Abstract
Terbinafine-resistant dermatophytes in patients were exceptional before the second decade of this century. However, acquired resistance to commonly used antifungal compounds has recently emerged in several countries. Resistance towards terbinafine is generated by missense mutations in the squalene epoxidase enzyme targeted by the drug, while recorded resistance towards azoles is due to the overexpression of genes encoding multidrug transporters of the ABC family. At present, approximately 1% of Trichophyton rubrum isolates from Tinea pedis and onychomycosis in Switzerland are resistant to terbinafine. Terbinafine-resistant T. rubrum was also isolated from extended Tinea corporis in patients more susceptible to fungal infections and requiring continuous treatment. Repeated topical and systemic treatments with terbinafine have likely contributed to the development of terbinafine resistance in patients. The prevalence of T. rubrum resistant to terbinafine in Europe contrasts with that of resistant Trichophyton mentagrophytes isolates in India (30–70%). If drugs on the open market and overmedication can partly explain this alarming situation, several indications also allow the suspicion of an origin linked to environmental problems.
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References
Sanglard D, Ischer F, Koymans L, Bille J. Amino acid substitutions in the cytochrome P-450 lanosterol 14alpha-demethylase (CYP51A1) from azole-resistant Candida albicans clinical isolates contribute to resistance to azole antifungal agents. Antimicrob Agents Chemother. 1998;42:241–53.
Perea S, López-Ribot JL, Kirkpatrick WR, McAtee RK, Santillán RA, Martínez M, et al. Prevalence of molecular mechanisms of resistance to azole antifungal agents in Candida albicans strains displaying high-level fluconazole resistance isolated from human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. 2001;45:2676–84.
Mellado E, Garcia-Effron G, Alcazar-Fuoli L, Cuenca-Estrella M, Rodriguez-Tudela JL. Substitutions at methionine 220 in the 14alpha-sterol demethylase (Cyp51A) of Aspergillus fumigatus are responsible for resistance in vitro to azole antifungal drugs. Antimicrob Agents Chemother. 2004;48:2747–50.
Chen J, Li H, Li R, Bu D, Wan Z. Mutations in the cyp51A gene and susceptibility to itraconazole in Aspergillus fumigatus serially isolated from a patient with lung aspergilloma. J Antimicrob Chemother. 2005;55:31–7.
Mellado E, Garcia-Effron G, Alcázar-Fuoli L, Melchers WJ, Verweij PE, Cuenca-Estrella M, et al. A new Aspergillus fumigatus resistance mechanism conferring in vitro cross-resistance to azole antifungals involves a combination of cyp51A alterations. Antimicrob Agents Chemother. 2007;51:1897–904.
Hagiwara D, Watanabe A, Kamei K, Goldman GH. Epidemiological and genomic landscape of azole resistance mechanisms in Aspergillus fungi. Front Microbiol. 2016;7:1382.
Sanglard D, Kuchler K, Ische F, Pagani JL, Monod M, Bille J. Mechanisms of resistance to azole antifungal agents in Candida albicans isolates from AIDS patients involve specific multidrug transporters. Antimicrob Agents Chemother. 1995;39:2378–86.
Sanglard D, Ischer F, Monod M, Bille J. Cloning of Candida albicans genes conferring resistance to azole antifungal agents: characterization of CDR2, a new multidrug ABC transporter gene. Microbiology. 1997;143(Pt 2):405–16.
Sanglard D, Ischer F, Bille J. Role of ATP-binding-cassette transporter genes in high-frequency acquisition of resistance to azole antifungals in Candida glabrata. Antimicrob Agents Chemother. 2001;45:1174–83.
Fraczek MG, Bromley M, Buied A, Moore CB, Rajendran R, Rautemaa R, et al. The cdr1B efflux transporter is associated with non-cyp51a-mediated itraconazole resistance in Aspergillus fumigatus. J Antimicrob Chemother. 2013;68:1486–96.
Sanglard D, Ischer F, Calabrese D, Micheli M, Bille J. Multiple resistance mechanisms to azole antifungals in yeast clinical isolates. Drug Resist Update. 1998;1:255–65.
Leyden J. Pharmacokinetics and pharmacology of terbinafine and itraconazole. J Am Acad Dermatol. 1998;38(5 Pt 3):S42–7.
Odds FC, Brown AJ, Gow NA. Antifungal agents: mechanisms of action. Trends Microbiol. 2003;11:272–9.
