Title | Comparative in vivo activity of BAL4815, the active component of the prodrug BAL8557, in a neutropenic murine model of disseminated Aspergillus flavus. |
Publication Type | Journal Article |
Year of Publication | 2006 |
Authors | Warn PA, Sharp A, Mosquera J, Spickermann J, Schmitt-Hoffmann A, Heep M, Denning DW |
Journal | J Antimicrob Chemother |
Volume | 58 |
Issue | 6 |
Pagination | 1198-207 |
Date Published | 2006 Dec |
ISSN | 0305-7453 |
Keywords | Animals, Antifungal Agents, Aspergillosis, Aspergillus flavus, Brain, Caspofungin, Colony Count, Microbial, Disease Models, Animal, Echinocandins, Fluorescence Resonance Energy Transfer, Immunocompromised Host, Immunosuppression, Itraconazole, Kidney, Lipopeptides, Liver, Lung, Male, Mice, Neutropenia, Nitriles, Peptides, Cyclic, Polymerase Chain Reaction, Pyrimidines, Survival Analysis, Triazoles, Voriconazole |
Abstract | BACKGROUND: BAL8557 (WSA) is the water-soluble prodrug of the triazole BAL4815 with in vitro anti-Aspergillus activity. We compared the activity of oral BAL8557 with oral itraconazole, oral voriconazole and intravenous caspofungin in a temporarily neutropenic murine model of disseminated Aspergillus flavus. METHODS: Mice were immunosuppressed using cyclophosphamide, then infected. Mice were treated either 2 h pre-infection (PRE), or 4 or 24 h post-infection (4POST and 24POST, respectively). Treatment was for 10 days followed by 4 days of observation. Surviving mice were killed and liver, kidneys, lungs and brain cultured. BAL8557 groups included doses corresponding to approximately 30, 15, 6 and 3 mg/kg of the active BAL4815; comparators included itraconazole 25 and 10 mg/kg/dose, voriconazole (plus oral grapefruit) 25 and 10 mg/kg/day or caspofungin 1 mg/kg/day. In a simultaneous tissue burden study mice were treated for 3 days, kidneys removed and homogenized and burden measured by quantitative culture and quantitative PCR using fluorescence resonance energy transfer (FRET). RESULTS: Control mice had 83-100% mortality. Over 66% of BAL8557-treated mice survived after >6 mg/kg PRE or >15 mg/kg POST. In the PRE models BAL8557 (6 mg/kg) and caspofungin were 100% protective and itraconazole 67% protective, but voriconazole 10 mg/kg had 100% mortality (P = 0.0016). In the 4POST and 24POST models survival was >66% with BAL8557 30 and 15 mg/kg/dose and similar to voriconazole or itraconazole. In the 24POST groups, sterilization of all organs was achieved in 11/16 survivors treated with BAL8557. The quantitative PCR correlated with kidney fungal burden (r2 = 0.59). Earlier treatment reduced burdens. CONCLUSIONS: BAL8557 demonstrated impressive antifungal activity against A. flavus in this model, in both survival and tissue burden. |
DOI | 10.1093/jac/dkl396 |
Alternate Journal | J Antimicrob Chemother |
PubMed ID | 17071636 |
Related Faculty:
Juan Miguel Mosquera, M.D.