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  • Writer's pictureIvan Bristow

Terbinafine resistance - a growing reality

In 2021, I wrote a blog highlighting the growing problem of dermatophyte resistance. In the post I discussed the emerging cases from the Asia which have surfaced in the literature of dermatophytes not responding to regular antifungal agents with one study in 202 showing 71% of dermatophyte samples collected in India showing terbinafine resistance (1). A recent headline in the Mail on Sunday highlights the effects to public health explaining how antifungal creams soon may not work as well as they did as resistant fungal strains emerge. Media scaremongering? So, what has been developing since my last post?


A newspaper article

Headline from the Mail Health pages on Sunday 21st May 2023 (UK edition)



For those who watch the HBO series “The Last of Us” you will be aware of the story documenting the spread of a fungal disease that had a catastrophic effect on the population, turning people in zombies. That’s the story in Hollywood but the reality remains that a growing threat exists from a fungal enemy when many heads were turned believing only bacteria or virus could be a threat to our health. A recent headline in the Mail on Sunday highlights the effects to public health explaining how antifungal creams soon may not work as well as they did as resistant fungal strains emerge.


Tinea or dermatophytosis is a very common skin infection which can spread to the hair and nails. For most it’s an inconvenience or a cause of discomfort but most importantly it is generally considered treatable, but the immunosuppressed it can become something far more serious.



A culture of dermatophytes in a petri dish


The threat it seems has emerged from a type of dermatophyte widely known to podiatrists - Trichophyton mentagrophytes (var. interdigitale). In 2017, “Trichophyton mentagrophytes internal transcriber space (ITS) genotype VIII” was identified as a new sub-type discernible by 3 specific gene variations when sequenced (1). These genetic mutations conferred resistance to the antifungal drug terbinafine. Consequently, in 2020, after much debate, the sub-type was considered sufficiently distinct to be renamed as T. indotineae (Ti, for short)(2).


Terbinafine is a drug which works by targeting an enzyme responsible for manufacture of the fungal cell wall (squalene epoxidase [SQE]) preventing cell wall formation and consequently fungal growth. With the Ti strain the drug is no longer effective.


Where is the terbinafine resistance coming from?

The Ti strain appears to be endemic in India but is spreading globally with cases arising in Europe, the Middle East, and North America, most likely through immigration and travel (3). So far up to 2022, 76% of the genetic variant, T. indotineae, have been identified in India, 12.8% in the Middle East, 9.6% in Europe, and 1.1% in other countries (4). Clinically the manifestations are similar to other dermatophyte infections but with a more inflammatory component spreading rapidly with livid red borders. The majority of reported cases have been tinea corporis, faciei with small numbers of cases of case of tinea pedis and toenail onychomycosis (1, 2).


As I alluded to in my earlier blog, it is speculated that the emergence of this strain has probably come about in an environment where potent topical steroids are freely available to the public and often cheaper than antifungal drugs. Consequently, misuse has led to immune suppression and the perfect conditions for a resistant strain to emerge.


In a recent study, researchers have been attempting to identify which dermatophytes have the SQE mutation. They examined 15683 nail samples from patients with suspected fungal toenail infection who visited their dermatologists and podiatrists in the USA. They then examined each to determine the species and whether it had the SQE mutation. Of these 5432 were identified as T rubrum or T mentagrophytes and underwent a DNA analysis to detect terbinafine drug resistance. Overall, 3.7% of these (200/5432) were identified as having a SQE mutation. The majority were T mentagrophytes and fewer of the T rubrum species (5).


What are the implications for Podiatrists?

For those practising outside of Asia, the likelihood of seeing such an infection is small but increasing as case numbers grow globally. Case numbers are highly likely to increase and spread further. Most cases appear to be on the body (as tinea corporis). If we follow the current evidence, any patient with extensive symptoms of athlete’s foot which is not clearing with terbinafine one should be remain vigilant and consider the possibility of resistance (alongside other causes such as reinfection, relapse or poor patient compliance).


It is also important to highlight that if a scraping or clipping is sent to a laboratory for testing, T. indotineae under the microscope has a near identical appearance to T mentagrophytes and so is likely to be identified as such on reporting unless highly specialist DNA sequencing techniques are used. This is not commonplace at time in UK hospital laboratories at this time.

In addition, the issue around treatment remains to be clarified with these emerging strains. Terbinafine resistance appears to be a common feature but resistance to other agents is less well researched. Clinical cases of the strain have been reported demonstrating successful treatment with other antifungal agents (2). Nenoff (1) advises patients should be encouraged to apply an antifungal regularly (twice daily) for three weeks covering the infected areas and 2cms onto unaffected skin, which is easily achieved by treating the whole foot. As this problem grows, we would hope to see more research into all aspects with the development of guidelines including treatment and the development of new antifungal drugs to combat this growing problem.



A published article by Bristow on terbinafine resistance



Authors note: I published the above article in October 2023 on this subject in the Journal of Foot and Ankle Research on this topic.




References

1. Nenoff P, Verma SB, Vasani R, Burmester A, Hipler U-C, Wittig F, et al. The current Indian epidemic of superficial dermatophytosis due to Trichophyton mentagrophytes—A molecular study. Mycoses. 2019;62(4):336-56. https://doi.org/10.1111/myc.12878

2. Gupta AK, Venkataraman M, Hall DC, Cooper EA, Summerbell RC. The emergence of Trichophyton indotineae: Implications for clinical practice. Int J Dermatol. 2023;62(7):857-61. https://doi.org/10.1111/ijd.16362

3. Gupta AK, Venkataraman M, Hall DC, Cooper EA, Summerbell RC. The emergence of Trichophyton indotineae: Implications for clinical practice. Int J Dermatol. 2022 https://doi.org/10.1111/ijd.16362

4. Jabet A, Brun S, Normand AC, Imbert S, Akhoundi M, Dannaoui E, et al. Extensive Dermatophytosis Caused by Terbinafine-Resistant Trichophyton indotineae, France. Emerg Infect Dis. 2022;28(1):229-33. https://doi.org/10.3201/eid2801.210883

5. Gupta AK, Cooper EA, Wang T, Ravi SP, Lincoln SA, Piguet V, et al. Detection of squalene epoxidase mutations in U.S. onychomycosis patients: implications for management. J Invest Dermatol. 2023. https://doi.org/https://doi.org/10.1016/j.jid.2023.04.032

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