High-dose induction liposomal amphotericin B followed by de-escalation is effective in experimental Aspergillus terreus pneumonia

Abstract

Aspergillus terreus is considered to be resistant to amphotericin B (AMB). However, it is unknown whether higher daily doses of liposomal AMB (L-AMB) can overcome this resistance in vivo. We evaluated the efficacy and total lung homogenate AMB concentrations of escalating intravenous doses of L-AMB (3-20 mg/kg daily) versus an induction-de-escalation dosing strategy (10 mg/kg/day ×3 days, then 3 mg/kg/day) in an experimental neutropenic murine model of A. terreus pneumonia. BALB/c mice were rendered neutropenic with cyclophosphamide and administered cortisone acetate prior to intranasal inoculation (3.5 × 10(6) conidia) with A. terreus (Etest MIC 8 mg/L). Mice were then treated with L-AMB regimens for 5-7 days. The efficacy was assessed by animal survival and quantitative PCR lung fungal burden. Total AMB lung homogenate concentrations were determined by HPLC. Compared with untreated controls, 10 mg/kg/day L-AMB prolonged survival (mean >7 versus 3-4 days, P < 0.003) and reduced A. terreus lung fungal burden (median log10 conidial DNA 5.0 versus 6.7, P < 0.05). Daily L-AMB regimens >10 mg/kg/day were associated with poorer survival and higher lung fungal burden. The induction-de-escalation strategy of 10 mg/kg/day ×3 days followed by 3 mg/kg/day was as effective as 10 mg/kg daily dosing, and resulted in higher mean AMB lung homogenate concentrations compared with a continuous 10 mg/kg regimen (23.2 ± 6.7 versus 16.4 ± 4.4 μg/g, P = 0.09). A high-dose induction-de-escalation L-AMB dosing strategy was an effective treatment for experimental A. terreus pneumonia in neutropenic mice.