The Safe and Non-Toxic Dose of Intravitreal Micafungin and Caspofungin in a Rabbit Model

Abstract

Purpose: : Determine safe intravitreal (IV) dosing of the antifungal echinocandins, caspofungin (C) and micafungin (M), utilizing a multitest regimen in a New Zealand albino rabbit model.

Methods: : Experiments were carried out in accordance with ARVO principles of animal care/Animal Care Committee at University of Illinois, Chicago. 17 rabbits (34 eyes) were randomized to IV injections of normal saline (NS) (n=5), micafungin (2 mg/0.1ml (n=2), 0.5 mg/0.1 ml (n=2), 0.2 mg/0.1 ml (n=3), 0.05 mg/0.1 ml (n=5), 0.025 mg/0.1 ml (n=4)) & caspofungin (0.5 mg/0.1 ml (n=2), 0.2 mg/0.1 ml (n=2), 0.05 mg/0.1ml (n=5), 0.025 mg/0.1 ml (n=4)). Rabbits were sacrificed at post-operative day (POD) 1 or 7. Anterior/posterior segment inflammation grading, spectral domain optical coherence tomography (OCT) and full field electroretinograms (ERG) were performed on POD 0 & day of sacrifice. ERGs with scotopic, maximal combined, & photopic responses were recorded. A decrease of 30% in a/b wave amplitudes was considered significant. Histopathology was performed to assess for inflammation/structural damage.

Results: : Only eyes administered ≥ 0.2 mg/0.1ml concentrations of micafungin or caspofungin displayed signs of anterior segment inflammation &/or retinal whitening. Lower concentrations (M&C) and the NS group showed no clinically detectable changes. A dose response was noted for significant changes in a & b wave amplitude in both M & C groups. The 0.025 mg/0.1 ml dose of M & the NS group demonstrated no significant changes on ERG. OCT demonstrated no change in retinal thickness regardless of dose, drug, or duration. Loss of the outer photoreceptor complex was noted in a dose response fashion for both M & C. The 0.025 mg/0.1 ml dose of M & the NS group demonstrated no architectural changes on OCT. Histopathology also demonstrated increasing retinal damage & inflammation in a dose related response in both the M & C groups except for the 0.025 mg/0.1 ml concentration of M & the NS group which were within normal limits.

Conclusions: : Our multitest regimen established that IV Micafungin at a dose of 0.025 mg/0.1 ml (8.3X minimum inhibitory concentrations (MIC) for Candida species in rabbit vitreous and 3.1X MIC for Candida species in human vitreous) is a non-toxic starting point for animal studies of antimicrobial efficacy and future use in humans for treatment of fungal endophthalmitis.

Keywords: endophthalmitis • fungal disease • drug toxicity/drug effects