Mechanism of the synergistic action of oxythiamine and ketoconazole against the yeast Malassezia pachydermatis.

This article explains the biochemical basis of the synergistic effect of oxythiamine and ketoconazole against Malassezia pachydermatis yeast, which was isolated from dogs exhibiting clinical signs of otitis externa. All strains were incubated on MLNA medium supplemented with oxythiamine, ketoconazole or a mixture of both compounds. We found that the ergosterol content was reduced by the compounds tested, both separately (20-50%) and in combination (80%). Oxythiamine alone and in combination with ketoconazole reduced NADPH levels. However, we found no differences in acetyl-CoA levels under the influence of the compounds tested. We suggest that the synergism of oxythiamine and ketoconazole is due to a reduction in the rate of the mevalonate pathway by inhibition of NADPH influx from the pentose phosphate pathway (transketolase inhibition by oxythiamine) and inhibition of C14-α-lanosterol demethylase by ketoconazole. The proposed mechanism may be versatile for other yeasts-like species, making the combination of oxythiamine and ketoconazole a promising treatment option for superficial, opportunistic yeast-like infections.