What is the recommended treatment for histoplasmosis?

Treatment of Histoplasmosis

For severe or moderately severe histoplasmosis, initiate liposomal amphotericin B (3.0-5.0 mg/kg IV daily) for 1-2 weeks, then transition to itraconazole (200 mg twice daily) to complete 12 weeks of total therapy. 1

Disease Severity Assessment and Treatment Selection

Severe or Moderately Severe Disease

Liposomal amphotericin B is superior to conventional amphotericin B deoxycholate, demonstrating 88% vs 64% response rates and 2% vs 13% mortality in AIDS patients with progressive disseminated histoplasmosis. 1

• Initial therapy: Liposomal amphotericin B 3.0-5.0 mg/kg IV daily for 1-2 weeks 1, 2
• Alternative lipid formulation: Amphotericin B lipid complex 5.0 mg/kg daily may be used due to lower cost 1
• Budget-constrained option: Amphotericin B deoxycholate 0.7-1.0 mg/kg IV daily is acceptable in patients at low risk for nephrotoxicity 1
• Step-down therapy: Transition to itraconazole 200 mg twice daily after clinical improvement to complete 12 weeks total treatment 1

For respiratory compromise with hypoxemia or significant distress, add methylprednisolone 0.5-1.0 mg/kg IV daily during the first 1-2 weeks of antifungal therapy. 1, 2

Mild to Moderate Disease

Itraconazole monotherapy is appropriate for mild to moderate presentations. 1

• Dosing: Itraconazole 200 mg three times daily for 3 days (loading), then 200 mg once or twice daily for 6-12 weeks 1, 2
• Self-limited cases: Treatment is unnecessary if symptoms resolve within 4 weeks 1, 2
• Persistent symptoms: Treat with itraconazole if symptoms continue beyond 1 month 1

Disease-Specific Treatment Durations

Chronic Cavitary Pulmonary Histoplasmosis

• Itraconazole 200 mg once or twice daily for at least 12 months is required, though 18-24 months may be preferred given the 15% relapse rate 1, 2

Progressive Disseminated Histoplasmosis

• Moderately severe to severe: Liposomal amphotericin B 3.0 mg/kg daily for 1-2 weeks, then itraconazole 200 mg twice daily for at least 12 months 1
• Mild to moderate: Itraconazole 200 mg twice daily for at least 12 months 1
• Immunosuppressed patients: Lifelong suppressive therapy with itraconazole 200 mg daily may be required if immunosuppression cannot be reversed 1

CNS Histoplasmosis

• Amphotericin B deoxycholate 1.0 mg/kg daily for 4-6 weeks is recommended 1
• Alternative: Amphotericin B deoxycholate 1.0 mg/kg daily for 2-4 weeks, then itraconazole 5.0-10.0 mg/kg daily (divided doses) to complete 3 months 1

Critical Monitoring Requirements

Itraconazole Therapeutic Drug Monitoring

Blood levels must be obtained after 2 weeks of steady-state therapy to ensure adequate drug exposure. 1, 2

• Target concentration: At least 1 mcg/mL (MIC90 for H. capsulatum is 0.02 mcg/mL) 1
• Monitor in these situations: Suspected treatment failure, absorption concerns, drug interactions, or when reducing from twice to once daily dosing 1
• Hepatic enzyme monitoring: Measure at baseline, then at 1,2, and 4 weeks, then every 3 months during therapy 1, 2

Histoplasma Antigen Monitoring

Antigen levels should be measured during therapy and for 12 months after treatment completion to monitor for relapse. 1

• Antigen clears from urine and serum at rates of 0.2 and 0.3 units per week, respectively 3
• Persistent low-level antigenuria may not require prolonged treatment in patients who completed appropriate therapy without active infection 1

Critical Absorption and Drug Interaction Considerations

Itraconazole Formulation Selection

The oral solution is preferred over capsules due to higher bioavailability. 1

• Capsules: Require high gastric acidity; take with food or cola beverage 1, 2
• Contraindication for capsules: Patients on antacids, H2 blockers, or proton pump inhibitors due to decreased absorption 1, 2
• Solution: Take on empty stomach for optimal absorption, though some patients experience gastrointestinal intolerance 1

When Treatment is NOT Indicated

Do not treat asymptomatic patients with healed histoplasmosis manifestations: 1, 2

• Asymptomatic pulmonary nodules
• Mediastinal lymphadenopathy (especially if calcified)
• Calcified splenic lesions
• Presumed ocular histoplasmosis syndrome (does not respond to antifungal therapy) 1, 2

Alternative Agents for Salvage Therapy

Fluconazole is less effective than itraconazole (70% efficacy in non-AIDS disseminated disease), and resistance can develop in treatment failures. 1

• Posaconazole has shown success in small case series as salvage therapy when amphotericin B and itraconazole have failed 4
• Isavuconazole has been used successfully in isolated cases where first-line and second-line therapies failed or were contraindicated (excluding meningitis) 5