What is the recommended treatment for aspergillosis?

Treatment of Aspergillosis

Voriconazole is the first-line treatment for invasive aspergillosis, with demonstrated superior efficacy and survival compared to amphotericin B formulations. 1, 2, 3

Invasive Aspergillosis (Primary Treatment)

Initial Therapy - Voriconazole Dosing

• Loading dose: 6 mg/kg IV every 12 hours for the first 24 hours 1, 4
• Maintenance dose: 4 mg/kg IV every 12 hours for minimum 7 days 1, 4
• Oral transition: Switch to 200 mg PO every 12 hours once clinically improved and able to tolerate oral intake 1, 4
• Pediatric dosing (≥2 years): 5-7 mg/kg IV every 12 hours 5, 2

The landmark randomized trial demonstrated 52.8% successful outcomes with voriconazole versus 31.6% with amphotericin B, with 12-week survival of 70.8% versus 57.9% respectively 3. This represents a 21.2 percentage point absolute difference in response rates 3.

Critical Monitoring Requirement

• Therapeutic drug monitoring is mandatory due to variable pharmacokinetics and narrow therapeutic window 5, 2
• Target trough levels must be monitored to ensure adequate serum concentrations 5
• Approximately 15-20% of Asian populations and 3-5% of Caucasians/Blacks are CYP2C19 poor metabolizers with 4-fold higher voriconazole exposure 4

Alternative Primary Therapy

• Liposomal amphotericin B (L-AmB): 3-5 mg/kg/day IV for patients with voriconazole contraindications or intolerance 1, 5, 2
• Isavuconazole: 200 mg every 8 hours for 6 doses, then 200 mg daily 1
• Posaconazole: Non-inferior to voriconazole with 15% mortality at day 42 versus 21% with voriconazole, and better tolerability (30% versus 40% treatment-related adverse events) 6

Treatment Duration

• Minimum 6-12 weeks or until complete resolution/stabilization of clinical and radiographic findings 1, 5, 2
• Continue therapy throughout immunosuppression period 5
• Median IV duration in clinical trials was 10 days (range 2-85 days), followed by median oral duration of 76 days (range 2-232 days) 1, 4

Salvage Therapy Options (for refractory or intolerant patients)

• Lipid formulations of amphotericin B: ABLC 5 mg/kg/day IV or L-AmB 3-5 mg/kg/day IV 1, 5
• Caspofungin: 70 mg IV loading dose day 1, then 50 mg/day IV 1, 5
• Micafungin: 100-150 mg/day IV 1
• Posaconazole: Multiple formulations available (oral suspension 200 mg TID, tablet 300 mg BID day 1 then 300 mg daily, IV 300 mg BID day 1 then 300 mg daily) 1
• Itraconazole suspension: 200 mg PO every 12 hours 1

Site-Specific Aspergillosis Management

CNS Aspergillosis

• Voriconazole is strongly recommended as primary therapy due to superior CNS penetration 1, 2
• L-AmB reserved for voriconazole-intolerant or refractory cases 1
• Highest mortality among all invasive aspergillosis patterns 1
• Monitor for drug interactions with anticonvulsants 1

Invasive Sinus Aspergillosis

• Surgical debridement plus systemic antifungal therapy (voriconazole or L-AmB) 1
• Surgical removal alone sufficient for aspergilloma (fungal ball) of paranasal sinus 1
• Enlargement of sinus ostomy may prevent recurrence 1

Cardiac Aspergillosis (Endocarditis/Pericarditis/Myocarditis)

• Early surgical intervention combined with antifungal therapy to prevent embolic complications and valvular decompensation 1
• Voriconazole or L-AmB as initial therapy 1
• Lifelong antifungal therapy should be considered following valve replacement 1
• Aspergillus pericarditis usually requires pericardiectomy 1

Osteomyelitis and Septic Arthritis

• Surgical resection of devitalized bone and cartilage combined with voriconazole 1
• Surgical intervention is critical for curative intent 1

Endophthalmitis

• Systemic voriconazole (IV or oral) plus intravitreal voriconazole or intravitreal amphotericin B deoxycholate 1

Cutaneous Aspergillosis

• Voriconazole plus evaluation for primary disseminated focus 1
• Surgical debridement required for burns or massive soft tissue wounds 1

Tracheobronchial Aspergillosis

• Similar to invasive pulmonary aspergillosis 1
• Adjunctive inhaled amphotericin B may be useful 1

Chronic and Allergic Forms

Chronic Pulmonary Aspergillosis

• Itraconazole or voriconazole are preferred for protracted therapy 2
• Itraconazole 200 mg PO every 12 hours is the preferred long-term oral option 2
• Long-term therapy measured in months is required 2

Aspergilloma

• Observation or surgical resection are primary management strategies 2
• Medical therapy role remains uncertain 2
• Itraconazole has excellent cavity penetration if medical therapy attempted 2

Allergic Bronchopulmonary Aspergillosis (ABPA)

• Itraconazole combined with corticosteroids is treatment of choice 2
• Provides demonstrable corticosteroid-sparing effect 2

Allergic Fungal Rhinosinusitis

• Polypectomy and sinus washout as optimal means of symptom control 1
• Topical nasal steroids to reduce symptoms and increase time to relapse, especially post-surgery 1
• Oral mold-active triazoles for refractory/rapidly relapsing disease (weak recommendation, only partially effective) 1

Critical Pitfalls to Avoid

Never Use Amphotericin B Deoxycholate When Alternatives Exist

• Substantial nephrotoxicity and infusion-related adverse events make this agent inappropriate when other options are available 1, 2
• IDSA guidelines recommend it only for resource-limited settings 7

Always Perform Therapeutic Drug Monitoring for Voriconazole

• Variable pharmacokinetics necessitate monitoring 5, 2
• Genetic polymorphism in CYP2C19 causes 4-fold exposure differences 4

Reversal of Immunosuppression is Critical

• Essential for favorable outcomes in invasive aspergillosis 2
• Must be addressed concurrently with antifungal therapy

Consider Surgical Intervention for Specific Sites

• Mandatory for: endocarditis (valve replacement), osteomyelitis (debridement), invasive sinus disease (debridement), localized refractory lesions 1, 2

Drug Interactions Require Vigilance

• Particularly with voriconazole and anticonvulsants in CNS aspergillosis 1
• Dose adjustments needed with phenytoin or efavirenz co-administration 4

Combination Therapy Not Routinely Recommended

• Primary combination therapy lacks evidence for routine use 1
• May be considered for salvage therapy in individual refractory cases 1