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1、革兰阳性球菌感染与达托霉素的临床实践,上海交通大学医学院附属瑞金医院院感科 临床微生物科倪语星,1,医疗运用,一、达托霉素（Daptomycin）的杀菌特性,2,医疗运用,3,环脂肽类抗生素,Cyclic lipopeptide Streptomyces roseosporus 的天然發酵物分子式 C72H101N17O26分子量 1620.67無菌、無熱原淡黃色淺棕色塊狀凍晶賦形劑為NaOH (調整pH值),Clinical Infectious Diseases2004;38:994-1000,3,医疗运用,4,Anti MRSA 比较 分类,4,医疗运用,Daptomycin,达托霉素作
2、用机制为插入革兰阳性菌细胞膜内，由于细菌膜结构的不同，对革兰阴性菌无作用。达托霉素具有杀菌性，相比其他抗菌药物，达托霉素对于静止期细菌的杀菌率有显著性升高。达托霉素对附着于医疗装置表面及生物被膜的细菌有显著有效性。,Pharmacology 2008;81:7991.,5,医疗运用,达托霉素的快速杀菌活性- in vitro,对于金葡菌，2-4倍MIC的达托霉素达到杀菌作用（降低3log)只需要1小时左右；对于VRE，则需要2-6小时,Clinical Microbiology Newsletter:Vol. 24, No. 5; March 1,2002,6,医疗运用,7,0,2,4,6,8
3、,10,12,14,0,12,24,36,48,60,72,Time (hours),CFU/g (log10),对静止生长期金黄色葡萄球菌有快速杀菌活性,Pharmacodynamic model utilizing simulated endocardial vegetations (Tedesco and Rybak, ICAAC 2003),对照,达托霉素,利奈唑胺,奈夫西林,万古霉素,7,医疗运用,Rapid Bactericidal Activity of Daptomycin Against MRSA Peritonitis in Healthy Mice,Mortin LI,
4、LI T, Van Praagh ADG, Zhang S, Zhang X-X, Alder JD. Rapid bactericidal activity of daptomycin against methicillin-resistant and methicillin-susceptible Staphylococcus aureus peritonitis in mice as measured with bioluminescent bacteria. Antimicrob Agents Chemother. 2007;51:1787-1794.,8,医疗运用,Rapid Bac
5、tericidal Activity of Daptomycin Against MRSA Peritonitis in Neutropenic Mice,Mortin LI, LI T, Van Praagh ADG, Zhang S, Zhang X-X, Alder JD. Rapid bactericidal activity of daptomycin against methicillin-resistant and methicillin-susceptible Staphylococcus aureus peritonitis in mice as measured with
6、bioluminescent bacteria. Antimicrob Agents Chemother. 2007;51:1787-1794.,9,医疗运用,体外超微结构电镜显示:达托霉素不会使MSSA/MRSA的死亡后崩解,A) 没有抗生素,(B) 达托霉素 8 mg/L，1 h,C) 达托霉素 8 mg/L，24 h,.Wale LJ, et al., J Med Microbiol. 1989;30(1):45-49.,10,A) 没有抗生素,(B) 达托霉素 8 mg/L，4 h,C) 达托霉素 8 mg/L，24 h,MSSA,MRSA,10,医疗运用,Biofilms 细菌生物膜
7、常见于植入导管，假体等的表面,ASM Microbe Libraryhttp:/www.microbe/library.org,11,医疗运用,达托霉素对于形成生物被膜的导管葡萄球菌感染具有很强的的穿透力,ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 2007, p. 16561660,12,医疗运用,达托霉素的杀菌速度很快,Raad, et al. Antimicrobial Agents and Chemotherapy, 2007, 51:16561660,13,医疗运用,二、指南推荐GUIDELINES,14,医疗运用,美国IDSA MRSA 感
8、染治疗指南,Liu et al. Clin Infect Dis 2011 Jan 4,15,医疗运用,关于达托霉素的推荐要点,达托霉素作为MRSA血流感染和自身瓣膜感染性心内膜炎的治疗方案, 证据等级及推荐度( AI)高于万古霉素( AII) 达托霉素在成人复杂性SSTI治疗推荐中与万古霉素、利奈唑胺等药物为同等级( AI)骨髓炎和化脓性关节炎治疗中与万古霉素、利奈唑胺等药物同等级( BII),16,医疗运用,IDSA MRSA 指南: 患有菌血症或自体瓣膜感染性心内膜炎的成人1,推荐的治疗持续时间非复杂性菌血症 至少 2 周复杂性菌血症 4-6 周自体瓣膜感染性心内膜炎 6 周,*推荐度和
9、证据等级分类,1. Liu C, Bayer A, Cosgrove SE et al. Clinical practice guidelines by the Infectious Diseases Society of America for the 药剂 of methicillin-resistant Staphylococcus aureus infections in 成人s and children. Clin Infect Dis. 2011 Jan 4 Epub ahead of print,万古霉素是此类治疗的主流治疗药物达托霉素是万古霉素的替代治疗药物,17,医疗运用,三
