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


METHODS
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.


RESULTS
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).


CONCLUSIONS
A high-dose induction-de-escalation L-AMB dosing strategy was an effective treatment for experimental A. terreus pneumonia in neutropenic mice.
Clinic of Infectious Diseases, Department of Internal Medicine, Geriatrics and Nephrologic Diseases, S'Orsola Malpighi Hospital, University of Bologna, Bologna 40138, Italy. russeledward.lewis@unibo.it
Russell E
RE
Lewis
Nathaniel P
NP
Albert
Guangling
G
Liao
Weiqun
W
Wang
Randall A
RA
Prince
Dimitrios P
DP
Kontoyiannis
D061605:Administration, Intravenous; D000666:Amphotericin B / Q000008:administration & dosage*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage*; D001230:Aspergillus / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D009503:Neutropenia / Q000150:complications; D055732:Pulmonary Aspergillosis / Q000188:drug therapy* / Q000382:microbiology*; D016019:Survival Analysis; D016896:Treatment Outcome
D000935:Antifungal Agents; C068538:liposomal amphotericin B; D000666:Amphotericin B