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1、CVC相关性念珠菌感染与治疗策略山东大学齐鲁医院重症医学科丁士芳,内容,念珠菌生物被膜形成生物被膜念珠菌耐药机制念珠菌生物被膜危害棘白菌素药物治疗CVC相关念珠菌感染优势,生物被膜相关念珠菌感染,The Pathogenesis of Candida Infections in a Human SkinModel: Scanning ElectronMicroscope Observations. ISRN Dermatol. 2011;2011:150642Candida albicans-Endothelial Cell Interactions: a Key Step in the Pa
2、thogenesis of Systemic Candidiasis. INFECTION AND IMMUNITY, 2008, 76(10):43704377Biofilm formation by the fungal pathogen Candida albicans : development, architecture, and drug resistance J. J Bacteriol, 2001, 183(18):5385Candida albicans morphogenesis and host defence: discriminating invasion from
3、colonization. Nat Rev Microbiol. ; 10(2): 112122.Hyphal growth in human fungal pathogens and its role in virulence. Int J Microbiol. 2012;2012:517529.,血和主动脉瓣培养为近平滑念珠菌，静脉联合滴注两性霉素B和科塞斯，2周后症状消失、血培养无真菌生长Candida parapsilosis bioprosthetic valve endocarditis inducing aortic valve stenosis.。Tex Heart Inst
4、J. 2013;40(4):502-4,伪膜性口咽部念珠菌感染Oral Candida albicans isolates from HIV-positive individuals have similar in vitro biofilm-forming ability and pathogenicity as invasive Candida isolates.BMC Microbiol. 2011 Nov 4;11:247.,NIH in PA-03-047报道80%微生物感染与生物被膜形成相关多数研究以浮游念珠菌为主，念珠菌危害主要与其形成生物被膜有关,真菌生物被膜,生物被膜是指细(
5、真)菌吸附于机体腔道或生物材料表面，分泌多糖基质、纤维蛋白、脂蛋白等，将自身包绕其中形成的膜样多细(真)菌复合体生物膜不断释放脱落细(真)菌，形成新的感染灶，引起感染持续状态，导致细(真)菌耐药、感染被彻底治愈机会减少、临床治疗失败死而复生，生命不息,生根发芽，咬定青山不放松(臭名昭著)钢筋混凝土构成的社区群体,念珠菌生物被膜相关感染,随时间延长，形成类似生物被膜白色念珠菌皮肤感染模型生根发芽，咬定青山不放松,The Pathogenesis of Candida Infections in a Human SkinModel: Scanning ElectronMicroscope Obse
6、rvations. ISRN Dermatol. 2011;2011:150642Candida albicans-Endothelial Cell Interactions: a Key Step in the Pathogenesis of Systemic Candidiasis. INFECTION AND IMMUNITY, 2008, 76(10):43704377,热带念珠菌,白色念珠菌,beta-glucan与念珠菌生物被膜,beta-1,3和beta-1,6 glucans (50 to 60%), mannoproteins (30 to 40%), and chitin
7、(0.6 to 9%),.,Putative Role of -1,3 Glucans in Candida albicans Biofilm Resistance. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2007, 51(2):510520Nat Rev Microbiol. ; 10(2): 112122,念珠菌生物被膜相关感染,Biofilm Formation by the Fungal Pathogen Candida albicans: Development, Architecture, and Drug Resistance。OURNAL
8、 OF BACTERIOLOGY, Sept. 2001, p. 53855394Vol. 183, No. 18,产生物被膜的念珠菌菌株附着的有机玻璃或硅胶片，在0.05% (v/v) Calcofluor-White浸染1 min，该染料特异性与真菌细胞壁中的几丁质和葡聚糖特异性结合荧光显微镜下观察早期(0 to 11 h), 微小菌落 中期(12 to 30 h), 类似细胞壁构成无定形物质覆盖菌落 成熟期(38 to 72 h), 菌落被覆盖,生物材料影响念珠菌生物被膜构成,Biofilm Formation by the Fungal Pathogen Candida albican
