Voriconazole-Induced Inhibition of the Fungicidal Activity of Amphotericin B in CandidaStrains with Reduced Susceptibility to Voriconazole: an Effect Not Predicted by the MIC Value Alone

ABSTRACTAn antagonistic effect of voriconazole on the fungicidal activity of sequential doses of amphotericin B has previously been demonstrated in Candida albicansstrains susceptible to voriconazole. Because treatment failure and the need to switch to other antifungals are expected to occur more often in infections that are caused by resistant strains, it was of interest to study whether the antagonistic effect was still seen in Candidastrains with reduced susceptibility to voriconazole. With the hypothesis that antagonism will not occur in voriconazole-resistant strains, C. albicansstrains with characterized mechanisms of resistance against voriconazole, as well as Candida glabrataand Candida kruseistrains with differences in their degrees of susceptibility to voriconazole were exposed to voriconazole or amphotericin B alone, to both drugs simultaneously, or to voriconazole followed by amphotericin B in an in vitrokinetic model. Amphotericin B administered alone or simultaneously with voriconazole resulted in fungicidal activity. When amphotericin B was administered after voriconazole, its activity was reduced (median reduction, 61%; range, 9 to 94%). Levels of voriconazole-dependent inhibition of amphotericin B activity differed significantly among the strains but were not correlated with the MIC values (correlation coefficient, −0.19; P= 0.65). Inhibition was found in C. albicansstrains with increases in CDR1and CDR2expression but not in the strain with an increase in MDR1expression. In summary, decreased susceptibility to voriconazole does not abolish voriconazole-dependent inhibition of the fungicidal activity of amphotericin B in voriconazole-resistant Candidastrains. The degree of interaction could not be predicted by the MIC value alone.