Aerosolized AmBisome treatment of pulmonary Cryptococcus neoformans infection in mice

AmBisome, a liposomal formulation of amphotericin B (ampB-lip), was tested as an aerosol for delivery to the lungs for the treatment of pulmonary fungal diseases. AmBisome (4.6 mg of ampB/ml) was generated with an AeroTech II (AT) nebulizer, producing an aerosol during 20 of nebulization of 111.3 mu g of ampB/L and with a mass median aerodynamic diameter of 1.8 mu m. Antifungal activity of AmBisome was not affected by aerosolization. When mice were treated with aerosolized AmBisome(4.5 mg of ampB/ml) every other day for a total of 3 treatments (0.6 mg/kg/20 min), lungs rapidly accumulated ampB. Some hours after aerosolization, there was a gradual loss of drug from the lungs. Multiple treatments led to an accumulation of ampB with a maximum concentration after the third treatment of 43 mg of ampB/gm of lung tissue. AmpB was detected in lung tissue 14 days after treatment (24 mg/g). AmpB was not detected in the blood. The prophylactic and therapeutic efficacy of aerosolized AmBisome in an intranasal Cryptococcus-mouse model was studied. Both the number of organisms colonizing the lungs and the gross lung scores were significantly reduced in all treated groups compared to controls, whether treatment was begun before or after infection. Delaying infection for 14 days after prophylactic treatment still was protective. Thus, AmBisome aerosol was effective in protecting mice from pulmonary cryptococcal infection.