Antifungal resistance in dermatophytes – review of the epidemiology, diagnostic challenges and treatment strategies for managing trichophyton indotineae infections

ABSTRACT

Introduction

There is an increasing number of reports of Trichophyton indotineae infections. This species is usually poorly responsive to terbinafine.

Areas covered

A literature search was conducted in May 2024. T. indotineae infections detected outside the Indian subcontinent are generally associated with international travel. Reports of local spread are mounting.

As a newly identified dermatophyte species closely related to the T. mentagrophytes complex with limited genetic and phenotypic differences, there is an unmet need to develop molecular diagnosis for T. indotineae. Terbinafine has become less effective as a first-line agent attributed to mutations in the squalene epoxidase gene (Leu393Phe, Phe397Leu). Alternative therapies include itraconazole for a longer time-period or a higher dose (200 mg/day or higher). Generally, fluconazole and griseofulvin are not effective. In some cases, especially when the area of involvement is relatively small, topical non-allylamine antifungals may be an option either as monotherapy or in combination with oral therapy. In instances when the patient relapses after apparent clinical cure then itraconazole may be considered. Good antifungal stewardship should be considered at all times.

Expert Opinion

When both terbinafine and itraconazole are ineffective, options include off-label triazoles (voriconazole and posaconazole). We present four patients responding to these newer triazoles.

Plain Language Summary

Ringworm (dermatophytosis, tinea) is a fungal infection of the skin, hair and nails that is commonly seen by primary and secondary healthcare providers. An estimated 20-25% of the global population is affected by this condition. In Europe and the United States, tineas are often treated empirically using over-the-counter medications, which can increase the risk of resistance development.

While antifungal resistance is not a new problem, this topic has garnered the attention of physicians and researchers in recent years due to an outbreak from South Asia caused by a new pathogen known as Trichophyton indotineae. In this review, we summarize the global prevalence, diagnosis methods, antifungal resistance profile and treatment options for T. indotineae. While most cases outside of South Asia are linked to international travel, there is evidence suggesting local person-to-person transmission and transmission via animal contact. One hurdle to surveilling the spread of this pathogen is the requirement of complex molecular diagnosis, tackling this challenge will require the development of newer assays.

Terbinafine, a widely available antifungal drug, is becoming less effective owing to resistance mutations of the squalene epoxidase gene. Itraconazole has shown effectiveness, especially with a higher dose and a longer treatment duration. There is a significant risk of T. indotineae infections becoming chronic with episodes of relapse. When both terbinafine and itraconazole fail, newer agents such as posaconazole and voriconazole can be considered. Combination therapy using oral and topical medications should also be considered.

KEYWORDS:

• Antifungal drug resistance
• Dermatophytosis
• Ringworm
• superficial mycoses
• Tinea
• trichophyton indotineae

Disclaimer

As a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also.

Article Highlights

• Trichophyton indotineae – a newly described dermatophytic fungi causing unusually severe dermatophytoses – is emerging globally. While most reported cases are associated with recent international travel, recent studies point to additional transmission routes (e.g., sexual and zoonotic transmission)

• For those working outside the high prevalence regions, diagnosing T. indotineae poses a significant challenge as patients may present with atypical presentations and traditional mycology testing is inadequate. Several molecular markers have been identified that can help address this challenge.

• Treatment of T. indotineae infections is complicated by frequent relapses and lack of efficacy concerning the use of terbinafine, griseofulvin and fluconazole. An option is updosing itraconazole with an extended treatment duration. In cases of itraconazole failure, alternative triazoles (posaconazole, voriconazole) and combination regimens (oral and topical non-allylamine antifungals) have been tried empirically.

Declaration of interests

AK Gupta, T Wang, A Mann, SP Ravi, M Talukder, B Kaplan, E Galili and A Shemer report no conflict of interest. SA Lincoln, H-C Foreman and WL Bakotic are employees of Bako Diagnostics. V Piguet has no personal financial ties with any pharmaceutical company. VP has received honoraria for speaker and/or advisory board member roles from AbbVie, Celgene, Janssen, Kyowa Kirin Co. Ltd, LEO Pharma, Novartis, Pfizer, Sanofi, UCB, and Union Therapeutics. In his role as Department Division Director of Dermatology at the University of Toronto, VP has received departmental support in the form of unrestricted educational grants from AbbVie, Bausch Health, Celgene, Janssen, LEO Pharma, Lilly, L’Oréal, NAOS, Novartis, Pfizer, Sandoz and Sanofi in the past 36 months. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Data availability statement

The data that support the findings of this study are available from the corresponding author, AKG, upon reasonable request.

Consent to participate

The patients consented to the publication of all clinical photographs.

Ethics statement

Patients have provided informed consent for publication.

Additional information

Funding

This paper was not funded.