronidazole was used initially:
- Oral vancomycin 125 mg four times daily for 10 days 1
- This switches away from metronidazole due to inferior sustained response rates and neurotoxicity risk with repeated courses 1
If vancomycin was used initially:
- Fidaxomicin 200 mg twice daily for 10 days is preferred 1, 2
- Fidaxomicin reduces subsequent recurrence from 35.5% to 19.7% compared to standard vancomycin (P = 0.045) 2
- Alternative: 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
Second and Subsequent Recurrences
For patients with ≥2 recurrences (meaning ≥3 total CDI episodes), you have three antibiotic options before considering FMT:
Vancomycin tapered and pulsed regimen (as detailed above) 1
- Taper-plus-pulse regimens show superior outcomes (58-100% success) compared to pulse-only regimens (26-81% success) 3
Vancomycin 125 mg four times daily for 10 days followed by rifaximin 400 mg three times daily for 20 days 1
- This combination reduced recurrence from 31% to 15% in one trial, though not statistically significant (P = 0.11) 1
Fidaxomicin 200 mg twice daily for 10 days 1
- Limited data for multiply recurrent CDI; post-approval experience suggests less efficacy after ≥2 recurrences 1
Fecal Microbiota Transplantation
FMT is strongly recommended for patients with multiple recurrences who have failed appropriate antibiotic treatments (strong recommendation, moderate quality evidence). 1
- The IDSA/SHEA guideline specifies that at least 2 recurrences (meaning 3 total CDI episodes) should be treated with antibiotics before offering FMT 1
- European guidelines report FMT success rates of 81-93% for recurrent CDI 1
- Route of administration matters: colonoscopy-delivered FMT shows consistent efficacy, while a single enema administration was not superior to vancomycin taper in one randomized trial 4
Critical Management Principles
Avoid metronidazole for recurrent CDI due to lower cure rates and risk of cumulative neurotoxicity with repeated or prolonged courses 1, 5
Discontinue inciting antibiotics as soon as medically feasible, as continued antibiotic exposure is a major risk factor for further recurrence 1
Do not use antiperistaltic agents or opiates in any patient with CDI 5
Special Consideration: Prolonged Vancomycin Prophylaxis
For elderly patients with frequently relapsing CDI who have failed FMT or cannot access it:
- Prolonged oral vancomycin 125 mg once daily can be used as secondary prophylaxis 6
- In one case series of 20 patients (median age 80 years, median 4 prior CDI episodes), only 1 relapse occurred during 200 patient-months of follow-up on daily vancomycin 6
- However, 31% relapsed within 6 weeks of stopping prophylaxis 6
- This approach lacks guideline support but represents a pragmatic option when standard treatments have failed 6
Monitoring Treatment Response
Clinical response typically requires 3-5 days after starting therapy 1, 5
Do not perform "test of cure" stool testing after treatment completion, as PCR can remain positive from colonization without active infection 1, 5
Common Pitfall to Avoid
The most critical error is using metronidazole for recurrent CDI—this is explicitly not recommended due to inferior outcomes and neurotoxicity risk with repeated exposure 1. Always escalate to vancomycin-based regimens or fidaxomicin for any recurrence.