9、s: Development, Architecture, and Drug Resistance。OURNAL OF BACTERIOLOGY, Sept. 2001, p. 53855394Vol. 183, No. 18,代谢活跃细胞，胞浆内FUN-1呈橘红色，ConA主要与真菌细胞壁多糖中的甘露糖结合，成绿色a 单个白色念珠菌粘附b 8h后，白念趋向粘附聚集c 11h后，形成微菌落d 成熟期，微菌落被类似细胞壁物质覆盖,硅胶片形成厚约1012um白色念珠菌菌株层，其上形成厚约450um、富含念珠菌菌丝和细胞外基质的基质层强行剥离基质层，可见念珠菌菌落,念珠菌生物被膜模型,Fungal
10、Biofilms and Drug Resistance. Emerging Infectious Diseases www.cdc.gov/eid Vol. 10, No. 1, January 2004Fungal Biofilms: Relevance in the Setting of Human Disease. Curr Fungal Infect Rep. 2010 December 1; 4(4): 266275.,白色念珠菌在多孔滤网形成生物被膜，显示孢子和菌丝被细胞外基质包绕SEM of a C. albicans biofilm grown on a cellulose
11、acetate filter in a perfused biofilm fermentor. SEM revealed a complex mixture of yeasts and hyphae enmeshed in a dense matrix material. Each biofilm consisted mainly of a cell monolayer, but in some areas biofilms were three cells deep.,大鼠白色念珠菌相关CVC 感染模型(24h) 显示酵母细胞与菌丝倍细胞外基质覆盖Scanning electron micr
12、oscopy image of mature (24-h) Candida albicans biofilms formed on a rat central venous catheter model showed a network comprising yeast cells and hyphae surrounded by moderate amounts of exopolymeric matrix. 5 m,念珠菌形成生物被膜存在差异,瑞典临床微生物实验室2005年9月-2006年8月收集393株念珠菌，40%白色念珠菌形成生物被膜，88.7%非白念形成生物膜(p0.05)非白念容
13、易形成复杂、厚密生物被膜,Prevalence of biofilm formation in clinical isolates of candida species causing bloodstream infection. Mycoses. 2013 May;56(3):264-72.,产生物被膜念珠菌的超微结构beta-1,3glucan的作用,形成生物被膜过程中，念珠菌形态发生改变生物被膜念珠菌细胞壁厚度为浮游念珠菌的2倍The cell walls of the in vivo biofilm cells were up to two times thicker than pla
14、nktonic cellsIn addition, the periplasmic layer was more prominent in the biofilm cells,Putative Role of -1,3 Glucans in Candida albicans Biofilm Resistance. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2007, 51(2):510520,beta-glucan在产生物被膜念珠菌的作用,形成生物被膜念珠菌细胞壁-1,3 glucan 含量显著高于静止期和对数生长期念珠菌(P 0.001),Putative
15、 Role of -1,3 Glucans in Candida albicans Biofilm Resistance. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2007, 51(2):510520,beta-glucan在产生物被膜念珠菌的作用,生物被膜念珠菌合成、释放更多-1,3 glucan示意图,A Candida Biofilm-Induced Pathway for Matrix Glucan Delivery: Implications for Drug Resistance. PLoS Pathog 8(8): e1002848,生物被膜
16、念珠菌细胞膜固醇成分改变,生物被膜与浮游白念珠菌麦角固醇水平在6h时相同，生物膜成熟期减少50%，而浮游细胞在612h减少18%，其他固醇水平在两者之间也有明显差异麦角固醇比例改变影响抗真菌药物进入念珠菌通透性，进而防止或阻滞抗真菌药物进入念珠菌细胞壁改变固醇成分比例影响生物被膜内念珠菌对氟康唑耐药性,Mechanism of Fluconazole Resistance in Candida albicans Biofilms: Phase-Specific Role of Efflux Pumps and Membrane Sterols. Infect Immun. 2003 Augus
17、t; 71(8): 43334340.,念珠菌耐抗真菌药物机制,(1) 细胞外基质阻止药物渗透入深部组织；(2) 营养和生长速度限制，敏感性下降；(3) 药物与生物被膜接触，诱导表达耐药基因与浮游念珠菌比较，生物被膜念珠菌对氟康唑耐药性高达1000倍,A sticky situation: untanglingthetranscriptionalnetworkcontrollingbiofilmdevelopmentinCandidaalbicans. Transcription. 2012;3(6):315-22.TRENDS in Microbiology Vol.11 No.1 Janu
