icu陽性菌感染規(guī)范化治療

1、ICU陽性菌感染規(guī)范化治療,蘭州軍區(qū)蘭州總醫(yī)院 劉 東,VAN-3-20140605-372,主要內(nèi)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-

2、2329.2. Vincent JL, Bihari DJ, Suter PM, et al. The prevalence of nosocomial infection in intensive care units in Europe. Results of the European Prevalence of Infection in Intensive Care (EPIC) Study. EPIC Internationa

3、l Advisory Committee. JAMA 1995; 274(8):639-644.,重癥感染抗生素治療的三大原則1,1. This official statement of the American Thoracic Society and the Infectious Diseases Society of America was approved by the ATS Board of Directors,

4、 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.

5、2. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock, 2012. Intensive Care Med 2013; 39:165–228,主要內(nèi)容,,ICU感染的分布,Vincent JL, Re

6、llo J, Marshall J, et al. International Study of the Prevalence and Outcomes of Infection in Intensive Care Units. JAMA 2009; 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,金黃色葡萄球菌是ICU感染中最為常見的菌株,Vincent JL, Rello J, Marsha

7、ll J, et al. International Study of the Prevalence and Outcomes of Infection in Intensive Care Units. JAMA 2009; 302(21):2323-2329.,,ICU較普通病房金葡菌感染中MRSA的檢出率增加,于沁, 楊莉, 丁玲等. 重癥監(jiān)護(hù)病房與普通病房細(xì)菌分布及耐藥性比較. 內(nèi)科理論與實踐 2008; 3(5):347-350

8、.,MRSA檢出率 (%),MRSA所致ICU病死率顯著高于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 EPI

9、C II study. Int J Antimicrob Agents 2011; 38(4):331-335.,革蘭陽性菌國內(nèi)監(jiān)測結(jié)果與全球一致，金葡菌持續(xù)增高,檢出菌株數(shù),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

10、(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,et al. Diagn Microbiol Infect Dis.2013 Jun;76(2):20

11、6-13. 6. Mendes RE,et al. J Antimicrob Chemother.2014 Jun;69(6):1582-8.7.汪復(fù) 等.中國感染與化療雜志.2008;8(5):325-333. 8.汪復(fù) 等.中國感染與化療雜志.2009;9(5):321-329. 9.汪復(fù) 等.中國感染與化療雜志.2010;10(5):325-334.10.朱德妹 等.中國感染與化療雜志.2011;11

12、(5):321-329. 11.胡付品 等.中國感染與化療雜志.2012;12(5):321-329. 12.汪復(fù) 等.中國感染與化療雜志.2013;13(5):321-330.,檢出率%,全球ZAAPS監(jiān)測結(jié)果：革蘭陽性菌檢出逐年增高,國內(nèi)CHINET監(jiān)測表現(xiàn)出相似結(jié)果，以金葡菌為首,發(fā)布2013年細(xì)菌耐藥報告美國疾病預(yù)防控制中心CDC,,,,首次根據(jù)威脅程度將耐藥細(xì)菌分為三級,MRSA感染重要的高危因素,

13、MRSA感染的8大高危因素1,2,1. 鄒紅波, 江凌曉.耐甲氧西林金黃色葡萄球菌院內(nèi)感染研究進(jìn)展. 實用醫(yī)學(xué)雜志 2008;24(8):1280-1282.2. Pea F, Viale P. The antimicrobial therapy puzzle: could phamacokinetic-phamacodynamic relationships be helpful in addressing the issu

14、e of appropriate pneumonia treatment in critically III patients? Clin Infect Dis 2006;42(12):1764-1771.,主要內(nèi)容,,全球眾多醫(yī)師協(xié)會制定MRSA感染的治療指南,2011 IDSAMRSA肺炎感染的治療推薦,Liu C, Bayer A, Cosgrove SE, et al. Clinical Practice Guidelines

15、 by the Infectious Diseases Society of America for theTreatment of Methicillin-Resistant Staphylococcus Aureus Infections in Adults and Children. CID 2011:52.,2011 IDSAMRSA菌血癥與感染性心內(nèi)膜炎中的治療推薦,Liu C, Bayer A, Cosgrove SE,

