Molecular Microbiology Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
Antimicrob Agents Chemother. 2010 Jun;54(6):2303-11. doi: 10.1128/AAC.00153-10. Epub 2010 Apr 12.
We analyzed 71 clinical and environmental Cryptococcus gattii strains that had been isolated before or after the advent of azole antifungals to determine their level of heteroresistance to fluconazole (LHF). All strains of C. gattii manifested heteroresistance, with LHFs that ranged between 4 microg/ml and 32 microg/ml. A considerably higher proportion of the C. gattii strains (86%) than Cryptococcus neoformans strains (46%) exhibited LHFs that were > or =16 microg/ml. No significant correlation was observed between the molecular type or serotypes of strains and their respective LHF. The strains which expressed a higher LHF were also more resistant to xenobiotics than the strains with a low LHF, and the level of resistance to xenobiotics was significantly higher than that reported for C. neoformans. The heteroresistant subpopulation, whose level of drug resistance had been raised in a stepwise manner to 64 microg/ml, reverted to the original LHF upon daily transfers in drug-free medium. Importantly, the strains with high LHFs were significantly more virulent than those with low LHFs. Since all the clinical isolates that had not been exposed to azole drugs as well as the environmental strains manifested heteroresistance to fluconazole, heteroresistance of C. gattii to azoles is an intrinsic mechanism as in C. neoformans and is associated with the strain's virulence.
我们分析了 71 株临床和环境分离的隐球菌 gattii 株，这些菌株在唑类抗真菌药物出现之前或之后被分离出来，以确定它们对氟康唑的异质性耐药程度（LHF）。所有隐球菌 gattii 株均表现出异质性耐药性，LHF 范围在 4μg/ml 至 32μg/ml 之间。与新型隐球菌株（46%）相比，隐球菌 gattii 株（86%）表现出 LHFs>或=16μg/ml 的比例要高得多。菌株的分子型或血清型与各自的 LHF 之间没有观察到显著相关性。表达更高 LHF 的菌株比 LHF 较低的菌株对细胞外毒物的耐药性更强，而且对细胞外毒物的耐药水平明显高于新型隐球菌。异质性耐药亚群的耐药水平逐渐提高到 64μg/ml，在无药物的培养基中每日传代后，其耐药水平恢复到原来的 LHF。重要的是，具有高 LHF 的菌株比具有低 LHF 的菌株的毒力显著更高。由于所有未接触过唑类药物的临床分离株和环境株均表现出对氟康唑的异质性耐药性，因此隐球菌 gattii 对唑类药物的异质性耐药性是与新型隐球菌相似的固有机制，与菌株的毒力有关。
