What is the treatment for invasive aspergillosis?

Treatment of Invasive Aspergillosis

Voriconazole is the recommended first-line treatment for invasive aspergillosis in most patients. 1 This recommendation is based on a large randomized clinical trial demonstrating superior efficacy compared to conventional amphotericin B, with better survival rates (70.8% vs 57.9% at 12 weeks) and fewer severe drug-related adverse events. 2, 3

First-Line Treatment Algorithm

1. Initial therapy:

   • Voriconazole:
     • Loading dose: 6 mg/kg IV every 12 hours for first 24 hours
     • Maintenance dose: 4 mg/kg IV every 12 hours (minimum 7 days)
     • Then switch to oral: 200 mg every 12 hours 1, 2
   • Pediatric dosing: 5-7 mg/kg IV every 12 hours 2

2. Duration of therapy:

   • Minimum 6-12 weeks 2
   • Continue until resolution or stabilization of all clinical and radiographic manifestations
   • Factors affecting duration: site of infection, level of immunosuppression, extent of disease 1

3. Monitoring during treatment:

   • Regular clinical evaluation of symptoms and signs
   • CT imaging at regular intervals
   • Serial serum galactomannan assays
   • Note: Volume of pulmonary infiltrates may increase during first 7-10 days of therapy (not necessarily treatment failure) 2
   • Regular liver function tests (voriconazole can cause hepatotoxicity) 2
   • Monitor for visual disturbances (occur in ~45% of patients on voriconazole) 3

Alternative First-Line Options

If voriconazole is contraindicated or not tolerated:

• Liposomal amphotericin B (L-AMB): 3-5 mg/kg/day IV 1, 2
• Posaconazole: Recent evidence shows non-inferiority to voriconazole for primary treatment with fewer treatment-related adverse events 4
  • Dosing: 300 mg twice on day 1, followed by 300 mg once daily 4

Salvage Therapy Options

For patients refractory to or intolerant of primary therapy:

1. Lipid formulations of amphotericin B (LFAB): 5 mg/kg/day IV 1
2. Posaconazole: 200 mg QID initially, then 400 mg BID after stabilization 1, 5
3. Caspofungin: 70 mg day 1 IV, then 50 mg/day IV thereafter 1
4. Micafungin: 100-150 mg/day IV 1
5. Itraconazole: Dosage depends on formulation 1

Combination Therapy

• Not routinely recommended for primary therapy due to lack of clinical data 1
• May be considered in salvage settings or for severe cases, especially in patients with hematologic malignancy or profound neutropenia 2
• Common combination: voriconazole plus an echinocandin 2

Critical Adjunctive Measures

1. Reduce or eliminate immunosuppression when feasible - this is crucial for favorable outcomes 1, 2
2. Consider surgical resection for:
   • Lesions contiguous with great vessels or pericardium
   • Invasion of chest wall
   • Emphysema
   • Persistent hemoptysis from a single cavitary lesion 2

Special Considerations

1. Drug interactions: Voriconazole has significant interactions with other medications, particularly anticonvulsants in patients with CNS involvement 2

2. Pharmacogenomics: CYP2C19 polymorphisms affect voriconazole metabolism:

   • Poor metabolizers (15-20% of Asian populations, 3-5% of Caucasians and Blacks) have 4-fold higher voriconazole exposure
   • Heterozygous extensive metabolizers have 2-fold higher exposure 6

3. Prevention of recurrence: For patients requiring subsequent immunosuppression after successful treatment, secondary prophylaxis should be initiated 2

Common Pitfalls to Avoid

1. Inadequate duration of therapy: Premature discontinuation before clinical and radiographic resolution
2. Failure to monitor drug levels: Therapeutic drug monitoring is important, especially for azoles
3. Missing drug interactions: Always check for potential interactions before starting therapy
4. Overlooking immunosuppression management: Reducing immunosuppression when possible is critical for successful outcomes
5. Relying solely on galactomannan normalization: Resolution of galactomannan antigenemia is not sufficient as a sole criterion for discontinuation of therapy 2

Invasive aspergillosis remains a serious infection with significant mortality despite advances in antifungal therapy. Early diagnosis and prompt initiation of appropriate antifungal therapy, along with reduction of immunosuppression when possible, are essential for improving outcomes.