16、 et al. Clinical Practice Guidelines by the Infectious Diseases Society of America for theTreatment of Methicillin-Resistant Staphylococcus Aureus Infections in Adults and Children. CID 2011:52.,主要內(nèi)容,,,ZEPHyR研究引發(fā)了廣泛的學(xué)術(shù)關(guān)

17、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. 4. Masuta K, et al. Clin Infect Dis. 2012;5

18、5(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, Po

19、gue JM. Ann Pharmacother. 2012;46(10):1432-1435.,利奈唑胺治療MRSA肺炎是否優(yōu)于萬古霉素？,9項研究共4026例患者的薈萃分析利奈唑胺和萬古霉素死亡率差異為0.01% (P=0.992)MRSA人群臨床反應(yīng)率差異為7.7% (P=0.076)MRSA清除率差異為6.4% (P=0.230),Kalil AC, Klompas M, Haynatzki G, et al. Treat

20、ment of hospital-acquired pneumonia with linezolid or vancomycin: a systematic review and meta-analysis. BMJ Open 2013; 3(10):e003912.,利奈唑胺或萬古霉素治療陽性菌HAP：系統(tǒng)回顧和薈萃分析,Kalil AC, Klompas M, Haynatzki G, et al. Treatment of hos

21、pital-acquired pneumonia with linezolid or vancomycin: a systematic review and meta-analysis. BMJ Open 2013; 3(10):e003912.,臨床反應(yīng)率,隨機雙盲研究(RD 5.0%)和隨機開放標(biāo)簽研究(RD -1.4%)之間無統(tǒng)計學(xué)差異 符合方案的MRSA人群(N=507)中絕對RD為7.7%(P=0.076),醫(yī)院獲得性肺炎：

22、利奈唑胺 vs 萬古霉素：臨床反應(yīng)率*,,9項研究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,,,,,,,71/107,114/168,95/165,19/23,19/26,318/489,12/23,9/10,11/51,15/23,4

23、7/107,365/596,0.790,0.566,0.041,0.731,0.131,0.114,0.907,0.409,0.881,0.406,0.820,0.192,0.113,0.130,0.216,0.191,0.426,0.112,0.263,0.137,0.182,0.423,0.108,0.092,-0.149,-0.071,0.005,-0.272,-0.055,-0.012,-0.297,-0.337,-0.212,

24、-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,*臨床可評價/符合方案人群. Z=1.303;P=0.132;異質(zhì)性:Q=6.458;P=0.596;I2=0%,有利于萬古霉素 有利于利奈唑胺,Kalil AC, Klompas M, Haynatzki G

25、, 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,微生物學(xué)可評價且符合方案的人群(N=416)中，利奈唑胺和萬古霉素的MRSA清除率絕對RD為6.4% (P=0.230)隨機

26、雙盲研究(RD 8.4%)和隨機開放標(biāo)簽研究(RD 3.0%)之間無統(tǒng)計學(xué)差異,醫(yī)院獲得性肺炎：利奈唑胺 vs 萬古霉素：MRSA清除率*,,9項研究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

27、,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,-0.033,-0.095,-0.324,-0.267,-0.211,-0.140,-0.041,-0.126,0.197,0.084,0.254,0.044,0.000,0.003,0.09

28、2,0.030,0.064,,,,,,,,,,,-0.75,-0.38,0.00,0.38,0.75,*MRSA微生物學(xué)可評價/符合方案人群. Z=1.958;P=0.050;異質(zhì)性:Q=32.45;P=0.001;I2=78%,有利于萬古霉素 有利于利奈唑胺,死亡率,Kalil AC, Klompas M, Haynatzki G, et al. Treatment of hospital-acquir

29、ed pneumonia with linezolid or vancomycin: a systematic review and meta-analysis. BMJ Open 2013; 3(10):e003912.,ITT人群(N=4026)28天全因死亡率絕對風(fēng)險差異(RD)為0.01% (P=0.992)隨機雙盲研究(RD -1.3%)和隨機開放標(biāo)簽研究(RD 1.9%)之間無統(tǒng)計學(xué)差異,醫(yī)院獲得性肺炎：利奈唑胺 vs 萬

