Dose Response in Neutropenic Mice with Disseminated Infection of Multiple Strains of Aspergillus fumigatus with widely Varying MIC and MFC Values Treated with Isavuconazole

P.A. WARN, A. PARMAR, A. SHARP, and D.W. DENNING

Author address: 

School Of Medicine, University of Manchester, Manchester, UK

Abstract: 

Objectives: Isavuconazole (BAL4815, ISA) a broad spectrum triazole antifungal is administered as its water soluble prodrug BAL8557. Dose response curves to treatment with ISA were determined in murine models against strains of Aspergillus fumigatus with low and high MIC (=2mg/L respectively) and low and high MFC (4mg/L respectively). Strains were selected that had previously demonstrated either treatment success or failure when treated with itraconazole. Methods: In vitro susceptibility tests were performed according to the CLSI guidelines. A. fumigatus strains isolated from clinical samples were selected with ISA MIC/MFC values classed as either Low/Low, Low/High or High/High (including AF91 which has previously been shown as resistant in vitro and in vivo to itraconazole). Male CD1 mice 21-24g were immunosuppressed with a single dose of 200mg/kg cyclophosphamide IV then 3 days later infected IV with a sub-lethal inoculum of Aspergillus (4 strains of fumigatus). 5 hours after infection mice were treated orally once daily with either solvent or ISA (2.5 250mg/kg) for 4 days (ISA 1.33-132mg/kg active compound). 100 hours post infection mice were killed and the kidneys removed for quantitative culture. Results: All strains generated moderately severe non-lethal infections with moderate/heavy tissue burdens in the kidneys of infected animals (Cmax 3.4 4.5 log10 cfu/g). Treatment resulted in Emax of 1.2-1.9 log10 the entire dose range. In all cases the steepest part of the dose response curve was in the range of 5.3-40mg/kg ISA (regardless of the MIC or MFC of the isolate). The magnitude of the drug effect was up to 1.2 log10 cfu/g and similar regardless of the ISA MIC (AF10 MIC = 0.25mg/L and AF91 MIC = 2mg/L both had an Emax 1.2 log10 cfu/g). Conclusion: ISA was effective in reducing the tissue burden of all isolates of A. fumigatus including a strain with an MIC of 4mg/L that demonstrates in vivo was noted over a wide therapeutic range (up to 250mg/kg). In this model once a day therapy with ISA was effective despite a half life in mice
2007

abstract No: 

P1951

Full conference title: 

17th European Congress of Clinical Microbiology and Infectious Diseases and 25th International Congress of Chemotherapy
    • ECCMID 17th (2007)