What is the recommended treatment for aspergillosis?

Treatment of Aspergillosis

Voriconazole is the first-line treatment for invasive aspergillosis, with superior efficacy and survival compared to amphotericin B formulations, and should be initiated immediately in patients with suspected or confirmed disease. 1, 2, 3

Primary Treatment Regimen

Invasive Pulmonary Aspergillosis

• 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
• The landmark randomized trial demonstrated 52.8% successful outcomes at 12 weeks with voriconazole versus 31.6% with amphotericin B deoxycholate, with 12-week survival of 70.8% versus 57.9% (hazard ratio 0.59), representing a significant mortality benefit 3, 5

CNS Aspergillosis

• Same voriconazole dosing as pulmonary disease (loading 6 mg/kg IV q12h × 24h, then maintenance 4 mg/kg IV q12h) 6
• Surgical resection is strongly recommended as adjunct therapy whenever feasible, as it significantly improves survival (p=0.02) 6
• Voriconazole penetrates well into the CNS, unlike other antifungal agents, making it uniquely suited for CNS infections 6

Alternative Primary Therapy

Liposomal amphotericin B (L-AmB) 3-5 mg/kg/day IV is the preferred alternative when voriconazole is contraindicated or not tolerated 1, 2, 3

• A randomized trial comparing L-AmB doses of 3 mg/kg/day versus 10 mg/kg/day showed similar efficacy but greater toxicity in the higher-dose arm, establishing 3 mg/kg/day as appropriate 1
• L-AmB is particularly important for patients with renal insufficiency, as IV voriconazole contains sulfobutyl-ether cyclodextrin vehicle that accumulates in renal impairment 3

Posaconazole demonstrated non-inferiority to voriconazole in a 2021 phase 3 trial, with 15% mortality at day 42 versus 21% with voriconazole (treatment difference -5.3%), and fewer treatment-related adverse events (30% vs 40%) 7

• Dosing: 300 mg IV or PO twice on day 1, then 300 mg once daily 7
• This establishes posaconazole as a viable first-line alternative, though it is FDA-approved only for salvage therapy in the United States 1

Salvage Therapy Options

When voriconazole fails, switch drug classes rather than to another azole 1, 3

Options include:

• Lipid formulations of amphotericin B (A-II recommendation) 1, 3
• Posaconazole (B-II recommendation) 1, 3
• Itraconazole (B-II recommendation) 1, 3
• Caspofungin (loading 70 mg day 1, then 50 mg/day IV) or micafungin (B-II recommendation) 1, 2

Treatment Duration

• Minimum 6-12 weeks for invasive pulmonary aspergillosis 1, 2
• Continue throughout the period of immunosuppression and until lesions have resolved 1, 2
• In the pivotal trial, median IV voriconazole duration was 10 days (range 2-85), followed by median oral duration of 76 days (range 2-232) 1, 4
• CNS aspergillosis requires long-term therapy measured in months 6

Therapeutic Drug Monitoring

TDM is mandatory for voriconazole due to highly variable pharmacokinetics and narrow therapeutic window 2, 3, 8

• Target trough concentrations: 1-4 mg/L (measured by HPLC) 3, 8
• Voriconazole exhibits genetic polymorphism via CYP2C19, with poor metabolizers (15-20% of Asians, 3-5% of Caucasians/Blacks) having 4-fold higher exposure 4

Dose Adjustments

If inadequate response:

• Increase oral maintenance from 200 mg q12h to 300 mg q12h 4
• For patients <40 kg, increase from 100 mg q12h to 150 mg q12h 4

If intolerance:

• Reduce oral dose by 50 mg steps to minimum 200 mg q12h 4
• Reduce IV maintenance from 4 mg/kg q12h to 3 mg/kg q12h 4

Critical Pitfalls and Considerations

Drug Interactions

• Voriconazole has significant interactions with phenytoin and other anticonvulsants commonly used in CNS infections 6
• Dose increases required when co-administered with phenytoin or efavirenz 4

Hepatic Impairment

• Reduce maintenance dose in hepatic impairment, as voriconazole is hepatically metabolized with minimal renal excretion 3

Renal Impairment

• Avoid IV voriconazole in renal insufficiency due to cyclodextrin vehicle accumulation; use oral formulation if tolerated 3

Resistance Considerations

• Switch to L-AmB for isolates with voriconazole MIC >2 mg/L 3
• Consider combination therapy with echinocandin or L-AmB monotherapy for MIC = 2 mg/L (intermediate) 3

Breakthrough Infections

• Breakthrough invasive aspergillosis during mould-active azole prophylaxis requires switching to another drug class 1

Monitoring

• Serial clinical evaluation and CT imaging at regular intervals 1
• Pulmonary infiltrate volume may increase for first 7-10 days, especially with granulocyte recovery 1
• Serial galactomannan assays are promising but resolution to normal is not sufficient alone for discontinuing therapy 1

Adjunctive Measures

• Reversal of immunosuppression is critical for favorable outcomes 6
• For patients requiring subsequent immunosuppression after successful treatment, resumption of antifungal therapy prevents recurrent infection (A-III) 1