JAC Advance Access originally published online on October 27, 2006
Journal of Antimicrobial Chemotherapy 2006 58(6):1198-1207; doi:10.1093/jac/dkl396
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Comparative in vivo activity of BAL4815, the active component of the prodrug BAL8557, in a neutropenic murine model of disseminated Aspergillus flavus
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 Wythenshawe Hospital Southmoor Road, Manchester M23 9PL, UK
Received 14 May 2006; returned 20 July 2006; revised 4 September 2006; accepted 9 September 2006
*Corresponding author. Tel: +44-161-606-7251; Fax: +44-161-275-5656; E-mail: peter.warn{at}manchester.ac.uk
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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