title: Mechanism of increased fluconazole resistance in Candida glabrata during prophylaxis.
abstract: Candida glabrata can become resistant to fluconazole, causing persistent colonization and invasive infection during prolonged exposure to the drug. To determine the mechanism of resistance in this setting, weekly oropharyngeal cultures for C. glabrata were obtained over a 2-year period from hematopoietic stem cell transplant recipients who were receiving fluconazole prophylaxis. In 20 patients from whom at least two isolates of the same karyotype were obtained more than two weeks apart, fluconazole MICs doubled every 31 days on average. The mechanism of fluconazole resistance in isolates from the 14 of the 20 patients studied in whom MICs changed at least fourfold was studied. Cellular resistance was accompanied by increased drug efflux as measured by decreased accumulation of fluconazole and rhodamine 6G and increased abundance of transcripts from two drug transporters, CgCDR1 and PDH1. The rapidity and regularity of the rising resistance indicated that C. glabrata is able to upregulate drug efflux without losing the ability to maintain colonization.
authors.affiliation: Clinical Mycology Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. jbennett@niaid.nih.gov
authors.forename: John E
authors.initials: JE
authors.lastname: Bennett
authors.forename: Koichi
authors.initials: K
authors.lastname: Izumikawa
authors.forename: Kieren A
authors.initials: KA
authors.lastname: Marr
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D015152:Blotting, Northern; D041221:Candida glabrata / Q000187:drug effects* / Q000235:genetics; D002177:Candidiasis / Q000382:microbiology / Q000517:prevention & control*; D025141:Drug Resistance, Fungal; D026141:Drug Resistance, Multiple, Fungal / Q000235:genetics; D016521:Electrophoresis, Gel, Pulsed-Field; D015725:Fluconazole / Q000494:pharmacology*; D005456:Fluorescent Dyes; D007621:Karyotyping; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012235:Rhodamines
chemical_list: D000935:Antifungal Agents; D005456:Fluorescent Dyes; D012235:Rhodamines; C026188:rhodamine 6G; D015725:Fluconazole