title: Nebulization of four commercially available amphotericin B formulations in persistently granulocytopenic rats with invasive pulmonary aspergillosis: evidence for long-term biological activity.
abstract: The nebulization of amphotericin B desoxycholate (AMB-DOC), liposomal amphotericin B (L-AMB), amphotericin B lipid complex (ABLC) and amphotericin B colloidal dispersion (ABCD) has been investigated. Particle sizes of generated aerosol droplets were measured. Pulmonary amphotericin B deposition and amphotericin B concentration in blood directly after nebulization and at six weeks after nebulization was measured in healthy rats. The efficacy of nebulized amphotericin B formulations was evaluated in persistently granulocytopenic rats with invasive pulmonary aspergillosis. Treatment was given either after or before fungal inoculation. The endpoint was survival of animals. Aerosol particle sizes, expressed as the values for the mass median diameter were 1.38, 2.43, 0.90 and 2.29 microm for AMB-DOC, L-AMB, ABLC and ABCD, respectively. Amphotericin B concentrations in the lungs directly after nebulization exceeded the minimum inhibitory concentration of Aspergillus fumigatus and amphotericin B was still detected in lungs of rats at six weeks after nebulization. Treatment, started at 16 h after fungal inoculation, resulted in a significantly prolonged survival as compared with sham-treated rats for all four formulations. Prophylactic treatment at one week before fungal inoculation resulted in a significantly prolonged survival for all four formulations. Aerosol treatment given at two weeks before inoculation was effective only for AMB-DOC and L-AMB, whereas treatment given at six weeks resulted in a significantly prolonged survival for L-AMB only. All commercially available amphotericin B preparations could be nebulized efficiently and may be of value in the prophylactic treatment of invasive pulmonary aspergillosis.
authors.affiliation: Department of Medical Microbiology & Infectious Diseases, Erasmus University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands. ruijgrokl@mcrz.nl
authors.forename: Elisabeth J
authors.initials: EJ
authors.lastname: Ruijgrok
authors.forename: Marcel H A
authors.initials: MH
authors.lastname: Fens
authors.forename: Irma A J M
authors.initials: IA
authors.lastname: Bakker-Woudenberg
authors.forename: Els W M
authors.initials: EW
authors.lastname: van Etten
authors.forename: Arnold G
authors.initials: AG
authors.lastname: Vulto
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000380:Agranulocytosis / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D000666:Amphotericin B / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001229:Aspergillosis, Allergic Bronchopulmonary / Q000150:complications / Q000188:drug therapy*; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000302:isolation & purification; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008826:Microbial Sensitivity Tests / Q000379:methods; D010316:Particle Size; D011358:Product Surveillance, Postmarketing / Q000379:methods; D011663:Pulmonary Surfactants / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D013047:Specific Pathogen-Free Organisms; D016019:Survival Analysis; D013997:Time Factors
chemical_list: D000336:Aerosols; D000935:Antifungal Agents; D011663:Pulmonary Surfactants; D000666:Amphotericin B