常用抗菌藥物在 MRSA HAP的臨床應(yīng)用

1、常用抗菌藥物在 MRSA HAP的臨床應(yīng)用汕頭大學醫(yī)學院第一附屬醫(yī)院呼吸內(nèi)科吳潔文HAP的流行病學 HAP發(fā)病率為0.5%1.0%， 居院內(nèi)感染第二位，占所有院內(nèi)感染的15%20%。在ICU，HAP發(fā)病率高達18%60%。Chest,2002,122:2115-2121.肺炎患病危險每日增加1% 在美國，HAP病死率達30%50%，入住ICU者HAP病死率超過50%（有報道達70%），為院內(nèi)感染首要的死亡原因。不同人群HAP發(fā)病率主要研究人群論文數(shù)發(fā)病率(%)相對危險度RRRR的95CI普通住院人群71.40老年55.393.853.554.18ICU患者417.8712.7811.6214.

2、05人工氣道/機械通氣460.5343.2738.8848.17其他123.062.192.022.3788篇論文總計8705例HAP的meta分析VAP的病原體: NNIS database86% 的醫(yī)院內(nèi)肺炎和機械通氣相關(guān)革蘭陽性金黃色葡萄球菌非常常見Richards et al. Crit Care Med 1999;27:887892EnterococciS. aureusP. aeruginosaEnterobacter spp.Frequency (%)01020305引起ICU內(nèi)HAP的病原體NNIS（19862003年）病原菌肺炎(n = 4365)血流感染 (n = 2351

3、)革蘭陰性大腸桿菌5.03.3肺炎克雷伯桿菌7.24.2腸桿菌屬10.04.4粘質(zhì)沙雷菌4.72.3銅綠假單胞菌18.13.4不動桿菌屬6.92.4其他14.13.8革蘭陽性凝固酶陰性葡萄球菌1.842.9金黃色葡萄球菌27.814.3腸球菌1.314.5其他3.24.5Clinical Infectious Diseases 2005; 41:84854MRSA引起的感染（2004-2005 美國）JAMA. 2007;298(15):1763-1771 ICU內(nèi)耐藥菌的增加 (NNIS, 2002 vs 19972001)Resistance (%)0102030405060708090萬

4、古霉素/腸球菌甲氧西林/金葡菌甲氧西林/CNS3rd Ceph/E. coli3rd Ceph/K. pneumoniaeImipenem/P. aeruginosaQuinolone/P. aeruginosa3rd Ceph/P. aeruginosa3rd Ceph/Enterobacter spp.+11+13+1+142+32+27+225Change in resistance (%)JanDec 200219972001 ( sd)Ceph = cephalosporin;NNIS = National Nosocomial Infections Surveillance Sys

5、tem; CNS = coagulase-negative staphylococciNNIS. Am J Infect Control 2003;31:48198ICU病人與MRSAAccessed August 30, 2005.Lowy FD. J Clin Invest. 2003;111:1265-1273.63%MRSA 在中國不同時期甲氧西林耐藥葡萄球菌的檢出率檢出率（%）中國CHINET（2006）Prevalence of MRSA in China798 isolates, 2005, 12 Cities, China%Wang H et al. Int J Antimic

6、rob Agents 2008; (online) Pathogenic MechanismsCell wallPeptidoglycanTeichoic acidsProtein AEnzymesCatalaseCoagulaseClumping factorToxins-toxin-toxin/-toxin/-toxinLeukocidinSuper antigensToxic Shock SyndromeEnterotoxinsExfoliativeHA-MRSA主要感染住院病人，幾乎都是通過接觸傳播，通常感染年紀大、病情較嚴重、皮膚有傷口（例如褥瘡）或有導管（如導尿管）的人，健康人很少

