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Liposomal Amphotericin B and Echinocandins as Monotherapy or Sequential or Concomitant Therapy in Murine Disseminated and Pulmonary Aspergillus fumigatus Infections
Author(s) -
Jon Olson,
Ancy George,
David Constable,
Peter J. Smith,
Richard T. Proffitt,
Jill Adler-Moore
Publication year - 2010
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.01554-09
Subject(s) - amphotericin b , micafungin , echinocandin , caspofungin , aspergillus fumigatus , aspergillosis , concomitant , pharmacology , medicine , immunology , fluconazole , antifungal , dermatology
Monotherapy and combination therapy were compared using optimal doses of liposomal amphotericin B, micafungin, or caspofungin inAspergillus fumigatus pulmonary and disseminated infections. Mice were challenged intravenously (2.8 × 104 to 5.7 × 104 conidia) or intranasally (5.8 × 107 conidia) withA. 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 ≤ 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 ≤ 0.002). In summary, treatment ofA. 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.

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