2393. Evaluation of Antifungal Treatment in a Neutropenic Mouse Model of Scedosporiosis

Abstract

BackgroundScedosporiosis is a rare fungal infection with high mortality rates. Because clinical trials are hard to conduct, we developed a murine model for evaluating the efficacy of currently used antifungals in treating scedosporiosis.MethodsMIC of isavuconazole (ISAV), posaconazole (POSA), voriconazole (VORI), and micafungin (MICA) were determined against 9 clinical isolates of Scedosporium apiospermum, S. boydii and Lomentospora prolificans using the CLSI M38 method. ICR mice were immunosuppressed with cyclophosphamide (200 mg/kg) and cortisone acetate (500 mg/kg) on days −2, +3, and +8 relative to intratracheal infection with 3.0 × 107 cells of S. apiospermum. For survival studies, treatment with placebo (vehicle control), ISAV (110 mg/kg, tid, po), POSA (30 mg/kg, tid, po), VORI (40 mg/kg, qd, po), MICA (3 or 10 mg/kg, qd, ip) or a combination of MICA (10 mg/kg) + ISAV (110 mg/kg) began 16 h post infection and continued for 7 days. For fungal burden studies, dosing began 8 h post infection and continued for 3 days. Mice were sacrificed on day +4. Survival and tissue fungal burden (by qPCR) served as efficacy endpoints.Results S. apiospermum was the most susceptible to all 4 antifungals with MICA MIC of 0.25 μg/mL and azole MICs of 1 μg/mL. S. boydii was also susceptible to MICA (0.125–0.5 μg/mL) but with variable susceptibility to azoles (1–16 μg/mL). In contrast, L. prolificans strains were resistant (MICA MIC 2–4 μg/mL and azole MIC >16 μg/mL). S. apiospermum DI16-478 was used to test in vivo efficacy. Only MICA (10 mg/kg) treatment prolonged survival of mice (n = 10) vs. placebo (median survival time = 8 days for MICA vs. 5 for placebo, P < 0.03 by log rank) and reduced fungal burden in lungs (primary target organ), brains and kidneys (P ≤ 0.02, by Wilcoxon rank sum). None of the azoles prolonged survival despite the significant reduction in the lung fungal burden (P < 0.002), possibly due to lack of reduction of fungal burden in kidneys and brains. MICA+ISAV did not enhance survival nor reduce tissue fungal burden vs. placebo.ConclusionDespite the in vitro activity of tested antifungals, only MICA demonstrated modest efficacy in mice infected with S. apiospermum. A combination of MICA+ISAV was ineffective in this model. Continued investigations of other drug combinations to treat scedosporiosis are needed.Disclosures T. Kitt, Astellas Pharma Inc.: Employee, Salary. A. S. Ibrahim, Astellas: Investigator and Research Contractor, Research grant.