1、ICU阳性菌感染规范化治疗,兰州军区兰州总医院 刘 东,VAN-3-20140605-372,主要内容,ICU感染概述,1. Vincent JL, Rello J, Marshall J, et al. International Study of the Prevalence and Outcomes of Infection in Intensive Care Units. JAMA 2009; 302(21):2323-2329.2. Vincent JL, Bihari DJ, Suter PM, et al. The prevalence of nosocomial infecti
2、on in intensive care units in Europe. Results of the European Prevalence of Infection in Intensive Care (EPIC) Study. EPIC International Advisory Committee. JAMA 1995; 274(8):639-644.,重症感染抗生素治疗的三大原则1,1. This official statement of the American Thoracic Society and the Infectious Diseases Society of A
3、merica was approved by the ATS Board of Directors, December 2004 and the IDSA Guideline Committee Guidelines for the Management of Adults with Hospital-acquired, Ventilator-associated, and Healthcare-associated Pneumonia Am J Respir Crit Care Med 2005;171:388-416.2. Dellinger RP, Levy MM, Rhodes A,
4、et al. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock, 2012. Intensive Care Med 2013; 39:165228,主要内容,ICU感染的分布,Vincent JL, Rello J, Marshall J, et al. International Study of the Prevalence and Outcomes of Infection in Intensive Care Units. JAMA 20
5、09; 302(21):2323-2329.,肺部感染、腹部感染和血流感染位居ICU感染前三位,金黄色葡萄球菌是ICU感染中最为常见的菌株,Vincent JL, Rello J, Marshall J, et al. International Study of the Prevalence and Outcomes of Infection in Intensive Care Units. JAMA 2009; 302(21):2323-2329.,ICU较普通病房金葡菌感染中MRSA的检出率增加,于沁, 杨莉, 丁玲等. 重症监护病房与普通病房细菌分布及耐药性比较. 内科理论与实践 20
6、08; 3(5):347-350.,MRSA检出率 (%),MRSA所致ICU病死率显著高于MSSA,Hanberger H, Walther S, Leone M, et al. Increased mortality associated with methicillin-resistant Staphylococcus aureus (MRSA) infectionin the intensive care unit: results from the EPIC II study. Int J Antimicrob Agents 2011; 38(4):331-335.,革兰阳性菌国内监
7、测结果与全球一致，金葡菌持续增高,检出菌株数,1.Jones Rn,et al. Diagn Microbiol Infect Dis.2009 Jun;64(2):191-201. 2. Jones RN,et al. Diagn Microbiol Infect Dis.2009 Dec;65(4):404-13. 3. Biedenbach DJ,et al. Diagn Microbiol Infect Dis.2010 Dec;68(4):459-67. 4. Flamm RK,et al. J Chemother.2012 Dec;24(6):328-37. 5. Flamm RK
8、,et al. Diagn Microbiol Infect Dis.2013 Jun;76(2):206-13. 6. Mendes RE,et al. J Antimicrob Chemother.2014 Jun;69(6):1582-8.7.汪复 等.中国感染与化疗杂志.2008;8(5):325-333. 8.汪复 等.中国感染与化疗杂志.2009;9(5):321-329. 9.汪复 等.中国感染与化疗杂志.2010;10(5):325-334.10.朱德妹 等.中国感染与化疗杂志.2011;11(5):321-329. 11.胡付品 等.中国感染与化疗杂志.2012;12(5):
9、321-329. 12.汪复 等.中国感染与化疗杂志.2013;13(5):321-330.,检出率%,全球ZAAPS监测结果：革兰阳性菌检出逐年增高,国内CHINET监测表现出相似结果，以金葡菌为首,发布2013年细菌耐药报告美国疾病预防控制中心CDC,首次根据威胁程度将耐药细菌分为三级,MRSA感染重要的高危因素,MRSA感染的8大高危因素1,2,1. 邹红波, 江凌晓.耐甲氧西林金黄色葡萄球菌院内感染研究进展. 实用医学杂志 2008;24(8):1280-1282.2. Pea F, Viale P. The antimicrobial therapy puzzle: could ph