18、ary 2003,金刚罩！铁布衫！反导系统！钢筋混凝土构成的社区群体,阻挡药物穿透,The density of the mature biofilm may act as a physical barrierECM is produced to “soak” and deplete antifungal agents.,念珠菌生物被膜影响氟康唑分布念珠菌耐抗真菌药物机制,B 绝大部分氟康唑分布在非白色念珠菌生物被膜、非白色念珠菌细胞壁或细胞浆内极少或无氟康唑分布生物被膜念珠菌细胞壁结合氟康唑是浮游念珠菌的45倍，意味相当一部分氟康唑分布在生物被膜和细胞壁，不能进入细胞浆，增加念珠菌耐药性,R
19、ole of matrix glucan in antifungal resistance of non-albicans candida biofilms. Antimicrob Agents Chemother. 2013 Apr;57(4):1918-20,抗真菌药物对生物被膜念珠菌疗效,两性霉素B对生物被膜念珠菌MIC增加脂质体两性霉素B对生物被膜念珠菌MIC无显著变化氟康唑和伏立康唑对浮游念珠菌MIC低，对生物被膜念珠菌MIC极高米卡芬净和卡泊芬净对浮游和生物被膜念珠菌MIC无显著差异,MICs in Candida biofilms increase 1001000 times c
20、ompared with planktonic cells.,Antifungal Susceptibility of Candida Biofilms: Unique Efficacy of Amphotericin B Lipid Formulations and Echinocandins. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, June 2002, p. 17731780 Vol. 46, No. 6,真菌耐药机制,细胞膜通透性改变，Erg11基因突变和过表达，作用唑类药物的Cdr1, Cdr2 (ABCT)过表达，特异性作用氟康唑的Mdr1 (
21、MF)过表达多烯类耐药少见，可通过ERG3功能缺失，导致麦角固醇合成障碍，不能形成药物-脂质复合体，避免内容物丢失,Clinical, Cellular, and Molecular Factors That Contribute to Antifungal Drug Resistance. CLINICAL MICROBIOLOGY REVIEWS, . 1998, 11(2):382402Fungal Biofilm Resistance. International Journal of Microbiology. 2012, 528521,抗真菌药物药代动力学-药效动力学,Pharma
22、cokineticpharmacodynamic optimization of triazole antifungal therapy. Curr Opin Infect Dis 24 (suppl 2):S14S29Crit Care Med 2013; 41:580637 International Journal of Antimicrobial Agents 39 (2012) 1 10,2003，2008，2012脓毒症指南：初始经验性抗感染治疗包括一种或多种对可能致病菌(细菌，和/或真菌，或病毒)敏感，且以足够药物浓度抵达导致脓毒症的感染部位的药物 (I-B),抗生物被膜活性药物
23、改善患者预后,Risk factors and outcomes of candidemia caused by biofilm-forming isolates in a tertiary care hospital. PLoS One. 2012;7(3):e33705.,2005年-2007年，84例为形成生物被膜念珠菌血症，123例为不能形成生物被膜念珠菌血症两者患者30天生存率不同(p = 0.004) 生物被膜念珠菌血症患者分别接受卡泊芬净和氟康唑治疗，其30天生存率不同(p = 0.05),重症患者侵袭性念珠菌感染危险因素：解剖生理屏障完整性破坏,Revisiting the s
24、ource of candidemia: skin or gut? Clin Infect Dis 2001; 33:195967.,侵袭性念珠菌感染常由肠道念珠菌大量繁殖进入血流所致最易受累：肾、心、脑、肺,急性胰腺炎并腹腔真菌感染齐鲁医院病例,男性患者，68岁2007年7月22日急性胰腺炎。7月31日收住ICU，8月2日剖腹探查，术中见腹腔内大量渗液、肠系膜根部有脓苔、肝肾隐窝处组织炎性坏死8月2日 腹腔引流液 孢子和假菌丝；8月3日 腹水培养 白假丝酵母,高碘酸无色品红(PAS) 法染色显示术中送检网膜组织存在大量真菌菌丝及孢子,重症患者侵袭性念珠菌感染危险因素：解剖生理屏障完整性破坏,
25、据美国CDC统计, ICU医院获得性感染约20%为血流感染(BSI)，87%与中心静脉导管(CVC)有关血管内导管分离的病原体，白色念珠菌占第二位ICU患者最突出特点是其解剖生理屏障完整性破坏, 定植体表皮肤和体腔粘膜表面的条件致病真菌，以及环境中真菌侵入原本无菌深部组织和血液,Nucci M, Anaissie E. Revisiting the source of candidemia: skin or gut? Clin Infect Dis 2001; 33:195967.,股静脉置管,血管内侵袭性操作相关真菌血症,导管感染方式：( 1) 皮肤表面细菌、真菌在穿刺时或之后，通过皮下致导
