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Antimicrobial Agents and Chemotherapy, July 2009, p. 2804-2815, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.00295-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Heteroresistance to Fluconazole in Cryptococcus neoformans Is Intrinsic and Associated with Virulence{triangledown} ,{dagger}

Edward Sionov,1 Yun C. Chang,1 H. Martin Garraffo,2 and Kyung J. Kwon-Chung1*

Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases,1 Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland2

Received 4 March 2009/ Returned for modification 15 April 2009/ Accepted 23 April 2009

In 1999, heteroresistance to triazoles was reported in Cryptococcus neoformans strains isolated from an azole therapy failure case of cryptococcosis in an AIDS patient and in a diagnostic strain from a non-AIDS patient. In this study, we analyzed 130 strains of C. neoformans isolated from clinical and environmental sources before 1979, prior to the advent of triazoles, and 16 fluconazole (FLC)-resistant strains isolated from AIDS patients undergoing FLC maintenance therapy during 1990 to 2000. All strains isolated prior to 1979 manifested heteroresistance (subset of a population that grows in the presence of FLC) at concentrations between 4 and 64 µg/ml, and all 16 FLC-resistant AIDS isolates manifested heteroresistance at concentrations between 16 and 128 µg/ml. Upon exposure to stepwise increases in the concentration of FLC, subpopulations that could grow at higher concentrations emerged. Repeated transfer on drug-free media caused the highly resistant subpopulations to revert to the original level of heteroresistance. The reversion pattern fell into four categories based on the number of transfers required. The strains heteroresistant at ≥32 µg/ml were significantly more resistant to other xenobiotics and were also more virulent in mice than were those heteroresistant at ≤8 µg/ml. During FLC treatment of mice infected by strains with low levels of heteroresistance, subpopulations exhibiting higher levels of heteroresistance emerged after a certain period of time. The ABC transporter AFR1, known to efflux FLC, was unrelated to the heteroresistance mechanism. Our study showed that heteroresistance to azole is universal and suggests that heteroresistance contributes to relapse of cryptococcosis during azole maintenance therapy.

* Corresponding author. Mailing address: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892. Phone: (301) 496-1602. Fax: (301) 480-3458. E-mail: June_Kwon-Chung{at}nih.gov

{triangledown} Published ahead of print on 4 May 2009.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, July 2009, p. 2804-2815, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.00295-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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