Heteroresistance to Fluconazole in Cryptococcus neoformans Is Intrinsic and Associated with Virulence

作者：Edward Sionov, Yun Cheong Chang, Hugo Martin Garraffo, Kyung Joo Kwon-Chung · 发表于：Antimicrobial Agents and Chemotherapy · 年份：2009 · DOI：10.1128/aac.00295-09 · 被引用次数：180 · 研究领域：Fungal Infections and Studies、Antifungal resistance and susceptibility、Nail Diseases and Treatments

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 microg/ml, and all 16 FLC-resistant AIDS isolates manifested heteroresistance at concentrations between 16 and 128 microg/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 > or =32 microg/ml were significantly more resistant to other xenobiotics and were also more virulent in mice than were those heteroresistant at < or =8 microg/ml. During FLC treatment of mice infected by strains with low levels of heteroresistance, subpopulations exhibiting higher levels of heteroresistance emerged after a certain...