Antifungal Activity of Melaleuca alternifolia Essential Oil (TTO) and Its Synergy with Itraconazole or Ketoconazole against Trichophyton rubrum

Abstract

Over the past 20–30 years, Trichophyton rubrum represented the most widespread dermatophyte with a prevalence accounting for 70% of dermatophytosis. The treatment for cutaneous infections caused by Trichophyton spp. are imidazoles (ketoconazole (KTZ)) and triazoles (itraconazole (ITZ)). T. rubrum can develop resistance to azoles after prolonged exposure to subinhibitory concentrations resulting in therapeutic failures and chronic infections. These problems have stimulated the search for therapeutic alternatives, including essential oils, and their potential use in combination with conventional antifungals. The purpose of this study was to evaluate the antifungal activity of tea tree oil (TTO) (Melaleuca alternifolia essential oil) and the main components against T. rubrum and to assess whether TTO in association with KTZ/ITZ as reference drugs improves the antifungal activity of these drugs. We used a terpinen-4-ol chemotype (35.88%) TTO, and its antifungal properties were evaluated by minimum inhibitory and minimum fungicidal concentrations in accordance with the CLSI guidelines. The interaction between TTO and azoles was evaluated through the checkerboard and isobologram methods. The results demonstrated both the fungicide activity of TTO on T. rubrum and the synergism when it was used in combination with azoles. Therefore, this mixture may reduce the minimum effective dose of azole required and minimize the side effects of the therapy. Synergy activity offered a promise for combination topical treatment for superficial mycoses.

Meta-analysis of the antifungal activities of three essential oils as alternative therapies in dermatophytosis infections

“…For T. mentagrophytes sp. and T. rubrum , the MIC values are 0.3% and 0.06–0.3% and the MFC values are 0.5% and 0.06–0.25%, respectively (Hammer, 2002; Roana et al, 2021) (see Table 1).…”

Antifungal Combinations in Dermatophytes

“…Combination included: azoles or terbinafine or griseofulvin plus plant extracts including essential oils (19/30 studies), azoles or terbinafine or amorolfine plus immunosuppressant agents (3 studies), azoles or terbinafine plus peptides (3 studies), azoles plus disinfectants (3 studies), and other combinations including antifungal agents plus efflux pump inhibitors and statins. Checkerboard titration methodology was the most common procedure for testing the combination, followed by agar methods (i.e., disk diffusion and agar dilution) [ 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 ].…”

“…They act in two ways: by neutralizing free radicals (the antioxidant effect) and as anti-inflammatory agents by inhibiting the release of pro-inflammatory mediators. Secondary metabolites produced by plants are also capable of acting in a third way, as antifungal agents [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ]. A synergistic interaction between antifungal agents and natural products was often seen ( Table 2 ).…”

Isoflavaspidic Acid PB Extracted from Dryopteris fragrans (L.) Schott Inhibits Trichophyton rubrum Growth via Membrane Permeability Alternation and Ergosterol Biosynthesis Disruption

“…As the special fungi in keratin degradation, dermatophytes belong to three genera: Trichophyton, Epidermophyton, and Microsporum [5]. Trichophyton rubrum is the main etiological agent, accounting for about 70% of dermatophytosis [6].…”