1585. Isavuconazonium Sulfate plus Micafungin Improves Survival in an Immunocompromised Murine Model of Disseminated Fusariosis

BACKGROUND: Disseminated fusariosis in patients with hematological malignancies is a frequently fatal and emerging invasive mycosis. Fusarium spp. are often resistant to safely achievable concentrations of mould active triazoles and amphotericin B. We aimed to determine the efficacy of isavuconazonium sulfate (ISA) alone or in combination with micafungin (MICA) in a murine model of disseminated fusariosis caused by Fusarium solani. METHODS: Groups of five 5-week-old Swiss Webster female mice, 20–22 g, were rendered neutropenic by intraperitoneal (IP) injection of cyclophosphamide at 200 mg/kg on day −2 and 150 mg/kg on day +3. Mice were infected with 5 × 10E(5) CFU F. solani intravenously (IV) via the lateral tail vein on day 0. To prevent bacterial infection, ceftazidime was administered 50 mg/kg/day IP. Therapy began 18 h post-challenge for 6 days. MICA was given at dosages of 10, 5, 2.5 and 1.25 mg/kg IP Q12h combined with ISA 14 mg/kg/day IP. Six groups of mice received ISA orogastrically (OG) Q8h, Q12h and Q24h at 224 mg/kg alone or combined with MICA at 10 mg/kg Q12h IP. Kaplan–Meier survival analysis was performed. RESULTS: ISA at 14 mg/kg Q12h combined with 10 mg/kg MICA doses resulted in improved survival but with no significant reduction of residual fungal burden compared with monotherapy or other ISA/MICA dose combinations. Improved survival with dose-escalated oral monotherapy was observed at ISA 224 mg/kg Q12h (50% survival) and Q8h OG (60%) compared with other monotherapy or combination, or untreated groups (18–20%). The residual fungal burden in kidney between monotherapy and combination therapy groups was 5.81 10Log (untreated), 4.03 10Log (ISA 224 mg/kg, OG Q12h), 5.19 10Log (ISA 224 mg/kg Q12h + MICA 10 mg/kg, Q12h), 4.67 10Log (ISA 224 mg/kg, Q24h), and 4.82 10Log (ISA 224 mg/kg Q24h + MICA 10 mg/kg, Q12h). CONCLUSION: High doses of isavuconazole (exceeding currently approved human dosages) in combination with micafungin improved survival in experimental murine disseminated fusariosis. Given the excellent safety profile of ISA, exploration of higher dosages that are necessary to achieve this antifungal effect is warranted for successful management of disseminated fusariosis. DISCLOSURES: All authors: No reported disclosures.