7、會感染CA-MRSA能夠感染健康人擁擠的監(jiān)獄中頗為流行近年在美國各地的城鎮(zhèn)社區(qū)（包括洛杉磯、舊金山、紐約、波士頓、邁阿密等大城市）也出現(xiàn)了多次小規(guī)模爆發(fā)CA-MRSA：現(xiàn)狀美國弗吉尼亞州貝德福德一名17歲高中生就因感染MRSA而死亡，21所學校停課 美國每年有逾9萬人感染MRSA；每年致死人數(shù)可能超過艾滋病阿什頓邦茲，07年10月4日感到身體一側(cè)疼痛，就到當?shù)匾患裔t(yī)院就診。 10月17日死亡。 Zeller JL, et al. JAMA patient page. MRSA infectionsJAMA. 2007 Oct 17;298(15):1826. CA-MRSACA-MRSA全球范

8、圍內(nèi)社區(qū)獲得性MRSA的發(fā)病率呈上升趨勢社區(qū)獲得性MRSA可從以下情況中隱匿獲得 醫(yī)療保健 日常生活 過去一年中住院超過5天 社區(qū)獲得性MRSA，表達Panton-Valentine leukocidin (p-v)潘頓-瓦倫丁殺白細胞素JAC 2004; 53: 4749. Infect Control Hosp Epidemiol 2003; 24: 40914.Emerg Infect Dis 2003; 9: 97884. Emerg Infect Dis 2003; 9: 97884 Infect Control Hosp Epidemiol 2003; 24: 4515Clin I

9、nfect Dis 2003; 36: 1319. PVL Positive Community-acquired PneumoniaGillet et al, Clin Infect Disease,200750 cases over 9 years from 39 hospitals in 9 countriesSelection biasOnly 12% MRSA casesInfluenza-like illness 67%,confirmed in 4/924% concomitant skin infectionsPleural effusion 53%, multilobar i

10、nfil 79%Mech vent 78%, ARDS 51%Mortality 56%, all due to pneumoniaCommunity-acquired MRSA PneumoniaSurvey of IDSA Emerging Infection Network After 06-07 influenza season30% reported a case of hospitalized CAPCharacteristics 440 adults,117 children72% MRSA49% mechanical ventilation13% mortality43% ba

11、cteremiaInfluenza suspected 26%CA-MRSA PneumoniaCA-MRSA CAP will be an increasing problemMay correlate more with skin colonization than nasalPVL is necessary but not sufficient to define high risk pathogenCavitary/necrotizing pneumonia +/- effusionCombination with influenza appears to be particularl

12、y lethal, even if MSSAMassive hemoptysis, neutropeniaToxin suppression appears to be an important component of effective treatmeantHAP的病原體構(gòu)成主要影響因素住院的時間 早發(fā) 晚發(fā)肺炎本身的嚴重程度：重癥 非重癥基礎(chǔ)疾病 先前的治療（抗生素、免疫抑制）早期中期晚期1 3 5 10 15 20鏈球菌流感桿菌金葡菌 MRSA腸桿菌肺克，大腸綠膿桿菌不動桿菌嗜麥芽窄食單胞菌入院天數(shù)住院時間與HAP致病菌的關(guān)系早發(fā)性HAP和晚發(fā)性HAP的病原菌早發(fā)HAP晚發(fā)HAPPMS

13、SA13 (19.40) 22 (11.00) 0.063MRSA8 (11.94) 47 (23.50) 0.028肺炎鏈球菌8 (11.94) 7 (3.50) 0.015腸桿菌屬2 (2.99) 6 (3.00) 0.639大腸桿菌1 (1.49) 7 (3.50) 0.361肺炎克雷伯菌3 (4.48) 12 (6.00) 0.454粘質(zhì)沙雷菌2 (2.99) 3 (1.50) 0.369不動桿菌屬2 (2.99) 7 (3.50) 0.598嗜麥芽窄食單胞菌1 (1.49) 2 (1.00) 0.581銅綠假單胞菌2 (2.99) 23 (11.50) 0.026莫他卡拉菌3 (4.

