What is the best course of action for a patient with a persistent infection that partially responded to clotrimazole and fluconazole after developing a herpes-like ulcer following initial treatment with metronidazole and local antibiotics?

Diagnostic Workup and Definitive Treatment Recommendation

This patient requires immediate diagnostic testing to identify the causative pathogen, as the clinical presentation suggests a persistent infection that is not responding appropriately to empiric antifungal therapy—most likely representing either resistant Candida species, a non-Candida fungal infection, or a misdiagnosed viral infection (HSV). 1

Critical Diagnostic Steps

Obtain tissue biopsy and culture immediately from any active lesions, as skin lesions in patients with persistent infections despite antifungal therapy may be caused by resistant microbes, yeasts, or molds 1. The sensitivity of serum fungal antigen tests is low, particularly in patients already receiving antifungal agents 1.

• PCR testing for HSV and VZV should be performed on peripheral blood and any lesional tissue, as the "herpes-like ulcer" that developed during treatment strongly suggests viral reactivation 1
• Fungal culture with speciation and susceptibility testing is mandatory to identify azole-resistant Candida species (particularly C. krusei and C. glabrata) or non-albicans Candida 1

Treatment Algorithm Based on Likely Diagnoses

If HSV/VZV is Confirmed or Highly Suspected:

Initiate intravenous acyclovir immediately for suspected or confirmed cutaneous HSV or VZV infection 1. The development of a herpes-like ulcer after initial improvement with antibiotics is highly characteristic of viral reactivation 1.

• Acyclovir should be administered at appropriate doses until clinical resolution 1
• Do not delay antiviral therapy while awaiting PCR results if clinical suspicion is high 1

If Azole-Resistant Candidiasis is Confirmed:

For fluconazole-refractory mucocutaneous candidiasis, the treatment hierarchy is:

1. First-line: Itraconazole solution 200 mg daily (or higher doses up to 400 mg daily for refractory disease) 1

   • Itraconazole solution is superior to capsules due to better absorption 1
   • Response rates of 64-80% for fluconazole-refractory infections 1

2. Second-line: Echinocandin therapy (micafungin 150 mg daily, caspofungin 70 mg loading then 50 mg daily, or anidulafungin 200 mg daily) 1

   • Particularly appropriate if C. krusei is identified, as it has intrinsic fluconazole resistance 1

3. Third-line: Voriconazole 200 mg twice daily (oral or IV) 1

4. Last resort: Amphotericin B deoxycholate 0.3-0.7 mg/kg daily IV 1

Critical Management Pitfalls to Avoid:

• Do not continue fluconazole monotherapy in this patient—the partial response followed by persistence indicates either resistance or wrong diagnosis 1
• Clotrimazole topical therapy alone is inadequate for persistent mucocutaneous infections; systemic therapy is required 1
• Metronidazole has no role in treating fungal or viral infections and should not be continued 1
• Patients with recurrent or persistent infections have significantly lower cure rates (33/84 vs 177/266, p<0.001) and require more aggressive, prolonged therapy 2

Duration and Monitoring

Treatment duration must be extended beyond symptom resolution:

• For mucocutaneous candidiasis: Continue therapy for 14-21 days minimum 1
• For azole-refractory disease: May require chronic suppressive therapy 1
• Follow-up evaluation at 1-2 weeks to confirm response; if no improvement, escalate therapy immediately 1

The combination of initial metronidazole use, development of a herpes-like ulcer, and failure of standard azole therapy strongly suggests either HSV reactivation or azole-resistant Candida—both require immediate diagnostic confirmation and treatment escalation as outlined above.