Isavuconazole Protects Immunosuppressed Mice from Rhizopus oryzae Infection

Ref ID: 19281

Author:

G. Luo, T. Gebremariam, H. Lee, J. E. Edwards, Jr., A. S. Ibrahim;

Author address:

Habor-UCLA Med. Ctr., Torrance, CA.

Full conference title:

53rd Interscience Conference on Antimicrobial Agents and Chemotherapy

Date: 10 September 2014

Abstract:

Background: Mucormycosis is a life-threatening infection with very high mortality that occurs predominantly in immunocompromised patients. Isavuconazole (ISA) is a new investigational broad-spectrum azole in clinical phase III with promising activity against Mucorales, the fungi that cause mucormycosis. Here we assessed the in vitro and in vivo activity of ISA against Rhizopus oryzae, the most common cause of mucormycosis. Methods: Eight clinical isolates of R. oryzae were tested for their susceptibility to ISA (BAL4815) after 24 or 48 h of incubation using the Clinical and Laboratory Standards Institute (CLSI) M38-A method. For in vivo efficacy, ICR mice were immunosuppressed by injecting cyclophosphamide (200 mg/kg, i.p.) and cortisone acetate (500mg/kg, sq) on day -2 and +3 relative to intratracheal infection with 2x105cells of R. oryzae 99-880. ISA (prodrug BAL8557) treatment started 8 h post infection at 80, 110, or 215 mg/kg given three times daily and continued through day +4 by oral gavage. Survival time served as the primary efficacy endpoint. Results: All tested R. oryzae strains were susceptible to ISA with MIC and MFC values ranging from 0.125 to 1.0 μg/ml after 48 h of incubation [median MIC or MFC (25th quartile, 75th quartile) = 0.25 (0.0, 0.06) μg/ml]. Consistent with the in vitro efficacy, ISA treatment with 215 mg/kg 3x daily significantly improved survival of mice (n=10 per arm) when compared to placebo (14 days survival of 10% for placebo vs. 70% of ISA-treated mice, P=0.04 by Log Rank test). Treatment with lower doses also
enhanced survival compared to placebo treated mice but
this survival improvement was not statistically significant
(survival rate is 30%, and 40% for 80 and 110 mg/kg
doses, respectively). Conclusion: ISA demonstrated
potent, cidal activity against R. oryzae clinical isolates in
vitro and protected immunosuppressed mice from
mucormycosis. Continued investigation into the use of ISA therapy against mucormycosis is warranted.

Abstract Number: NULL

Conference Year: 2013

Link to conference website: NULL

New link: NULL

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