Treatment of Histoplasmosis
Initial Treatment Selection Based on Disease Severity
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 treatment. 1, 2, 3
Defining Severe Disease
Severe disease is characterized by:
- Respiratory insufficiency requiring ventilatory support 2
- Hypoxemia or significant respiratory distress 1, 2
- Hemodynamic compromise 2
- Patients requiring hospitalization 1
Amphotericin B Formulation Selection
Liposomal amphotericin B is superior to amphotericin B deoxycholate, demonstrating 88% versus 64% response rates and 2% versus 13% mortality in AIDS patients with disseminated disease 1, 2, 3. Amphotericin B lipid complex is an acceptable alternative at lower cost 1, 2. Amphotericin B deoxycholate (0.7-1.0 mg/kg IV daily) remains a reasonable option for patients at low risk for nephrotoxicity 1, 4.
Adjunctive Corticosteroid Therapy
Add methylprednisolone (0.5-1.0 mg/kg IV daily, maximum 80 mg) during the first 1-2 weeks for patients with respiratory complications or hypoxemia 2, 3. Concurrent itraconazole is mandatory to prevent progressive infection from corticosteroid-induced immunosuppression 2, 3.
Mild to Moderate Disease
Itraconazole (200 mg three times daily for 3 days, then 200 mg once or twice daily for 6-12 weeks) is the treatment of choice for mild to moderate histoplasmosis 1, 2, 3. For patients with symptoms lasting less than 4 weeks, treatment may be unnecessary as the condition is often self-limited 1, 3.
Disease-Specific Treatment Durations
Chronic Cavitary Pulmonary Histoplasmosis
Itraconazole 200 mg once or twice daily for at least 12 months 1, 2, 3. Relapse occurs in approximately 15% of cases 3.
Disseminated Histoplasmosis in AIDS
Amphotericin B formulation for 1-2 weeks, then itraconazole 200 mg twice daily, with lifelong maintenance therapy 1, 2. Suppressive therapy can be discontinued when CD4 count increases to >150 cells/mm³ on antiretroviral therapy for at least 6 months, with negative Histoplasma antigen 1.
CNS Histoplasmosis
Liposomal amphotericin B (5.0 mg/kg daily for a total of 175 mg/kg given over 4-6 weeks) followed by itraconazole (200 mg 2 or 3 times daily) for at least 1 year until resolution of CSF abnormalities 1, 2.
Progressive Disseminated Histoplasmosis in Infants
Amphotericin B deoxycholate (1.0 mg/kg daily for 4-6 weeks) 1. An alternative is amphotericin B deoxycholate (1.0 mg/kg daily for 2-4 weeks) followed by itraconazole (5.0-10.0 mg/kg daily in 2 divided doses) to complete 3 months of therapy 1, 5.
Critical Monitoring Requirements
Itraconazole Blood Levels
Measure itraconazole blood levels after 2 weeks of therapy to ensure adequate drug exposure, with a target concentration of ≥1 mg/mL 1, 2, 3. Blood concentrations should be monitored in cases of suspected treatment failure, concerns about absorption or compliance, drug interactions, or when adjusting dosage 1.
Hepatic Monitoring
Measure hepatic enzymes before starting azole therapy, and recheck at 1,2, and 4 weeks, then every 3 months during treatment 1, 2, 3.
Antigen Monitoring
Monitor Histoplasma antigen levels during therapy and for 12 months after therapy ends to detect relapse 1. Therapy should continue until antigen concentrations are <4 units in urine and serum 1.
Common Pitfalls to Avoid
Itraconazole Absorption Issues
Itraconazole capsules require high gastric acidity and must be taken with food or cola 1, 2, 3. Do not use itraconazole capsules in patients taking antacids, H2 blockers, or proton pump inhibitors due to severely impaired absorption 1, 2, 3. The oral solution formulation should be used whenever possible as it achieves 30% higher blood concentrations than capsules 1.
Fluconazole Should Be Avoided
Fluconazole should be avoided as primary therapy due to lower efficacy (70% response rate versus 100% with itraconazole) and potential for resistance development 1, 2. Fluconazole is reserved only for CNS histoplasmosis after initial amphotericin B therapy 1, 2.
Drug Interactions
Itraconazole should not be given to patients receiving contraindicated medications including pimozide, quinidine, dofetilide, lovastatin, simvastatin, midazolam, and triazolam 1.
Unnecessary Treatment
Do not treat asymptomatic patients with healed manifestations such as pulmonary nodules, mediastinal lymphadenopathy, or calcified splenic lesions 1, 3. Presumed ocular histoplasmosis syndrome does not respond to antifungal therapy 1, 3.