title: Posaconazole against Candida glabrata isolates with various susceptibilities to fluconazole.
abstract: We investigated the in vitro activities of posaconazole (POS), fluconazole (FLC), amphotericin B (AMB), and caspofungin (CAS) against four clinical isolates of Candida glabrata with various susceptibilities to FLC (FLC MICs ranging from 1.0 to >64 microg/ml). POS MICs ranged from < or =0.03 to 0.5 microg/ml; AMB MICs ranged from 0.25 to 2.0 microg/ml, while CAS MICs ranged from 0.03 to 0.25 microg/ml. When FLC MICs increased, so did POS MICs, although we did not observe any isolate with a POS MIC greater than 0.5 mug/ml. Time-kill experiments showed that POS, FLC, and CAS were fungistatic against all isolates, while AMB at eight times the MIC was fungicidal against three out of four isolates of C. glabrata tested. Then, we investigated the activity of POS in an experimental model of disseminated candidiasis using three different isolates of C. glabrata: one susceptible to FLC (S; FLC MICs ranging from 1.0 to 4.0 microg/ml; POS MIC of < or =0.03 microg/ml), one susceptible in a dose-dependent manner (SDD; FLC MICs ranging from 32 to 64 microg/ml; POS MICs ranging from 0.125 to 0.25 microg/ml), and another one resistant to FLC (R; FLC MIC of >64 microg/ml; POS MIC of 0.5 microg/ml). FLC significantly reduced the kidney burden of mice infected with the S strain (P = 0.0070) but not of those infected with the S-DD and R strains. POS was significantly effective against all three isolates at reducing the kidney fungal burden with respect to the controls (P ranging from 0.0003 to 0.029). In conclusion, our data suggest that POS may be a useful option in the management of systemic infections caused by C. glabrata. Additionally, the new triazole may be a therapeutic option in those cases where an FLC-resistant isolate is found to retain a relatively low POS MIC.
authors.affiliation: Istituto di Malattie Infettive e Medicina Pubblica, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Spreghini
authors.forename: Carmelo Massimo
authors.initials: CM
authors.lastname: Maida
authors.forename: Serena
authors.initials: S
authors.lastname: Tomassetti
authors.forename: Fiorenza
authors.initials: F
authors.lastname: Orlando
authors.forename: Daniele
authors.initials: D
authors.lastname: Giannini
authors.forename: Maria Eleonora
authors.initials: ME
authors.lastname: Milici
authors.forename: Giorgio
authors.initials: G
authors.lastname: Scalise
authors.forename: Francesco
authors.initials: F
authors.lastname: Barchiesi
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D041221:Candida glabrata / Q000187:drug effects* / Q000254:growth & development; D002177:Candidiasis / Q000188:drug therapy* / Q000382:microbiology; D025141:Drug Resistance, Fungal; D015725:Fluconazole / Q000494:pharmacology*; D006801:Humans; D007668:Kidney / Q000382:microbiology; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D016896:Treatment Outcome; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D000935:Antifungal Agents; D014230:Triazoles; C101425:posaconazole; D015725:Fluconazole