Survey on the Prevalence of Terbinafine-Resistant Trichophyton spp. with Squalene Epoxidase Mutations.

Terbinafine (TBF) and azoles are commonly used to treat fungal infections such as tinea pedis and tinea unguium. TBF-resistant Trichophyton species have been increasingly reported globally; however, the research has primarily focused on Trichophyton rubrum. In other words, there are limited studies that exist on other causative Trichophyton species, such as Trichophyton interdigitale, Trichophyton mentagrophytes, and Trichophyton indotineae. This study aimed to determine the prevalence and resistance mechanisms of TBF-resistant Trichophyton isolates in Japan. Screening of 701 clinical isolates preserved at the Medical Mycology Research Center, Chiba University, Japan, identified 20 resistant strains (2.9% prevalence), including 16 T. rubrum, two T. interdigitale, one T. mentagrophytes, and one T. indotineae. Minimum inhibitory concentrations (MICs) to TBF ranged from 1 to ≥ 32 µg/mL. Additionally, strains showing TBF resistance and reduced susceptibility to azoles were identified in T. rubrum, T. mentagrophytes, and T. indotineae. The squalene epoxidase gene sequencing targeted by TBF revealed amino acid mutations, such as Leu393Ser, Leu393Phe, and Phe397Leu in T. rubrum and Ser392Ala and Leu419Phe in other species. Notably, the Phe397 mutation correlated with high MICs (≥ 32 μg/mL), indicating its significant role in TBF resistance. This study detected a novel isolate of T. mentagrophytes showing TBF resistance and reduced susceptibility to azoles. The study underscores the need for ongoing surveillance and monitoring of antifungal resistance patterns for TBF and azole antifungal agents, considering the increasing prevalence of resistant isolates.