14、48) 4 (2.00) 0.244流感嗜血桿菌4 (5.97) 4 (2.00) 0.122所有病原體67200Infect Control Hosp Epidemiol 2007; 28:825-831Etiology of HAP In Asian CountriesRank KoreaChinaTaiwanThailandMalaysiaPhilippines*IndiaPakistan1P. aerug(23 %)P. aeru(18 %)P. aeru(21 %)A. baum(28 %)A. baum(23 %)P. aeru(42.1 %)A. baum(38 %)A. bau

15、m(58 %)2MRSA(23 %)MRSA(16 %)A. baum(20 %)P. aeru(18 %)P. aeru(17.6 %)K. pn(26.3 %) K. pn(23 %)MRSA(18 %)3K. pn(11 %)A. baum(16 %)MRSA(16 %)K. pn(7.7 %)MRSA(11.8 %)A. baum(13.1 %)P. aeru(20 %)P. aeru(18 %)4A.baum(9 %) K. pn(14 %)K. pn(9 %)MRSA(7.6 %)S. malto(11.8 %)MRSA(5 %)5E. cloa(8 %)E. cloa(8 %)E

16、. coli(3.6 %)E. coli(2.8 %)K. pn(5.8 %)* Philippines: VAP dataAsian HAP Working Group. Am J Infect Control 2008;36:S83-92.Adapted from Kollef MH et al. Chest. 1999;115:462-474.ATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416.“selection of initial appropriate antibiotic therapy (ie, getting the

17、antibiotic treatment right the first time) is an important aspect of care for hospitalized patients with serious infections.” ATS/IDSA GuidelinesA Study by Kollef and Colleagues Evaluating the Impact of Inadequate Antimicrobial Therapy on Mortality不充分的抗生素治療(n=169) 充分的抗生素治療(n=486) 0102030405060總死亡率感染

18、相關(guān)死亡率2442*18住院死亡率 (%)52*P.001充分起始抗生素治療降低ICU內(nèi)肺炎死亡率1. Ibrahim EH, et al. Chest. 2000;118:146-155. 2. Valles J, et al. Chest. 2003;123:1615-1624. 3. Khatib R, et al. Eur J Clin Microbiol Infect Dis. 2006;25:181-185. 4. Teixeira PJZ, et al. J Hosp Infect. 2007;65:361-367. 5. The American Thoracic Societ

19、y and the Infectious Diseases Society of America. Am J Respir Crit Care Med. 2005;171:388-416. 01020304050607080菌血癥社區(qū)獲得性-菌血癥金葡菌菌血癥呼吸機相關(guān)肺炎病死率(患者% )正確的抗菌治療不恰當?shù)目咕委烶 .0011a3P 5 days)HAP或 MDR病原體的危險因素否是窄譜抗菌藥物廣譜抗菌藥物針對MDR病原體HAP初始經(jīng)驗性抗菌藥物治療的流程圖ATS. Am J Respir Crit Care Med 2005;171:388-416Risk Factors for M

20、ultidrug-Resistant Pathogens (MDRP)HAP, VAP, HCAPAntimicrobial therapy in preceding 90 daysCurrent hospitalization of 5 days or moreHigh frequency of antibiotic resistance in the community or in the specific hospital unitPresence of risk factor for HCAPHospitalization for 2 days or more in preceding

21、 90 daysResidence in a nursing home or extended care facilityHome infusion therapy (including antibiotics)Chronic dialysis within 30 daysHome wound careFamily member with MDRPImmunosuppressive disease and/or therapyBonten MJ et al. Am J Respir Crit Care Med 2005;171:388-416.經(jīng)驗性治療: 晚期發(fā)病或存在MDR病原菌感染聯(lián)合抗

