Comparisons of the Ocular Penetration of Topical and Intravenous Voriconazole and Amphotericin B in Fungal Endophthalmitis

Abstract

Abstract: : Purpose:To compare the relative ocular penetration of voriconazole and amphotericin, applied either intravenously or topically in rabbit eyes infected with Aspergillus fumigatus. Both drugs previously have demonstrated efficacy in conserving ERG function in this experimental model. Methods:In a randomized, masked study, 6 groups of 5 NZ white rabbits (n=30) received a 0.6 ml midvitreal inoculum of 1 million CFU of aspergillus in the right eye, and 0.6 ml of sterile saline in the left. Four groups of animals received either 1 mg/kg body wt amphotericin or 2 mg/kg body wt voriconazole, administered either IV or topically (in combination with latanoprost as a presumptive adjuvant to transscleral penetration) twice daily. Treatment was initiated 12 hours after the fungal inoculation OD. Two additional groups received single 12 hr post–infection doses of either 150 micrograms voriconazole or 75 micrograms amphtotericin intravitreally in both eyes. All animals were sacrificed within 8 days according to protocol–based IACUC–approved criteria, and aqueous, vitreous, and chorioretial drug concentrations in both eyes were analyzed by HPLC–MS (limit of quantitation 0.01 microgram/ml). Results:Initial intravitreal injections of amphotericin persisted in high concentration in the vitreous and chorioretina of both eyes upon sacrifice; voriconazole was by that time detectable but minimal in all 3 compartments of both eyes (P<0.0001). Ongoing twice–daily IV amphotericin was concentrated in all 3 compartments of the infected eye, but only in the chorioretina of the noninfected fellow eye. IV voriconazole was largely absent from all compartments OU. Topical amphotericin was present in the vitreous and chorioretina of both eyes, while voriconazole was selectively concentrated in the chorioretina of the infected eye only. Conclusions:Topical therapy may be a viable option with both drugs while ocular uptake of voriconazole via the IV route appears quite limited. Strategies to maximize therapeutic efficacy and minimize toxicity of the two drugs might beneficially exploit combined modes of drug administration.

Keywords: fungal disease • endophthalmitis • antibiotics/antifungals/antiparasitics