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JAC Advance Access published online on October 27, 2006
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl396
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Received May 14, 2006
Revised September 4, 2006
Accepted September 9, 2006

Original article

Comparative in vivo activity of BAL4815, the active component of the prodrug BAL8557, in a neutropenic murine model of disseminated Aspergillus flavus

Peter A. Warn 1 *, Andrew Sharp 1, Juan Mosquera 1, Jochen Spickermann 2, Anne Schmitt-Hoffmann 2, Markus Heep 2, and David W. Denning 3

1 School of Medicine, University of Manchester, 1.800 Stopford Building, Oxford Road, Manchester M13 9PT, UK
2 Basilea Pharmaceutica, Ltd, PO Box 3255, 4002 Basel, Switzerland
3 School of Medicine, University of Manchester, 1.800 Stopford Building, Oxford Road, Manchester M13 9PT, UK; Wythenshawe Hospital, Southmoor Road, Manchester M23 9PL, UK

* To whom correspondence should be addressed.
Peter A. Warn, E-mail: peter.warn{at}.manchester.ac.uk


  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 ~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.

Keywords: antifungal; susceptibility; mouse; itraconazole; voriconazole; caspofungin; amphotericin B; water-soluble azole; WSA.
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