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Updated: May 14, 2026
Histological Quantification to Determine Lung Fungal Burden in Experimental Aspergillosis
Published on: March 9, 2018
High-dose induction liposomal amphotericin B followed by de-escalation is effective in experimental Aspergillus
Russell E Lewis1, Nathaniel P Albert, Guangling Liao
1Clinic 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
Objectives:
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.
Insights
An induction-de-escalation dosing strategy using liposomal amphotericin B (L-AMB) effectively treated Aspergillus terreus pneumonia in mice. This dosing regimen improved survival and reduced fungal burden, offering a promising approach for invasive fungal infections.
Area of Science:
- Medical Mycology
- Pharmacology
- Infectious Diseases
Background:
- Aspergillus terreus exhibits resistance to conventional amphotericin B (AMB).
- The efficacy of higher doses of liposomal amphotericin B (L-AMB) against A. terreus in vivo remains unclear.
- Neutropenic murine models are crucial for evaluating antifungal therapies.
Purpose of the Study:
- To assess the efficacy of escalating intravenous doses of L-AMB against A. terreus pneumonia in a neutropenic murine model.
- To compare continuous high-dose L-AMB with an induction-de-escalation dosing strategy.
- To determine AMB concentrations in lung homogenates under different dosing regimens.
Main Methods:
- Neutropenic BALB/c mice were infected intranasally with A. terreus (MIC 8 mg/L).
- Mice received L-AMB at daily doses ranging from 3-20 mg/kg or an induction-de-escalation strategy (10 mg/kg/day ×3 days, then 3 mg/kg/day).
- Efficacy was measured by survival rates and quantitative PCR for lung fungal burden; AMB concentrations were analyzed via HPLC.
Main Results:
- L-AMB at 10 mg/kg/day significantly improved survival and reduced lung fungal burden compared to controls.
- Higher daily L-AMB doses (>10 mg/kg/day) were associated with worse outcomes.
- The induction-de-escalation strategy was as effective as continuous 10 mg/kg/day dosing and yielded higher AMB lung concentrations.
Conclusions:
- An induction-de-escalation L-AMB dosing strategy is effective for treating experimental A. terreus pneumonia in neutropenic mice.
- This dosing approach may overcome AMB resistance in A. terreus infections.
- Optimized L-AMB dosing strategies are critical for managing invasive fungal infections.
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