Synergistic and antagonistic effects of immunomodulatory drugs on the action of antifungals against Candida glabrata and Saccharomyces cerevisiae

Candidemia and other forms of invasive fungal infections caused by Candida glabrata and to a lesser extent Saccharomyces cerevisiae are a serious health problem, especially if their steadily rising resistance to the limited range of antifungal drugs is taken into consideration. Various drug combinations are an attractive solution to the resistance problem, and some drug combinations are already common in the clinical environment due to the nature of diseases or therapies. We tested a few of the common antifungal-immunomodulatory drug combinations and evaluated their effect on selected strains of C. glabrata and S. cerevisiae. The combinations were performed using the checkerboard microdilution assay and interpreted using the Loewe additivity model and a model based on the Bliss independence criterion. A synergistic interaction was confirmed between calcineurin inhibitors (Fk506 and cyclosporine A) and antifungals (fluconazole, itraconazole, and amphotericin B). A new antagonistic interaction between mycophenolic acid (MPA) and azole antifungals was discovered in non-resistant strains. A possible mechanism that explains this is induction of the Cdr1 efflux pump by MPA in C. glabrata ATCC 2001. The Pdr1 regulatory cascade plays a role in overall resistance to fluconazole, but it is not essential for the antagonistic interaction. This was confirmed by the Cgpdr1Δ mutant still displaying the antagonistic interaction between the drugs, although at lower concentrations of fluconazole. This antagonism calls into question the use of simultaneous therapy with MPA and azoles in the clinical environment.