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. 2004 May;48(5):1773-7.
doi: 10.1128/AAC.48.5.1773-1777.2004.

Mechanism of increased fluconazole resistance in Candida glabrata during prophylaxis

John E Bennett  1 , Koichi Izumikawa, Kieren A Marr
Affiliations

Mechanism of increased fluconazole resistance in Candida glabrata during prophylaxis

John E Bennett et al. Antimicrob Agents Chemother. 2004 May.

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.

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Figures

FIG. 1.
FIG. 1.
CHEF gel showing representatives of 16 karyotypes (I to XVI), distinguished at 90% identity.
FIG. 2.
FIG. 2.
Fluconazole MICs during fluconazole prophylaxis of 20 patients. Each line represents a single patient. The dashed line is the best-fit line. mcg, micrograms
FIG. 3.
FIG. 3.
Rhodamine 6G accumulation in 14 pairs of isolates as a function of fluconazole MIC. Two lines overlap and appear as one line. The dashed line represents the same patient as the dashed line in Fig. 4. mcg, micrograms.
FIG. 4.
FIG. 4.
Fluconazole accumulation in 14 pairs of isolates as a function of fluconazole MIC. The dashed line represents the same patient as the dashed line in Fig. 3.
FIG. 5.
FIG. 5.
Abundance of PDH1 transcript divided by that of ACT1 transcript in paired susceptible and resistant isolates from 14 patients.
FIG. 6.
FIG. 6.
Abundance of CgCDR1 transcript divided by that of ACT1 transcript in paired susceptible and resistant isolates from 14 patients.
See this image and copyright information in PMC

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