Susceptibilidade in vitro de agentes da cromoblastomicose à sinvastatina e à pravastatina isoladas e em combinação com antifúngicos

Abstract

Chromoblastomycosis is a subcutaneous, granulomatous and chronic infection caused by a traumatic implantation of fungi of the family Herpotrichiellaceae. There is no therapy of choice for this mycosis. Thus, the relocation of the commercially available drugs may be an alternative. Statins are a class of molecules that reduces the serum cholesterol levels by inhibiting the enzyme 3-hydroxy-3-methylglutaryl-CoA reductase, which is involved in the biosynthesis of sterols, such as cholesterol an ergosterol. The latter is considered one of the main components of fungal cell membrane. Considering the mechanism of action of statins, it is expected that these drugs have antifungal activity. Thus, this work aimed to evaluate the in vitro susceptibility of chromoblastomycosis agents to simvastatin and pravastatin alone and in combination with four antifungals (itraconazole, posaconazole, terbinafine e amphotericin B). The susceptibility assesment was carried out according to Clinical and Laboratory Standards Institute-protocol M38-A2. The interaction between simvastatin and the antifungal agents was evaluated through chessboard technique. This interaction was determined by calculating the Fractional Inhibitory Concentration Index (FICI). For the analysis of morphological changes against Fonseacaea pedrosoi ATCC 46428, caused by the combination that presented lower FICI values, images were obtained by atomic force microscopy Simvastatin and pravastatin could not inhibit anyone of the strains (n=19), even when the higher concentration was tested (MIC > 256 μg/mL). However, the combinations itraconazole-simvastatin and posaconazole-simvastatin demonstrate synergism against all of the investigated isolates (FICI = 0.24 – 0.5). Regarding pravastatin, the best result was achieved by combining it wwith posaconazole, in which there was synergism for eight of the nineteen isolates. The other combinations were synergics for only some of the fungal isolates. Antagonism was not observed. By analyzing the microscopic images of the itraconazole/simvastatin association, it was possible to observe the rupture of the fungal cell membrane and extravasation of the intracellular fluido, when compared to the controls. In accordance with the results, it can be observed that pravastatin combined with antifungals showed variable results against the isolates tested. Therefore, simvastin in combination with triazole antifungals presented a synergistic profile, being these associations promising in the treatment of chromoblastomycosis.