title: Anticandidal effects of voriconazole and caspofungin, singly and in combination, against Candida glabrata, extracellularly and intracellularly in granulocyte-macrophage colony stimulating factor (GM-CSF)-activated human monocytes.
abstract: OBJECTIVE
  The antifungal effects of voriconazole and caspofungin, singly and in combination, were determined against Candida glabrata in time-kill curves in broth, in human monocyte-derived macrophages (MDMs) and in MDMs activated by granulocyte-macrophage colony-stimulating factor (GM-CSF).
  
  
  METHODS
  Three strains of fluconazole-resistant C. glabrata were evaluated. For intracellular studies, MDM monolayers, with or without GM-CSF activation, were infected with C. glabrata and treated with voriconazole and caspofungin at 2.5x and 5x MIC, respectively, or at 1x MIC. Extracellular studies in broth were performed using drug concentrations from 0.1 to 10x MIC. Viable yeast were enumerated at 0, 24 and 48 h.
  
  
  RESULTS
  Significantly greater killing of C. glabrata occurred with the drug combination than with either single drug, both intracellularly and extracellularly (P < 0.01). For voriconazole, the antifungal activity in MDM activated by GM-CSF was greater than that in unactivated MDM, regardless of antibiotic concentration or time of exposure. However, for caspofungin and for the two-drug combination, enhanced activity in GM-CSF-activated MDM depended on the drug concentration and time of exposure.
  
  
  CONCLUSIONS
  Our data suggest that combinations of voriconazole and caspofungin may be efficacious for the treatment of serious C. glabrata infections. With single-drug therapy, especially voriconazole, GM-CSF activation of monocytes could be considered.
authors.affiliation: Stratton Veterans Affairs Medical Center, Albany, NY 12208, USA.
authors.forename: Aldona L
authors.initials: AL
authors.lastname: Baltch
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Bopp
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Smith
authors.forename: William J
authors.initials: WJ
authors.lastname: Ritz
authors.forename: Phyllis B
authors.initials: PB
authors.lastname: Michelsen
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D041221:Candida glabrata / Q000187:drug effects*; D000077336:Caspofungin; D002478:Cells, Cultured; D004347:Drug Interactions; D054714:Echinocandins / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D006801:Humans; D055666:Lipopeptides; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability; D009000:Monocytes / Q000382:microbiology*; D011743:Pyrimidines / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D011743:Pyrimidines; D014230:Triazoles; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000077336:Caspofungin; D065819:Voriconazole