深部真菌感染的耐藥機制研究進展_West China Medical Journal

Authors：

代華 , 陳木英 , 陳立宇 ,  王曉輝

Corresponding?author：

王曉輝, Email: auhiad0208@126.com

Keywords：

真菌; 耐藥機制; 真菌外排泵; 靶酶CYP51; FKS1基因

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【摘要】 隨著深部真菌感染日益增加及抗真菌藥物的廣泛應用，深部真菌耐藥現象也日益突出。近十年以來，雖有較多新型抗真菌感染藥物相繼研發并應用于臨床，但國內外已有較多對其耐藥的病案報道。真菌面對唑類等強大的抗真菌藥物也不斷產生著嚴重的耐藥性，并迅速使一些院內真菌感染陷入了無藥可選的境地。因此，研究真菌的耐藥機制并尋找新的抗真菌藥物已成當務之急。現就按照抗真菌藥物分類，對近年來國內外深部真菌感染的耐藥機制的研究進展進行綜述，以明確深部真菌耐藥發生的誘因、機制，為指導臨床合理使用抗真菌藥物；盡可能減少深部真菌耐藥的發生及研究新一代抗真菌藥物提供參考。

Citation： 代華,陳木英,陳立宇,王曉輝. 深部真菌感染的耐藥機制研究進展. West China Medical Journal, 2011, 26(1): 142-145. doi: Copy

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14.	于維林, 朱元祺, 劉蓬蓬, 等. 唑類耐藥白色念珠菌羊毛甾醇14α-去甲基化酶基因的研究[J]. 中國實驗診斷學, 2009, 10(13): 1357-1359.
15.	綦穎, 夏國光. 侵襲性真菌感染的流行病學和抗真菌藥物的作用效力[J]. 中華醫院感染學雜志, 2009, 19(16): 2217-2220.
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19.	李婷婷, 朱若華, 蔡光明, 等. 抗真菌藥物的研究進展[J]. 中國藥房, 2010, 21(16): 1533-1536.
20.	Akings RA. An update on antifungal targets and mechanisms of resistance in Candida albicans[J]. Med Mycol, 2005, 43(4): 285-318.
21.	田偉, 王育英. 特比奈芬治療淺部真菌病的臨床應用[J]. 臨床皮膚科雜志, 2008, 09(51): 622-623.
22.	陳螟, 曹國穎, 傅得興, 等. 棘白菌素類抗真菌藥物的研究進展[J]. 中國新藥雜志, 2007, 16(14): 1082-1083.
23.	葉麗娟, 王輅, 朱輝. 抗真菌藥物的作用機制及真菌耐藥機制的研究進展[J]. 中國新藥雜志, 2007, 16(14): 1082-1083.
24.	Katiyar S, Pfaller M, Edlind T. Candida albicans and Candida glabrata clinical isolates exhibiting reduced echinocandin susceptibility[J]. Antimicrob Agents Chemother, 2006, 50(8): 2892-2894.
25.	Gardiner RE, Souteropoulos P, Park S, et al. Characterization of Aspergillus fumigatus mutants with reduced suscepti-bility to caspofungin[J]. Med Mycol, 2005, 43(l1): 299-305.
26.	Balashov SV, Park S, Perlin DS. Assessing resistance to the echinocandin antifungal drug caspofungin in Candida albicans by profiling mutations in FKS1[J]. Antimicrob Agents Chemother, 2006, 50(6): 2058-2063.
27.	Park S, Kelly R, Kahn JN, et al. Specific substitutions in the echinocandin target Fks1p account for reduced susceptibility of rare laboratory and clinical Candida sp. isolates[J]. Antimicrob Agents Chemother, 2005, 49(8): 3264-3273.

