Terbinafine‐Resistant Trichophyton Dermatophytosis in Australia

We thank Gupta et al. for their insightful commentary on our review regarding the emerging issue of terbinafine-resistant Trichophyton dermatophytosis in Australia. In their letter, they express concerns regarding the proposed adaptation of a provisional minimum inhibitory concentration (MIC) threshold of 1.69 μg/mL and the recommendation for routine squalene epoxidase (SQLE) sequencing in suspected cases. Additionally, they provide an overview of overseas testing models and referral pathways, suggesting potential applications within the Australian context. We agree with Gupta et al. that the establishment of a fixed MIC threshold for terbinafine resistance in Trichophyton species is problematic, given the absence of global clinical break points for dermatophytes. In our study, we suggested a provisional MIC value of 1.69 μg/mL, derived from a meta-analysis of clinical resistance data and MIC measurements. However, we emphasised that this value is not robust due to the heterogeneity of the underlying studies, which involve variable antifungal susceptibility testing protocols, inoculum concentrations, incubation conditions and end point criteria for fungal growth. Additionally, we noted that several studies documented clinical resistance with MIC values lower than 1.69 μg/mL (see Table 3 in our publication). Given these limitations, we caution against using MIC values alone to guide clinical decision-making in dermatophytosis. Moreover, MIC testing is inherently limited by its in vitro nature, failing to account for patient-specific factors such as drug absorption, distribution, comorbidities and adherence [1]. Therefore, while MIC testing can provide valuable insight into fungal susceptibility, its use in clinical practice is likely insufficient without additional context [1]. We suggest that a more reliable approach to determining resistance could involve mutation testing of SQLE, as we document an association between SQLE mutations and terbinafine resistance in Trichophyton species. As Gupta et al. highlight, a pragmatic model currently employed across several European centres utilises EUCAST agar-based screening plates for identifying non-wild-type isolates. These isolates are then confirmed with MIC determination and sequencing, providing a scalable and resource-efficient strategy that reserves advanced testing for the minority of resistant strains [2]. They further highlight that in the United Kingdom, Trichophyton indotineae accounts for approximately 38% of referred isolates, but testing is centralised and conducted only when clinically indicated or when epidemiological risk factors are present [2]. Similarly, the US Centers for Disease Control and Prevention (CDC) advises that susceptibility testing should be prioritised for surveillance and outbreak investigations rather than routine patient management [3]. However, the lack of access to SQLE mutation testing in Australia remains a major barrier to effectively identifying and managing resistant cases. While it is possible to access susceptibility testing through the national mycology reference centre in Adelaide, Australia, such testing is currently prohibitively expensive, costing up to $225 per isolate. Furthermore, this centre performs disc diffusion assays for terbinafine, without follow-up MIC testing and with a typical turnaround time of several weeks. As a result, the capacity for resistance testing is extremely limited in Australia. PCR-based resistance testing could be a viable option in non-reference laboratories as it requires fewer specialised techniques and materials or specialised staff to perform it. Gupta et al. refer to The Indian Association of Dermatologists, Venereologists and Leprologists (IADVL) recommendation for the use of itraconazole as first-line therapy for recalcitrant cases [4]. From a clinical perspective, the situation is complicated by the fact that terbinafine is the only Pharmaceutical Benefits Scheme (PBS)–reimbursed medication for onychomycosis in Australia, and terbinafine and griseofulvin are the only PBS-subsidised therapies for dermatophytosis. Given the substantial costs associated with itraconazole (approximately AUD 110 for 2 months of treatment), it is neither practical nor cost-effective to treat all patients without first considering resistance. The introduction of laboratory-guided resistance testing would greatly enhance treatment decisions, particularly for immunosuppressed patients, and would also offer a clearer understanding of the resistance landscape within Australia. The recommendation by Gupta et al. to adopt high-dose terbinafine (e.g., 500 mg BD) based on pharmacokinetic modelling, lacks clinical data demonstrating efficacy or safety in patients with confirmed terbinafine-resistant infections [5]. Similarly, combination regimens involving terbinafine and itraconazole, or the addition of systemic retinoids, remain poorly studied and are based on anecdotal reports or small, uncontrolled studies [6]. These strategies may pose considerable risks, including hepatotoxicity, drug–drug interactions and poor tolerability—especially in patients with comorbidities or polypharmacy. Without more rigorous clinical trials or robust safety data, such recommendations should be approached with caution. Effective antifungal stewardship necessitates a multidisciplinary approach, engaging dermatologists, pharmacists and microbiologists to promote appropriate prescribing practices and robust surveillance. Such collaboration optimises therapeutic outcomes, minimises unnecessary or prolonged therapy and safeguards the efficacy of existing antifungal agents against the escalating threat of resistance [7]. In summary, the development of a standardised and accessible resistance testing protocol for Trichophyton dermatophytosis is urgently needed in Australia. While mutation testing and alternative methods such as PCR offer promise, the current limitations of these technologies, particularly their availability, must be addressed to facilitate timely and accurate clinical decision-making. Authors T.J., Z.P.H., C.M., C.K., C.V., D.S., G.R. and J.S.K. have all had substantial contributions to conception and design, acquisition of data or analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Dr. Gemma Robertson is an employee of Melbourne Pathology. Prof Johannes Kern is an Editorial Board member of the Australasian Journal of Dermatology and a co-author of this article. To minimise bias, they were excluded from all editorial decision-making related to the acceptance of this article for publication. This article is a linked to https://doi.org/10.1111/ajd.70008. The data that support the findings of this study are available from the corresponding author upon reasonable request.