Objectives: The prodrug isavuconazonium sulfate is in phase 3 clinical development for the treatment of invasive fungal disease including infections caused by Zygomycetes and in the SECURE trial achieved its primary objective in demonstrating non-inferiority versus voriconazole for the primary treatment of invasive fungal disease caused by Aspergillus species and certain other filamentous fungi. It has recently been granted Qualified Infectious Disease Product (QIDP) status for the treatment of invasive aspergillosis. Absidia corymbifera (Lichtheimia corymbifera) causes highly invasive pulmonary, CNS, rhinocerebral, and cutaneous infections with limited treated options as voriconazole, fluconazole and the echinocandins are not indicated. The objective of the following study was to assess the efficacy of Isavuconazole in a mouse model of disseminated Absidia with survival and tissue burden outcomes determined.
Methods: Male CD1 mice were used in these studies (mice were naïve and received no immunosuppression). Mice were infected with 2.6x104 cfu of a clinical strain of Absidia corymbifera spores by intravenous injection into the lateral tail vein. Treatment was initiated 4 hours post infection and continues once or twice daily for 5 days (either 5 or 10 doses administered). Treatment groups (6 mice per treatment group) included oral isavuconazonium sulfate, designed to deliver the acive moiety, Isavuconazole, at a single or BID doses of 250, 125, 62.5 and 31.25 mg/kg/day or as a single dose of 15.6mg/kg/day. Groups of mice were also treated 1 and 3.3mg/kg/day IP amphotericin B and vehicle. Mice were observed for survival for 7 days with the kidneys and liver cultured at the time of euthanasia.
Results: Vehicle treated mice rapidly developed lethal infection with 83% of animals succumbing to disease within 72 hours post infection (Mean survival time 2 days). Modest burdens were recovered from the kidneys and liver of vehicle treated animals (~103 and 2 x 103 cfu/g in kidneys and liver respectively) highlighting the high pathogenicity of this strain in mice. Treatment with Isavuconazole had little effect on the recovered burdens which may be a reflection of the later timepoints sampled. Treatment with Isavuconazole numerically increased the survival in most treatment groups with survival rates of up to 67% with little dose dependency of outcomes (all mean survival times exceeded vehicle). Treatment with amphotericin B was most effective with 100 (3.3mg/kg) and 83% (1mg/kg) of mice surviving.
Conclusions: Isavuconazole increased survival compared to vehicle treated mice when administered orally once or twice daily using doses between 15.6-250 mg/kg/day. Isavuconazole was equally effective whether administered once or twice daily.
- ECCMID 24th (2014)