Dermatology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milan, Italy.
Mycoses. 2023 Aug;66(8):680-687. doi: 10.1111/myc.13597. Epub 2023 May 4.
Numerous reports of resistance to terbinafine in Trichophyton spp. from all over the world are arousing justified attention and concern. Point mutations in the gene that encodes the squalene epoxidase (SQLE) enzyme are responsible for these therapeutic resistances.
Primary objective of the study was to describe first isolates of Trichophyton spp. resistant to terbinafine among the patients treated between September 2019 and June 2022 at the Dermatology Units of Ospedale Maggiore Policlinico and San Bortolo Hospital. Secondary objective was to study the resistance mechanism.
Patients with confirmed Trichophyton spp. infection has been treated with systemic and topical terbinafine. Patients were then re-evaluated 12 weeks after the therapy. Patients with incomplete or absent response to terbinafine underwent a new skin scraping for direct mycological examination, new identification of dermatophyte species from culture and MALDI-TOF, molecular species identification, antifungal susceptibility testing and molecular analysis of SQLE gene.
We identified five patients without clinical response to treatment with terbinafine. The DNA sequencing of the ITS region identified one Trichophyton rubrum and four Trichophyton indotineae. The T. rubrum strain showed minimum inhibitory concentration (MIC) (90% growth inhibition) of 4 mg/L for terbinafine. The four T. indotineae strains showed a MICs range of 0.25-4 mg/L for terbinafine. The analysis of the SQLE gene in the T. rubrum strain showed a nucleotide substitution generating a missense mutation (L393F). The SQLE gene sequencing in the T. indotineae strains showed a nucleotide substitution generating a missense mutation (F397L) in two strains, a nucleotide substitution L393S in one strain and a nucleotide substitution F415C in another strain.
We report the first cases of terbinafine-resistant Trichophyton isolates in the Italian population. Solid antifungal management programs will be needed to promote more responsible use of antimycotics and preserve their therapeutic efficacy to control antifungal resistance.
来自世界各地的大量关于特比萘芬在 Trichophyton spp. 中耐药的报告引起了合理的关注和担忧。编码角鲨烯环氧化酶（SQLE）酶的基因突变是这些治疗耐药的原因。
本研究的主要目的是描述 2019 年 9 月至 2022 年 6 月期间在 Ospedale Maggiore Policlinico 和 San Bortolo 医院皮肤科接受治疗的患者中特比萘芬耐药的 Trichophyton spp. 的首次分离株。次要目的是研究耐药机制。
确诊为 Trichophyton spp. 感染的患者接受了系统和局部特比萘芬治疗。治疗 12 周后，对患者进行重新评估。对特比萘芬治疗不完全或无反应的患者进行新的皮肤刮片直接进行真菌学检查、从培养物和 MALDI-TOF 中重新鉴定真菌物种、分子物种鉴定、抗真菌药敏试验和 SQLE 基因的分子分析。
我们发现五例患者对特比萘芬治疗无临床反应。ITS 区域的 DNA 测序鉴定出一株红色毛癣菌和四株堇毛癣菌。T. rubrum 株对特比萘芬的最小抑菌浓度（MIC）（90%生长抑制）为 4 mg/L。四株 T. indotineae 株对特比萘芬的 MIC 范围为 0.25-4 mg/L。T. rubrum 株 SQLE 基因分析显示核苷酸取代导致错义突变（L393F）。T. indotineae 株 SQLE 基因测序显示两株菌核苷酸取代导致错义突变（F397L），一株菌核苷酸取代 L393S，另一株菌核苷酸取代 F415C。
我们报告了意大利人群中首例特比萘芬耐药 Trichophyton 分离株。需要制定有效的抗真菌管理方案，以促进更负责任地使用抗真菌药物，并保持其治疗效果，以控制抗真菌耐药性。
