Terbinafine Resistance in Trichophyton rubrum and Trichophyton indotineae: A Literature Review

Abstract

Background/objectives: Terbinafine has been the gold standard for the management of superficial fungal infections. The etiological agent generally is Trichophyton rubrum (T. rubrum); however, there has been increased reporting of a new terbinafine-resistant strain of the T. mentagrophytes complex (T. mentagrophytes ITS genotype VIII otherwise known as T. indotineae). Here, we review the epidemiology, clinical features, diagnosis, and treatment of T. rubrum and T. indotineae infections.

Methods: We conducted a systematic literature search using PubMed, Embase (Ovid), and Web of Science, resulting in 83 qualified studies with data summarized for clinical features, antifungal susceptibility, and terbinafine resistance mechanisms and mutations.

Results: Dermatophytosis is most commonly caused by T. rubrum; however, in certain parts of the world, especially in the Indian subcontinent, T. indotineae infections have been reported more frequently. The majority of T. rubrum isolates remain susceptible to terbinafine (over 60% of isolates show MIC₅₀ and MIC₉₀ < 0.5 µg/mL). In contrast, for T. indotineae, 30% of isolates exhibit MIC₅₀ ≥ 0.5 µg/mL and 80% exhibit MIC₉₀ ≥ 0.5 µg/mL. Frequently detected squalene epoxidase (SQLE) mutations in T. rubrum are Phe397Leu/Ile (41.6%) and Leu393Phe (20.8%); in T. indotineae, these include Phe397Leu (33.0%) and Ala448Thr (24.5%). Other potential terbinafine resistance mechanisms in T. rubrum and T. indotineae are discussed.

Conclusions: T. rubrum generally remain susceptible in vitro to terbinafine in contrast to T. indotineae. The essential components of an effective antifungal stewardship emphasize accurate clinical and laboratory diagnosis, susceptibility testing, and appropriate antifungal therapy selection with a multidisciplinary approach.

Keywords: Trichophyton indotineae; Trichophyton rubrum; antifungal drug resistance; squalene epoxidase; terbinafine.

Figure 1

PRISMA flow diagram illustrating the selection process for studies included in the review. Literature searches were performed in PubMed, Embase (Ovid), and Web of Science. The retrieved records (n = 1122) were deduplicated with 398 duplicates removed (124 manually and 274 by Covidence). Then, 641 studies were filtered through critical inclusion criteria, resulting in 83 studies selected.

Figure 2

Terbinafine susceptibility patterns of T. indotineae and T. rubrum [25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69]. Terbinafine resistance studies reporting MIC values for 50% (MIC₅₀) and 90% (MIC₉₀) inhibition of isolate growth, respectively, under CLSI (green: MIC₅₀; blue: MIC₉₀) and EUCAST protocols (yellow: MIC₅₀).

Figure 3

Mechanisms of terbinafine resistance in dermatophytes, encompassing disruption of terbinafine binding to squalene epoxidase (1), overexpression of efflux channel (2), biofilm production (3), heat shock proteins (4), and target degradation via the salA gene (5).

Figure 4

SQLE gene mutation distribution (in percentage) in T. rubrum (top panel, 24 isolates) vs. T. indotineae (bottom panel, 212 isolates) [28,29,30,31,34,36,37,39,42,44,45,50,51,52,55,61,62,66,76,77,78,79,80]. SNVs are indicated on the y-axis; isolate proportions are indicated on the x-axis.

Figure 5

Critical Strategies for Antifungal Stewardship.