title: Dose-response relationships of three amphotericin B formulations in a non-neutropenic murine model of invasive aspergillosis.
abstract: New lipid-associated formulations of amphotericin B (AmB) have been developed in order to reduce toxicity and enhance the efficacy of AmB by allowing administration of higher doses of the drug. We determined the in vivo dose-response relationships of 1 day and 7 day treatment of AmB, Ambisome (AmBi) and Abelcet (ABLC) in a non-neutropenic murine model of invasive aspergillosis by using survival as an endpoint. Female CD-1 mice were infected intravenously 48 h prior to start therapy with Aspergillus fumigatus (1 x 10(7) conidia/mouse). Groups of 10 mice were treated iv for 1 day or 7 days with increasing 2-fold doses of AmB, ABLC and AmBi up to a maximum of 20 mg/kg/day. Mortality was determined twice daily until day 15. Results were analyzed using product-moment survival analysis and by determining the dose response relationships on day 15. Survival at day 15 of mice with 7 day AmBi or ABLC treatment was significantly better than that of controls or AmB. The ED50s of AmBi and ABLC were 0.06 (95% CI: 0.03-0.127) mg/kg and 0.21 (0.06-0.66) mg/kg respectively. In addition, the maximum effect was higher for AmBi than ABLC, 90% survival versus 68%, respectively. Most of the effects of treatment with AmBi were reached after 1 day of treatment, indicating that the first dose given is most important in predicting survival. This study shows that AmBi and ABLC were significantly more efficacious than AmB in a non-neutropenic murine model of invasive aspergillosis, and that the effect observed was primarily dependent on the first dose administered.
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Ziekenhuis Nijmegen, Nijmegen, The Netherlands. Mouton@cwz.nl
authors.forename: J W
authors.initials: JW
authors.lastname: Mouton
authors.forename: D T A
authors.initials: DT
authors.lastname: te Dorsthorst
authors.forename: J F G M
authors.initials: JF
authors.lastname: Meis
authors.forename: P E
authors.initials: PE
authors.lastname: Verweij
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology*; D000818:Animals; D001228:Aspergillosis / Q000188:drug therapy* / Q000382:microbiology; D001232:Aspergillus fumigatus; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D051379:Mice; D009503:Neutropenia / Q000382:microbiology; D017711:Nonlinear Dynamics; D016019:Survival Analysis
chemical_list: C068538:liposomal amphotericin B; D000666:Amphotericin B