In recent years, cases involving terbinafine-resistant Trichophyton isolates have been reported increasingly, particularly in India. We present 14 cases of terbinafine treatment failure in Trichophyton-infected Danish patients due to acquired resistance. Patients infected with Trichophyton rubrum (n = 12) or Trichophyton interdigitale (n = 2) with elevated terbinafine MICs during 2013–2018 were included. Antifungal susceptibility testing (AFST) was performed following a modified EUCAST E.Def 9.3.1 method (5 days of incubation) with or without cycloheximide and chloramphenicol (CC) supplementation of the growth medium. The squalene epoxidase (SE) target gene was sequenced, and 3-dimensional enzyme homology modeling was performed. Most patients (12/14 [86%]) were male. The mean age was 53.5 years (range, 11 to 77 years). The mean duration of infections was 4.8 years at the time of resistance detection. Prior systemic terbinafine treatment was documented for all patients, and topical therapy for 62% (information was missing in one case). Overall, nine isolates (64%) displayed high terbinafine resistance (MICs, 4 to >8 mg/liter), while two (14%) displayed moderate (MICs, 1 to 2 mg/liter) and three (21%) displayed low (MICs, 0.125 to 0.25 mg/liter) terbinafine resistance compared with control isolates. MICs generated with or without CC supplementation were similar, but CC prevented contamination. Known and novel SE amino acid substitutions (F397L, L393F, L393S, F415S, H440Y F484Y, and I121M V237I) were detected in resistant but not control isolates. Three-dimensional homology modeling suggested a role of the novel I121M and V237I alterations. Terbinafine resistance has been detected in Denmark using a modified EUCAST method, which facilitated susceptibility testing of dermatophytes. Action is needed for this emerging public health problem.
Bibliografisk noteFunding Information:
LEO Pharma. R.K.H. has received a research grant from Gilead and travel grants from Gilead, Astellas, MSD, and Pfizer. K.M.J. has received travel grants from Amplyx and F2G and a meeting grant from MSD. M.C.A. has received personal speaker’s honoraria from Astellas, Basilea, Gilead, MSD, Pfizer, T2 Biosystems, and Novartis. She has received research grants and obtained contract work (for which the Statens Serum Institute was paid) from Amplyx, Astellas, Basilea, Cidara, F2G, Gilead, MSD, Novabiotics, Pfizer, Scynexis, and T2 Biosystems over the past 5 years. C.O.Z. has served as a scientific consultant for AbbVie, Pfizer, Janssen-Cilag, Merck & Co., Inc., Eli Lilly, Takeda, CSL, and Novartis and as a clinical study investigator for AbbVie, Amgen, Eli Lilly, Merck & Co., Inc., Takeda, LEO Pharma, and Novartis. S.F.T. has been a paid speaker for AbbVie, LEO Pharma, Eli Lilly, Novartis, Pierre Fabre, and Sanofi, has served on advisory boards for AbbVie, Celgene, Eli Lilly, Janssen, LEO Pharma, Novartis, Roche, and Sanofi, and has received research grants from AbbVie, Novartis, Sanofi, UCB, and LEO Pharma. M.D. has been a paid advisor, speaker, and/or investigator for AbbVie, LEO Pharma, Eli Lilly, Pfizer, Pierre Fabre, Meda, Galapagos, Sanofi Genzyme, and Regeneron. K.K. has been a paid speaker for AbbVie, LEO Pharma, Eli Lilly, Meda, Takeda, Merck, Bristol-Myers Squibb, and Galderma, has served on advisory boards for AbbVie, Celgene, LEO Pharma, and Novartis, and has received research grants from Novartis. L.B.-H. and R.J. have nothing to disclose.
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