The lipophilic azoles itraconazole (ICZ), ketoconazole (KCZ) and miconazole (MCZ) have two things in common regarding their effect on Candida albicans. First, these azoles cause a growth inhibition that persists for at least 24 h after exposure (post-antibiotic effect), although this is only occasionally observed for ICZ. Secondly, these substances cause a decrease in the fungicidal activity of amphotericin B (AMB, 1 mg l-1) upon subsequent exposure to this drug. In contrast, fluconazole (FCZ) exhibits neither of these two effects. Further tests suggest that both of these phenomena observed may be related to the non-covalent binding of the three lipophilic azoles to lipophilic cytoplasmic components of yeast cells. With fluconazole, such bonds seem to be much weaker. The amount of relatively hydrophilic fluconazole that is bound non-specifically to the fungal cell is evidently too low to produce long-lasting post-exposure effects like those caused by lipophilic azoles.
Antagonism between fluconazole (FCZ) and amphotericin B (AMB) was determined with an agar diffusion technique using series of agar plates containing no or 10 mgl-1 FCZ (comparative diffusion assay). Serial dilutions of AMB produced concentration-dependent inhibition zones that varied between the two agar plate series. This technique served as screening method to determine FCZ-AMB interactions in 18 Candida albicans strains. The critical concentrations of AMB were enhanced 1.33- to 7.0-fold by FCZ. The critical time, T0, was reduced by half by FCZ.
With the lipophilic azoles itraconazole (ICZ), ketoconazole (KCZ), and miconazole (MCZ) two effects, occurring in parallel, on Candida albicans were observed: Firstly, these azoles caused a growth inhibition which persisted for at least 24 hours (post-antibiotic effect, found regularly with KCZ and MCZ, with ICZ only occasionally). Furthermore, the fungicidal activity of amphotericin B (AMB, 1 mg/1) after exposure to the azoles was reduced. In contrast, to this, fluconazole (FCZ) produced neither of these effects. Additional experiments indicate that both actions of the three lipophilic azoles may be related to their noncovalent binding to lipophilic cytoplasmatic components of the yeast cells. In the case of fluconazol such bonds seem to be much weaker. Presumably, the amount of the relatively hydrophilic fluconazole, which will be bound to the cell, is too low as to produce long lasting post-exposure effects like those caused by the lipophilic azoles.
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