30、古霉素：死亡率*,,,,,,,,,,-0.50,-1.25,0.00,0.25,0.50,49/193,61/302,100/587,23/301,2/71,235/1454,33/220,3/101,7/51,6/74,49/445,284/1900,36/203,64/321,94/597,17/304,5/71,216/1496,44/240,13/215,14/100,4/75,75/630,291/2126,0.063,0.9

31、35,0.549,0.310,0.243,0.342,0.337,0.189,0.963,0.498,0.253,0.992,0.004,0.060,0.029,0.019,0.113,0.014,0.101,0.077,0.119,0.053,0.052,0.021,-0.157,-0.066,-0.055,-0.060,-0.029,-0.040,-0.035,-0.015,-0.114,-0.108,-0.014,-0.021,-

32、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 有利于萬古霉素,*意向治療人群. Z=0,010;P=0.092;異質(zhì)性:Q=9.251;P=0.322;I2=13.5%,,9項研究N=4026,,,腎衰竭發(fā)生率,ITT人群(N=3421)利奈唑胺和萬古霉素腎衰竭的絕對RD為-0.

33、7% (P=0.249)對腎衰竭的不同定義可能導(dǎo)致異質(zhì)性較大,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.,其他安全性分析

34、,*定義之間的差異可能導(dǎo)致異質(zhì)性較大；較短的療程可能預(yù)防血小板減少癥的發(fā)生# 利耐唑胺導(dǎo)致胃腸道不良反應(yīng)較多,9項研究N=4026,Kalil AC, Klompas M, Haynatzki G, et al. Treatment of hospital-acquired pneumonia with linezolid or vancomycin: a systematic review and meta-analysis. B

35、MJ Open 2013; 3(10):e003912.,萬古霉素 vs. 利奈唑胺治療醫(yī)院獲得性肺炎的系統(tǒng)回顧和薈萃分析[2013],Kalil AC, Klompas M, Haynatzki G, et al. Treatment of hospital-acquired pneumonia with linezolid or vancomycin: a systematic review and meta-analysis.

36、BMJ Open 2013; 3(10):e003912.,本薈萃分析與既往多項薈萃分析得到一致的結(jié)果,VAN-3-20140505-265,總結(jié)與結(jié)論：在死亡率和臨床反應(yīng)率方面，萬古霉素和利奈唑胺的有效性差異接近于零在不同患者人群、設(shè)計和質(zhì)量的研究之間具有一致性檢測出死亡率和臨床反應(yīng)率之間差異的統(tǒng)計學(xué)效能將近100% 萬古霉素和利奈唑胺治療HAP/VAP的有效性無統(tǒng)計學(xué)差異,Kalil AC, Klompas M, Hayna

37、tzki G, et al. Treatment of hospital-acquired pneumonia with linezolid or vancomycin: a systematic review and meta-analysis. BMJ Open 2013; 3(10):e003912.,萬古霉素 vs. 利奈唑胺治療醫(yī)院獲得性肺炎的系統(tǒng)回顧和薈萃分析[2013],在MRSA NP診療流程中，將萬古霉素可能治療失

38、敗的因素作為藥物選擇的分界點,,,年齡≥65歲；腎功能不全或正在使用腎毒性藥物；萬古霉素MIC值≥1.5mg/L或VISA/hVISA（萬古霉素中介金黃色葡萄球菌／異質(zhì)性金黃色葡萄球菌）病例是萬古霉素治療失敗或無法耐受萬古霉素治療的高危因素，此時應(yīng)選用利奈唑胺作為MRSA肺炎治療的一線藥物。,Consensus statement on MRSA NP in Asia. Clin Respir J 2014; ??: ??–??..,

39、Antibiotic treatment algorithm for MRSA NP,穩(wěn)可信說明書用法用量,腎功能正?；颊撸撼扇耍?g / 天，500mg q6h 或 1g q12h，可根據(jù)年齡、體重、癥狀適量增減兒童：40mg / kg / 天，分2-4次靜滴新生兒：10 – 15mg / kg / 次 出生1周內(nèi)，q12h給藥 出生1周到1月，q8h給藥老年人：500 mg q12h 或 1g qd 給藥 腎功能受

