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 Algorithm
Severe or Moderately Severe Disease
Initial therapy with amphotericin B formulations is mandatory for patients requiring hospitalization, those with respiratory compromise, or disseminated disease. 1
Liposomal amphotericin B (3.0 mg/kg IV daily) is the preferred formulation, demonstrating superior outcomes with 88% response rate versus 64% for conventional amphotericin B, and dramatically lower mortality (2% vs 13%) in AIDS patients with disseminated disease 1
Amphotericin B lipid complex (5.0 mg/kg daily) is an acceptable alternative when cost is a limiting factor 1
Amphotericin B deoxycholate (0.7-1.0 mg/kg daily) remains appropriate for patients at low risk for nephrotoxicity 1
After 1-2 weeks of amphotericin B and clinical improvement, transition to itraconazole (200 mg three times daily for 3 days, then 200 mg twice daily) to complete 12 weeks total therapy 1, 2
Add methylprednisolone (0.5-1.0 mg/kg IV daily) during the first 1-2 weeks if respiratory complications develop, including hypoxemia or significant respiratory distress. 1, 2 The inflammatory response contributes to respiratory compromise in severe pulmonary histoplasmosis 1
Mild to Moderate Disease
Itraconazole monotherapy (200 mg three times daily for 3 days, then 200 mg once or twice daily for 6-12 weeks) is appropriate for outpatient management. 1, 2
Treatment is unnecessary for symptoms lasting less than 4 weeks, as mild acute pulmonary histoplasmosis is often self-limited 1, 2
Consider treatment only if symptoms persist 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 preferable 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, followed by 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
Lifelong suppressive therapy with itraconazole (200 mg daily) is required in immunosuppressed patients if immunosuppression cannot be reversed 1
CNS Histoplasmosis (Meningitis)
Amphotericin B deoxycholate (1.0 mg/kg daily) for 4-6 weeks is recommended, or 2-4 weeks followed by itraconazole to complete 3 months 1
Critical Monitoring Requirements
Itraconazole Therapeutic Drug Monitoring
Measure itraconazole serum levels after 2 weeks of therapy to ensure adequate drug exposure. 1, 2 This is strongly recommended for life-threatening infections given wide intersubject variability in absorption 1
Indications for drug level monitoring include: 1
- Suspected treatment failure
- Concerns about compliance or absorption
- Concomitant medications affecting itraconazole metabolism
- Dose adjustment considerations
Target serum concentration should be ≥1 mg/mL, as the MIC90 for H. capsulatum is 0.02 mg/mL 1
Hepatotoxicity Monitoring
Measure hepatic enzyme levels before starting azole therapy, then at 1,2, and 4 weeks, followed by every 3 months during treatment. 1, 2
Antigen Monitoring
Monitor Histoplasma antigen levels during therapy and for 12 months after completion to detect relapse. 1 Antigen clears from urine and serum at rates of 0.2 and 0.3 units per week, respectively 3
Critical Absorption Considerations for Itraconazole
Itraconazole capsules require high gastric acidity for absorption and must be taken with food or a cola beverage. 1, 2
Do not use itraconazole capsules in patients receiving antacids, H2 blockers, or proton pump inhibitors due to severely impaired absorption. 1, 2 Use the oral solution instead, taken on an empty stomach for optimal absorption 1
The oral solution achieves approximately 30% higher serum concentrations than capsules, though wide variability persists 1
When Treatment Is NOT Indicated
Do not treat asymptomatic patients with healed histoplasmosis manifestations: 1, 2
- Pulmonary nodules
- Mediastinal lymphadenopathy
- Calcified splenic lesions
Presumed ocular histoplasmosis syndrome does not respond to amphotericin B and should not be treated with antifungals. 1, 2
Alternative Agents When First-Line Therapy Fails
Fluconazole is less effective than itraconazole (70% vs higher response rates) and should be reserved for patients intolerant of itraconazole 1
Posaconazole and isavuconazole have shown promise in salvage therapy when amphotericin B and itraconazole have failed or are contraindicated, though data remain limited to case series 4, 5