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Antimicrobial Agents and Chemotherapy, January 2001, p. 52-59, Vol. 45, No. 1
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.1.52-59.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Inducible Azole Resistance Associated with a Heterogeneous Phenotype in Candida albicans

Kieren A. Marr,1,2,* Christopher N. Lyons,3 Kien Ha,1 Tige R. Rustad,4 and Theodore C. White3,4

Program in Infectious Diseases, Fred Hutchinson Cancer Research Center,1 Departments of Medicine2 and Pathobiology,4 University of Washington, and Seattle Biomedical Research Institute,3 Seattle, Washington

Received 14 June 2000/Returned for modification 2 August 2000/Accepted 2 October 2000

The development of azole resistance in Candida albicans is most problematic in patients with AIDS who receive long courses of drug for therapy or prevention of oral candidiasis. Recently, the rapid development of resistance was noted in other immunosuppressed patients who developed disseminated candidiasis despite fluconazole prophylaxis. One of these series of C. albicans isolates became resistant, with an associated increase in mRNA specific for a CDR ATP-binding cassette transporter efflux pump (K. A. Marr, C. N. Lyons, T. R. Rustad, R. A. Bowden, and T. C. White, Antimicrob. Agents Chemother. 42:2584-2589, 1998). Here we study this series of C. albicans isolates further and examine the mechanism of azole resistance in a second series of C. albicans isolates that caused disseminated infection in a recipient of bone marrow transplantation. The susceptible isolates in both series become resistant to fluconazole after serial growth in the presence of drug, while the resistant isolates in both series become susceptible after serial transfer in the absence of drug. Population analysis of the inducible, transiently resistant isolates reveals a heterogeneous population of fluconazole-susceptible and -resistant cells. We conclude that the rapid development of azole resistance occurs by a mechanism that involves selection of a resistant clone from a heterogeneous population of cells.

* Corresponding author. Mailing address: Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N. D3-100, Seattle, WA 98109-1024. Phone: (206) 667-6702. Fax: (206) 667-4411. E-mail: Kmarr{at}fhcrc.org.

Antimicrobial Agents and Chemotherapy, January 2001, p. 52-59, Vol. 45, No. 1
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.1.52-59.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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