Emerging Terbinafine Resistance in Trichophyton: Clinical Characteristics, Squalene Epoxidase Gene Mutations, and a Reliable EUCAST Method for Detection

Ditte M. L. Saunte; Rasmus K. Hare; Karin M. Jorgensen; Rene Jorgensen; Mette Deleuran; Claus O. Zachariae; Simon F. Thomsen; Lars Bjornskov-Halkier; Kristian Kofoed; Maiken C. Arendrup

doi:10.1128/aac.01126-19

Emerging Terbinafine Resistance in Trichophyton: Clinical Characteristics, Squalene Epoxidase Gene Mutations, and a Reliable EUCAST Method for Detection

Ditte M. L. Saunte, Rasmus K. Hare, Karin M. Jorgensen, Rene Jorgensen, Mette Deleuran, Claus O. Zachariae, Simon F. Thomsen, Lars Bjornskov-Halkier, Kristian Kofoed, Maiken C. Arendrup

42 Citations (Scopus)

Abstract

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, L3935, F4155, 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.

Original language	English
Article number	e01126-19
Journal	Antimicrobial Agents and Chemotherapy
Volume	63
Issue number	10
Number of pages	9
ISSN	0066-4804
DOIs	https://doi.org/10.1128/aac.01126-19
Publication status	Published - 2019

Keywords

Trichophyton
antifungal resistance
dermatophytes
squalene epoxidase mutations
terbinafine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1128/aac.01126-19

https://aac.asm.org/content/aac/63/10/e01126-19.full.pdf

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Saunte, D. M. L., Hare, R. K., Jorgensen, K. M., Jorgensen, R., Deleuran, M., Zachariae, C. O., Thomsen, S. F., Bjornskov-Halkier, L., Kofoed, K., & Arendrup, M. C. (2019). Emerging Terbinafine Resistance in Trichophyton: Clinical Characteristics, Squalene Epoxidase Gene Mutations, and a Reliable EUCAST Method for Detection. Antimicrobial Agents and Chemotherapy, 63(10), Article e01126-19. https://doi.org/10.1128/aac.01126-19

Emerging Terbinafine Resistance in Trichophyton: Clinical Characteristics, Squalene Epoxidase Gene Mutations, and a Reliable EUCAST Method for Detection. / Saunte, Ditte M. L.; Hare, Rasmus K.; Jorgensen, Karin M. et al.
In: Antimicrobial Agents and Chemotherapy, Vol. 63, No. 10, e01126-19, 2019.

Research output: Contribution to journal › Journal article › Research › peer-review

Saunte, DML, Hare, RK, Jorgensen, KM, Jorgensen, R, Deleuran, M, Zachariae, CO , Thomsen, SF, Bjornskov-Halkier, L, Kofoed, K & Arendrup, MC 2019, 'Emerging Terbinafine Resistance in Trichophyton: Clinical Characteristics, Squalene Epoxidase Gene Mutations, and a Reliable EUCAST Method for Detection', Antimicrobial Agents and Chemotherapy, vol. 63, no. 10, e01126-19. https://doi.org/10.1128/aac.01126-19

@article{2872eaae95a840ebb89c170fc7d207a4,

title = "Emerging Terbinafine Resistance in Trichophyton: Clinical Characteristics, Squalene Epoxidase Gene Mutations, and a Reliable EUCAST Method for Detection",

abstract = "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, L3935, F4155, 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.",

keywords = "Trichophyton, antifungal resistance, dermatophytes, squalene epoxidase mutations, terbinafine",

author = "Saunte, {Ditte M. L.} and Hare, {Rasmus K.} and Jorgensen, {Karin M.} and Rene Jorgensen and Mette Deleuran and Zachariae, {Claus O.} and Thomsen, {Simon F.} and Lars Bjornskov-Halkier and Kristian Kofoed and Arendrup, {Maiken C.}",

year = "2019",

doi = "10.1128/aac.01126-19",

language = "English",

volume = "63",

journal = "Antimicrobial Agents and Chemotherapy",

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T1 - Emerging Terbinafine Resistance in Trichophyton: Clinical Characteristics, Squalene Epoxidase Gene Mutations, and a Reliable EUCAST Method for Detection

AU - Saunte, Ditte M. L.

AU - Hare, Rasmus K.

AU - Jorgensen, Karin M.

AU - Jorgensen, Rene

AU - Deleuran, Mette

AU - Zachariae, Claus O.

AU - Thomsen, Simon F.

AU - Bjornskov-Halkier, Lars

AU - Kofoed, Kristian

AU - Arendrup, Maiken C.

PY - 2019

Y1 - 2019

N2 - 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, L3935, F4155, 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.

AB - 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, L3935, F4155, 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.

KW - Trichophyton

KW - antifungal resistance

KW - dermatophytes

KW - squalene epoxidase mutations

KW - terbinafine

U2 - 10.1128/aac.01126-19

DO - 10.1128/aac.01126-19

M3 - Journal article

C2 - 31383665

SN - 0066-4804

VL - 63

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

IS - 10

M1 - e01126-19

ER -

Emerging Terbinafine Resistance in Trichophyton: Clinical Characteristics, Squalene Epoxidase Gene Mutations, and a Reliable EUCAST Method for Detection

Abstract

Keywords

UN SDGs

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