26、管皮内段至导管尖端定植，随后引起局部或全身感染(2) 另一感染灶微生物血行播散到导管、黏附定植，引起CRBSI(3) 微生物污染导管接头和内腔(手污染)，导致腔内细菌繁殖、感染,世界临床药物, 2011年 , 第07期中国真菌学杂志，2006年，第1卷，第五期Valls J, et al. Infect Dis Clin North Am, 2009, 23 : 557-569,中心静脉导管相关真菌血症与生物膜,(A) 450; (B) 1100; (C) 4500.,由塔状或蘑菇状微菌落组成，其余空间被网状分布的胞外多聚基质所占据,一张牢不可破的网,Assessment of the typ
27、es of catheter infectivity caused by Candida species and their biofilm formation. First study in an intensive care unit in Algeria. Int J Gen Med. 2013; 6: 17.,35,中心静脉导管相关真菌血症与生物膜,24h大鼠颈内静脉置管白色念珠菌生物被膜模型生物被膜内存活念珠菌、菌丝,Development and characterization of an in vivo central venous catheter Candida albic
28、ans biofilm model. Infect Immun. 2004 Oct;72(10):6023-31.,扫描电镜显示中心静脉导管腔内形成念珠菌生物被膜相关感染念珠菌孢子形成假菌丝、菌丝和细胞外基质,(A) 50; (B) 1000,唑类药物作用机制,ckCYP51 活性部位(白色)；氟康唑结合位点(蓝色)；伏立康唑结合位点(黄色). 伏立康唑结合位点比氟康唑多,Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease. MICROBIOLOGY AND MOLECULAR BIOL
29、OGY REVIEWS, June 2011, p. 213267 Vol. 75, No. 2Stress,drugs, andevolution: theroleofcellularsignalinginfungaldrug resistance. Eukaryot Cell. 2008;7(5):747-64.Dodds-Ashley ES, et al. Clin Infect Dis. 2006;43:S28-39.,Nett J et al. Antimicrob. Agents Chemother. 2007;51:510-520,破坏生物被膜有助改善氟康唑疗效,超大剂量氟康唑(
30、为浮游念珠菌MIC 1000 倍)对生物被膜念珠菌感染无效大剂量-1,3 glucanase 能破坏念珠菌生物被膜小剂量-1,3 glucanase 不能破坏念珠菌生物被膜小剂量-1,3 glucanase 联合超大剂量氟康唑，清除念珠菌生物被膜,The Activity of micafungin and voriconazole against Candida albicans Biofilms,Representative scanning electron micrographs of SEVs of Candida albicans. (A) Control at 72 h with
31、 dense biofilm network; (B) markedly reduced number of organisms due to flucytosine at 24 h; (C) limited effect of voriconazole on organism load at 72 h; (D) markedly deformed cells after exposure to micafungin for 48 h.,Activities and Ultrastructural Effects of Antifungal Combinations against Simul
32、ated Candida Endocardial Vegetations. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, July 2008, p. 23672376 Vol. 52, No. 7,伏立康唑与氟康唑交叉耐药性,采用最新K-B法判断标准耐氟康唑念珠菌，对伏立康唑保持高的耐药率伏立康唑 BI,Results from the ARTEMIS DISK Global Antifungal Surveillance Study, 1997 to 2007: a 10.5-year analysis of susceptibilities of Candi
33、da Species to fluconazole and voriconazole as determined by CLSI standardized disk diffusion. J Clin Microbiol. 2010 ;48(4):1366-77.,两性霉素B作用机制,Antifungal Resistance and New Strategies to Control Fungal Infections. International Journal of Microbiology Volume 2012, Article ID 713687, 26 pagesPharmaco
