Aerosolized liposomal amphotericin B for treatment of pulmonary and systemic Cryptococcus neoformans infections in mice

Abstract

Cryptococcus infections of the lung and central nervous system have become major problems in immuno-compromised patients, leading to the need for additional treatment protocols. We have utilized a Cryptococcus-mouse model that mimics human cryptococcal disease to evaluate the efficacy of amphotericin B-liposomes (AmpB-Lip) when delivered by small-particle aerosol (SPA). In the model, initial intranasal inoculation leads to a pulmonary infection that spreads after 2 to 3 weeks to distant organs, including the brain. Aerosols of AmpB-Lip that were generated by a Collison nebulizer had mass median aerodynamic diameters of 1.8 microns and contained 10.3 micrograms of AmpB per liter. When AmpB-Lip SPA was begun at 24 h postinoculation, a single 2-h treatment (0.3 mg of AmpB per kg of body weight) was effective in reducing pulmonary Cryptococcus infection. This regimen was more effective than intravenous administration of AmpB-Lip given for 3 continuous days. This single 2-h exposure to AmpB-Lip also was effective in reducing pulmonary Cryptococcus infection when treatment was delayed for 7 or 14 days. At day 21, when organisms had spread to the brain in all animals, the single 2-h aerosol treatment reduced the number of cryptococci in the brain as well as in the lungs. AmpB-Lip SPA administered once for 2 h on days 7, 14, and 21 also was effective in increasing the duration of survival of infected animals. These results demonstrate that aerosolized AmpB-Lip can be effective in treating both local, pulmonary Cryptococcus disease and systemic disease.

Strategies in prevention of invasive pulmonary aspergillosis in immunosuppressed or neutropenic patients

“…However, in the same animal model a single 1.6-mg/kg aerosol amB dose was not effective for secondary prophylaxis once the infection was established and immunosuppression was reintroduced (57). Liposomal amB can also be administered as an aerosol and has been investigated in mice for prophylaxis and treatment of Cryptococcus infections (29). No data are available on aerosolized liposomal amB for prophylaxis of IPA.…”

Immune response of mice to Echinococcus multilocularis infection after therapy with amphotericin B colloidal dispersion

“…We suppose that the slow release of free AMB from the lipid complexes could be a cause of the failure of our ABCD therapy for murine alveolar echinococcosis. The severity of the infection was increased, when there was a decrease in the susceptibility of the metacestode to ABCD, as has been observed in protozoal and bacterial infections (Gilbert et al, 1992;Karyotakis & Anaissie, 1994). Our experimental ABCD therapy with the intention of halt-ing the larval development of E. multilocularis in a murine host failed.…”

Aerosolized amphotericin B-liposomes for treatment of systemic Candida infections in mice

“…We have shown recently (6) that AmpB-Lip can be successfully aerosolized, generating particles with mass median aerodynamic diameters of 1.8 jim which are capable of depositing the drug throughout the respiratory tract (9,11). AmpB-Lip aerosol was effective in the treatment of mice infected intranasally with Cryptococcus neoformans (6). Aerosol administration reduced the number of cryptococci in the lungs and brain and increased the mean duration of survival.…”

“…However, the toxicity associated with this drug has limited its usefulness and has led to the development of preparations of AmpB-liposomes (AmpB-Lip) which retain antifungal activity but which have reduced toxicity (1,7,13,15). We have shown recently (6) that AmpB-Lip can be successfully aerosolized, generating particles with mass median aerodynamic diameters of 1.8 jim which are capable of depositing the drug throughout the respiratory tract (9,11). AmpB-Lip aerosol was effective in the treatment of mice infected intranasally with Cryptococcus neoformans (6).…”