Emergence of Terbinafine Resistant Trichophyton mentagrophytes in Iran, Harboring Mutations in the Squalene Epoxidase (SQLE) Gene

Figures & data

Table 1 MIC Values (μg/mL) of 8 Antifungal Agents Against 141 Trichophyton interdigitale and T. mentagrophytes Isolates

Species	Antifungal MICs	TRB	ITC	EFN	LUZ	CLT	AHC	CPO	GRE
T. interdigitale (n=96)	MICGM	0.038	0.36	0.0057	0.0016	1.43	0.92	0.45	1.1
	MIC50	0.062	0.5	0.007	0.003	1	1	0.5	1
	MIC90	0.125	1	0.015	0.001	4	2	1	2
	MIC range	0.003–0.25	0.062–8	0.001–0.125	0.0004–0.015	0.25–16	0.125–4	0.062–1	0.062–4
T. mentagrophytes (n=45)	MICGM	0.12	0.32	0.009	0.0024	3.25	0.92	0.56	1.8
	MIC50	0.625	0.25	0.0075	0.003	4	1	0.5	2
	MIC90	>32	0.5	0.031	0.001	16	2	1	4
	MIC range	0.007–>32	0.062–2	0.001–0.125	0.0004–0.015	0.5–32	0.125–4	0.062–1	0.25–4

Abbreviations: TRB, terbinafine; ITC, itraconazole; EFN, efinaconazole; LUZ, luliconazole; CLT, clotrimazole; AHC, amorolfine hydrochloride; CPO, ciclopirox olamine; GRE, griseofulvin.

Table 2 MIC Values (μg/mL) of Used Antifungal Agents Against 10 Terbinafine Resistant/Susceptible T. mentagrophytes Isolates and Corresponding GenBank Accession with Consequential Amino Acid Substitutions in SQLE Gene

	Resistant	Sensitive
SQLE accession number	MN901906–MN901910	MN901902–MN901905, MN893286
Amino Acid Substitution
Phe397Leu/Ala448Thr	4	0
Leu393Ser/ Ala448Thr	1	0
Ala448Thr	0	3
Wild type	0	2
MIC Values (μg/mL)
TRB	≥32	0.125–0.25
ITC	0.125–2	0.25–2
EFN	0.002–0.008	0.008–0.125
LUZ	0.008–0.004	0.008–0.015
CLT	1–8	2–16
AHC	0.5–2	0.25–4
CPO	0.5–1	0.5–1
GRE	1–4	1–4

Table 3 Number of Terbinafine (TRB) Resistant Isolates Showing Mutations in the Squalene Epoxidase (SQLE) Gene in Regards to the ITS Genotypes and TRB MIC Values in Different Studies

Row	Species	ITS Genotype	Country of Origin	MIC Rates of Resistant Isolates (μg/mL)	Number of Resistant Isolates	Amino Acid Substitution Found in Resistance Isolates	Study
1	T. interdigitale^a	ND	Switzerland	3.2	1	Phe397Leu	Yamada et al., 2017^Citation11
2	T. interdigitale	II	Japan	2	1	Wild type	Hiruma et al., 2018^Citation13
3	T. mentagrophytes^b	VIII	India	1–≥32	20	Phe397Leu Leu393Phe	Singh et al., 2018^Citation5
4	T. interdigitale^a	ND	India	4–>16	4	Phe397Leu Wild type	Rudramurthy et al., 2018^Citation12
5	T. interdigitale^a	ND	India	4–≥32	13	Phe397Leu Leu393Phe Wild type	Khurana et al., 2018^Citation14
6	T. interdigitale	II	Denmark	4–>8	2	Phe397Leu Leu393Phe	Saunte et al., 2019^Citation18
7	T. mentagrophytes	VIII	Finland	4–8	4	Phe397Leu	Järv et al., 2019 TIMM^Citation17
8	T. mentagrophytes^a	ND	Switzerland	≥1	1	Gln408Leu	Hsieh et al., 2019^Citation16
9	T. mentagrophytes	VIII	Bahrain	–^c	1	Phe397Leu	Süß et al., 2019^Citation19
10	T. mentagrophytes	VIII	India	–^c	1	Phe397Leu	Burmester et al., 2019^Citation15
11	T. mentagrophytes		Iran	≥32	5	Phe397Leu/Ala448Thr Leu393Ser/Ala448Thr	Current study

Notes: ^aNo ITS sequence accession numbers were mentioned. ^bThe TRB resistant isolates were reported as T. interdigitale but the true identity of isolates based on ITS-sequencing is T. mentagrophytes. ^cResistance was not determined by the broth microdilution method, but by the agar diffusion method using Sabouraud’s dextrose agar containing 0.2 µg/mL terbinafine.

Abbreviation: ND, not determined.

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