40、損患者：每天劑量應(yīng)適當(dāng)減少 (參照穩(wěn)可信®產(chǎn)品說明書),萬古霉素說明書,萬古霉素在腎功能減退者中的清除,萬古霉素體內(nèi)基本不代謝，給藥劑量的90%以原型經(jīng)腎臟清除,研究證實，特殊人群中應(yīng)用萬古霉素時，需調(diào)整劑量方案,腎功能損害患者的給藥穩(wěn)可信®產(chǎn)品說明書指出，腎功能損害患者同健康人相比，血中藥物濃度的半衰期延長有必要對其用藥量加以修正，從下圖根據(jù)肌酐清除率可計算出給藥量的修正值,摘自萬古霉素說明書,肌酐值以μmol

41、/L表示時：K=0.814肌酐值以mg/dL表示：K=72本公式應(yīng)用于女性值，求得值×0.85首次負(fù)荷劑量：15mg/kg,說明書推薦調(diào)整法：腎功能減退時萬古霉素劑量調(diào)整方法,1.中華人民共和國衛(wèi)生部醫(yī)政司 《國家抗微生物治療指南》人民衛(wèi)生出版社 2012年12月第1版 :2212. Rybak MJ et al. Vancomycin therapeutic guidelines: a summary of con

42、sensus 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：腎功

43、能正常成人患者首劑量基于實際體重，包括肥胖患者，之后的劑量根據(jù)測定的血清谷濃度進(jìn)行調(diào)整劑量大于1g時，輸注時間大于1.5-2h,《國家抗微生物治療指南》推薦調(diào)整法：腎功能減退時萬古霉素劑量及給藥間隔時間,萬古霉素的劑量應(yīng)用原則,萬古霉素臨床應(yīng)用劑量專家組. 萬古霉素臨床應(yīng)用劑量中國專家共識. 中華傳染病雜志 2012; 30(11):641-648.,萬古霉素在兒童與老年人中的維持劑量調(diào)整,萬古霉素臨床應(yīng)用劑量專家組. 萬古霉素臨床

44、應(yīng)用劑量中國專家共識. 中華傳染病雜志 2012; 30(11):641-648.,IDSA、ASHP、SIDP聯(lián)合推出的治療監(jiān)測實踐指南萬古霉素對成人MRSA感染的治療推薦,Rybak M, Lomaestro B, Rotschafer JC, et al. Vancomycin therapeutic guidelines: a summary of consensus recommendations fromthe infe

45、ctious 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-infusion vancomycin,OBJ

46、ECTIVE: 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 Scho

47、lar, using the terms vancomycin, continuous, discontinuous, infusion, pharmacokinetics, pharmacodynamics, and nephrotoxicity. In addition, reference citations from publications identified were reviewed.Fourteen clinical

48、 trials were reviewed (2 prospective, 1 meta-analysis, 11 retrospective).Continuous-infusion therapy did not significantly improve the efficacy of vancomycin in the treatment of invasive MRSA infections. Conflicting res

49、ults 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 ther

50、apy 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:

51、 Currently available evidence is insufficient to conclude whether an improvement in vancomycin efficacy exists when it is administered as a continuous infusion. The risk of nephrotoxicity associated with continuous-infus

52、ion vancomycin requires further investigation in prospective randomized trials.,萬古霉素的MIC與臨床療效,若MIC≤2μg/ml，應(yīng)根據(jù)臨床實際效果來使用，不依賴于MIC的值。MIC大于2μg/ml，需使用替代萬古霉素的其他藥物進(jìn)行治療,[中國 2005-2010年 GPRS監(jiān)測項目]金葡菌對萬古霉素MIC值穩(wěn)定,Zhao C, Sun H, Wan

53、g 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):17

54、4-81.,,2005-2010年在中國為期4年的GPRS細(xì)菌耐藥監(jiān)測數(shù)據(jù)結(jié)果顯示：絕大多數(shù)菌株的MIC值集中在0.5 μg/ml和1 μg/ml；2008年分布在1 μg/ml的菌株為45%，較2007年的80%有所減少，說明萬古霉素MIC值持續(xù)穩(wěn)定。,推薦進(jìn)行萬古霉素谷濃度監(jiān)測的人群,IDSA和美國醫(yī)院藥師學(xué)會(ASHP)推薦應(yīng)用大劑量萬古霉素并且推薦療程較長的患者腎功能不穩(wěn)定(如明顯惡化或明

