Clinical Trichophyton rubrum Strain Exhibiting Primary Resistance to Terbinafine (original) (raw)
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Discovery of Terbinafine Low Susceptibility Trichophyton rubrum strain in Japan
Biocontrol Science, 2018
This is the first confirmed report of terbinafine low susceptibility Trichophyton rubrum, BGUTR13, in Japan collected from the whole sole of the elderly over 65s with cotton swab sampling method at the special nursing care-home in 2016. We revealed BGUTR13 showed low susceptibility MIC, >128 µg/mL against terbinafine. But, BGUTR13 exhibited normal susceptibility to itraconazole, did not showed cross-resistance. Also, the squalene epoxidase gene of terbinafine low susceptibility strain BGUTR13 which is the target of terbinafine contained newly confirmed one mismatch. We suggested the possibility that the resistance mechanism of terbinafine low susceptibility strains is due to the loss of sensitivity of squalene epoxidase inhibitors and does not affect antifungal drugs with other different mechanisms of action.
Antimicrobial Agents and Chemotherapy, 2005
There has only been one clinically confirmed case of terbinafine resistance in dermatophytes, where six sequential Trichophyton rubrum isolates from the same patient were found to be resistant to terbinafine and cross-resistant to other squalene epoxidase (SE) inhibitors. Microsomal SE activity from these resistant isolates was insensitive to terbinafine, suggesting a target-based mechanism of resistance (B. Favre, M. Ghannoum, and N. S. Ryder, Med. Mycol. 42:525-529, 2004). In this study, we have characterized at the molecular level the cause of the resistant phenotype of these clinical isolates. Cloning and sequencing of the SE gene and cDNA from T. rubrum revealed the presence of an intron in the gene and an open reading frame encoding a protein of 489 residues, with an equivalent similarity (57%) to both yeast and mammalian SEs. The nucleotide sequences of SE from two terbinafine-susceptible strains were identical whereas those of terbinafine-resistant strains, serially isolated from the same patient, each contained the same single missense introducing the amino acid substitution L393F. Introduction of the corresponding substitution in the Candida albicans SE gene (L398F) and expression of this gene in Saccharomyces cerevisiae conferred a resistant phenotype to the transformants when compared to those expressing the wild-type sequence. Terbinafine resistance in these T. rubrum clinical isolates appears to be due to a single amino acid substitution in SE.
Scientific Reports
Dermatophytosis has gained interest in India due to rise in terbinafine resistance and difficulty in management of recalcitrant disease. The terbinafine resistance in dermatophytes is attributed to single nucleotide polymorphisms (SNPs) in squalene epoxidase (SE) gene. We evaluated the utility of amplified refractory mutation system polymerase chain reaction (ARMS PCR) for detection of previously reported point mutations, including a mutation C1191A in the SE gene in Trichophyton species. ARMS pcR was standardized using nine non-wild type isolates and two wild type isolates of Trichophyton species. Study included 214 patients with dermatophyte infection from March through December 2017. Antifungal susceptibility testing of isolated dermatophytes was performed according to CLSI-M38A2 guidelines. Among dermatophytes isolated in 68.2% (146/214) patients, Trichophyton species were predominant (66.4%). High (>2 mg/L, cut off) minimum inhibitory concentrations to terbinafine were noted in 15 (15.4%) Trichophyton mentagrophytes complex isolates. A complete agreement was noted between ARMS PCR assay and DNA sequencing. C to A transversion was responsible for amino acid substitution in 397 th position of SE gene in terbinafine resistant isolates. Thus, the ARMS PCR assay is a simple and reliable method to detect terbinafine-resistant Trichophyton isolates.