34、kinetics and Pharmacodynamics of Amphotericin B Deoxycholate, Liposomal Amphotericin B, and Amphotericin B Lipid Complex in an In Vitro Model of Invasive Pulmonary Aspergillosis. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY. 2010, 54(8): 34323441Proc Natl Acad Sci U S A. 2011; 108(17): 67336738.,70100 nm i
35、n diameter,千里之堤溃于蚁穴两性霉素B主要在肝、脾、肺、骨髓和肾脏分布两性霉素B脂质体剂型分布在肝、脾、肺、骨髓，较少分布在肾脏,两性霉素B与氟康唑不能抑制生物被膜念珠菌生长,C. krusei ATCC 6258,C. parapsilosis ATCC 22019,C. albicans HK1Sa,(A) Control (B) exposed to 600ug/mlamphotericin B for 4 h(C) exposed to 600ug/ml fluconazole for 4 h,The wrinkled, shrunk, ruptured, and ballo
36、oning effect of the drug on yeast cells,In Vitro Method To Study Antifungal Perfusion in Candida Biofilms. JOURNAL OF CLINICAL MICROBIOLOGY, 2005, 43(2):818825,两性霉素B脂质体抑制生物被膜念珠菌生长,Rabbit Model of Candida albicans Biofilm Infection: Liposomal Amphotericin B Antifungal Lock Therapy. ANTIMICROBIAL AGEN
37、TS AND CHEMOTHERAPY, 2004, 48(5):17271732,7d兔颈静脉生物膜模型,3d兔颈静脉生物膜模型,对照,两性霉素B脂质体1mg/100ul,氟康唑1mg/100ul,念珠菌感染兔CVC3天后，每天导管内局部灌注8h，连续7天氟康唑生物被膜有所减少，但念珠菌感染部位生物被膜形态与对照组相似(念珠菌生长)脂质体两性霉素B几乎完全清除CVC表面生物被膜相关念珠菌，12处残存感染部位缺乏生物被膜(无念珠菌生长)脂质体两性霉素B有效治疗生物被膜念珠菌感染，但机制不明，脂质体无真菌抑制作用,棘白菌素类药物作用机制,Stress,drugs, andevolution: t
38、heroleofcellularsignalinginfungaldrug resistance. Eukaryot Cell. 2008;7(5):747-64.Resistance to echinocandin-class antifungal drugs. Drug Resist Updat. 2007 June ; 10(3): 121130.Stress,drugs, andevolution: theroleofcellularsignalinginfungaldrug resistance. Eukaryot Cell. 2008;7(5):747-64.Resistance
39、to echinocandin-class antifungal drugs. Drug Resist Updat. 2007 June ; 10(3): 121130.Fungal echinocandin resistance. Fungal Genet Biol.2010 ;47(2):117-26. Choi HW et al. Antimicrob Agents Chemother 2007; 51:1520-23,棘白菌素类抗真菌药物作用靶点为真菌细胞壁-1.3-葡聚糖，生物被膜基质中含有-1.3-葡聚糖通过减少、抑制-葡聚糖产生，破坏生物被膜完整性，有利控制念珠菌生物被膜感染,卡
40、泊芬净抑制生物被膜念珠菌存活,In Vitro Activity of Caspofungin against Candida albicans Biofilms. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY. 2002, 46(11):35913596,卡泊芬净治疗组(0.5 ug/ml)生物被膜内念珠菌菌丝少、孢子形态异常未治疗组，存在大量活性代谢念珠菌(从绿色到红色，以红色为主)；卡泊芬净治疗组(0.5 ug/ml) ，为弥漫性绿色，提示存在大量死亡念珠菌,Uppuluri P et al. Antimicrob. Agents Chemother. 20
41、11;55:3591-3593,抗真菌药物抑制生物被膜相关念珠菌播散,超大剂量氟康唑不能抑制生物被膜内白色念珠菌生长高浓度两性霉素B仅仅中等程度抑制生物被膜内白色念珠菌生长卡泊芬净抑制生物被膜内白色念珠菌生长作用最强,抗真菌药物对生物被膜念珠菌疗效,绿色念珠菌细胞壁，红色代表有活性念珠菌。黄色提示念珠菌无活性， A-D依次为对照组、卡泊芬净、脂质体两性霉素B、伏立康唑卡泊芬净治疗组念珠菌细胞壁严重破坏，且无活性；两性霉素B脂质体治疗组念珠菌胞浆内弥漫性黄染，提示念珠菌无活性；伏立康唑组念珠菌亦无活性，但形态破坏较卡泊芬净组轻,Antifungal Susceptibility of Candi
42、da Biofilms: Unique Efficacy of Amphotericin B Lipid Formulations and Echinocandins. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, June 2002, 46(6):17731780,浮游白色念珠菌暴露抗真菌药物24h后形态变化,抗真菌药物对生物被膜念珠菌疗效,A-D依次为对照组、卡泊芬净、脂质体两性霉素B、伏立康唑卡泊芬净治疗组念珠菌细胞壁严重破坏，且无活性两性霉素B脂质体治疗组念珠菌胞浆内弥漫性黄染，提示念珠菌无活性，且念珠菌皱缩尽管伏立康唑组有少量无活性念珠菌，且细胞壁轻度
