title: Liposomal amphotericin B and echinocandins as monotherapy or sequential or concomitant therapy in murine disseminated and pulmonary Aspergillus fumigatus infections.
abstract: Monotherapy and combination therapy were compared using optimal doses of liposomal amphotericin B, micafungin, or caspofungin in Aspergillus fumigatus pulmonary and disseminated infections. Mice were challenged intravenously (2.8 x 10(4) to 5.7 x 10(4) conidia) or intranasally (5.8 x 10(7) conidia) with A. fumigatus. Drugs (5, 10, or 15 mg/kg of body weight) were given for 3 or 6 days as single, concomitant, or sequential therapy (i.e., days 1 to 3 and then days 4 to 6). Mice were monitored for survival, and tissues were assayed for fungal burden and drug concentrations. Treatments starting 24 h postchallenge significantly prolonged survival in disseminated aspergillosis (P < 0.002), but only liposomal amphotericin B treatments or treatments beginning with liposomal amphotericin B increased survival to 100% in the pulmonary aspergillosis model. Fungi in kidneys and spleens (disseminated) and lungs (pulmonary) were significantly decreased (P < or = 0.04) by liposomal amphotericin B, liposomal amphotericin B plus echinocandin, or liposomal amphotericin B prior to echinocandin. In the disseminated infection, liposomal amphotericin B and micafungin (10 or 15 mg/kg) had similar kidney drug levels, while in the spleen, 5 and 15 mg/kg liposomal amphotericin B gave higher drug levels than micafungin (P < 0.02). In the pulmonary infection, drug levels in lungs and spleen with 5-mg/kg dosing were significantly higher with liposomal amphotericin B than with caspofungin (P < or = 0.002). In summary, treatment of A. fumigatus infections with liposomal amphotericin B plus echinocandin or liposomal amphotericin B prior to echinocandin was as effective as liposomal amphotericin B alone, and a greater decrease in the fungal burden with liposomal amphotericin B supports using liposomal amphotericin B prior to echinocandin.
authors.affiliation: Dept. of Biological Sciences, California State Polytechnic University, 3801 West Temple Avenue, Pomona, CA 91768, USA.
authors.forename: Jon A
authors.initials: JA
authors.lastname: Olson
authors.forename: Ancy
authors.initials: A
authors.lastname: George
authors.forename: David
authors.initials: D
authors.lastname: Constable
authors.forename: Peter
authors.initials: P
authors.lastname: Smith
authors.forename: Richard T
authors.initials: RT
authors.lastname: Proffitt
authors.forename: Jill P
authors.initials: JP
authors.lastname: Adler-Moore
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001232:Aspergillus fumigatus / Q000187:drug effects; D054714:Echinocandins / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D051379:Mice; D008826:Microbial Sensitivity Tests; D055732:Pulmonary Aspergillosis / Q000188:drug therapy*
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; C068538:liposomal amphotericin B; D000666:Amphotericin B