1. 　周巧霞, 張經碩. 抗真菌藥物及其臨床應用進展[J]. 抗感染藥物, 2008, 5(1): 11-18.
2. 　Kanafani ZA, Perfect JR. Antimicrobial resistance: resistance to antifungal agents: mechanisms and clinical impact[J]. Clin Infect Dis, 2008, 46 (1): 120-128.
3. 　周露, 斯拉普, 艾白. 抗深部真菌感染藥物的研究進展[J]. 藥學進展, 2010, 7(7): 898-900.
4. 　Macbashi K, Niimi M, Kudoh M, et al. Mechanisms of fluconazole resistance in Candida albicans isolates from Japanese AIDS patients[J]. Antimicrob Chemother, 2001, 47(5): 527.
5. 　Marr KA, Lyons CN, Ha K, et al. Inducible azole resistance associated with a heterogeneous phenotype in Candida albicans[J]. Anti Agents Chemo, 2001, 45(1): 52.
6. 　Micheli M, Bille J, Schueller C, et al. A common drug-responsive element mediates the upregulation of the Candida albicans ABC transporters CDR1 and CDR2, two genes involved in antifungal drugresistance[J]. Mol Microbiol, 2002, 43(5): 1197-1214.
7. 　Mar MC, Felix GR. Antifungal drug resistance to azole and polyenes[J]. Lancet Infect Dis, 2002, 9(2): 550-563.
8. 　Edlind TD, Henry KW, Metera KA, et al. Aspergillus fumigatus CYP51 sequence: potential basis for fluconazole resistance[J]. Med Mycol, 2001, 39(3): 299.
9. 　Kontoyiannis DP, Lewis RE. Antifungal drug resistance of pathogenic fungi[J]. Lancet, 2002, 359 (9312): 1135-1144.
10. 　喬建軍, 劉偉, 李若瑜. 白色念珠菌耐藥的分子研究機制研究進展[J]. 微生物學通報, 2007, 34(2): 393-396.
11. 　Kohli A, Smriti, Mukhopadhyay K, et al. In vitro low-level resistance to azole in Candida albicans is associated with changes in membrane lipid fluidity and asymmetry[J]. Anti Agents Chemo, 2002, 46(4): 1046.
12. 　Emter R, Heese-Peck A, Kralli A. ERG6 and PDR5 regulate small lipophilic drug accumulation in yeast cells via distinct mechanisms[J]. FEBS Lett, 2009, 521(1-3): 57-61.
13. 　Espinel-Ingroff A. Mechanisms of resistance to antifungalag-ents: Yeasts and filamentous fungi[J]. Rev Iberoam Micol, 2008, 25(2): 101-106.
14. 　于維林, 朱元祺, 劉蓬蓬, 等. 唑類耐藥白色念珠菌羊毛甾醇14α-去甲基化酶基因的研究[J]. 中國實驗診斷學, 2009, 10(13): 1357-1359.
15. 　綦穎, 夏國光. 侵襲性真菌感染的流行病學和抗真菌藥物的作用效力[J]. 中華醫院感染學雜志, 2009, 19(16): 2217-2220.
16. 　Rock FL, Mao W, Anya YA, et al. An antifungal agentinhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site[J]. Science, 2007, 316(5832): 1759-1761.
17. 　胡輝, 白色念珠菌生物被膜形成和由其產生的耐藥機制[J]. 國外醫藥?抗生素分冊, 2008, 29(1): 1-6.
18. 　Hope WW, Tabemero L, Denning DW, et al. Molecular mechanisms of primary resistance to flucytosine in Candida albicans[J]. Anti Agents Chemo, 2004, 48: 4377-4386.
19. 　李婷婷, 朱若華, 蔡光明, 等. 抗真菌藥物的研究進展[J]. 中國藥房, 2010, 21(16): 1533-1536.
20. 　Akings RA. An update on antifungal targets and mechanisms of resistance in Candida albicans[J]. Med Mycol, 2005, 43(4): 285-318.
21. 　田偉, 王育英. 特比奈芬治療淺部真菌病的臨床應用[J]. 臨床皮膚科雜志, 2008, 09(51): 622-623.
22. 　陳螟, 曹國穎, 傅得興, 等. 棘白菌素類抗真菌藥物的研究進展[J]. 中國新藥雜志, 2007, 16(14): 1082-1083.
23. 　葉麗娟, 王輅, 朱輝. 抗真菌藥物的作用機制及真菌耐藥機制的研究進展[J]. 中國新藥雜志, 2007, 16(14): 1082-1083.
24. 　Katiyar S, Pfaller M, Edlind T. Candida albicans and Candida glabrata clinical isolates exhibiting reduced echinocandin susceptibility[J]. Antimicrob Agents Chemother, 2006, 50(8): 2892-2894.
25. 　Gardiner RE, Souteropoulos P, Park S, et al. Characterization of Aspergillus fumigatus mutants with reduced suscepti-bility to caspofungin[J]. Med Mycol, 2005, 43(l1): 299-305.
26. 　Balashov SV, Park S, Perlin DS. Assessing resistance to the echinocandin antifungal drug caspofungin in Candida albicans by profiling mutations in FKS1[J]. Antimicrob Agents Chemother, 2006, 50(6): 2058-2063.
27. 　Park S, Kelly R, Kahn JN, et al. Specific substitutions in the echinocandin target Fks1p account for reduced susceptibility of rare laboratory and clinical Candida sp. isolates[J]. Antimicrob Agents Chemother, 2005, 49(8): 3264-3273.

West China Medical Journal

深部真菌感染的耐藥機制研究進展

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