43、受损，但伏立康唑组念珠菌受影响最小,Antifungal Susceptibility of Candida Biofilms: Unique Efficacy of Amphotericin B Lipid Formulations and Echinocandins. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, June 2002, 46(6):17731780,生物被膜相关白色念珠菌生长48h暴露抗真菌药物48h后形态变化,抗真菌药物对生物被膜念珠菌疗效,评价伏立康唑、泊沙康唑、卡泊芬净、阿尼芬净治疗白色念珠菌、近平滑念珠菌生物被膜感染疗效伏立康唑和泊沙
44、康唑MIC分别为256 and 64 mg/liter卡泊芬净和阿尼芬MIC分别为1 and 2 mg/liter,Differential Activities of Newer Antifungal Agents against Candida albicans and Candida parapsilosis Biofilms. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY. 2008, 51(1)：357360,白色念珠菌,近平滑念珠菌,棘白菌素类药物治疗重症患者念珠菌感染优势,5,(6)-carboxyfluorescein diacetate (CFD
45、A), 羧基荧光素二醋酸酯5(6)-CFDA是膜透性染料，可通过孵化进入细胞。一旦进入细胞后，CFDA被细胞内酯酶水解形成羧基荧光素bis-(1,3-dibutylbarbituric acid) trimethine oxonol (DiBAC), DiBAC4(3)是一种检测细胞膜电位的亲脂性阴离子荧光染料，它本身无荧光，当进人细胞与胞浆内的蛋白质结合后才发出荧光。DiBAC4(3)进入细胞，细胞内荧光强度增加，即膜电位增加表示细胞去极化;反之，细胞内荧光强度降低即膜电位降低表示细胞超极化,耐氟康唑念珠菌对棘白菌素敏感性高,卡泊芬净对耐氟康唑念珠菌，仍保持杀菌活性与唑类无交叉耐药,Acti
46、vities of micafungin against 315 invasive clinical isolates of fluconazole-resistant Candida spp. J Clin Microbiol. 2006 Feb;44(2):324-6.,1.Expert Opin. Pharmacother. Fungicidal versus Fungistatic: whats in a word? 2008, 9(6): 927-935.2.Eur J Clin Microbiol Infect Dis. 2004; 23: 805812.The Antifunga
47、l Echinocandin Caspofungin Acetate Kills Growing Cells of Aspergillus fumigatus In Vitro. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Sept. 2002, p. 30013012 Vol. 46, No. 9Current pharmacological concepts for wise use of echinocandins in the treatment of candida infections in septic critically ill patien
48、ts. Expert Rev. Anti infect ther. 2013, 11(3):989-9971.Expert Opin. Pharmacother. Fungicidal versus Fungistatic: whats in a word? 2008, 9(6): 927-935.2.Eur J Clin Microbiol Infect Dis. 2004; 23: 805812.,棘白菌素类药物治疗重症患者念珠菌感染优势杀菌剂vs抑菌剂,治疗侵袭性念珠菌感染，初始治疗选用杀菌作用的抗真菌药物与氟康唑比较，棘白菌素类药物治疗优势Rapid fungicidal activi
49、tyAnti-biofilm activityUnchanged activity against Candida spp. Showing decreased susceptibility to fluconazole and to other azolesAnti-cytokine and anti-chemokine activity,2009指南推荐中心静脉导管相关血流感染处理原则,对于经验性治疗疑似导管相关念珠菌血症，选用棘白菌素类药物，或者，在部分患者，选用氟康唑 (A-II)For empirical treatment of suspected catheter-related
50、 candidemia, use an echinocandin or, in selected patients, fluconazole. A-II氟康唑用于近3个月内唑类无药物暴露史，且克柔念珠菌或光滑念珠菌感染风险非常低 (A-III)Fluconazole can be used for patients without azole exposure in the previous 3 months and in health care settings where the risk of Candida krusei or Candida glabrata infection is
