title: 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 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. 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.
authors.affiliation: Department of Medical Sciences, Section of Infectious Diseases, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. anders.lignell@akademiska.se
authors.forename: Anders
authors.initials: A
authors.lastname: Lignell
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Löwdin
authors.forename: Otto
authors.initials: O
authors.lastname: Cars
authors.forename: Dominique
authors.initials: D
authors.lastname: Sanglard
authors.forename: Jan
authors.initials: J
authors.lastname: Sjölin
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D002175:Candida / Q000187:drug effects*; D002176:Candida albicans / Q000187:drug effects; D041221:Candida glabrata / Q000187:drug effects; D004347:Drug Interactions; D025141:Drug Resistance, Fungal / Q000235:genetics / Q000502:physiology; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D026901:Membrane Transport Proteins; D008826:Microbial Sensitivity Tests; D011743:Pyrimidines / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; C094693:CDR1 protein, Candida albicans; D005656:Fungal Proteins; D026901:Membrane Transport Proteins; D011743:Pyrimidines; D014230:Triazoles; D000666:Amphotericin B; D065819:Voriconazole