22、菌治療銅綠假單胞菌有抗假單胞菌活性的頭孢菌素(頭孢吡肟 ，頭孢他定)或肺炎克雷伯菌(ESBL陽性)有抗假單胞菌活性的碳青霉烯類(亞胺培南或美羅培南)不動桿菌或-內(nèi)酰胺/-內(nèi)酰胺酶抑制劑(哌拉西林-他唑巴坦)有抗綠膿桿菌活性的氟喹諾酮類(環(huán)丙沙星或左氧氟沙星)或氨基糖苷類(阿米卡星，慶大霉素或妥布霉素)甲氧西林耐藥金葡菌(MRSA)萬古霉素或利奈唑胺嗜肺軍團菌2006年亞洲HAP工作組抗生素選擇策略特殊耐藥菌感染的抗生素方案病原菌等級推薦抗生素方案MRSA12萬古霉素 或 替考拉寧利奈唑胺 或 替加環(huán)素MDR 銅綠假單胞菌12哌拉西林-他唑巴坦 或 碳青霉烯類+/-氨基糖苷類或氟喹諾酮 （環(huán)丙沙

23、星）多粘菌素B 或 多粘菌素E +/- 環(huán)丙沙星MDR 不動桿菌12頭孢哌酮/舒巴坦和/或替加環(huán)素多粘菌素B 或 多粘菌素E 肺炎克雷伯菌(ESBL+)12碳青霉烯類 或 替加環(huán)素哌拉西林-他唑巴坦大腸埃細菌(ESBL+)12碳青霉烯類 或 替加環(huán)素哌拉西林-他唑巴坦 Jae-Hoon Song, and the Asian HAP Working Group. Am J Infect Control 2008;36:S83-92.金葡肺炎：女，26歲，宮腔術(shù)后金葡菌Nosocomial Pneumonia due to MRSASputum and blood: MRSABetter 1st

24、-line Anti-MRSA Agents,Glycopeptide orLinezolid ?萬古霉素、利奈唑胺和替考拉寧分子結(jié)構(gòu)比較萬古霉素是微生物發(fā)酵產(chǎn)生的天然抗生素,屬糖肽類抗生素利奈唑胺是人工合成的抗菌藥,屬于噁唑烷酮類抗菌藥物替考拉寧是微生物發(fā)酵產(chǎn)生的抗生素,屬于糖肽類抗生素萬古霉素、利奈唑胺和替考拉寧 抗菌譜比較萬古霉素、替考拉寧和利奈唑胺的抗菌譜相似，都是窄譜抗生素，治療革蘭陽性菌感染 金葡菌，包括MRSA 肺炎鏈球菌，包括PRSP 凝固酶陰性葡萄球菌，包括MRCNS 腸球菌，有少數(shù)耐藥菌株萬古霉素、利奈唑胺和替考拉寧 適應(yīng)證的比較35、穩(wěn)可信、他格適和斯沃產(chǎn)品說明書適應(yīng)證萬

25、古霉素利奈唑胺替考拉寧皮膚感染肺炎感染性心內(nèi)膜炎？骨髓炎關(guān)節(jié)炎肺膿腫膿胸腹膜炎導管相關(guān)感染？腦膜炎萬古霉素抗菌素作用機制萬古霉素屬快效殺菌劑具有三重作用機制1.抑制細菌細胞壁的合成抑制細菌細胞壁粘肽鏈合成的第二步 與五肽末端氨基酸分子結(jié)合，阻斷轉(zhuǎn)肽交叉連接 轉(zhuǎn)糖作用發(fā)生障礙2. 影響細菌細胞膜的通透性3. 抑制細菌孢漿中RNA的合成MGMGMGMG糖肽類糖肽類抗菌機制VancomycinIt is not obsoleteIt works mostlyResistance is rareIt is cheapIt is obsoleteTissue concentrationProtein b

26、indingNeed high trough concentrationsMIC creepPoor target attainment when MICs1VISA and hVISA hVancoS. aureus with reduced vancomycin susceptibilityS. aureus strainDefinitionVRSAMIC 16 g/mLVISAMIC 48 g/mLhVISASubpopulations of VISA at rates of 1 per 105106 organismsMICs: variable2000(n=945)2001(n=10