Increasing Terbinafine Resistance in Danish Trichophyton Isolates 2019–2020
Journal of Fungi, 2022
Terbinafine resistance in Trichophyton species has emerged and appears to be increasing. A new EUCAST susceptibility testing method and tentative ECOFFs were recently proposed for Trichophyton. Terbinafine resistance and target gene mutations were detected in 16 Danish isolates in 2013–2018. In this study, samples/isolates submitted for dermatophyte susceptibility testing 2019–2020 were examined. Species identification (ITS sequencing for T. mentagrophytes/T. interdigitale species complex (SC) isolates), EUCAST MICs and squalene epoxidase (SQLE) profiles were obtained. Sixty-three isolates from 59 patients were included. T. rubrum accounted for 81% and T. mentagrophytes/T. interdigitale SC for 19%. Approximately 60% of T. rubrum and T. mentagrophytes/interdigitale SC isolates were terbinafine non-wildtype and/or had known/novel SQLE mutations with possible implications for terbinafine MICs. All infections with terbinafine-resistant T. mentagrophytes/interdigitale SC isolates were ca...
In Vitro Analysis of the Ability of Trichophyton rubrum To Become Resistant to Terbinafine
Antimicrobial Agents and Chemotherapy, 2003
In this study, we have investigated in vitro the resistance frequency and development of resistance to terbinafine of Trichophyton rubrum. Results demonstrated that naturally occurring mutants are rare and that T. rubrum appears to have little capacity to develop resistance to terbinafine even after prolonged exposure.
The prevalence of dermatophytosis has increased in recent years due to a rise in resistance of etiologic dermatophytes to terbinafine which could be attributed in part to point mutation in the squalene epoxidase (SQLE) gene. In this study, the point mutation in the SQLE gene was studied in Trichophyton rubrum and T. mentagrophytes/T. indotineae species complex as two main causative agents of dermatophytosis. Antifungal susceptibility of clinical isolates of T. rubrum (n = 27) and T. mentagrophytes/T. indotineae (n = 56) was assessed using the M38-3rd edition CLSI method. The SQLE gene and ITS region were sequenced in all the fungal strains, and terbinafine resistant strains were characterized by mutation sites and the genotype. The results demonstrated that in T. rubrum, the minimum inhibitory concentration of terbinafine, was 0.03 µg/ml and GM was equal to 0.02. In T. mentagrophytes complex, MIC50 and MIC90 were 0.03 and 1.0 µg/ml and GM was equal to 0.04 µg/ml. Four out of five re...
International journal of …, 2008
The in vitro antifungal activity of terbinafine against 521 clinical isolates of seven species of dermatophytes, including four onychomycosiscausative species, as well as five Scopulariopsis brevicaulis isolates was determined by a modified Clinical and Laboratory Standards Institute microdilution method. Results showed a high antifungal activity of terbinafine against all dermatophyte isolates (geometric minimal inhibitory concentration (MIC) = 0.026 g/mL; concentration inhibiting 50% of mycological growth (MIC 50 ) = 0.03 g/mL; and concentration inhibiting 90% of mycological growth (MIC 90 ) = 0.06 g/mL). The geometric mean MICs against onychomycosis-causative dermatophyte species was lower (0.024 g/mL) than the global MIC. However, the in vitro activity of terbinafine against S. brevicaulis was considerably lower (geometric mean MIC = 1.38 g/mL) in comparison with dermatophytes. The antifungal activity of itraconazole was lower than that of terbinafine against these fungi. These data confirm the high in vitro antifungal activity of terbinafine against dermatophytes, under standardised conditions.
Terbinafine Preferred Antifungal with a Focus on Dermatophytes (A Review)
Acta Scientific Microbiology, 2020
17 years ago, Terbinafine was hailed in the global drug market to use as antifungal. In the treatment of superficial dermatophytosis terbinafine is become the first choice of drug, because of its effective mode of action, pharmacologic action and microbiologic profiles. Appropriate use of terbinafine as a topical and systemic drug needs to be used with appropriate guidelines. Terbinafine is primarily indicated and also discussed a contraindication for the treatment of non-dermatophyte infections. Terbinafine act by inhibiting the enzyme squalene epoxidase which is an important component of fungal cell membrane resulting in disintegration of fungal cell was allowing terbinafine to exert its fungicidal action. As per the recent advancement significant clinical relevance seen in activity of terbinafine when used in combination of other antifungal leads to decrease in resistance. This article reviews mode of action, antimycotic spectrum and disposition profile of terbinafine. we have also done a comparative analysis of terbinafine over other antifungals (griseofulvin, itraconazole, fluconazole) in the management of dermatophytes infection.