FARIÑA Julia Ines
Synergistic antifungal activity of statin-azole associations as witnessed by Saccharomyces cerevisiae- and Candida utilis-bioassays and ergosterol quantification
M.E. CABRAL; L.I.C. FIGUEROA; J.I. FARIÑA
REVISTA IBEROAMERICANA DE MICOLOGIA
ASOCIACION ESPANOLA MICOLOGIA-AEM
Lugar: Barcelona; Año: 2013 vol. 30 p. 31 - 31
Background: Frequent opportunist fungal infections and the resistance to available antifungal drugs promoted the development of new alternatives for treatment, like antifungal drug combinations. Aims: This work aimed to detect the antifungal synergism between statins and azoles by means of an agar-well diffusion bioassay with Saccharomyces cerevisiae ATCC 32051 and Candida utilis Pr1-2 as test strains. Methods: Synergistic antifungal effects were tested by simultaneously adding a sub-inhibitory concentration (SIC) of statin (atorvastatin, lovastatin, pravastatin, rosuvastatin or simvastatin) plus a minimal inhibitory concentration (MIC) of azole (clotrimazole, fluconazole, itraconazole, ketoconazole or miconazole) to yeast-embedded YNB agar plates, and a positive result corresponded to a yeast growth inhibition halo higher than that produced by the MIC of the azole alone. Yeast cell ergosterol quantification by RP-HPLC was used to confirm statin-azole synergism, and ergosterol rescue bioassays were performed for evaluating statin-induced ergosterol synthesis blockage. Results: Growth inhibition was significantly increased when clotrimazole, fluconazole, itraconazole, ketoconazole and miconazole were combined with atorvastatin, lovastatin, rosuvastatin and simvastatin. Highest growth inhibition increments were observed on S. cerevisiae (77.5%) and C. utilis (43.2%) with a SIC of simvastatin plus a MIC of miconazole, i.e. 4 + 2.4 mg/ml or 20 + 4.8 mg/ml, respectively. Pravastatin showed almost no significant effects (0-7.6% inhibition increase). Highest interaction ratios between antifungal agents corresponded to simvastatin-miconazole combinations and were indicative of synergism. Synergism was also confirmed by the increased reduction in cellular ergosterol levels (S. cerevisiae, 40% and C. utilis, 22%). Statin-induced ergosterol synthesis blockage was corroborated by means of ergosterol rescue bioassays, being pravastatin the most easily abolished inhibition whilst rosuvastatin, the most ergosterol-refractory. Conclusions: Selected statin-azole combinations might be viable alternatives for the therapeutic management of mycosis at lower administration doses or with a higher efficiency.