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

Abstract

An antagonistic effect of voriconazole on the fungicidal activity of sequential doses of amphotericin B has previously been demonstrated in Candida albicans strains 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 Candida strains with reduced susceptibility to voriconazole. With the hypothesis that antagonism will not occur in voriconazole-resistant strains, C. albicans strains with characterized mechanisms of resistance against voriconazole, as well as Candida glabrata and Candida krusei strains 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 vitro kinetic 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 voriconazoledependent 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. albicans strains with increases in CDR1 and CDR2 expression but not in the strain with an increase in MDR1 expression. In summary, decreased susceptibility to voriconazole does not abolish voriconazole-dependent inhibition of the fungicidal activity of amphotericin B in voriconazole-resistant Candida strains. The degree of interaction could not be predicted by the MIC value alone.Combination antifungal therapy may be one method to improve outcome in invasive Candida infections. Because animal model pharmacodynamic studies may have difficulties in simulating human pharmacokinetics, in vitro pharmacodynamic studies with simulated human pharmacokinetics represent an additional tool in the study of antifungal combinations in that they can yield data on drug-specific antifungal activities that will be of interest before initiating clinical trials.Recently, an in vitro kinetic model for the study of combination treatment with drugs having different elimination rates has been presented and validated (12). This model has been used to demonstrate an antagonistic effect of voriconazole on the fungicidal activity of sequential doses of amphotericin B against Candida albicans (12, 13). These studies investigated C. albicans strains fully susceptible to voriconazole. The postulated mechanism is that inhibition of ergosterol synthesis leads to decrease of ergosterol content and thus diminishes the effect of amphotericin B, which uses this sterol to mediate its inhibitory effect. Consequently, it is reasonable to hypothesize that voriconazole-induced inhibition of the fungicidal activity of amphotericin B will not be observed in voriconazole-resistant stra...

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