What is the recommended treatment for aspergillosis?

Treatment of Aspergillosis

Voriconazole is the first-line treatment for invasive aspergillosis, with a loading dose of 6 mg/kg IV every 12 hours for 24 hours, followed by 4 mg/kg IV every 12 hours (or 200 mg orally every 12 hours after clinical improvement), demonstrating superior efficacy and survival compared to amphotericin B. 1, 2, 3

Primary Treatment Algorithm for Invasive Aspergillosis

Initial Therapy Selection

• Start voriconazole immediately as primary therapy for invasive pulmonary aspergillosis (IPA), invasive sinus aspergillosis, tracheobronchial aspergillosis, and CNS aspergillosis 1
• Voriconazole achieved 52.8% successful outcomes versus 31.6% with amphotericin B at 12 weeks, with 70.8% survival versus 57.9% 4
• The drug demonstrates superior efficacy across all forms of invasive disease, including disseminated infections 1, 2, 5

Dosing Regimen

Adults:

• Loading dose: 6 mg/kg IV every 12 hours for the first 24 hours 1, 3
• Maintenance dose: 4 mg/kg IV every 12 hours for minimum 7 days 1, 3
• Switch to oral: 200 mg every 12 hours once clinically improved and able to tolerate oral intake 1, 3
• For patients <40 kg: reduce oral maintenance dose by half 3

Pediatric patients (≥2 years, not neonates):

• 5-7 mg/kg IV every 12 hours 1, 2

Neonates:

• Use liposomal amphotericin B as first choice instead of voriconazole 2

Treatment Duration

• Continue IV therapy for minimum 7 days before considering oral switch 1, 3
• Total treatment duration: 6-12 weeks minimum 2, 5
• Continue therapy throughout immunosuppression period until complete resolution or stabilization of clinical and radiographic findings 2, 5
• Median duration in clinical trials: 10 days IV followed by 76 days oral 1, 3

Alternative Primary Therapy Options

When voriconazole is contraindicated or not tolerated:

• Liposomal amphotericin B (L-AmB): 3-5 mg/kg/day IV 1, 2, 5
• 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% versus 40%) 6

Salvage Therapy for Refractory Disease

If inadequate response to primary therapy:

• Switch drug class: Consider lipid formulations of amphotericin B (ABLC 5 mg/kg/day IV) 1, 5
• Echinocandins: Caspofungin (70 mg loading dose day 1, then 50 mg/day IV) or micafungin (100-150 mg/day IV) 1, 5
• Alternative azoles: Posaconazole or itraconazole with therapeutic drug monitoring 1, 5
• Combination therapy: May be considered for salvage but not routinely recommended for primary treatment 1, 5

Dose Adjustment Strategy

If response is inadequate:

• Increase oral maintenance from 200 mg to 300 mg every 12 hours 3
• For patients <40 kg: increase from 100 mg to 150 mg every 12 hours 3

If intolerance occurs:

• Reduce oral dose by 50 mg increments to minimum 200 mg every 12 hours 3
• Reduce IV maintenance from 4 mg/kg to 3 mg/kg every 12 hours 3

Critical Monitoring Requirements

• Therapeutic drug monitoring (TDM) is mandatory for voriconazole due to variable pharmacokinetics and narrow therapeutic window 2, 7, 5
• Monitor trough levels to ensure adequate serum concentrations, particularly in treatment failure 2, 7, 5
• Regular clinical and radiographic assessments to evaluate treatment response 7

Site-Specific Considerations

CNS Aspergillosis:

• Voriconazole is particularly recommended due to blood-brain barrier penetration 7
• This infection carries the highest mortality among all invasive aspergillosis patterns 1
• Monitor for drug interactions with anticonvulsant therapy 1

Invasive Sinus Aspergillosis:

• Surgical debridement as adjunct to medical therapy 1

Cardiac Aspergillosis:

• Endocardial lesions require surgical resection 1
• Pericarditis usually requires pericardiectomy 1

Osteomyelitis/Septic Arthritis:

• Surgical resection of devitalized bone and cartilage is important for curative intent 1

Treatment of Allergic Forms

Allergic Fungal Rhinosinusitis:

• Polypectomy and sinus washout as optimal 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) 1

Allergic Bronchopulmonary Aspergillosis in Cystic Fibrosis:

• Oral itraconazole with TDM for patients with frequent exacerbations and/or falling FEV1 to minimize corticosteroid use 1

Critical Pitfalls and Caveats

• Amphotericin B deoxycholate should be avoided when other options are available due to significant nephrotoxicity and infusion-related adverse events 1, 7
• Aspergillus terreus is clinically resistant to amphotericin B, necessitating azole therapy 5
• Visual disturbances occur in approximately 30-45% of voriconazole patients but are typically transient 3, 8, 4
• CYP2C19 polymorphism affects voriconazole metabolism: poor metabolizers (15-20% of Asians, 3-5% of Caucasians/Blacks) have 4-fold higher exposure, requiring dose adjustment 3
• Primary combination therapy is not routinely recommended based on lack of clinical data supporting improved outcomes 1, 5
• Voriconazole must be administered at least one hour before or after meals 3