How to manage reoccurring diarrhea while on treatment for Clostridioides difficile (C. diff) infection for a second time with vancomycin?

Management of Recurrent Diarrhea During Second C. difficile Treatment with Vancomycin

For a patient experiencing recurrent diarrhea while on their second course of vancomycin for C. difficile infection, you should first confirm this represents true recurrent CDI (not treatment failure or an alternative diagnosis), then transition to either a vancomycin tapered-and-pulsed regimen or proceed directly to fecal microbiota-based therapy, which achieves 87-92% clinical resolution compared to 40-50% with antibiotics alone. 1, 2

Initial Assessment: Distinguish True Recurrence from Other Causes

Before escalating therapy, you must determine what you're actually treating:

• True recurrent CDI is defined as return of clinically significant diarrhea (≥3 unformed stools in 24 hours) with a positive C. difficile test within 8 weeks of completing the previous treatment course 1, 3
• Consider alternative diagnoses if symptoms are atypical (diarrhea alternating with constipation) or if there's no response to vancomycin therapy 1, 3
• Do not perform "test of cure" after treatment, as C. difficile can persist asymptomatically and PCR can remain positive for weeks despite clinical resolution 2, 4

Treatment Algorithm for Second Recurrence (Third Episode)

Option 1: Vancomycin Tapered-and-Pulsed Regimen (If FMT Not Immediately Available)

For patients with multiple recurrences, use vancomycin in a prolonged tapered-and-pulsed regimen rather than a standard 10-14 day course: 1

• 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, 2, 4

This extended regimen allows C. difficile vegetative forms to be suppressed while permitting restoration of normal gut microbiota, though no randomized controlled trials have validated this approach for second or subsequent recurrences 1

Option 2: Fecal Microbiota-Based Therapy (Preferred for Multiple Recurrences)

Fecal microbiota-based therapy should be offered after at least 2 recurrences in patients who have failed appropriate antibiotic treatments, as it demonstrates superior outcomes with 87-92% clinical resolution versus 40-50% with antibiotics alone: 1, 2, 4

When to administer:

• Give fecal microbiota-based therapy upon completion of a standard course of antibiotics for recurrent CDI—it prevents recurrence, not treats active infection 1
• Use suppressive vancomycin to bridge until FMT can be administered 1
• Stop CDI antibiotics 1-3 days before conventional FMT (1 day if bowel purge given, 3 days if no purge) 1

Available formulations:

• Conventional FMT via colonoscopy, nasojejunal tube, or enema (efficacy 77-100% depending on route, with highest success via colon) 1
• FDA-approved oral formulations: fecal microbiota live-jslm and fecal microbiota spores live-brpk 1, 2

Consider FMT earlier (after first recurrence) in select high-risk patients who have recovered from severe/fulminant CDI or have significant comorbidities 1, 2

Option 3: Fidaxomicin (Alternative if Available)

• Fidaxomicin 200 mg twice daily for 10 days reduces subsequent recurrence rates to 19.7% compared to 35.5% with standard vancomycin 1, 4
• However, no prospective randomized trials exist for fidaxomicin in patients with multiple recurrences 1
• Post-approval data suggests less efficacy in multiply recurrent cases (≥2 recurrences) 1

Critical Supportive Measures

Discontinue inciting factors immediately:

• Stop all non-essential antibiotics if clinically possible—continued antibiotic use is the strongest predictor of treatment failure and recurrence 2, 3, 4
• Discontinue proton pump inhibitors unless absolutely required, as they increase CDI recurrence risk 1, 2, 4
• Avoid antimotility agents (loperamide, opiates) as they can precipitate toxic megacolon 2, 3

For patients requiring ongoing antibiotics:

• Carefully consider before proceeding with FMT, as ongoing antibiotics may diminish efficacy 1
• If systemic antibiotics are needed during or shortly after CDI treatment, consider secondary prophylaxis with low-dose vancomycin 125 mg once daily while systemic antibiotics are administered 1

Monitor for Severe or Fulminant Disease

Watch for warning signs requiring immediate escalation:

• WBC ≥15,000-25,000 cells/mL or rising 2, 4
• Serum lactate ≥5.0 mmol/L 2, 4
• Serum creatinine >1.5 mg/dL or rising 2
• Ileus, toxic megacolon, or peritoneal signs 2, 4
• Hemodynamic instability 4

If severe disease develops:

• Provide aggressive fluid resuscitation, electrolyte replacement, and consider albumin supplementation if serum albumin <2 g/dL 1
• Obtain prompt surgical consultation if perforation, toxic megacolon, severe ileus, or clinical deterioration despite antibiotics 4

Common Pitfalls to Avoid

• Do not delay FMT in multiply recurrent cases waiting for additional antibiotic courses—each recurrence increases risk of subsequent recurrence and FMT has superior efficacy 4
• Do not use intravenous vancomycin for CDI, as it is not excreted into the colon and has no efficacy 4
• Do not use metronidazole for recurrent CDI, as sustained response rates are lower than vancomycin and it should not be used long-term due to cumulative neurotoxicity risk 1
• Do not continue standard-dose vancomycin indefinitely—if staying with antibiotics, transition to tapered-and-pulsed regimen 1

Additional Considerations for High-Risk Patients

Consider adding bezlotoxumab (monoclonal antibody against C. difficile toxin B) 10 mg/kg as a single IV infusion to standard antibiotic therapy for patients at high risk of recurrence, particularly those with severe CDI presentation 4