title: Effects of voriconazole, granulocyte-macrophage colony-stimulating factor, and interferon gamma on intracellular fluconazole-resistant Candida glabrata and Candida krusei in human monocyte-derived macrophages.
abstract: Infections caused by fluconazole-resistant Candida glabrata and Candida krusei are increasingly common causes of morbidity and mortality. We investigated the intracellular killing of fluconazole-resistant C. glabrata and C. krusei by cytokine-activated human monocyte-derived macrophages (MDM) in the presence and absence of voriconazole. For C. glabrata, MDM were activated with either granulocyte-macrophage colony-stimulating factor (GM-CSF) or interferon gamma (IFN-gamma) before infection, after infection, or both before and after infection, whereas for C. krusei MDM were activated with cytokines both before and after infection. Activated MDM were infected, treated with voriconazole, and then lysed, and viable yeast in the lysates enumerated at 0, 24, or 48 h after infection. In the presence of voriconazole (2.5 x MIC), the best activity against C. glabrata occurred when MDM were activated with GM-CSF for 24 h before infection as well as after infection or when they were activated for 24 h before infection alone. A lesser effect was observed when MDM were activated for at least 1 h before infection or when they were treated with cytokines only after infection. IFN-gamma activation had a significant but lesser effect than GM-CSF. Activity against C. krusei in the presence of voriconazole was greatest when MDM were activated with IFN-gamma rather than GM-CSF. Our results suggest that cytokines increase the intracellular anticandidal effect of voriconazole and may be useful as therapeutic adjuvants to voriconazole for treatment of infections caused by fluconazole-resistant C. glabrata and C. krusei.
authors.affiliation: Infectious Disease Section, Medical Service, Stratton VA Medical Center, Albany, NY 12208, USA. Aldona.Baltch@med.va.gov
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: Cynthia J
authors.initials: CJ
authors.lastname: Carlyn
authors.forename: Phyllis B
authors.initials: PB
authors.lastname: Michelsen
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D002175:Candida / Q000187:drug effects* / Q000254:growth & development; D041221:Candida glabrata / Q000187:drug effects* / Q000254:growth & development; D015169:Colony Count, Microbial; D025141:Drug Resistance, Fungal; D015725:Fluconazole / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology*; D009000:Monocytes / Q000382:microbiology; D011743:Pyrimidines / Q000494:pharmacology*; D013045:Species Specificity; D014230:Triazoles / Q000494:pharmacology*; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D015725:Fluconazole; D065819:Voriconazole