10、amacokinetic-phamacodynamic relationships be helpful in addressing the issue of appropriate pneumonia treatment in critically III patients? Clin Infect Dis 2006;42(12):1764-1771.,主要内容,全球众多医师协会制定MRSA感染的治疗指南,2011 IDSAMRSA肺炎感染的治疗推荐,Liu C, Bayer A, Cosgrove SE, et al. Clinical Practice Guidelines by the
11、 Infectious Diseases Society of America for theTreatment of Methicillin-Resistant Staphylococcus Aureus Infections in Adults and Children. CID 2011:52.,2011 IDSAMRSA菌血症与感染性心内膜炎中的治疗推荐,Liu C, Bayer A, Cosgrove SE, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America for th
12、eTreatment of Methicillin-Resistant Staphylococcus Aureus Infections in Adults and Children. CID 2011:52.,主要内容,ZEPHyR研究引发了广泛的学术关注,1. Taccone FS, et al. Clin Infect Dis. 2012;55(1):161-163. 2. Lahey T. Clin Infect Dis. 2012;55(1):159-160. 3. Wolff M, Mourvillier B. Clin Infect Dis. 2012;55(1):160-161
13、. 4. Masuta K, et al. Clin Infect Dis. 2012;55(1):161. 5. Grayson ML, et al. Clin Infect Dis. 2012;55(1):165. 6. Richard GW, et al. Clin Infect Dis.2012;55(1):163-165. 7. Brian Blackburn. Infectious Disease Alert. 2012;31(9):100-102. 8. Alaniz C, Pogue JM. Ann Pharmacother. 2012;46(10):1432-1435.,利奈
14、唑胺治疗MRSA肺炎是否优于万古霉素？,9项研究共4026例患者的荟萃分析利奈唑胺和万古霉素死亡率差异为0.01% (P=0.992)MRSA人群临床反应率差异为7.7% (P=0.076)MRSA清除率差异为6.4% (P=0.230),Kalil AC, Klompas M, Haynatzki G, et al. Treatment of hospital-acquired pneumonia with linezolid or vancomycin: a systematic review and meta-analysis. BMJ Open 2013; 3(10):e003912.
15、,利奈唑胺或万古霉素治疗阳性菌HAP：系统回顾和荟萃分析,Kalil AC, Klompas M, Haynatzki G, et al. Treatment of hospital-acquired pneumonia with linezolid or vancomycin: a systematic review and meta-analysis. BMJ Open 2013; 3(10):e003912.,临床反应率,随机双盲研究(RD 5.0%)和随机开放标签研究(RD -1.4%)之间无统计学差异 符合方案的MRSA人群(N=507)中绝对RD为7.7%(P=0.076),医院获
16、得性肺炎：利奈唑胺 vs 万古霉素：临床反应率*,9项研究N=4026,-0.75,-0.38,0.00,0.38,0.75,49/193,61/302,100/587,23/301,2/71,235/1454,33/220,3/101,7/51,6/74,49/445,284/1900,71/107,114/168,95/165,19/23,19/26,318/489,12/23,9/10,11/51,15/23,47/107,365/596,0.790,0.566,0.041,0.731,0.131,0.114,0.907,0.409,0.881,0.406,0.820,0.192,0.1
17、13,0.130,0.216,0.191,0.426,0.112,0.263,0.137,0.182,0.423,0.108,0.092,-0.149,-0.071,0.005,-0.272,-0.055,-0.012,-0.297,-0.337,-0.212,-0.171,-0.136,-0.019,-0.018,0.029,0.110,-0.041,0.185,0.050,-0.017,-0.100,-0.015,0.126,-0.014,0.037,*临床可评价/符合方案人群. Z=1.303;P=0.132;异质性:Q=6.458;P=0.596;I2=0%,有利于万古霉素 有利于利奈
18、唑胺,Kalil AC, Klompas M, Haynatzki G, et al. Treatment of hospital-acquired pneumonia with linezolid or vancomycin: a systematic review and meta-analysis. BMJ Open 2013; 3(10):e003912.,MRSA清除率,微生物学可评价且符合方案的人群(N=416)中，利奈唑胺和万古霉素的MRSA清除率绝对RD为6.4% (P=0.230)随机双盲研究(RD 8.4%)和随机开放标签研究(RD 3.0%)之间无统计学差异,医院获得性肺
