Successful treatment of terbinafine-resistant Trichophyton indotineae with fluconazole and resveratrol: A novel approach

Dear Editor, Trichophyton indotineae (T. indotineae), a newly recognized species within the Trichophyton mentagrophytes complex, has rapidly emerged as a global cause of dermatophytosis.[1] First identified in India in 2020, T. indotineae has been increasingly reported across Asia, the Middle East, Europe, and America, often associated with recalcitrant tinea infections.[2] Unlike other dermatophytes, it frequently presents with chronic, inflammatory lesions resistant to terbinafine due to mutations in the squalene epoxidase (SQLE) gene.[3] This growing prevalence of underscores the need for heightened clinical awareness and effective strategies to combat this evolving dermatological challenge. Herein, we present a case of T. indotineae in a 29-year-old male clinically resistant to systemic terbinafine, successfully treated with oral fluconazole 200 mg/day and resveratrol. A 29-year-old male presented to the dermatology outpatient clinic with a 6-month history of a rash localized to his trunk and genital region. He worked as a nurse in an operating room and had no exposure to animals or recent travel. His medical history was unremarkable, and, no other family members reported similar dermatological issues. The patient underwent treatment with oral terbinafine at 250 mg/day for 2 months, alongside topical agents, including 1% isoconazole, 1% naftifine hydrochloride, and 1% oxiconazole creams, without improvement. Additionally, he had previously used itraconazole irregularly at 100 mg/day for 1 month. Dermatological examination identified large, ring-shaped, scaly, and erythematous plaques with sharply demarcated red borders on the lower abdomen, inguinal region, and mons pubis [Supplementary Figure 1a]. The lesions were intensely pruritic and accompanied by burning, indicative of possible dermatophyte etiology. Physical examination yielded no additional findings. Laboratory investigations, including hematological and routine biochemical analyses, revealed no systemic disease. The patient was immunocompetent, with negative anti-HIV results. Direct microscopic examination of the skin scraping sample revealed filamentous structures and arthrospores, consistent with a fungal infection. The initial scrapings were cultured on Sabouraud–Chloramphenicol–Cycloheximide agar and incubated at 28°C. After 10 days, the colonies exhibited a velvety white appearance with a flat structure and slightly elevated center; the reverse showed a pale-yellow pigmentation [Supplementary Figure 2a and b]. Microscopic features under lactophenol cotton blue stain demonstrated small and large round to oval microconidia and spindle-shaped septate macroconidia [Supplementary Figure 2c]. Fungal DNA was extracted from T. indotineae cultured on Sabouraud’s dextrose agar using the QIAamp® DNA Mini Kit (Qiagen, Germany). The SQLE gene of the terbinafine-resistant isolate was amplified by polymerase chain reaction (PCR) with specific primers (TrSQLE-F1 and TrSQLE-R1), and chromosomal DNA served as the template. The resulting ~ 1300 bp PCR product was sequenced at Microsynth Seqlab GmbH (Göttingen, Germany) and analyzed for missense mutations using MEGA version 10.0.5. The F397 L mutation showed 100% homology with GenBank ID OM313310, corroborating data reported by Astvad et al.[4] According to the EUCAST guidelines, antifungal susceptibility testing revealed a high minimum inhibitory concentration (MIC) of 4 mg/L for terbinafine, confirming resistance. In contrast, low MICs were recorded for voriconazole (0.06 mg/L), fluconazole (0.12 mg/L), and itraconazole (0.12 mg/L), indicating potential efficacy. Given the medical history, dermatological findings, and diagnostic results, T. indotineae infection was postulated. Therefore, further laboratory investigations were undertaken to confirm this hypothesis. Due to the disease’s resistance, treatment was initiated with oral fluconazole at 200 mg/day, oral resveratrol at 200 mg/day, and 1% luliconazole cream once daily. Oral fluconazole was chosen over itraconazole due to prior irregular use, which may have compromised its efficacy. This choice aimed to ensure adherence and utilize the promising MIC results for fluconazole. Additionally, ketoconazole shampoo and one containing tea tree oil, azelaic acid, and salicylic acid was recommended, alternating every other day for a month. This regimen resulted in clinical improvement, with lesion size reduction and scaling cessation. Three weeks after therapy, complete recovery was achieved, leaving only postinflammatory pigmentation [Supplementary Figure 1b]. To date, no recurrence has been observed.Supplementary Figure 1: (a) Ring-shaped, scaly, erythematous plaques with sharply defined red borders on the lower abdomen and groin. (b) Lesions resolved after 3 weeks, leaving only postinflammatory pigmentation.Supplementary Figure 2: (a and b) Fungal colonies on Sabouraud agar after 10 days, showing velvety white surface and light-yellow reverse pigmentation. (c) Microscopic morphology (lactophenol cotton blue, ×400).The rising incidence of treatment-resistant T. indotineae presents significant challenges in dermatophytosis management, particularly due to widespread terbinafine resistance.[5,6] Mutations in the SQLE gene, such as Phe397 Leu and Leu393Ser, have been implicated in conferring this resistance, reducing the efficacy of standard antifungal therapies.[7] These mutations disrupt ergosterol biosynthesis, an essential component of fungal cell membranes, thus impeding terbinafine’s ability to act effectively.[5-7] In this context, alternative treatments such as fluconazole and itraconazole have shown promise, yet resistance to these agents is also increasing.[6-8] Recent reports suggest voriconazole may also be effective against resistant T. indotineae strains, offering an alternative to terbinafine-resistant cases.[6] Resveratrol, a polyphenol with antioxidant, anti-inflammatory, and antifungal properties, has emerged as a potential adjunct therapy. It exerts its antifungal action by disrupting fungal biofilms and modulating immune responses.[9] Resveratrol achieves its fungicidal effects by disrupting fungal cell membranes and inducing structural collapse, as demonstrated through morphological changes observed in fungal cells, supporting its potential as an effective antifungal agent against resistant strains such as T. indotineae.[10] It has demonstrated significant antifungal activity against dermatophytes, with effective doses ranging from 25 to 50 μg/mL, primarily targeting fungal keratinocytes without inducing cytotoxicity in human skin cells, making it a promising adjunct for managing skin dermatophyte infections.[11] While clinical data on resveratrol’s use in dermatophytosis is limited, its inclusion in this case led to successful resolution when combined with fluconazole and topical agents. The observed rapid clinical improvement following the combination treatment highlights the potential synergistic effects of resveratrol, emphasizing its role as an adjunctive therapy in enhancing antifungal efficacy. The introduction of resveratrol in antifungal regimens could offer a novel approach in cases where standard therapies fail. However, further studies are required to establish its efficacy and mechanism of action against resistant strains like T. indotineae. This case underscores the importance of adapting treatment protocols to emerging fungal resistance, exploring novel antifungal agents to combat this growing public health concern. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent form. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Data availability statement The datasets generated during and/or analyzed during the current study are publicly available. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.