What is the recommended treatment for an adult patient with recurrent Clostridioides difficile (C diff) infection who has failed standard antibiotic therapy with vancomycin or fidaxomicin?

Fecal Microbiota Transplantation for Recurrent C. difficile Infection

For adults with recurrent Clostridioides difficile infection who have failed standard antibiotic therapy, fecal microbiota transplantation (FMT) should be offered after at least 2 recurrences (meaning 3 total CDI episodes), as it achieves superior resolution rates compared to continued antibiotic therapy alone. 1

When to Use FMT

FMT is specifically indicated for patients with multiple recurrences of CDI who have failed appropriate antibiotic treatments (at least 2 recurrences, meaning 3 total episodes). 1 The most recent 2024 AGA guidelines and 2021 IDSA/SHEA guidelines both strongly support this approach, with FMT demonstrating a large increase in resolution rates (RR 1.92,95% CI 1.36-2.71) compared to antibiotics alone. 1, 2

Treatment Algorithm for Recurrent CDI:

First Recurrence:

• Preferred: Fidaxomicin 200 mg twice daily for 10 days, OR fidaxomicin 200 mg twice daily for 5 days followed by once every other day for 20 days 1
• Alternative: Vancomycin in a tapered and pulsed regimen (125 mg 4 times daily for 10-14 days, then 2 times daily for 7 days, once daily for 7 days, then every 2-3 days for 2-8 weeks) 1
• Alternative: Standard vancomycin 125 mg 4 times daily for 10 days if metronidazole was used initially 1

Second or Subsequent Recurrence (Before FMT):

• Fidaxomicin 200 mg twice daily for 10 days, OR extended-pulsed fidaxomicin 1
• Vancomycin tapered and pulsed regimen 1
• Vancomycin 125 mg 4 times daily for 10 days followed by rifaximin 400 mg 3 times daily for 20 days 1

After ≥2 Recurrences (3 total episodes):

• FMT is the recommended treatment 1

How to Administer FMT

FMT should be given upon completion of a standard course of antibiotics for recurrent CDI—it is for prevention of recurrence, not acute treatment. 1

Timing and Preparation:

• Use suppressive anti-CDI antibiotics (vancomycin) to bridge until FMT is administered 1
• Stop antibiotics 1-3 days before conventional FMT: if bowel purge is given, FMT can be administered 1 day after stopping antibiotics; if no purge, wait 3 days for antibiotic clearance 1
• For FDA-approved products (fecal microbiota spores live-brpk or fecal microbiota live-jslm), follow manufacturer package insert 1

Route of Administration:

• Conventional FMT can be delivered via multiple routes (colonoscopy, nasojejunal tube, or enema) 1
• There is insufficient evidence to recommend a specific route, though colonoscopic delivery was used in multiple successful trials 1, 2
• FMT must be performed with appropriately screened donor stool 1

Efficacy Evidence

The highest quality recent evidence demonstrates FMT's superiority:

• A 2019 randomized trial found FMT superior to fidaxomicin for recurrent CDI, with 71% achieving clinical and microbiological resolution with FMT versus 33% with fidaxomicin (P=0.009) 3
• A 2023 Cochrane review of 6 RCTs (320 participants) showed FMT likely leads to a large increase in resolution of rCDI (RR 1.92,95% CI 1.36-2.71; NNTB 3) 2
• Clinical resolution was achieved in 92% of FMT patients versus 42% with fidaxomicin in head-to-head comparison 3

Special Populations

Immunocompromised Patients:

• Mildly or moderately immunocompromised adults: FMT is suggested upon completion of standard antibiotics 1
• Severely immunocompromised adults: FMT is suggested against (includes active cytotoxic therapy, neutropenia, recent CAR-T or HCT with neutropenia, severe primary immunodeficiency, advanced HIV with CD4 <200/mm³) 1
• FDA-approved FMT products (fecal microbiota spores live-brpk or fecal microbiota live-jslm) have insufficient evidence in immunocompromised patients 1

High-Risk Patients:

• Select use of FMT may be considered in patients at high risk of recurrent CDI or morbid recurrence, including those recovered from severe/fulminant CDI or with significant comorbidities 1

Alternatives to FMT

If patients decline FMT or it is unavailable, reasonable alternatives include:

• Vancomycin tapered-pulsed regimen 1
• Tapered-pulsed fidaxomicin 1
• Bezlotoxumab 10 mg/kg IV once during antibiotic administration (caution in congestive heart failure) 1, 4

Critical Safety Considerations

FDA Safety Alerts:

• Three FDA safety alerts since June 2019 document transmission of pathogenic E. coli from donor to recipients, with some deaths 1
• Potential for SARS-CoV-2 transmission exists 1
• Appropriate screening of donor and donor fecal specimens is mandatory 1

Contraindications and Cautions:

• Patients requiring frequent antibiotics or long-term antibiotic prophylaxis may have diminished FMT efficacy 1
• Patients who recur rapidly (within 1-2 days of stopping CDI antibiotics) require individualized treatment windows 1

Common Pitfalls to Avoid

• Do not use FMT for acute CDI treatment—it is only for prevention of recurrence after completing antibiotics 1
• Do not offer FMT before trying at least 2 appropriate antibiotic recurrence treatments (meaning 3 total CDI episodes) 1
• Do not use inadequately screened donor stool—follow current FDA screening recommendations 1
• Do not use FMT in severely immunocompromised patients without careful risk-benefit assessment 1
• Do not perform "test of cure" after FMT—clinical resolution is the endpoint 1