19、炎：利奈唑胺 vs 万古霉素：MRSA清除率*,9项研究N=4026,7/9,10/23,54/135,11/21,26/82,12/16,7/19,9/19,28/54,82/189,15/23,12/19,76/157,14/18,35/97,9/12,13/35,13/23,35/70,111/227,0.461,0.194,0.213,0.083,0.537,1.000,0.983,0.553,0.727,0.230,0.209,0.494,0.216,0.541,0.183,0.324,0.273,0.394,0.201,0.169,-0.460,-0.100,-0.048,-0.0
20、33,-0.095,-0.324,-0.267,-0.211,-0.140,-0.041,-0.126,0.197,0.084,0.254,0.044,0.000,0.003,0.092,0.030,0.064,-0.75,-0.38,0.00,0.38,0.75,*MRSA微生物学可评价/符合方案人群. Z=1.958;P=0.050;异质性:Q=32.45;P=0.001;I2=78%,有利于万古霉素 有利于利奈唑胺,死亡率,Kalil AC, Klompas M, Haynatzki G, et al. Treatment of hospital-acquired pneumonia w
21、ith linezolid or vancomycin: a systematic review and meta-analysis. BMJ Open 2013; 3(10):e003912.,ITT人群(N=4026)28天全因死亡率绝对风险差异(RD)为0.01% (P=0.992)随机双盲研究(RD -1.3%)和随机开放标签研究(RD 1.9%)之间无统计学差异,医院获得性肺炎：利奈唑胺 vs 万古霉素：死亡率*,-0.50,-1.25,0.00,0.25,0.50,49/193,61/302,100/587,23/301,2/71,235/1454,33/220,3/101,7/5
22、1,6/74,49/445,284/1900,36/203,64/321,94/597,17/304,5/71,216/1496,44/240,13/215,14/100,4/75,75/630,291/2126,0.063,0.935,0.549,0.310,0.243,0.342,0.337,0.189,0.963,0.498,0.253,0.992,0.004,0.060,0.029,0.019,0.113,0.014,0.101,0.077,0.119,0.053,0.052,0.021,-0.157,-0.066,-0.055,-0.060,-0.029,-0.040,-0.035,
23、-0.015,-0.114,-0.108,-0.014,-0.021,-0.077,-0.003,-0.013,-0.020,0.042,-0.013,0.033,0.031,0.033,-0.028,0.019,-0.000,有利于利奈唑胺 有利于万古霉素,*意向治疗人群. Z=0,010;P=0.092;异质性:Q=9.251;P=0.322;I2=13.5%,9项研究N=4026,肾衰竭发生率,ITT人群(N=3421)利奈唑胺和万古霉素肾衰竭的绝对RD为-0.7% (P=0.249)对肾衰竭的不同定义可能导致异质性较大,Kalil AC, Klompas M, Haynatzki G,
24、 et al. Treatment of hospital-acquired pneumonia with linezolid or vancomycin: a systematic review and meta-analysis. BMJ Open 2013; 3(10):e003912.,其他安全性分析,*定义之间的差异可能导致异质性较大；较短的疗程可能预防血小板减少症的发生# 利耐唑胺导致胃肠道不良反应较多,9项研究N=4026,Kalil AC, Klompas M, Haynatzki G, et al. Treatment of hospital-acquired pneumon
25、ia with linezolid or vancomycin: a systematic review and meta-analysis. BMJ Open 2013; 3(10):e003912.,万古霉素 vs. 利奈唑胺治疗医院获得性肺炎的系统回顾和荟萃分析2013,Kalil AC, Klompas M, Haynatzki G, et al. Treatment of hospital-acquired pneumonia with linezolid or vancomycin: a systematic review and meta-analysis. BMJ Open 2
26、013; 3(10):e003912.,本荟萃分析与既往多项荟萃分析得到一致的结果,VAN-3-20140505-265,总结与结论：在死亡率和临床反应率方面，万古霉素和利奈唑胺的有效性差异接近于零在不同患者人群、设计和质量的研究之间具有一致性检测出死亡率和临床反应率之间差异的统计学效能将近100% 万古霉素和利奈唑胺治疗HAP/VAP的有效性无统计学差异,Kalil AC, Klompas M, Haynatzki G, et al. Treatment of hospital-acquired pneumonia with linezolid or vancomycin: a system
