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

• Published in: Journal of antimicrobial chemotherapy 2013-05, Vol.68 (5), p.1148-1151
• Main Authors: Lewis, Russell E, Albert, Nathaniel P, Liao, Guangling, Wang, Weiqun, Prince, Randall A, Kontoyiannis, Dimitrios P
• Format: Article
• Language: English
• Subjects: Administration, Intravenous; Amphotericin B - administration & dosage; Animals; Antifungal Agents - administration & dosage; Aspergillus - drug effects; Aspergillus terreus; Disease Models, Animal; Drug dosages; Drug resistance; Female; Fungal infections; Immunization; Lungs; Mice; Mice, Inbred BALB C; Neutropenia - complications; Pneumonia; Pulmonary Aspergillosis - drug therapy; Pulmonary Aspergillosis - microbiology; Rodents; Survival Analysis; Treatment Outcome
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dks521

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