Ryder NS. Specific inhibition of fungal sterol biosynthesis by SF 86-327, a new allylamine antimycotic agent. Antimicrob Agents Chemother. 1985;27:252–6.
Ryder NS, Mieth H. Allylamine antifungal drugs. Curr Top Med Mycol. 1991;4:158–88.
Favre B, Ryder NS. Characterization of squalene epoxidase activity from the dermatophyte Trichophyton rubrum and its inhibition by terbinafine and other antimycotic agents. Antimicrob Agents Chemother. 1996;40:443–7.
Gull K, Trinci AP. Griseofulvin inhibits fungal mitosis. Nature. 1973;244(5414):292–4.
Oxford AE, Raistrick H, Simonart P. Studies in the biochemistry of micro-organisms: Griseofulvin, C(17)H(17)O(6)Cl, a metabolic product of Penicillium griseo-fulvum Dierckx. Biochem J. 1939;33:240–8.
Gentles JC. Experimental ringworm in guinea pigs: oral treatment with griseofulvin. Nature. 1958;182(4633):476–7.
Barich LL, Nakai T, Schwarz J, Barich DJ. Tumour-promoting effect of excessively large doses of oral griseofulvin on tumours induced in mice by methylcholanthrene. Nature. 1960;187:335–6.
Knasmüller S, Parzefall W, Helma C, Kassie F, Ecker S, Schulte-Hermann R. Toxic effects of griseofulvin: disease models, mechanisms, and risk assessment. Crit Rev Toxicol. 1997;27:495–537. Review. Erratum in: Crit Rev Toxicol. 1998;28:102.
Hay RJ. Tinea capitis: current status. Mycopathologia. 2017;182:87–93.
Hay RJ. Therapy of skin, hair and nail fungal infections. J Fungi (Basel). 2018;4(3):99.
M38-A protocols. National Committee for Clinical Laboratory Standards. Reference method for broth dilution antifungal susceptibility testing of filamentous fungi. Approved standard M38-A2; 2nd ed. Wayne: Clinical and Laboratory Standards Institute; 2008.
Jessup CJ, Wamer J, Isham N, Hasan I, Ghannoum MA. Antifungal susceptibility testing of dermatophytes: establishing a medium for inducing conidial growth and evaluation of susceptibility of clinical isolates. J Clin Microbiol. 2000;38:341–4.
Laurent A, Monod M. Production of Trichophyton rubrum microspores in large quantities and its application to evaluate amorolfine/azole compound interactions in vitro. Mycoses. 2017;60:581–6.
Chin B, Knight S. Growth of Trichophyton mentagrophytes and Trichophyton rubrum in increased carbon dioxide tensions. J Gen Microbiol. 1957;16:642–6.
Baudraz-Rosselet F, Monod M, Jaccoud S, Frenk E. Efficacy of terbinafine treatment of tinea capitis in children varies according to the dermatophyte species. Br J Dermatol. 1996;135:1011–2.
Baudraz-Rosselet F, Ruffieux C, Lurati M, Bontems O, Monod M. Onychomycosis insensitive to systemic terbinafine and azole treatments reveals non-dermatophyte moulds as infectious agents. Dermatology. 2010;220:164–8.
Lurati M, Baudraz-Rosselet F, Vernez M, Spring P, Bontems O, Fratti M, et al. Efficacious treatment of non-dermatophyte mould onychomycosis with topical amphotericin B. Dermatology. 2011;223:289–92.
Mukherjee PK, Leidich SD, Isham N, Leitner I, Ryder NS, Ghannoum MA. Clinical Trichophyton rubrum strain exhibiting primary resistance to terbinafine. Antimicrob Agents Chemother. 2003;47:82–6.
Osborne CS, Leitner I, Favre B, Ryder NS. Amino acid substitution in Trichophyton rubrum squalene epoxidase associated with resistance to terbinafine. Antimicrob Agents Chemother. 2005;49:2840–4.
Osborne CS, Leitner I, Hofbauer B, Fielding CA, Favre B, Ryder NS. Biological, biochemical, and molecular characterization of a new clinical Trichophyton rubrum isolate resistant to terbinafine. Antimicrob Agents Chemother. 2006;50:2234–6.
Yamada T, Maeda M, Alshahni MM, Tanaka R, Yaguchi T, Bontems O, et al. Terbinafine resistance of Trichophyton clinical isolates caused by specific point mutations in the squalene epoxidase gene. Antimicrob Agents Chemother. 2017;61(7):e00115–17.
