Emerging Terbinafine Resistant Trichophyton Dermatophytosis, Testing Options and Alternative Treatments: A Systematic Review

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Dermatophytosis is a common superficial fungal infection of the skin, most often caused by dermatophytes from the Trichophyton genus. Terbinafine, which inhibits squalene epoxidase (SQLE), is widely used as first line treatment. However, resistance to terbinafine is increasing globally, including recent reports in Australia, with origins suspected to trace back to South Asia. Antifungal susceptibility testing is not routinely available in Australia, and globally, there are no standardised breakpoints for traditional culture-based methods. Although SQLE gene mutations have been associated with terbinafine resistance, a major research gap exists in the clinical interpretation of these mutations due to a lack of correlation between MIC values, genetic mutations and clinical treatment outcomes. This gap hampers the ability to guide clinical decision-making. Therefore, our objective was to assess the global prevalence of terbinafine-resistant Trichophyton infections, identify the most clinically relevant resistance testing methods, and determine effective alternative treatment options. The study was designed by systematic review. Ovid MEDLINE, Ovid Embase, Cochrane Database of Systematic Reviews (CDSR), Cochrane's Trials database (CENTRAL), Global Health (CABI), Trials registries, along with Google Scholar and Web of Science (WoS) for the tracking of included articles. Published human studies in English from 2000 to 2023 of Terbinafine-resistant Trichophyton Dermatophytosis with confirmed antifungal susceptibility tests and genotyping of dermatophytes, as well as details of effective alternative treatments. Identified cases were independently screened by two authors on the basis of predetermined criteria. Thirty four studies reported 743 samples for which mutation data of the SQLE gene and minimum inhibitory concentration (MIC) were available. Twenty three studies reported on 149 patients who had used terbinafine with available MIC data. Of these, 94 cases demonstrated evidence of clinical resistance to terbinafine with confirmed SQLE genotyping and MIC data. Seven studies reported on 13 cases of clinical resistance to terbinafine with a reported MIC and a successful alternative therapy. There are no published MIC breakpoints for terbinafine resistance in antifungal resistance testing, creating significant challenges for clinical interpretation. This study suggests that an estimate of a provisional MIC threshold for resistance is calculated to be 1.69 μg/mL. Importantly, SQLE mutation data, particularly the presence of F397L, L393F and A448T shows a robust association with clinical resistance to terbinafine (odds ratio: 7.58; 14.0, 7.78, respectively). Routine SQLE mutation testing in cases of suspected terbinafine-resistant dermatophytosis could enhance diagnostic accuracy and inform more effective, timely treatment decisions. Identifying specific mutations may guide clinicians in selecting alternative antifungal agents earlier in the treatment course, reducing morbidity and improving outcomes. Systematic review was registered with PROSPERO. Trial Registration: PROSPERO number: CRD42022382880.

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