What is the recommended treatment for histoplasmosis?

Management of Histoplasmosis

Initial Treatment Decision Based on Disease Severity

For severe or moderately severe histoplasmosis, initiate lipid formulation amphotericin B (3.0-5.0 mg/kg IV daily) or amphotericin B deoxycholate (0.7-1.0 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 any of the following:

• Respiratory insufficiency requiring ventilatory support 3
• Hypoxemia or significant respiratory distress 1, 2, 3
• Hemodynamic compromise 3
• Diffuse pulmonary infiltrates with hypoxemia following heavy exposure 1, 2

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. 2, 3 Amphotericin B lipid complex is an acceptable lower-cost alternative. 3

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, hypoxemia, or significant respiratory distress. 1, 2, 3 Concurrent itraconazole is mandatory to prevent progressive infection from corticosteroid-induced immunosuppression. 1, 3

Mild to Moderate Disease

For mild to moderate histoplasmosis, 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. 1, 2, 3

When Treatment Can Be Withheld

• Symptoms lasting less than 4 weeks in immunocompetent patients may not require treatment, as the condition is often self-limited and resolves within 3 weeks in approximately 95% of cases. 1, 2
• Do not treat based solely on positive antibody tests or antigen detection in patients with minimal symptoms, as these may reflect past exposure rather than active disease. 2
• Treatment is not indicated for asymptomatic patients with healed manifestations such as pulmonary nodules, mediastinal lymphadenopathy, or calcified splenic lesions. 2

Disease-Specific Treatment Durations

Chronic Cavitary Pulmonary Histoplasmosis

Itraconazole 200 mg once or twice daily for at least 12 months is required for chronic cavitary disease. 1, 2, 3 Relapse occurs in approximately 15% of cases. 1, 2

Disseminated Histoplasmosis in AIDS

Amphotericin B formulation for 1-2 weeks, then itraconazole 200 mg twice daily, with lifelong maintenance therapy is mandatory to prevent relapse. 1, 3 Patients with moderately severe or severe disease should first receive amphotericin B before transitioning to itraconazole. 4

CNS Histoplasmosis (Meningitis)

Amphotericin B for 3 months, then fluconazole for 12 months is recommended due to poor outcomes with shorter courses. 1, 3

Mediastinal Complications

• Mediastinal lymphadenitis with symptoms ≥4 weeks: Itraconazole 200 mg once or twice daily for 6-12 weeks 1
• If corticosteroids are required for airway/esophageal compression: Add itraconazole 200 mg once or twice daily for 6-12 weeks to prevent dissemination 1
• Pericarditis (mild): Nonsteroidal anti-inflammatory agents 1
• Pericarditis (severe): Prednisone 0.5-1.0 mg/kg daily in tapering doses over 1-2 weeks plus itraconazole 200 mg once or twice daily for 6-12 weeks 1

Critical Monitoring Requirements

Itraconazole Blood Levels

Measure itraconazole blood levels after at least 2 weeks of therapy to ensure adequate drug exposure, targeting a concentration ≥1 mg/mL. 2, 3 Recheck levels in cases of suspected treatment failure, concerns about absorption, drug interactions, or when adjusting dosage. 2

Hepatic Monitoring

Measure hepatic enzymes before starting azole therapy, then at 1,2, and 4 weeks, then every 3 months during treatment. 2, 3

Common Pitfalls and How to Avoid Them

Itraconazole Absorption Issues

Itraconazole capsules require high gastric acidity and must be taken with food or a cola drink. 2, 3 Do not use itraconazole capsules in patients taking antacids, H2 blockers, or proton pump inhibitors due to severely impaired absorption. 2, 3 Consider itraconazole oral solution or alternative antifungal agents in these patients.

Fluconazole Should Be Avoided

Fluconazole should not be used as primary therapy due to lower efficacy (64% response rate versus 75-85% for itraconazole) and potential for resistance development. 1, 3 Fluconazole is reserved only for CNS disease after initial amphotericin B therapy. 1, 3

Inappropriate Treatment of Ocular Disease

Presumed ocular histoplasmosis syndrome does not respond to antifungal therapy and should not be treated with antifungals. 2

Alternative Agents for Salvage Therapy

When first-line and second-line therapies fail or are contraindicated (excluding meningitis), posaconazole or isavuconazole may be considered as salvage options, though evidence is limited to case reports and small case series. 5, 6