Saunte DML, Hare RK, Jørgensen KM, Jørgensen R, Deleuran M, Zachariae CO, et al. Emerging terbinafine resistance in Trichophyton: Clinical characteristics, squalene epoxidase gene mutations, and a reliable EUCAST method for detection. Antimicrob Agents Chemother. 2019;63(10):e01126–19.
Rudramurthy SM, Shankarnarayan SA, Dogra S, Shaw D, Mushtaq K, Paul RA, et al. Mutation in the squalene epoxidase gene of Trichophyton interdigitale and Trichophyton rubrum associated with allylamine resistance. Antimicrob Agents Chemother. 2018;62(5):e02522–17.
Salehi Z, Shams-Ghahfarokhi M, Razzaghi-Abyaneh M. Antifungal drug susceptibility profile of clinically important dermatophytes and determination of point mutations in terbinafine-resistant isolates. Eur J Clin Microbiol Infect Dis. 2018;37:1841–6.
Suzuki S, Mano Y, Furuya N, Fujitani K. Discovery of terbinafine low susceptibility Trichophyton rubrum strain in Japan. Biocontrol Sci. 2018;23:151–4.
Noguchi H, Matsumoto T, Hiruma M, Kimura U, Kano R, Yaguchi T, et al. Tinea unguium caused by terbinafine-resistant Trichophyton rubrum successfully treated with fosravuconazole. J Dermatol. 2019;46(12):e446–7.
Ebert A, Monod M, Salamin K, Burmester A, Uhrlaß S, Wiegand C, et al. Alarming India wide phenomenon of antifungal resistance in dermatophytes: A multicentre study. Mycoses. 2020;63:717–28.
Hiruma J, Kitagawa H, Noguchi H, Kano R, Hiruma M, Kamata H, et al. Terbinafine-resistant strain of Trichophyton interdigitale strain isolated from a tinea pedis patient. J Dermatol. 2019;46:351–3.
Singh A, Masih A, Khurana A, Singh PK, Gupta M, Hagen F, et al. High terbinafine resistance in Trichophyton interdigitale isolates in Delhi, India harbouring mutations in the squalene epoxidase gene. Mycoses. 2018;61:477–84.
Süß A, Uhrlaß S, Ludes A, Verma SB, Monod M, Krüger C, et al. [Extensive tinea corporis due to a terbinafine-resistant Trichophyton mentagrophytes isolate of the Indian genotype in a young infant from Bahrain in Germany]. Hautarzt. 2019;70(11):888–96.
Hsieh A, Quenan S, Riat A, Toutous-Trellu L, Fontao L. A new mutation in the SQLE gene of Trichophyton mentagrophytes associated to terbinafine resistance in a couple with disseminated tinea corporis. J Mycol Med. 2019;29:352–5.
Taghipour S, Shamsizadeh F, Pchelin IM, Rezaei-Matehhkolaei A, Zarei Mahmoudabadi A, Valadan R, et al. Emergence of terbinafine resistant Trichophyton mentagrophytes in Iran, harboring mutations in the squalene epoxidase (SQLE) gene. Infect Drug Resist. 2020;13:845–50.
Shaw D, Singh S, Dogra S, Jayaraman J, Bhat R, Panda S, et al. MIC and upper limit of wild-type distribution for 13 antifungal agents against a Trichophyton mentagrophytes-Trichophyton interdigitale complex of Indian origin. Antimicrob Agents Chemother. 2020;64(4):e01964–19.
Digby SS, Hald M, Arendrup MC, Hjort SV, Kofoed K. Darier disease complicated by terbinafine-resistant Trichophyton rubrum: a case report. Acta Derm Venereol. 2017;97:139–40.
Schøsler L, Andersen LK, Arendrup MC, Sommerlund M. Recurrent terbinafine resistant Trichophyton rubrum infection in a child with congenital ichthyosis. Pediatr Dermatol. 2018;35:259–60.
Kelly SL, Lamb DC, Loeffler J, Einsele H, Kelly DE. The G464S amino acid substitution in Candida albicans sterol 14alpha-demethylase causes fluconazole resistance in the clinic through reduced affinity. Biochem Biophys Res Commun. 1999;262:174–9.
