Amorolfine Hydrochloride

This study reports the first isolation of a multidrug‐resistant Trichophyton rubrum strain in China, characterizing its drug resistance profile and mechanisms.

The isolate was identified by internal transcribed spacer (ITS) sequencing and phylogenetic analysis. In vitro antifungal susceptibility testing (AFST) was performed according to the M38‐A3 CLSI guideline to determine minimum inhibitory concentrations (MICs) against eight antifungals (terbinafine, itraconazole, fluconazole, amorolfine, griseofulvin, voriconazole, luliconazole and amphotericin B). Whole genome sequencing (WGS), transcriptome sequencing and qRT‐PCR were performed to explore the resistance mechanism.

The multidrug‐resistant T. rubrum strain L‐6424 was isolated from a Chinese patient with generalised tinea corporis/cruris, tinea unguium and tinea manuum. It exhibited elevated MICs to terbinafine (2 mg/L), itraconazole (0.5 mg/L), and amorolfine (0.5 mg/L). The phylogenetic tree based on genome‐wide single nucleotide polymorphisms (SNPs) showed L‐6424 is not a novel genotype of T. rubrum , with high genetic similarity (99.94%) with the reference strain (CBS 139224). There were three amino acid substitutions in the squalene epoxidase (SQLE), including the previously reported F397L and H440Y, as well as a newly discovered V105M, and one amino acid substitution in the CYP51A (R239C) was identified. Also, significant differences at the transcriptome level between the drug‐resistant and sensitive strains were observed, and it was screened and found that CYP51A, TruMDR5 and TERG_08139 may be related to azole resistance.

Drug‐resistant T. rubrum has emerged in China, indicating the possibly increasing severity of antifungal resistance. The complex mechanism of multidrug‐resistant dermophytes poses challenges to clinical treatment, needing more attention.

Trichophyton (T.) mentagrophytes ITS genotype VIII/T. indotineae (TMVIII/TINDO) is a new, anthropophilic dermatophyte from the T. mentagrophytes/T. interdigitale complex that has gained increasing importance worldwide in recent years. This pathogen is characterized by frequent terbinafine resistance and a clinical picture of pronounced, inflammatory, and therapy-resistant dermatophytoses that predominantly affect the groin, trunk, extremities, and face. Between 2018 and the end of 2024, all TMVIII/TINDO cases detected in patients from Germany by culture and/or molecular biology were systematically recorded at the Leipzig-Mölbis laboratory. Identification and genotyping were performed by sequencing the internal transcribed spacer (ITS) region of the rDNA. In vitro resistance testing for terbinafine and itraconazole was performed using a breakpoint test. Additionally, the squalene epoxidase (SQLE) gene was sequenced to analyze resistance-associated point mutations. A total of 242 isolates from 196 patients were identified; some patients were consecutively detected repeatedly. The majority of affected patients had a migration background, particularly from South Asia (especially India) and Arab countries. Only a few infections were diagnosed in patients of German descent. As part of the diagnostic workup an in vitro susceptibility testing was performed using a breakpoint test, which demonstrated terbinafine resistance in 61.8% of the TMVIII/TINDO strains. Point mutations in the SQLE gene that correlated with resistance were found in a total of 161 of 188 strains. The most frequently detected mutation was Phe³⁹⁷Leu, which was associated with terbinafine resistance and clinical treatment failure with terbinafine in all cases. In addition, double mutations were detected in 26 strains. In vitro itraconazole resistance was observed in 11 of 186 tested isolates, corresponding to 5.9%. Itraconazole is currently the drug of choice for the systemic treatment of TMVIII/TINDO dermatophytoses. The recommended dosage is 100 mg twice daily for a period of 4-8 weeks, or up to 12 weeks if needed. Concurrent topical treatment with azoles, amorolfine, or ciclopirox is always recommended. In the event of itraconazole treatment failure, there are currently no standardized treatment recommendations. The off-label use of voriconazole has been reported in isolated cases, and there is also experimental experience with other active ingredients. The spread of TMVIII/TINDO in Germany and worldwide is particularly worrying in view of the dermatophyte's resistance to terbinafine and itraconazole.