Emergence of Terbinafine-Resistant Trichophyton indotineae in Europe

Abstract

There is a recent growing global concern regarding the rise in antifungal resistance of dermatophytosis. The emergence of terbinafine-resistant Trichophyton indotineae (T. indotineae), previously known as Trichophyton mentagrophytes genotype VIII, is particularly alarming given that terbinafine is considered the treatment of choice for dermatophyte infections and the limited number of available antimycotics. This strain surfaced in the Indian subcontinent in the mid 2010s and more recently there have been reports of its arrival in Europe. The objective of this review is to document the presence of terbinafine-resistant T. indotineae in Europe with the aim to enlighten antifungal stewardship and ultimately prevent the spread of resistance. We extracted information from 16 studies published between 2019 and 2023 that described a total of 63 cases of antifungal-resistant dermatophytosis caused by T. indotineae in Europe. Antifungal susceptibility testing (AFST) revealed a wide range of terbinafine minimum inhibitory concentrations (MICs), varying from 0.014 to ≥ 16 μg/mL. However these values are hard to interpret due to variations among used methodologies as well as the lack of clinical breakpoints. In all cases included in this study, elevated terbinafine MICs was associated with mutations in the squalene epoxidase (SQLE) gene, including single mutations F397L and L393S, as well as double mutations such as F397L/A448T. Itraconazole was the most frequently used alternative to terbinafine in this study and complete remission of tinea lesions after treatment switch was shown. Nevertheless, relapse rates are concerningly high. To prevent the further spread of resistance across Europe and worldwide, we propose the implementation of surveillance programs for a fast identification of T. indotineae (and SQLE mutations) through sequencing and standardization of procedures for AFST to facilitate the establishment of clinical breakpoints. This may enable guidance on the appropriate use of antifungals and prevent the therapeutic challenges associated with resistance.