What is the next best treatment step for a patient with poorly controlled diabetes and a persistent positive Clostridioides difficile (C-diff) stool culture after completing a course of fidaxomicin (fidaxomicin)?

Treatment of Recurrent C. difficile After Fidaxomicin Failure

For this patient with persistent C. difficile infection after fidaxomicin, you should proceed directly to fecal microbiota transplantation (FMT), as this represents a second recurrence (third episode overall) and FMT demonstrates superior outcomes compared to additional antibiotic courses in this setting.

Understanding the Clinical Scenario

This patient has experienced:

• Initial CDI episode (treated with unknown agent)
• First recurrence (treated with fidaxomicin)
• Second recurrence/persistent infection (current presentation)

The positive stool culture "a few days" after completing fidaxomicin with ongoing diarrhea represents either treatment failure or early recurrence—both scenarios warrant escalation beyond standard antibiotic retreatment 1, 2.

Primary Recommendation: Fecal Microbiota Transplantation

FMT is the definitive treatment for multiple recurrences of CDI, with clinical resolution rates of 87-92% compared to 40-50% with antibiotics alone 1, 3, 4.

Evidence Supporting FMT at This Stage:

• The 2018 IDSA/SHEA guidelines provide a strong recommendation for FMT in patients with multiple recurrences who have failed appropriate antibiotic treatments 1.
• A 2019 randomized trial demonstrated FMT after vancomycin lead-in achieved 92% clinical resolution versus only 42% with fidaxomicin in recurrent CDI (P=0.0002) 4.
• The 2020 Taiwan guidelines recommend FMT for second and subsequent recurrences with strong evidence (Grade 1B) 1.
• Gastroenterology guidelines specifically recommend FMT after the second recurrence (third episode), which matches this patient's situation 5.

FMT Protocol:

• Administer oral vancomycin 125 mg four times daily for 4-10 days as a lead-in before FMT 1, 4.
• Stop vancomycin 1-3 days before the FMT procedure 5.
• FMT can be delivered via colonoscopy or nasojejunal tube with similar efficacy 4.
• Follow-up for at least 8 weeks post-FMT to assess efficacy and adverse events 1.

Alternative Antibiotic-Based Approaches (If FMT Unavailable)

If FMT cannot be arranged immediately or is declined by the patient, antibiotic options include:

Option 1: Vancomycin Tapered and Pulsed Regimen (Preferred)

This is the most evidence-supported antibiotic approach for multiple recurrences 1, 2:

• Vancomycin 125 mg every 6 hours × 10-14 days
• Then 125 mg every 12 hours × 7 days
• Then 125 mg every 24 hours × 7 days
• Then 125 mg every 48-72 hours × 2-8 weeks 1, 6

Rationale: The taper allows gradual microbiota recovery while suppressing C. difficile spores that germinate over time 1, 2.

Option 2: Extended-Pulsed Fidaxomicin Regimen

The 2020 Taiwan guidelines suggest (weak recommendation, Grade 2C):

• Fidaxomicin 200 mg twice daily × 5 days
• Then 200 mg once daily on alternate days for days 7-25 1

This regimen showed only 5-6% recurrence at 30-90 days in trials, significantly lower than standard dosing 1, 7.

Important caveat: Since this patient just failed standard fidaxomicin, repeating fidaxomicin (even extended regimen) is less appealing than switching to vancomycin taper or proceeding to FMT 1.

Option 3: Vancomycin Followed by Rifaximin

• Vancomycin 125 mg four times daily × 10-14 days
• Followed immediately by rifaximin 400 mg three times daily × 20 days 1

This "rifaximin chaser" approach has some support but less robust evidence than tapered vancomycin 6.

Critical Supportive Measures

Discontinue Contributing Factors:

• Stop all unnecessary antibiotics immediately if the patient is on any concurrent antimicrobials 1, 2.
• Discontinue proton pump inhibitors if not absolutely required, as they are associated with CDI recurrence 1, 5.
• Avoid antimotility agents (loperamide, opiates) which can precipitate toxic megacolon 8.

Assess for High-Risk Features:

This patient has multiple risk factors for recurrence and poor outcomes:

• Poorly controlled diabetes (comorbidity increases recurrence risk) 1
• Multiple recurrences already documented 1
• Potential ongoing antibiotic exposure for diabetes complications 1

Monitor for Severe/Fulminant Disease:

Watch for warning signs requiring escalation:

• WBC ≥25,000 or rising 1
• Lactate ≥5 mmol/L 1
• Ileus, toxic megacolon, or peritoneal signs 1, 8
• Worsening diarrhea or development of constipation (may indicate ileus) 8

If severe features develop, add IV metronidazole 500 mg every 8 hours to oral vancomycin and consider surgical consultation 1.

Why Not Repeat Standard Fidaxomicin?

• This patient just completed fidaxomicin with inadequate response 1.
• Standard 10-day fidaxomicin courses were designed for initial episodes, not multiple recurrences 1, 9.
• While fidaxomicin reduces recurrence compared to vancomycin in initial episodes (13-15% vs 24-25%), it has not been adequately studied for second or subsequent recurrences 1, 9.
• The 2018 IDSA/SHEA guidelines note "insufficient data" to support simply repeating the same antibiotic that just failed 1.

Common Pitfalls to Avoid

1. Do not order "test of cure" stool testing—C. difficile PCR can remain positive for weeks after successful treatment and does not distinguish colonization from active infection 1.

2. Do not use metronidazole for recurrent CDI—it has inferior outcomes and cumulative neurotoxicity risk with repeated courses 1, 2, 6.

3. Do not delay FMT indefinitely—each additional antibiotic course further disrupts the microbiome and reduces likelihood of spontaneous resolution 1, 3.

4. Optimize diabetes control—hyperglycemia may impair immune response and gut barrier function, contributing to recurrence risk 1.