Ocular Delivery of Natamycin in Fungal Keratitis: Barriers, Advanced Drug Delivery Systems, and Translational Challenges

Fungal keratitis is a sight-threatening corneal infection affecting over a million people annually. Natamycin, a polyene extracted from Streptomyces natalensis, remains the only FDA-approved drug for the treatment of fungal keratitis. The conventional treatment involves a 5% ophthalmic natamycin solution, administered at a high frequency during the initial treatment phase and subsequently tapered based on the observed clinical response. Although it demonstrates a broad spectrum of activity, its efficacy is hindered by limited corneal penetration due to its high molecular weight and low aqueous solubility.

This review consolidates current knowledge on fungal keratitis, including prevalence, risk factors, and etiology. It provides a comprehensive evaluation of natamycin, covering its pharmacology, mechanism of action, antifungal spectrum, and clinical applications while addressing the limitations of conventional natamycin therapy and ocular barriers that restrict drug delivery. Furthermore, the review highlights recent advances in both nanotechnology-based and non-nanotechnology-based natamycin delivery strategies to enhance corneal bioavailability.

Despite promising preclinical outcomes in terms of bioavailability and retention, no alternative natamycin formulations have yet progressed to clinical trials or commercialization. Further efforts are required to advance these delivery systems into clinical trials and realize their potential to improve outcomes in fungal keratitis.