Co-Treatment with Ritonavir or Sertraline Enhances Itraconazole Efficacy Against Azole-Resistant Trichophyton indotineae Isolates

The treatment of azole-resistant <i>Trichophyton indotineae</i> poses a significant challenge for clinicians worldwide. Resistance mechanisms include amino acid substitutions in the sterol 14-α demethylase gene <i>Erg11B</i>, as well as overexpression of <i>Erg11B</i>. Additionally, efflux mechanisms mediated by fungal transporter proteins contribute to antifungal resistance. Therefore, the inhibition of fungal efflux transporters using known inhibitors could be a promising strategy to prevent treatment failure. The inhibitory effects of itraconazole in combination with various efflux pump inhibitors were evaluated. Co-treatment with quinine hydrochloride and itraconazole did not lead to a significant reduction in the inhibitory concentration (IC) values in <i>T. indotineae</i> isolates. In contrast, ritonavir lowered IC values by approximately 50% without affecting fungal growth when applied as monotherapy. The most pronounced effect was observed with sertraline, which demonstrated intrinsic antifungal activity at higher concentrations. When combined with itraconazole, sertraline reduced IC values to below 10% in both susceptible and resistant strains, enhancing itraconazole efficacy markedly. The increasing prevalence of antifungal resistance is a growing global health concern. These findings suggest that sertraline holds considerable potential as an adjunctive therapy for the treatment of dermatomycoses.