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 x 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.
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.
A. Alqarihi, None
C. Baldin, None
N. P. Wiederhold, None
T. Kitt, Astellas Pharma Inc: Employee , Salary .
A. S. Ibrahim, Astellas: Investigator and Research Contractor , Research grant .