Nenoff P, Verma SB, Vasani R, Burmester A, Hipler UC, Wittig F, et al. The current Indian epidemic of superficial dermatophytosis due to Trichophyton mentagrophytes-a molecular study. Mycoses. 2019;62:336–56.
Lübbert C, Baars C, Dayakar A, Lippmann N, Rodloff AC, Kinzig M, et al. Environmental pollution with antimicrobial agents from bulk drug manufacturing industries in Hyderabad, South India, is associated with dissemination of extended-spectrum beta-lactamase and carbapenemase-producing pathogens. Infection. 2017;45:479–91.
Chatterjee A, Chattopadhyay D, Chatterjee D, Sengupta DN. Isolation of dermatophytes from rural and urban soil samples in premises of infected and non-infected animals. Int J Zoonoses. 1983;10:22–7.
Gugnani HC, Paliwal-Joshi A, Rahman H, Padhye AA, Singh TS, Das TK, et al. Occurrence of pathogenic fungi in soil of burrows of rats and of other sites in bamboo plantations in India and Nepal. Mycoses. 2007;50:507–11.
Snelders E, Huis In’t Veld RA, Rijs AJ, Kema GH, Melchers WJ, Verweij PE. Possible environmental origin of resistance of Aspergillus fumigatus to medical triazoles. Appl Environ Microbiol. 2009;75:4053–7.
Verweij PE, Snelders E, Kema GH, Mellado E, Melchers WJ. Azole resistance in Aspergillus fumigatus: a side-effect of environmental fungicide use? Lancet Infect Dis. 2008;9:789–95.
Monod M, Feuermann M, Salamin K, Fratti M, Makino M, Mahdi Alshahni M, et al. Trichophyton rubrum azole resistance mediated by a new ABC transporter, TruMDR3. Antimicrob Agents Chemother. 2019;63(11). pii: AAC.00863-19.
Cervelatti EP, Fachin AL, Ferreira-Nozawa MS, Martinez-Rossi NM. Molecular cloning and characterization of a novel ABC transporter gene in the human pathogen Trichophyton rubrum. Med Mycol. 2006;44:141–7.
Fachin AL, Ferreira-Nozawa MS, Maccheroni W Jr, Martinez-Rossi NM. Role of the ABC transporter TruMDR2 in terbinafine, 4-nitroquinoline N-oxide and ethidium bromide susceptibility in Trichophyton rubrum. J Med Microbiol. 2006;55(Pt 8):1093–9.
Martins MP, Franceschini ACC, Jacob TR, Rossi A, Martinez-Rossi NM. Compensatory expression of multidrug-resistance genes encoding ABC transporters in dermatophytes. J Med Microbiol. 2016;65:605–10.
Holmes AR, Lin YH, Niimi K, Lamping E, Keniya M, Niimi M, et al. ABC transporter Cdr1p contributes more than Cdr2p does to fluconazole efflux in fluconazole-resistant Candida albicans clinical isolates. Antimicrob Agents Chemother. 2008;52:3851–62.
Niimi K, Harding DR, Holmes AR, Lamping E, Niimi M, Tyndall JD, et al. Specific interactions between the Candida albicans ABC transporter Cdr1p ectodomain and a D-octapeptide derivative inhibitor. Mol Microbiol. 2012;85:747–67.
Silva LV, Sanguinetti M, Vandeputte P, Torelli R, Rochat B, Sanglard D. Milbemycins: more than efflux inhibitors for fungal pathogens. Antimicrob Agents Chemother. 2013;57:873–86.
Coste A, Turner V, Ischer F, Morschhäuser J, Forche A, Selmecki A, et al. A mutation in Tac1p, a transcription factor regulating CDR1 and CDR2, is coupled with loss of heterozygosity at chromosome 5 to mediate antifungal resistance in Candida albicans. Genetics. 2006;172:2139–56.
Camps SM, Dutilh BE, Arendrup MC, Rijs AJ, Snelders E, Huynen MA, et al. Discovery of a HapE mutation that causes azole resistance in Aspergillus fumigatus through whole genome sequencing and sexual crossing. PLoS One. 2012;7:e50034.
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Monod, M., Feuermann, M., Yamada, T. (2021). Terbinafine and Itraconazole Resistance in Dermatophytes. In: Bouchara, JP., Nenoff, P., Gupta, A.K., Chaturvedi, V. (eds) Dermatophytes and Dermatophytoses. Springer, Cham. https://doi.org/10.1007/978-3-030-67421-2_20
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