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



Kovanda, Laura L ORCID: 0000-0002-4493-4652, Sass, Gabriele, Martinez, Marife, Clemons, Karl V, Nazik, Hasan, Kitt, Therese M, Wiederhold, Nathan ORCID: 0000-0002-2225-5122, Hope, William W and Stevens, David A
(2021) Efficacy and Associated Drug Exposures of Isavuconazole and Fluconazole in an Experimental Model of Coccidioidomycosis. Antimicrobial agents and chemotherapy, 65 (6).

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Abstract

<i>Coccidioides</i> spp. are important pathogens in regions where they are endemic, and new treatment options are needed. Here, isavuconazonium sulfate (ISAVUSULF) and fluconazole (FLU) were evaluated in experimental disseminated coccidioidomycosis to characterize drug exposures associated with efficacy. Broth macrodilution was performed on <i>Coccidioides</i> isolates to measure minimal effective concentrations (MEC) and minimal fungicidal concentrations (MFC). Mice were inoculated with <i>Coccidioides posadasii</i> (Silveira strain). Treatment started 4 days postinoculation. In model 1, mice were treated for 19 days, followed by 30 days of 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 no treatment. 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 no treatment. Serial plasma and tissues samples were obtained for pharmacokinetics (PK) and fungal burden measurement, respectively. Fifty percent minimal effective concentration (MEC<sub>50</sub>) values were 0.39 mg/liter (isavuconazole [ISAV]) and 12.5 mg/liter (FLU). Treatment with ISAVUSULF186 or with either FLU dose resulted in higher survival compared to that in the untreated group. Treatment with ISAVUSULF186 or ISAVUSULF279 twice daily or FLU100 reduced fungal burden in all organs (model 1). In model 2, a >1 log<sub>10</sub> CFU/organ reduction was demonstrated, with ISAV area under the concentration-time curve (AUC) values achieved with 111.6 mg/kg twice daily (56.8 mg · h/liter) in the spleen and liver. FLU AUC values of 100 and 500 mg·h/liter for 20 and 100 mg/kg doses, respectively, resulted in a >1 log<sub>10</sub> 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.

Item Type: Article
Uncontrolled Keywords: Animals, Mice, Coccidioides, Coccidioidomycosis, Nitriles, Triazoles, Fluconazole, Pyridines, Pharmaceutical Preparations, Antifungal Agents, Models, Theoretical
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 07 Jul 2021 10:18
Last Modified: 19 Nov 2021 02:10
DOI: 10.1128/aac.02344-20
Open Access URL: https://doi.org/10.1128/AAC.02344-20
URI: https://livrepository.liverpool.ac.uk/id/eprint/3129128