55、顯改善)的患者聯(lián)合使用其他耳、腎毒性藥物的患者,萬古霉素臨床應(yīng)用劑量專家組. 萬古霉素臨床應(yīng)用劑量中國專家共識. 中華傳染病雜志 2012; 30(11):641-648.,IDSA、ASHP、SIDP聯(lián)合推出的治療監(jiān)測實踐指南關(guān)于萬古霉素血藥濃度的推薦,注：VISA vancomycin–intermediately susceptible S. aureus 萬古霉素中介的金黃色葡萄球菌Rybak M, Lomaestro

56、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 In

57、fectiousDiseases Pharmacists. Clin Infect Dis 2009; 49(3):325-327.,萬古霉素血藥濃度監(jiān)測要點,Rybak MJ, Lomaestro BM, Rotschafer JC, et al. Vancomycin therapeutic guidelines: a summary of consensus recommendations from the infectious

58、 diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists. Clin Infect Dis 2009; 49(3):325-327.,萬古霉素血藥濃度監(jiān)測時機,現(xiàn)有證據(jù)不支持通過監(jiān)測萬古霉素峰濃度來降低腎毒性發(fā)生率,中華醫(yī)學(xué)會甲氧西林

59、耐藥金黃色葡萄球菌感染治療策略專家組. 中華醫(yī)學(xué)會感染與抗微生物治療策略高峰論壇：甲氧西林耐藥金黃色葡萄球菌感染的治療策略——專家共識. 中國感染與化療雜志 2011; 11(6):401-416.,總 結(jié),ICU中肺部感染最為常見，肺部感染和血流感染預(yù)后不佳萬古霉素被多個指南推薦用于MRSA感染萬古霉素和利奈唑胺治療MRSA所致HAP/VAP的臨床轉(zhuǎn)歸相當(dāng) 合理應(yīng)用萬古霉素可達(dá)到臨床最大效用,,萬古霉素安

60、全性,休克、過敏樣癥狀（少于0.1%）；急性腎功能不全（0.5%）；多種血細(xì)胞減少（0.1%）；皮膚粘膜綜合征（Stevens-Johnson綜合征）；第八腦神經(jīng)損傷（少于0.1%）偽膜性大腸炎（頻率不明）肝功能損害、黃疸（頻率不明）,摘自萬古霉素說明書,穩(wěn)可信®簡短處方說明,【通用名稱】：注射用鹽酸萬古霉素【商品名稱】：穩(wěn)可信 Vancocin CP【適應(yīng)癥】 ：本品適用于耐甲氧西林金黃色葡萄球菌(M

61、RSA)及其他細(xì)菌所致的感染： 敗血癥、感染性心內(nèi)膜炎、骨髓炎、關(guān)節(jié)炎、灼傷、手術(shù)創(chuàng)傷等淺表性繼發(fā)感染、 肺炎、肺膿腫、膿胸、腹膜炎、腦膜炎。【用法用量】：成人：2g / 天，500mg q6h 或 1g q12h【不良反應(yīng)】：休克，過敏樣癥狀，急性腎功能不全，多種血細(xì)胞減少，皮膚粘膜綜合征，第八腦神經(jīng)損傷等【禁　　忌】：對本品有既往過敏者禁用 下列患者原則不予給藥，若有特殊需要需慎重：對本品、替考拉寧及糖肽類抗生素、

62、 氨基糖苷類抗生素有既往過敏史者；因糖肽類抗生素、替考拉寧及氨基糖苷類抗生素 所致耳聾及其他耳聾患者（可使耳聾加重）。【注意事項】：詳見藥品說明書,總結(jié),萬古霉素獲得眾多指南一致推薦，是治療MRSA感染的一線用藥。根據(jù)疾病及萬古霉素的PK/PD特性給以患者個性化治療，可以獲得療效與安全性的雙贏。MRSA對萬古霉素MIC值穩(wěn)定。綜合考慮患者的臨床反應(yīng)，谷濃度，藥敏試驗，感染灶的處理等。,Questions?,Thank Y