What is the best course of action for a patient with suspected recurrent Clostridioides (C. difficile) infection, presenting with diarrhea, abdominal cramping, and bloating, despite a recent negative C. difficile test result and previous treatment with Vancomycin (Vancomycin) and Dificid (Fidaxomicin)?

Management of Suspected Recurrent C. difficile Infection with Negative Test Results

For a patient with suspected recurrent C. difficile infection despite a negative test, a tapered and pulsed vancomycin regimen is recommended as the most appropriate treatment approach, given the high clinical suspicion and symptom pattern consistent with recurrent CDI.

Clinical Assessment of the Current Situation

The patient presents with classic symptoms of recurrent C. difficile infection:

• Return of diarrhea (applesauce to watery consistency, 2-4 times daily)
• Abdominal cramping and bloating
• New-onset urgency with incontinence
• Previous history of two courses of antibiotics for CDI (vancomycin followed by fidaxomicin)
• Symptom-free period of approximately 3 weeks before recurrence

Interpreting the Negative Test Result

Despite the negative C. difficile test, this clinical presentation strongly suggests recurrent CDI for several reasons:

• False-negative test results can occur, particularly if:
  • The test was performed on formed stool
  • The patient has ongoing diarrhea under CDI treatment 1
  • Sampling issues or laboratory variables affected results

Treatment Recommendations

First-line Approach

1. Initiate a tapered and pulsed vancomycin regimen 2:
   • 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
   • Finally 125 mg every 2-3 days for 2-8 weeks

This regimen is preferred for patients with recurrent CDI to reduce the risk of further recurrences and improve clinical outcomes.

Alternative Option

If the patient continues to deteriorate or does not respond to the tapered vancomycin approach:

• Consider fidaxomicin 200 mg twice daily for 10 days 2, 3
  • Fidaxomicin has shown lower recurrence rates (19.7%) compared to standard vancomycin courses (35.5%) in patients with recurrent CDI
  • The patient has already received fidaxomicin, but a second course may still be beneficial

Diagnostic Considerations

1. Repeat C. difficile testing using a two-step algorithm:

   • First test: Glutamate dehydrogenase (GDH) antigen enzyme immunoassay or nucleic acid amplification test
   • Second test: Toxin A/B enzyme immunoassay 1
   • Ensure testing is performed on liquid stool samples

2. Consider alternative diagnoses if repeat testing remains negative:

   • Post-infectious irritable bowel syndrome
   • Inflammatory bowel disease flare
   • Other infectious causes of diarrhea

Monitoring and Follow-up

• Monitor frequency and consistency of bowel movements daily
• Track abdominal pain, cramping, and other symptoms
• Follow up within 1 week to assess response to therapy
• Continue treatment for at least the full course even if symptoms resolve quickly

Special Considerations

Pitfalls to Avoid

1. Do not dismiss symptoms due to negative test results

   • Clinical presentation strongly suggests recurrent CDI despite negative testing
   • False-negative results are common, especially with ongoing symptoms

2. Do not use metronidazole for recurrent CDI

   • Lower response rates and risk of cumulative neurotoxicity with repeated courses 2

3. Do not wait for positive test results before initiating treatment

   • Empiric therapy is appropriate given the high clinical suspicion and previous history

Advanced Options for Multiple Recurrences

If the patient continues to experience recurrences after appropriate treatment:

1. Consider bezlotoxumab as adjunctive therapy to reduce recurrence risk 2

2. Evaluate for fecal microbiota transplantation (FMT) after failure of appropriate antibiotic treatments for at least two recurrences 1, 2

   • Clinical cure rates between 70-90% for recurrent CDI
   • Should be considered after failure of appropriate antibiotic treatments

Conclusion

The clinical presentation strongly suggests recurrent CDI despite the negative test result. A tapered and pulsed vancomycin regimen is the recommended approach, with close monitoring and consideration of fidaxomicin if symptoms persist. Further diagnostic workup should be pursued if symptoms do not improve with appropriate therapy.