CVC相关性念珠菌感染与治疗策略

CVC相关性念珠菌感染与治 疗策略 1 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 2 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;2011:150642 Candida albicans-Endothelial Cell Interactions: a Key Step in the Pathogenesis of Systemic Candidiasis. INFECTION AND IMMUNITY, 2008, 76(10):43704377 Biofilm formation by the fungal pathogen Candida albicans : development, architecture, and drug resistance J. J Bacteriol, 2001, 183(18):5385 Candida albicans morphogenesis and host defence: discriminating invasion from 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 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 3 真菌生物被膜 生物被膜是指细 (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 4 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 Observations. ISRN Dermatol. 2011;2011:150642 Candida 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 5 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 (0.6 to 9%) .Putative Role of -1,3 Glucans in Candida albicans Biofilm Resistance. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2007, 51(2):510520 Nat Rev Microbiol. ; 10(2): 112122 6 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 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 7 生物材料影响念珠菌生物被膜构成 Biofilm Formation by the Fungal Pathogen Candida albicans: 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 8 念珠菌生物被膜模型 Fungal Biofilms and Drug Resistance. Emerging Infectious Diseases /eid Vol. 10, No. 1, January 2004 Fungal 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 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 microscopy 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 9 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 (p 0.05) 非白念容易形成复杂、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. 10 产生物被膜念珠菌的超微结构 beta-1,3 glucan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 planktonic cells In 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 11 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 256 and 64 mg/liter 卡泊芬净和阿尼芬 MIC分别为 10% 或当地白念珠菌对氟康唑耐药率高，强烈 建议采用以两性霉素 B或棘白菌素类药物为基础的治疗 An Official American Thoracic Society Statement: Treatment of Fungal Infections in Adult Pulmonary and Critical Care Patients. Am J Respir Crit Care Med. 2011, 183: 96128 45 2012 ESCMID非粒缺成人患者 侵袭性念珠菌感染指南 血培养酵母菌阳性 (AII)或 经验 治 疗 (CIIu) 开始抗真菌 治 疗 Strongly recommended: 棘白菌素 (A-I) Moderately recommended: L-AMB or 伏立康 唑 (B-I) Marginally recommended: 氟康 唑 or ABLC (C-I) recommendation against use(D): AMB 伊曲康 唑 泊沙康 唑 联 合治 疗 Clin Microbiol Infect 2012; 18 (Suppl. 7): 18 Clin Microbiol Infect 2012; 18 (Suppl. 7): 918 Clin Microbiol Infect 2012; 18 (Suppl. 7): 1937 u-uncontrolled trials 2009 IDSA 2012 ESCMID 氟康 唑 A-I less critically ill and who have no recent azole exposure A-III C-I 棘白菌素 类药 物 A-I moderately severe to severe illness DOI: 10.1111/1469-0691.12039 r: 随机对照研究的 Meta分析或系统回顾 48 棘白菌素类药物局部封闭不能完全抑制 生物被膜念珠菌感染 Candida biofilms aged 12 h (young biofilm) and 5 days (mature biofilm) Possible role of azole and echinocandin lock solutions in the control of Candida biofilms associated with silicone. International Journal of Antimicrobial Agents 37 (2011) 380384 49 2009指南推荐中心静脉导管相关 血流感染处理原则 念珠菌和金葡菌导致 CRBSI，推荐拔出导管，而 不是保留导管和导管局部抗微生物药物治疗 (A-II) Catheter removal is recommended for CRBSI due to S. aureus and Candida species, instead of treatment with antibiotic lock and catheter retention, unless there are unusual extenuating circumstan