Efficacy and Associated Drug Exposures of Isavuconazole and Fluconazole in an Experimental Model of Coccidioidomycosis

Antimicrob Agents Chemother. 2021 Mar 29:AAC.02344-20. doi: 10.1128/AAC.02344-20. Online ahead of print.

ABSTRACT

Coccidioides spp. are important pathogens in endemic regions and new treatment options are needed. Isavuconazonium sulfate (ISAVUSULF) and fluconazole (FLU) were evaluated in experimental disseminated coccidioidomycosis to characterize drug exposures associated with efficacy.Macrobroth dilution was performed on Coccidioides isolates to measure minimal effective concentrations (MEC) and minimal fungicidal concentrations (MFC). Mice were inoculated with Coccidioides posadasii (Silveira strain). Treatment started 4 days post-inoculation. (Model 1) Mice were treated 19 days plus 30-day off-therapy observation, measuring survival through day 49 and residual fungal burden. Treatments included ISAVUSULF (prodrug: 186, 279, or 372 mg/kg twice-daily), FLU (20 or 100 mg/kg once-daily), and untreated. Model 2 included 7-day treatment with ISAVUSULF (prodrug: 74.4, 111.6, or 148.8 mg/kg twice-daily), FLU (20 or 100 mg/kg once-daily), and untreated. Serial plasma and tissues samples were obtained for PK and fungal burden measurement, respectively.MEC50 were 0.39 mg/L (ISAV) and 12.5 mg/L (FLU). Treatment with ISAVUSULF186 or both FLU doses resulted in higher survival compared to untreated. Treatment with ISAVUSULF 186 or 279 mg/kg twice-daily or FLU 100 mg/kg reduced fungal burden in all organs (Model 1). In model 2, >1 log10 CFU/organ reduction was demonstrated, with ISAV AUCs achieved with 111.6 mg/kg twice-daily (56.8 mg•h/L), in the spleen and liver. FLU AUCs, 100 and 500 mg•h/L, for 20 and 100 mg/kg doses, respectively, resulted in >1 log10 CFU/organ mean reduction in all organs.ISAVUSULF and FLU improved survival and reduced fungal burden. Increasing plasma drug exposures resulted in decreases in fungal burden.

PMID:33782009 | DOI:10.1128/AAC.02344-20