Standardization of an Experimental Murine Model of Invasive Pulmonary Aspergillosis

ABSTRACT Evaluating new therapeutic agents for invasive aspergillosis requires animal models that are reproducible among different laboratories. We therefore evaluated a murine model of aerosol infection in two independent laboratories and found a high level of both intra- and interlaboratory reproducibility of survival, fungal burden over time, and the efficacy of liposomal amphotericin B.

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Efficacy of Nebulized Liposomal Amphotericin B in Treatment of Experimental Pulmonary Aspergillosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.7.3028-3030.2005 ◽

2005 ◽

Vol 49 (7) ◽

pp. 3028-3030 ◽

Cited By ~ 37

Author(s):

Joan Gavaldà ◽

María-Teresa Martín ◽

Pedro López ◽

Xavier Gomis ◽

José-Luís Ramírez ◽

...

Keyword(s):

Amphotericin B ◽

Murine Model ◽

Liposomal Amphotericin ◽

Invasive Pulmonary Aspergillosis ◽

Liposomal Amphotericin B ◽

Pulmonary Aspergillosis ◽

Lower Lung

ABSTRACT The efficacy of therapeutic aerosolized amphotericin B (AMB) was studied in a steroid-immunosuppressed murine model of invasive pulmonary aspergillosis. Nebulized liposomal AMB can be a valid approach to the treatment of this infection, with subjects showing significantly improved survival relative to that of subjects given intravenous deoxycholate AMB, as well as lower lung weights and pulmonary glucosamine levels.

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Efficacy of Single-Dose Liposomal Amphotericin B or Micafungin Prophylaxis in a Neutropenic Murine Model of Invasive Pulmonary Aspergillosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00715-08 ◽

2008 ◽

Vol 52 (11) ◽

pp. 4178-4180 ◽

Cited By ~ 17

Author(s):

Russell E. Lewis ◽

Nathaniel D. Albert ◽

Dimitrios P. Kontoyiannis

Keyword(s):

Body Weight ◽

Amphotericin B ◽

Murine Model ◽

Liposomal Amphotericin ◽

Invasive Pulmonary Aspergillosis ◽

Liposomal Amphotericin B ◽

Potential Utility ◽

Pulmonary Aspergillosis ◽

Fungal Burden ◽

Animal Survival

ABSTRACT In a neutropenic murine model of invasive pulmonary aspergillosis, prophylaxis with single doses of liposomal amphotericin B or micafungin at ≥5 mg/kg of body weight improved animal survival and suppressed the lung fungal burden for up to 7 days after infection, demonstrating the potential utility of infrequent dosing with these antifungals.

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Pretreatment with Empty Liposomes Attenuates the Immunopathology of Invasive Pulmonary Aspergillosis in Corticosteroid-Immunosuppressed Mice

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01268-06 ◽

2006 ◽

Vol 51 (3) ◽

pp. 1078-1081 ◽

Cited By ~ 33

Author(s):

Russell E. Lewis ◽

Georgios Chamilos ◽

Randall A. Prince ◽

Dimitrios P. Kontoyiannis

Keyword(s):

Body Weight ◽

Antifungal Activity ◽

Amphotericin B ◽

Murine Model ◽

Liposomal Amphotericin ◽

Invasive Pulmonary Aspergillosis ◽

Pulmonary Aspergillosis ◽

Amphotericin B Deoxycholate ◽

Immunomodulatory Properties ◽

Immunosuppressed Mice

ABSTRACT In a nonneutropenic murine model of invasive pulmonary aspergillosis, pretreatment with empty liposomes (E-lipo) was nearly as effective as 10 mg/kg of body weight liposomal amphotericin B and superior to 1 mg/kg amphotericin B deoxycholate. The beneficial immunomodulatory properties of E-lipo appear to compensate for their lack of direct antifungal activity.

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Efficacy of Ambruticin Analogs in a Murine Model of Invasive Pulmonary Aspergillosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00558-06 ◽

2006 ◽

Vol 50 (10) ◽

pp. 3464-3466 ◽

Cited By ~ 8

Author(s):

Lisa Y. Chiang ◽

Daniele E. Ejzykowicz ◽

Zong-Qiang Tian ◽

Leonard Katz ◽

Scott G. Filler

Keyword(s):

Antifungal Activity ◽

Mouse Model ◽

Invasive Aspergillosis ◽

Murine Model ◽

Antifungal Agents ◽

Invasive Pulmonary Aspergillosis ◽

Vehicle Control ◽

Pulmonary Aspergillosis

ABSTRACT Ambruticins are a family of polyketides. The antifungal activity of an ambruticin, KOSN-2079, was tested in the mouse model of invasive aspergillosis. KOSN-2079 significantly reduced pulmonary fungal burdens and improved survival over that with the vehicle control. These results support the continued development of ambruticins as antifungal agents.

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Pharmacokinetics and Pharmacodynamics of Amphotericin B Deoxycholate, Liposomal Amphotericin B, and Amphotericin B Lipid Complex in an In Vitro Model of Invasive Pulmonary Aspergillosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01586-09 ◽

2010 ◽

Vol 54 (8) ◽

pp. 3432-3441 ◽

Cited By ~ 38

Author(s):

Jodi M. Lestner ◽

Susan J. Howard ◽

Joanne Goodwin ◽

Lea Gregson ◽

Jayesh Majithiya ◽

...

