Trichophyton rubrum is the major cause of chronic or recurrent human dermatophytosis included among the fungal diseases that most affect the worldwide population. Many azoles, such as itraconazole (ITC), often resulting in complete clearance of the lesions.T.rubrum can develop resistance to azoles after prolonged exposure to subinhibitory concentrations of these drugs leading to therapeutic failures and to persistence and chronicity of the infections.This problem has stimulated the search for therapeutic alternatives, including essential oils recognized for their potential antimicrobial role.The essential oil of Melaleuca alternifolia (Myrtaceae;Tea Tree Oil,TTO) has recently received much attention for its antifungal properties:due to its lipophilic nature, which facilitates skin penetration it is used as local formulation for dermatological disorders.This study aims to analyze the effects induced by TTO on T.rubrum and its potential synergism when used in combination with conventional drugs such as ITC or ketoconazole (KCZ). In vitro susceptibility testing assays of TTO or azoles on 4 T. rubrum clinical isolates were performed using the CLSI M38-A2 broth microdilution method,except for inoculum suspensions (Granade & Artis,1980).MICs were defined as the lowest concentration that induces 80% of mould growth inhibition.The synergic action of TTO with ITC was studied with the checkerboard method.The nature of interaction was defined by means of fractional inhibitory concentrations (FICs)calculated as the MIC of the combination of TTO with drug,divided by the MIC of TTO or drug alone.FIC index (FICI) was obtained by adding both FICs. FICI: ≤0.5,synergistic;0.5–4.0,no interaction; >4.0,antagonistic. Confirmation of the antimicrobial activity of the TTO and azoles was undertaken against the 4 test moulds.The MICs did not differ significantly with regard to tested fungal strains:the mean MIC value obtained for TTO was 1.08 µg/ml,while for ITC or KCZ was 0.5 µg/ml and 0.25 µg/ml, respectively.TTO was most effective in combination therapy,showing a strong synergy with azoles (FICI values 0.37 and 0.245, respectively) and reducing the MIC both of them up to 8-fold. Moreover, for each one of these interactions,the MIC for TTO alone was below the lowest testing concentration. The results obtained have demonstrated both the effects of TTO on T.rubrum and the synergism when it was used in combination with azoles.Synergy might permit lower doses of the individual drugs to be used more effectively and safely, offering a promise for combination topical treatment regimens for superficial mycoses.Therefore,we can hypothesize the use of this combination within future pharmaceutical preparation.
Antifungal effects of Melaleuca alternifolia essential oil (TTO) alone and in combination with itraconazole or ketoconazole against Trichophyton rubrum.
Roana J;Mandras N;Scalas D;Tullio V
2019-01-01
Abstract
Trichophyton rubrum is the major cause of chronic or recurrent human dermatophytosis included among the fungal diseases that most affect the worldwide population. Many azoles, such as itraconazole (ITC), often resulting in complete clearance of the lesions.T.rubrum can develop resistance to azoles after prolonged exposure to subinhibitory concentrations of these drugs leading to therapeutic failures and to persistence and chronicity of the infections.This problem has stimulated the search for therapeutic alternatives, including essential oils recognized for their potential antimicrobial role.The essential oil of Melaleuca alternifolia (Myrtaceae;Tea Tree Oil,TTO) has recently received much attention for its antifungal properties:due to its lipophilic nature, which facilitates skin penetration it is used as local formulation for dermatological disorders.This study aims to analyze the effects induced by TTO on T.rubrum and its potential synergism when used in combination with conventional drugs such as ITC or ketoconazole (KCZ). In vitro susceptibility testing assays of TTO or azoles on 4 T. rubrum clinical isolates were performed using the CLSI M38-A2 broth microdilution method,except for inoculum suspensions (Granade & Artis,1980).MICs were defined as the lowest concentration that induces 80% of mould growth inhibition.The synergic action of TTO with ITC was studied with the checkerboard method.The nature of interaction was defined by means of fractional inhibitory concentrations (FICs)calculated as the MIC of the combination of TTO with drug,divided by the MIC of TTO or drug alone.FIC index (FICI) was obtained by adding both FICs. FICI: ≤0.5,synergistic;0.5–4.0,no interaction; >4.0,antagonistic. Confirmation of the antimicrobial activity of the TTO and azoles was undertaken against the 4 test moulds.The MICs did not differ significantly with regard to tested fungal strains:the mean MIC value obtained for TTO was 1.08 µg/ml,while for ITC or KCZ was 0.5 µg/ml and 0.25 µg/ml, respectively.TTO was most effective in combination therapy,showing a strong synergy with azoles (FICI values 0.37 and 0.245, respectively) and reducing the MIC both of them up to 8-fold. Moreover, for each one of these interactions,the MIC for TTO alone was below the lowest testing concentration. The results obtained have demonstrated both the effects of TTO on T.rubrum and the synergism when it was used in combination with azoles.Synergy might permit lower doses of the individual drugs to be used more effectively and safely, offering a promise for combination topical treatment regimens for superficial mycoses.Therefore,we can hypothesize the use of this combination within future pharmaceutical preparation.
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