Therapeutic efficacy of isavuconazole in experimental Aspergillus fumigatus endophthalmitis

BACKGROUND: Fungal endophthalmitis remains a significant cause of vision impairment and blindness with poor prognosis, in part, due to delay in diagnosis and limited availability of antifungal agents without ocular toxicity. Thus, it is imperative to evaluate the therapeutic efficacy of newer antifungal agents such as Isavuconazole in fungal endophthalmitis. METHODS: Aspergillus fumigatus (AF) endophthalmitis was induced by intravitreal (IVT) injection of AF spores in C57BL/6 mice eyes. Therapeutic efficacy of isavuconazole was evaluated by administering the drug in five treatment groups (1) oral gavage, (2) IVT injections, (3) intravenous, (4) IVT injection followed by oral gavage, and (5) IVT injection followed by intravenous. In all treatment groups, isavuconazole therapy was starting at 6 h post AFinfection and continued daily for a maximum of three-day post infection (dpi). Disease progression was monitored by daily eye exam and the assessment of retinal function using the electroretinogram (ERG) diagnostic test. Enucleated eyes were used for histology and the determination of fungal burden and inflammatory cytokines. RESULTS: In comparison to placebo, isavuconazole treatment significantly (P < 0.001) retained retinal function in all treatment groups. This coincided with preservation of retinal architecture (histology analysis) and reduction in fungal burden and intraocular inflammation. Among various treatment groups, daily oral administration of isavuconazole alone was as effective as IVT alone, as evidenced by significant (P < 0.0001) inhibition of inflammatory cytokine levels (TNF-α, IL-1β, IL-6), drastic (P < 0.0001) reduction in fungal burden and retinal tissue damage, culminating in significant (P < 0.001) retention of retinal function (ERG response). Moreover, oral isavuconazole combined with single IVT injection also seems to be highly effective in comparison with IVT+ intravenous delivery of the drug. CONCLUSION: In this first proof-of-principle study, we show that isavuconazole can be potentially used for the treatment of fungal (Aspergillus) endophthalmitis. Moreover, the better efficacy of oral administration alone may avoid the need for an invasive procedure (IVT injection) to deliver antifungal agents into the eye. DISCLOSURES: A. Kumar, Astellas Pharma Global Development, Inc.: Grant Investigator, Research grant