• 四川大學(xué)華西醫(yī)院（成都，610041）;

【摘要】 隨著深部真菌感染日益增加及抗真菌藥物的廣泛應(yīng)用，深部真菌耐藥現(xiàn)象也日益突出。近十年以來(lái)，雖有較多新型抗真菌感染藥物相繼研發(fā)并應(yīng)用于臨床，但國(guó)內(nèi)外已有較多對(duì)其耐藥的病案報(bào)道。真菌面對(duì)唑類(lèi)等強(qiáng)大的抗真菌藥物也不斷產(chǎn)生著嚴(yán)重的耐藥性，并迅速使一些院內(nèi)真菌感染陷入了無(wú)藥可選的境地。因此，研究真菌的耐藥機(jī)制并尋找新的抗真菌藥物已成當(dāng)務(wù)之急?，F(xiàn)就按照抗真菌藥物分類(lèi)，對(duì)近年來(lái)國(guó)內(nèi)外深部真菌感染的耐藥機(jī)制的研究進(jìn)展進(jìn)行綜述，以明確深部真菌耐藥發(fā)生的誘因、機(jī)制，為指導(dǎo)臨床合理使用抗真菌藥物；盡可能減少深部真菌耐藥的發(fā)生及研究新一代抗真菌藥物提供參考。

引用本文： 代華,陳木英,陳立宇,王曉輝. 深部真菌感染的耐藥機(jī)制研究進(jìn)展. 華西醫(yī)學(xué), 2011, 26(1): 142-145. doi: 復(fù)制

1. 　周巧霞, 張經(jīng)碩. 抗真菌藥物及其臨床應(yīng)用進(jìn)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(jìn)展[J]. 藥學(xué)進(jìn)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(jī)制研究進(jìn)展[J]. 微生物學(xué)通報(bào), 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(lèi)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(guó)實(shí)驗(yàn)診斷學(xué), 2009, 10(13): 1357-1359.
15. 　綦穎, 夏國(guó)光. 侵襲性真菌感染的流行病學(xué)和抗真菌藥物的作用效力[J]. 中華醫(yī)院感染學(xué)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(chǎn)生的耐藥機(jī)制[J]. 國(guó)外醫(yī)藥?抗生素分冊(cè), 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(jìn)展[J]. 中國(guó)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(yīng)用[J]. 臨床皮膚科雜志, 2008, 09(51): 622-623.
22. 　陳螟, 曹?chē)?guó)穎, 傅得興, 等. 棘白菌素類(lèi)抗真菌藥物的研究進(jìn)展[J]. 中國(guó)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(jī)制及真菌耐藥機(jī)制的研究進(jìn)展[J]. 中國(guó)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. 1. 　周巧霞, 張經(jīng)碩. 抗真菌藥物及其臨床應(yīng)用進(jìn)展[J]. 抗感染藥物, 2008, 5(1): 11-18.
  2. 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. 3. 　周露, 斯拉普, 艾白. 抗深部真菌感染藥物的研究進(jìn)展[J]. 藥學(xué)進(jìn)展, 2010, 7(7): 898-900.
  4. 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. 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. 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. 7. 　Mar MC, Felix GR. Antifungal drug resistance to azole and polyenes[J]. Lancet Infect Dis, 2002, 9(2): 550-563.
  8. 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. 9. 　Kontoyiannis DP, Lewis RE. Antifungal drug resistance of pathogenic fungi[J]. Lancet, 2002, 359 (9312): 1135-1144.
  10. 10. 　喬建軍, 劉偉, 李若瑜. 白色念珠菌耐藥的分子研究機(jī)制研究進(jìn)展[J]. 微生物學(xué)通報(bào), 2007, 34(2): 393-396.
  11. 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. 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. 13. 　Espinel-Ingroff A. Mechanisms of resistance to antifungalag-ents: Yeasts and filamentous fungi[J]. Rev Iberoam Micol, 2008, 25(2): 101-106.
  14. 14. 　于維林, 朱元祺, 劉蓬蓬, 等. 唑類(lèi)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(guó)實(shí)驗(yàn)診斷學(xué), 2009, 10(13): 1357-1359.
  15. 15. 　綦穎, 夏國(guó)光. 侵襲性真菌感染的流行病學(xué)和抗真菌藥物的作用效力[J]. 中華醫(yī)院感染學(xué)雜志, 2009, 19(16): 2217-2220.
  16. 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. 17. 　胡輝, 白色念珠菌生物被膜形成和由其產(chǎn)生的耐藥機(jī)制[J]. 國(guó)外醫(yī)藥?抗生素分冊(cè), 2008, 29(1): 1-6.
  18. 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. 19. 　李婷婷, 朱若華, 蔡光明, 等. 抗真菌藥物的研究進(jìn)展[J]. 中國(guó)藥房, 2010, 21(16): 1533-1536.
  20. 20. 　Akings RA. An update on antifungal targets and mechanisms of resistance in Candida albicans[J]. Med Mycol, 2005, 43(4): 285-318.
  21. 21. 　田偉, 王育英. 特比奈芬治療淺部真菌病的臨床應(yīng)用[J]. 臨床皮膚科雜志, 2008, 09(51): 622-623.
  22. 22. 　陳螟, 曹?chē)?guó)穎, 傅得興, 等. 棘白菌素類(lèi)抗真菌藥物的研究進(jìn)展[J]. 中國(guó)新藥雜志, 2007, 16(14): 1082-1083.
  23. 23. 　葉麗娟, 王輅, 朱輝. 抗真菌藥物的作用機(jī)制及真菌耐藥機(jī)制的研究進(jìn)展[J]. 中國(guó)新藥雜志, 2007, 16(14): 1082-1083.
  24. 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. 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. 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. 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.