Previous in vitro studies had shown that voriconazole (VCZ) in two-drug combination with conventional and lipid formulations of amphotericin B (AMB) produced indifferent interaction against Aspergillus fumigatus. TO confirm our in vitro finding in an animal model, we investigated the susceptibility of A. fumigatus 73355 (ATCC 208996) highly susceptible to VCZ (MIC 0.25 t.J,g/mL) and AMB (MIC 0.5 ug/mL), to two-drug combination of AMB with VCZ using a guinea pig pulmonary aspergillosis model. Six-to-eight week old guinea pigs (350+50 gram) were made neutropenic by three successive injections of cyclophosphamide (100 mg/kg) on day -3, -1 and 1 where day 0 was the day of infection. The immunosuppressed animals (14 animals/ group) were challenged with 1~10~ conidia/guinea pig by intratracheal injection. Antifungal treatment was initiated on day 0 (AMB 1 mg/kg/day (i.p.), VCZ 10 mg/kg/b.i.d. (p.0.) and AMB 1 mg/kg/day + VCZ 10 mg/kg/b.i.d.) and continued for 7 days. The effectiveness of the antifungal treatments with VCZ or AMB or in two-drug combination was evaluated by the survival and the fungal burden in the lungs of infected animals. The mean survival of animals infected but not treated (controls) was 3.7225 days whereas those of the AMB, VCZ and AMB+VCZ treated groups were 5.3k1.9, 5.522.1 and 5.6 +1.7 days, respectively. The fungal burden in the lungs of infected animals treated with antifungal drugs was significantly lower than that obtained for the untreated (109733?33877 CFU/lungs) group. The fungal burden of the VCZ-treated (985 ?306 CFU/lung) group was significantly lower than that obtained for the AMB-treated (81912 1800 CFU/lung) group whereas no significant difference in the fungal burden was obtained for the groups treated with VCZ alone (985+306 CFU/lung) and VCZ+AMB (8135298 CFU/lung). We found no antagonism between VCZ and AMB. The results obtained in the guinea pig pulmonary aspergillosis model showed good agreement with our previous in vitro results suggesting indifferent interaction of VCZ in combination with AMB against A. fumigatus.
Full conference title:
12th International Symposium on Infections in the Immunocompromised Host
- ISIIH 12th