2393. Evaluation of Antifungal Treatment in a Neutropenic Mouse Model of Scedosporiosis. (26th November 2018)

• Record Type: Journal Article
• Authors: Alkhazraji, Sondus; Gebremariam, Teclegiorgis; Alqarihi, Abdullah; Baldin, Clara; Wiederhold, Nathan P; Kitt, Therese; Ibrahim, Ashraf S
• Is Part Of: Open forum infectious diseases. Volume 5(2018)Supplement 1
• Page Start: S713
• Page End: S714
• Publication Date: 2018-11-26
• Subjects: Communicable diseases -- Periodicals; Medical microbiology -- Periodicals; Infection -- Periodicals; 616.9
• DOI: 10.1093/ofid/ofy210.2046
• Languages: English
• ISSNs: 2328-8957

Abstract

Abstract: Background: Scedosporiosis 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. Methods: MIC 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 × 10 7 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. Conclusion: Despite 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.