Keyword(s):

Confocal Microscopy ◽

Amphotericin B ◽

Liposomal Amphotericin ◽

Invasive Pulmonary Aspergillosis ◽

Host Cells ◽

Pulmonary Aspergillosis ◽

Lipid Complex ◽

Amphotericin B Deoxycholate ◽

Amphotericin B Lipid Complex

ABSTRACT The pharmacodynamic and pharmacokinetic (PK-PD) properties of amphotericin B (AmB) formulations against invasive pulmonary aspergillosis (IPA) are not well understood. We used an in vitro model of IPA to further elucidate the PK-PD of amphotericin B deoxycholate (DAmB), liposomal amphotericin B (LAmB) and amphotericin B lipid complex (ABLC). The pharmacokinetics of these formulations for endovascular fluid, endothelial cells, and alveolar cells were estimated. Pharmacodynamic relationships were defined by measuring concentrations of galactomannan in endovascular and alveolar compartments. Confocal microscopy was used to visualize fungal biomass. A mathematical model was used to calculate the area under the concentration-time curve (AUC) in each compartment and estimate the extent of drug penetration. The interaction of LAmB with host cells and hyphae was visualized using sulforhodamine B-labeled liposomes. The MICs for the pure compound and the three formulations were comparable (0.125 to 0.25 mg/liter). For all formulations, concentrations of AmB progressively declined in the endovascular fluid as the drug distributed into the cellular bilayer. Depending on the formulation, the AUCs for AmB were 10 to 300 times higher within the cells than within endovascular fluid. The concentrations producing a 50% maximal effect (EC50) in the endovascular compartment were 0.12, 1.03, and 4.41 mg/liter for DAmB, LAmB, and ABLC, respectively, whereas, the EC50 in the alveolar compartment were 0.17, 7.76, and 39.34 mg/liter, respectively. Confocal microscopy suggested that liposomes interacted directly with hyphae and host cells. The PK-PD relationships of the three most widely used formulations of AmB differ markedly within an in vitro lung model of IPA.

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Successfully treated invasive pulmonary aspergillosis in a patient with diabetic ketoacidosis

Open Medicine ◽

10.2478/s11536-013-0188-z ◽

2013 ◽

Vol 8 (5) ◽

pp. 685-688

Author(s):

Ryo Kumagai ◽

Gen Ohara ◽

Shinya Sato ◽

Kunihiko Miyazaki ◽

Katsunori Kagohashi ◽

...

Keyword(s):

Early Intervention ◽

Invasive Aspergillosis ◽

Diabetic Ketoacidosis ◽

Amphotericin B ◽

Early Treatment ◽

Liposomal Amphotericin ◽

Invasive Pulmonary Aspergillosis ◽

Full Recovery ◽

Liposomal Amphotericin B ◽

Pulmonary Aspergillosis

AbstractWe report herein a case of diabetic ketoacidosis associated with invasive aspergillosis that was successfully treated with liposomal amphotericin-B (L-AMB). Early intervention after confirming the diagnosis of invasive pulmonary aspergillosis is very important, and initiating early treatment with L-AMB can lead to a full recovery.

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Pharmacodynamics of Amphotericin B Deoxycholate, Amphotericin B Lipid Complex, and Liposomal Amphotericin B against Aspergillus fumigatus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04723-14 ◽

2015 ◽

Vol 59 (5) ◽

pp. 2735-2745 ◽

Cited By ~ 14

Author(s):

Zaid Al-Nakeeb ◽

Vidmantas Petraitis ◽

Joanne Goodwin ◽

Ruta Petraitiene ◽

Thomas J. Walsh ◽

...

Keyword(s):

Amphotericin B ◽

Liposomal Amphotericin ◽

Invasive Pulmonary Aspergillosis ◽

Liposomal Amphotericin B ◽

Complete Suppression ◽

Pulmonary Aspergillosis ◽

Lipid Complex ◽

Amphotericin B Deoxycholate ◽

Amphotericin B Lipid Complex ◽

Dose Dependent

ABSTRACTAmphotericin B is a first-line agent for the treatment of invasive aspergillosis. However, relatively little is known about the pharmacodynamics of amphotericin B for invasive pulmonary aspergillosis. We studied the pharmacokinetics (PK) and pharmacodynamics (PD) of amphotericin B deoxycholate (DAMB), amphotericin B lipid complex (ABLC), and liposomal amphotericin B (LAMB) by using a neutropenic-rabbit model of invasive pulmonary aspergillosis. The study endpoints were lung weight, infarct score, and levels of circulating galactomannan and (1→3)-β-d-glucan. Mathematical models were used to describe PK-PD relationships. The experimental findings were bridged to humans by Monte Carlo simulation. Each amphotericin B formulation induced a dose-dependent decline in study endpoints. Near-maximal antifungal activity was evident with DAMB at 1 mg/kg/day and ABLC and LAMB at 5 mg/kg/day. The bridging study suggested that the “average” patient receiving LAMB at 3 mg/kg/day was predicted to have complete suppression of galactomannan and (1→3)-β-d-glucan levels, but 20 to 30% of the patients still had a galactomannan index of >1 and (1→3)-β-d-glucan levels of >60 pg/ml. All formulations of amphotericin B induce a dose-dependent reduction in markers of lung injury and circulating fungus-related biomarkers. A clinical dosage of liposomal amphotericin B of 3 mg/kg/day is predicted to cause complete suppression of galactomannan and (1→3)-β-d-glucan levels in the majority of patients.

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