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
Invasive Aspergillosis (Primary Treatment)
Initial Therapy
Voriconazole should be initiated with a loading dose of 6 mg/kg IV every 12 hours for the first 24 hours, followed by a maintenance dose of 4 mg/kg IV every 12 hours for a minimum of 7 days. 1, 3
- After clinical improvement and ability to tolerate oral medication, switch to oral voriconazole 200-300 mg every 12 hours 1, 3
- The 200 mg oral dose achieves exposure similar to 3 mg/kg IV; the 300 mg oral dose achieves exposure similar to 4 mg/kg IV 3
- Therapeutic drug monitoring is mandatory due to variable pharmacokinetics and narrow therapeutic window 4, 2
- In the pivotal trial, voriconazole achieved 52.8% successful outcomes versus 31.6% with amphotericin B, with 70.8% survival at 12 weeks versus 57.9% 5
Pediatric Dosing
- For patients ≥2 years (not neonates): 5-7 mg/kg IV every 12 hours 1, 4
- Neonates should receive liposomal amphotericin B as first choice 4
Alternative Primary Therapy
When voriconazole is contraindicated or not tolerated:
- Liposomal amphotericin B (L-AmB) 3-5 mg/kg/day IV 1, 2
- Isavuconazole 200 mg every 8 hours for 6 doses, then 200 mg daily 1
- Posaconazole demonstrated non-inferiority to voriconazole with 15% mortality versus 21%, and fewer treatment-related adverse events (30% vs 40%) 6
Salvage Therapy Options
For refractory disease or intolerance to primary therapy:
- ABLC (amphotericin B lipid complex) 5 mg/kg/day IV 1
- Caspofungin: 70 mg loading dose day 1, then 50 mg/day IV (pediatric: 50 mg/m²/day) 1
- Micafungin 100-150 mg/day IV 1
- Posaconazole (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
Treatment Duration
- Continue therapy for 6-12 weeks minimum 4, 7
- Treat throughout the period of immunosuppression and until complete resolution or stabilization of clinical and radiographic findings 4, 7
- Median IV voriconazole duration in clinical trials was 10 days (range 2-85 days), followed by median oral therapy of 76 days (range 2-232 days) 3
Combination Therapy
- Primary combination therapy is NOT routinely recommended based on lack of clinical data 1
- Consider adding another agent or switching drug class for salvage therapy in individual patients 1
Site-Specific Considerations
Invasive Sinus Aspergillosis
- Use same antifungal regimen as invasive pulmonary aspergillosis 1
- Surgical debridement is essential as adjunct to medical therapy 1
Tracheobronchial Aspergillosis
- Use same antifungal regimen as invasive pulmonary aspergillosis 1
- Adjunctive inhaled amphotericin B may be useful 1
CNS Aspergillosis
- Use same antifungal regimen as invasive pulmonary aspergillosis 1
- This infection carries the highest mortality among all patterns of invasive aspergillosis 1
- Monitor for drug interactions with anticonvulsant therapy 1
- Voriconazole is particularly advantageous due to CNS penetration 7
Cardiac Aspergillosis (Endocarditis, Pericarditis, Myocarditis)
- Use same antifungal regimen as invasive pulmonary aspergillosis 1
- Endocardial lesions require surgical resection 1
- Aspergillus pericarditis usually requires pericardiectomy 1
Aspergillus Osteomyelitis and Septic Arthritis
- Use same antifungal regimen as invasive pulmonary aspergillosis 1
- Surgical resection of devitalized bone and cartilage is essential for curative intent 1
Chronic Pulmonary Aspergillosis
- Itraconazole or voriconazole are preferred for protracted oral therapy 2
- Itraconazole 200 mg PO every 12 hours is the preferred option for long-term therapy 2
- Treatment duration measured in months is required 1, 2
Allergic Bronchopulmonary Aspergillosis (ABPA)
- Itraconazole combined with corticosteroids is the treatment of choice 2
- Itraconazole provides demonstrable corticosteroid-sparing effect, minimizing steroid-related side effects 2
- In CF patients with frequent exacerbations and/or falling FEV₁, treat with oral itraconazole with therapeutic drug monitoring 1
Allergic Fungal Rhinosinusitis
- Polypectomy and sinus washout are the optimal means of symptom control and inducing remission, though relapse is frequent 1
- Topical nasal steroids reduce symptoms and increase time to relapse, especially after surgery 1
- Oral antifungal therapy using mold-active triazoles for refractory infection and/or rapidly relapsing disease, though only partially effective 1
Aspergilloma
- Management prioritizes observation or surgical resection, as the role of medical therapy remains uncertain 2
- Itraconazole has excellent cavity penetration and can be used as medical therapy 2
Critical Pitfalls to Avoid
Never Use Amphotericin B Deoxycholate When Alternatives Exist
- Amphotericin B deoxycholate causes substantial nephrotoxicity, particularly at doses required for aspergillosis 1
- Nephrotoxicity is exacerbated by concomitant cyclosporine, tacrolimus, or underlying renal impairment 1
- Voriconazole and second-generation triazoles show significantly superior efficacy and safety compared to deoxycholate formulation 5, 8
Therapeutic Drug Monitoring is Mandatory for Voriconazole
- Variable pharmacokinetics and narrow therapeutic window require monitoring 4, 2
- Target trough levels ensure adequate serum concentrations 4
- CYP2C19 polymorphism significantly affects exposure: poor metabolizers (15-20% of Asians, 3-5% of Caucasians/Blacks) have 4-fold higher exposure 3
Monitor for Drug Interactions
- Voriconazole interacts with anticonvulsants in CNS aspergillosis 1, 2
- Increase voriconazole dose when co-administered with phenytoin or efavirenz 3
- Decrease dose in patients with hepatic impairment 3
Reversal of Immunosuppression is Critical
- Favorable outcomes depend on reversing underlying immunosuppression 2
- Consider surgical intervention for localized disease refractory to medical therapy 4, 2