10、、临床实践 REVIEWS,18,医疗运用,（一）金葡菌感染经验性用药,19,- do not use + use only as alternative + good drug for this indication + very good drug for this indication,Minerva Anestesiol 2011；77：821-827,19,医疗运用,（二）自体瓣膜心内膜炎的治疗,Donald P. Levine1，Kenneth C. Lamp DAPTOMYCIN FOR NATIVE VALVE ENDOCARDITIS: EXPERIENCE FROM A R
11、EGISTRY 10th International Symposium on Modern Concepts in Endocarditis and Cardiovascular Infections Naples, Italy, April 26-28, 2009,20,医疗运用,结果疗效,不同病原菌感染的治疗成功率相似,自体瓣膜心内膜炎的达托霉素治疗成功率为84%,21,医疗运用,（三）VANCOMYCIN MIC 1,22,医疗运用,Evaluation of a Clinical Pathway for the Treatment of Methicillin-Resistant S
12、taphylococcus aureus Bacteremia (MRSAB) with an MIC of 1 mg/L to Vancomycin,*Ravina Kullar1, Susan L. Davis1, Jason M. Pogue2, Jing J. Zhao2; Donald P. Levine2,3, Keith K. Kaye2,3; Michael J. Rybak1,2,3,PHARMACOTHERAPY Volume 33, Number 1, 2013,23,医疗运用,p0.001,Clinical Outcomes,24,医疗运用,（四）肿瘤及粒细胞缺乏患者,
13、25,医疗运用,达托霉素在血液肿瘤患者中导管相关血流感染的疗效,26,医疗运用,P=0.04,P 0.01,P=0.003,A.-M. Chaftari et al. / International Journal of Antimicrobial Agents 36 (2010) 182186,达托霉素48小时症状缓解比例显著高于万古霉素,患者百分比,症状缓解时间（天）,27,医疗运用,达托霉素48小时症状缓解，细菌学清除以及总体临床反应与万古霉素相比有统计学差异,Outcome of patients in the two study groups :daptomycin versus v
14、ancomycin,28,医疗运用,达托霉素在肿瘤合并中性粒细胞减少患者的应用,Kenneth VI Rolston, Scott A McConnell, Kenneth C Lamp DAPTOMYCIN USE IN NEUTROPENIC PATIENTS WITH DOCUMENTED GRAM-POSITIVE INFECTIONS 50th Interscience Conference on Antimicrobial Agents and Chemotherapy September 12 15, 2010, Boston, MA,29,医疗运用,P=0.13,Rolston
15、 KV et al.: Daptomycin use in patients with cancer and neutropenia: data from a retrospective registry. Clin Adv Hematol Oncol 2010;8(4):249-256, 290,Clinical outcomes by degree of neutropenia (neutrophils/mm3) for patients with cancer and neutropenia who were treated with daptomycin,Daptomycin Use
16、in Patients With Cancer and Neutropenia:Data From a Retrospective Registry,The efficacy of datomycin is irrelevant with the degree of neutropenia,30,医疗运用,P=0.20,Rolston KV et al.: Daptomycin use in patients with cancer and neutropenia: data from a retrospective registry. Clin Adv Hematol Oncol 2010;
17、8(4):249-256, 290,Clinical outcomes by primary pathogen for patients with cancer and neutropenia who were treated with daptomycin,Daptomycin Use in Patients With Cancer and Neutropenia:Data From a Retrospective Registry,The efficacy of datomycin is irrelevant with primary pathogens,31,医疗运用,Key points,达托霉素为环脂肽类抗菌药物，作用于革兰阳性菌细胞膜，发挥快速杀菌作用，对静止期细菌有杀菌作用。对形成生物被膜的细菌及附着于医疗装置表面的细菌有效。在BSI及IE中，用达托霉素治疗MRSA感染的推荐级别等同或优于万古霉素。对其他MRSA引起的感染，推荐级别与万古霉素相同。在CR-BSI，肿瘤，粒细胞缺乏合并革兰阳性球菌重症感染的治疗中有优势。 是万古霉素MIC 1 mg/L，耐药革兰阳性球菌（VISA，VRSA，VRE）全身感染治疗的首选。,32,医疗运用,Thank You!,33,医疗运用,