27、atic review and meta-analysis. BMJ Open 2013; 3(10):e003912.,万古霉素 vs. 利奈唑胺治疗医院获得性肺炎的系统回顾和荟萃分析2013,在MRSA NP诊疗流程中，将万古霉素可能治疗失败的因素作为药物选择的分界点,年龄65岁；肾功能不全或正在使用肾毒性药物；万古霉素MIC值1.5mg/L或VISA/hVISA（万古霉素中介金黄色葡萄球菌异质性金黄色葡萄球菌）病例是万古霉素治疗失败或无法耐受万古霉素治疗的高危因素，此时应选用利奈唑胺作为MRSA肺炎治疗的一线药物。,Consensus statement on MRSA NP in As
28、ia. Clin Respir J 2014; : .,Antibiotic treatment algorithm for MRSA NP,稳可信说明书用法用量,肾功能正常患者：成人：2g / 天，500mg q6h 或 1g q12h，可根据年龄、体重、症状适量增减儿童：40mg / kg / 天，分2-4次静滴新生儿：10 15mg / kg / 次 出生1周内，q12h给药 出生1周到1月，q8h给药老年人：500 mg q12h 或 1g qd 给药 肾功能受损患者：每天剂量应适当减少 (参照稳可信产品说明书),万古霉素说明书,万古霉素在肾功能减退者中的清除,万古霉素体内基本不代谢，
29、给药剂量的90%以原型经肾脏清除,研究证实，特殊人群中应用万古霉素时，需调整剂量方案,肾功能损害患者的给药稳可信产品说明书指出，肾功能损害患者同健康人相比，血中药物浓度的半衰期延长有必要对其用药量加以修正，从下图根据肌酐清除率可计算出给药量的修正值,摘自万古霉素说明书,肌酐值以mol/L表示时：K=0.814肌酐值以mg/dL表示：K=72本公式应用于女性值，求得值0.85首次负荷剂量：15mg/kg,说明书推荐调整法：肾功能减退时万古霉素剂量调整方法,1.中华人民共和国卫生部医政司 国家抗微生物治疗指南人民卫生出版社 2012年12月第1版 :2212. Rybak MJ et al. Va
30、ncomycin therapeutic guidelines: a summary of consensus recommendations from the infectious diseases Society ofAmerica, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists. Clin Infect Dis. 2009 Aug 1;49(3):325-7,注：肾功能正常成人患者首剂量基于实际体重，包括肥胖患者，之后的剂量根据测定
31、的血清谷浓度进行调整剂量大于1g时，输注时间大于1.5-2h,国家抗微生物治疗指南推荐调整法：肾功能减退时万古霉素剂量及给药间隔时间,万古霉素的剂量应用原则,万古霉素临床应用剂量专家组. 万古霉素临床应用剂量中国专家共识. 中华传染病杂志 2012; 30(11):641-648.,万古霉素在儿童与老年人中的维持剂量调整,万古霉素临床应用剂量专家组. 万古霉素临床应用剂量中国专家共识. 中华传染病杂志 2012; 30(11):641-648.,IDSA、ASHP、SIDP联合推出的治疗监测实践指南万古霉素对成人MRSA感染的治疗推荐,Rybak M, Lomaestro B, Rotscha
32、fer JC, et al. Vancomycin therapeutic guidelines: a summary of consensus recommendations fromthe infectious diseases Society of America, the American Society of Health-System Pharmacists, and the Society of InfectiousDiseases Pharmacists. Clin Infect Dis 2009; 49(3):325-327.,Review of continuous-inf
33、usion vancomycin,OBJECTIVE: To evaluate the efficacy and safety of administering vancomycin as a continuous infusion.DATA SOURCES: Literature was accessed through MEDLINE (1977-September 2012), Embase (1977-September 2012), and Google Scholar, using the terms vancomycin, continuous, discontinuous, i
34、nfusion, pharmacokinetics, pharmacodynamics, and nephrotoxicity. In addition, reference citations from publications identified were reviewed.Fourteen clinical trials were reviewed (2 prospective, 1 meta-analysis, 11 retrospective).Continuous-infusion therapy did not significantly improve the efficac
35、y of vancomycin in the treatment of invasive MRSA infections. Conflicting results exist regarding the safety profile of continuous-infusion compared with intermittent-infusion vancomycin. The only published prospective randomized clinical trial comparing continuous infusion with intermittent therapy
