Intrinsic resistance to terbinafine among human and animal isolates of Trichophyton mentagrophytes related to amino acid substitution in the squalene epoxidase

Abstract

Background Dermatomycoses are the most common fungal infections in the world affecting a significant part of the human and animal population. The majority of zoophilic infections in humans are caused by Trichophyton mentagrophytes. Currently, the first-line drug for both oral and topical therapy is terbinafine. However, an increasing number of cases that are difficult to be cured with this drug have been noted in Europe and Asia. Resistance to terbinafine and other allylamines is very rare and usually correlated with point mutations in the squalene epoxidase gene resulting in single amino acid substitutions in the enzyme, which is crucial in the ergosterol synthesis pathway. Purpose Here, we report terbinafine-resistant T. mentagrophytes isolates among which one was an etiological factor of tinea capitis in a man and three were obtained from asymptomatic foxes in Poland. Methods We used the CLSI protocol to determine antifungal susceptibility profiles of naftifine, amphotericin B, griseofulvin, ketoconazole, miconazole, itraconazole, voriconazole, and ciclopirox. Moreover, the squalene epoxidase gene of the terbinafine-resistant strains was sequenced and analysed. Results In the genomes of all four resistant strains exhibiting elevated MICs to terbinafine (16 to 32 µg/ml), single-point mutations leading to Leu393Phe substitution in the squalene epoxidase enzyme were revealed. Among the other tested substances, a MIC50 value of 1 µg/ml was shown only for griseofulvin. Conclusion Finally, our study revealed that the terbinafine resistance phenomenon might not be acquired by exposure to the drug but can be intrinsic. This is evidenced by the description of the terbinafine-resistant strains isolated from the asymptomatic animals.

Emerging antifungal treatment failure of dermatophytosis in Europe: take care or it may become endemic

“…Variable bioavailability of some generic antifungals may also contribute through underdosing during treatment. For some years, this has been considered to be an Indian problem only, but recently sporadic reports of resistance have been noted in Poland, Belgium, Germany, Switzerland and Denmark both as imported cases from endemic areas and amongst European residents 8–15 . Taking this into consideration and also the fact that dermatophyte susceptibility testing is not performed as a routine investigation in any country in Europe, we speculate that European antifungal resistance amongst dermatophytes may be an overlooked phenomenon.…”

Belgian National Survey on Tinea Capitis: Epidemiological Considerations and Highlight of Terbinafine-Resistant T. mentagrophytes with a Mutation on SQLE Gene

“…In the genomes of all resistant strains exhibiting elevated MICs to terbinafine (16 to 32 µg/mL), single-point mutations leading to Leu393Phe substitution in the squalene epoxidase enzyme were revealed. [54]. This confirms the need to be careful regarding the emergence of dermatophytes resistant to terbinafine that occur not only in humans but also in animals, which can rapidly give rise to extended outbreaks.…”

A global view on fungal infections in humans and animals: opportunistic infections and microsporidioses

“…Moreover, there are reports in the literature about the possibility of transmission of fungal pathogens from humans to animals (Łagowski et al, 2019a). The possibility of asymptomatic infections and the carrier status of the fungal pathogens in animals, which then become an undefined source of infection, is also extremely important (Ilhan et al, 2016;Gnat et al, 2018Gnat et al, , 2020bŁagowski et al, 2020).…”