Transungual Penetration and Antifungal Activity of Seven Prescription and Over-the-Counter Topical Antifungals: In Vitro Comparison

Abstract

Background: Onychomycosis is typically caused by dermatophytes of the species Trichophyton. Topical antifungals must penetrate the nail to reach the infection, though this can be inhibited by keratin binding within the nail. These in vitro experiments compared penetration of commercially available topical antifungals through keratin-free cellulose disks versus human nails to inhibit Trichophyton growth.
 Methods: Seven topical antifungals were tested: 3 FDA-approved products indicated for the treatment of onychomycosis (ciclopirox 8% lacquer; efinaconazole 10% solution; tavaborole 5% solution) and 4 over-the-counter (OTC) products for fungal infections (tolnaftate 1% solutions [Formula 3, Formula 7, Tolcylen] and undecylenic acid 25% solution [Terpenicol]). Antifungal efficacy was assessed via cellulose disk diffusion assay. Each product was applied to a 6-mm cellulose disk and placed in the center of an agar plate (85 mm radius) seeded with a clinical isolate of T. rubrum or T. mentagrophytes (2 strains each; 3 replicates/strain for each product). After 4-7 days incubation, the zone of inhibition (ZI)—defined as the radius of the area of no fungal growth—was recorded. To assess the impact of nail penetration on antifungal efficacy, products were applied to the tops of human cadaverous great toenails and allowed to dry. Five 4-mm disks were punched from the middle of each nail and placed treated side up on seeded plates prior to measurement of ZI (5 replicates/strain for each product). In both experiments, results were averaged across the 2 strains of each fungal species and untreated nails served as negative controls.
 Results: Among FDA-approved topicals in the cellulose disk diffusion assay, efinaconazole and tavaborole demonstrated maximal inhibition (ZI=85 mm) against both T. rubrum and T. mentagrophytes; for ciclopirox, average ZIs were lower (59.0 mm; 55.7 mm, respectively). For OTC products, ZIs were 31.2-57.8 mm against T. rubrum and 25.7-47.7 mm against T. mentagrophytes. In the nail penetration assay, average ZI for FDA-approved topicals against both species was greatest for efinaconazole (T. rubrum: 82.1 mm; T. mentagrophytes: 63.8 mm), followed by tavaborole (63.5 mm; 39.1 mm) and ciclopirox (7.4 mm; 3.6 mm). Average ZI of OTC products ranged from 10.5-34.2 mm against both species. ZIs were generally not affected by nail thickness.
 Conclusions: Our data show that FDA-approved and OTC topical antifungals penetrate cellulose disks more efficiently than cadaver nails, suggesting that keratin in the nails hampers nail penetration. Among all antifungals tested, ability to penetrate human toenails and inhibit growth of both T. rubrum and T. mentagrophytes was greatest for efinaconazole, followed by tavaborole. These results indicate superior transungual penetration of efinaconazole compared to the other antifungals, perhaps due to lower keratin binding in the nail.
 Funding: Ortho Dermatologics