36、 found no significant difference in the rates of nephrotoxicity. The data from retrospective studies are heterogeneous and show variable rates of nephrotoxicity.,36,Ann Pharmacother. 2013 Feb;47(2):219-27,CONCLUSIONS: Currently available evidence is insufficient to conclude whether an improvement in
37、 vancomycin efficacy exists when it is administered as a continuous infusion. The risk of nephrotoxicity associated with continuous-infusion vancomycin requires further investigation in prospective randomized trials.,万古霉素的MIC与临床疗效,若MIC2g/ml，应根据临床实际效果来使用，不依赖于MIC的值。MIC大于2g/ml，需使用替代万古霉素的其他药物进行治疗,中国 200
38、5-2010年 GPRS监测项目金葡菌对万古霉素MIC值稳定,Zhao C, Sun H, Wang H, et al. Antimicrobial resistance trends among 5608 clinical Gram-positive isolates in China: results from the Gram-Positive Cocci Resistance Surveillance program (2005-2010). Diagn Microbiol Infect Dis 2012; 73(2):174-81.,2005-2010年在中国为期4年的GPRS细菌耐
39、药监测数据结果显示：绝大多数菌株的MIC值集中在0.5g/ml和1g/ml；2008年分布在1g/ml的菌株为45%，较2007年的80%有所减少，说明万古霉素MIC值持续稳定。,推荐进行万古霉素谷浓度监测的人群,IDSA和美国医院药师学会(ASHP)推荐应用大剂量万古霉素并且推荐疗程较长的患者肾功能不稳定(如明显恶化或明显改善)的患者联合使用其他耳、肾毒性药物的患者,万古霉素临床应用剂量专家组. 万古霉素临床应用剂量中国专家共识. 中华传染病杂志 2012; 30(11):641-648.,IDSA、ASHP、SIDP联合推出的治疗监测实践指南关于万古霉素血药浓度的推荐,注：VISA van
40、comycinintermediately susceptible S. aureus 万古霉素中介的金黄色葡萄球菌Rybak M, Lomaestro B, Rotschafer JC, et al. Vancomycin therapeutic guidelines: a summary of consensus recommendations fromthe infectious diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infect
41、iousDiseases Pharmacists. Clin Infect Dis 2009; 49(3):325-327.,万古霉素血药浓度监测要点,Rybak MJ, Lomaestro BM, Rotschafer JC, et al. Vancomycin therapeutic guidelines: a summary of consensus recommendations from the infectious diseases Society of America, the American Society of Health-System Pharmacists, and
42、the Society of Infectious Diseases Pharmacists. Clin Infect Dis 2009; 49(3):325-327.,万古霉素血药浓度监测时机,现有证据不支持通过监测万古霉素峰浓度来降低肾毒性发生率,中华医学会甲氧西林耐药金黄色葡萄球菌感染治疗策略专家组. 中华医学会感染与抗微生物治疗策略高峰论坛：甲氧西林耐药金黄色葡萄球菌感染的治疗策略专家共识. 中国感染与化疗杂志 2011; 11(6):401-416.,总 结,ICU中肺部感染最为常见，肺部感染和血流感染预后不佳万古霉素被多个指南推荐用于MRSA感染万古霉素和利奈唑胺治疗MRSA所致H
43、AP/VAP的临床转归相当 合理应用万古霉素可达到临床最大效用,万古霉素安全性,休克、过敏样症状（少于0.1%）；急性肾功能不全（0.5%）；多种血细胞减少（0.1%）；皮肤粘膜综合征（Stevens-Johnson综合征）；第八脑神经损伤（少于0.1%）伪膜性大肠炎（频率不明）肝功能损害、黄疸（频率不明）,摘自万古霉素说明书,稳可信简短处方说明,【通用名称】：注射用盐酸万古霉素【商品名称】：稳可信 Vancocin CP【适应症】 ：本品适用于耐甲氧西林金黄色葡萄球菌(MRSA)及其他细菌所致的感染： 败血症、感染性心内膜炎、骨髓炎、关节炎、灼伤、手术创伤等浅表性继发感染、 肺炎、肺脓肿、脓
44、胸、腹膜炎、脑膜炎。【用法用量】：成人：2g / 天，500mg q6h 或 1g q12h【不良反应】：休克，过敏样症状，急性肾功能不全，多种血细胞减少，皮肤粘膜综合征，第八脑神经损伤等【禁忌】：对本品有既往过敏者禁用 下列患者原则不予给药，若有特殊需要需慎重：对本品、替考拉宁及糖肽类抗生素、 氨基糖苷类抗生素有既往过敏史者；因糖肽类抗生素、替考拉宁及氨基糖苷类抗生素 所致耳聋及其他耳聋患者（可使耳聋加重）。【注意事项】：详见药品说明书,总结,万古霉素获得众多指南一致推荐，是治疗MRSA感染的一线用药。根据疾病及万古霉素的PK/PD特性给以患者个性化治疗，可以获得疗效与安全性的双赢。MRSA对万古霉素MIC值稳定。综合考虑患者的临床反应，谷浓度，药敏试验，感染灶的处理等。,Questions?,Thank You !,
