title: In-vitro interactions of itraconazole with flucytosine against clinical isolates of Cryptococcus neoformans.
abstract: Treatment failures can occur in AIDS patients infected with Cryptococcus neoformans, despite aggressive antifungal therapy. Combination regimens with additive or synergic drugs could provide additional options for treating cryptococcosis. We studied the effects of itraconazole combined with flucytosine against 16 strains of C. neoformans var. neoformans. Combination therapy revealed different results for the various strains, including synergy (fractional inhibitory concentration (FIC) index 0.5, 63% of the interactions), addition (FIC >0.5 to 1.0, 31% of the interactions) and indifference (FIC >1.0 to <2.0, 6% of the interactions). Antagonism (FIC >2.0) was not observed. The efficacy of combination therapy was confirmed by quantitative cfu and killing curve assays. In particular, killing curves conducted in replicating cells showed that the addition of itraconazole prevented the development of flucytosine-resistant mutants of C. neoformans. These data show that the combination of itraconazole and flucytosine is significantly more active than either drug alone against C. neoformans in vitro.
authors.affiliation: Istituto di Malattie Infettive e Medicina Pubblica Università degli Studi di Ancona, Ospedale Umberto I, Italy. cmalinf@popcis.unian.it
authors.forename: F
authors.initials: F
authors.lastname: Barchiesi
authors.forename: D
authors.initials: D
authors.lastname: Gallo
authors.forename: F
authors.initials: F
authors.lastname: Caselli
authors.forename: L F
authors.initials: LF
authors.lastname: Di Francesco
authors.forename: D
authors.initials: D
authors.lastname: Arzeni
authors.forename: A
authors.initials: A
authors.lastname: Giacometti
authors.forename: G
authors.initials: G
authors.lastname: Scalise
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D015169:Colony Count, Microbial; D003455:Cryptococcus neoformans / Q000187:drug effects* / Q000254:growth & development; D004347:Drug Interactions; D004357:Drug Synergism; D005437:Flucytosine / Q000494:pharmacology*; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests
chemical_list: D000935:Antifungal Agents; D017964:Itraconazole; D005437:Flucytosine