27、26)2002(n=1317)2003(n=1297)2004(n=1418)萬古霉素對金葡菌的MIC值呈逐年上升趨勢Wang G et al. J Clin Microbiol. 2006;44:3883-3886*一項自2000年1月至2004年12月UCLA醫(yī)學中心對6003例臨床分離金黃色葡萄球菌菌株進行的分析監(jiān)測結(jié)果近年來，萬古霉素對70%金黃色葡萄球菌的MIC值1g/mL*分離菌株的百分比(%)Shift in Vancomycin MICs1Vancomycin MIC (mg/mL)YearS aureus Strains (n) 0.51200094579.9%19.9%20

28、04141828.8%70.4%aa PMIC或T3MIC以上時間應(yīng)40%萬古霉素PK與PD 以t1/2 6hr 1g 滴注 1hr 滴注結(jié)束，即刻峰濃60ug/ml ；2hr后峰濃 25ug/ml計用藥劑量：1.0g q12h MIC值TMICT3MIC0.5100%100%1.0100%100%1.5100%100%2.0100%100%4.0100%66%6.091.5%8.083.3%萬古霉素PK與PD 以t1/2 6hr 0.5g 滴注 30分滴注,結(jié)束即刻峰濃33ug/ml; 6hr后峰濃 計用藥劑量： 0.5g q8h MIC值TMICT3MIC0.5100%100%1.0100

29、% 62.5%1.5100%50%2.0100%萬古霉素小鼠 S. aureus 腿感染PK/PD(AUC24/MIC、Cmax/MIC、TMIC )R2=90%-4-202-4-2021010010001010010001-4-202401001200206080R2=56%R2=75%Free drug AUC24/MICFree drug Cmax/MICFree drug %TMICCFU change in Lg10/thignCID 2006,42(suppl 1):S35萬古霉素療效與 AUICs OutcomeParameters Satisfactory Unsatisfac

30、tory IndeterminateMIC 1.0 g/ml 1 4a 0MIC 1.0 g/ml 74 2 3AUIC 125 (76) 71 2 3Total Patients (84) 75 6 3Hyatt et al, Clinical Pharmacokinetics 1995, 28: 143萬古霉素MIC與MRSA敗血癥/肺炎感染治療Wilhelm KL. 2008 ICAAC abstract A-1905參數(shù)MIC1MIC1病例數(shù)2018萬古霉素谷濃度(mg/L)18.618.7AUIC50327726795AUIC400(%)6011Clinical response,

31、length of stay, mortality and nephrotoxicity were equal .萬古霉素MIC與MRSA 敗血癥療效 OutcomeLow MIC(7 days9/104 (8.65%)11/54 (20.4%)0.03Kaur I. 2008 ICAAC abstract K-564 國內(nèi)葡萄球菌對萬古霉素始終保持100%敏感率 葡萄球菌菌株數(shù)R%I%S%1998-199915270%0%100%2000217710%0%100%2001326160%0%100%2002475750%0%100%2003599010%0%100%2004-200561387

32、50%0%100%2005-20067135500%0%100%1998-2006全國細菌耐藥監(jiān)測結(jié)果1、李家泰, Allan J Weinstein, 楊敏等. 中國細菌耐藥監(jiān)測研究. 中華醫(yī)學雜志 2001;81(1):8-162-7. 國家細菌耐藥性監(jiān)測中心監(jiān)測數(shù)據(jù)總結(jié)RESIST研究中3100株耐甲氧西林葡萄球菌對12種抗生素的耐藥率耐藥率%RESIST研究中207株甲氧西林敏感葡萄球菌對12種抗生素的耐藥率耐藥率%RESIST研究的結(jié)論3307株葡萄球菌中：除一株MRCNS，所有菌株對萬古霉素保持100%敏感無論對甲氧西林耐藥還是對甲氧西林敏感的葡萄球菌對替考拉寧存在不同程度耐藥，尤

33、其是凝固酶陰性葡萄球菌MRCNS對替考拉寧的耐藥性高，其中耐甲氧西林溶血性葡萄球菌(MRSH)對替考拉寧的耐藥率高達48.2%對甲氧西林敏感的溶血性葡萄球菌(MSSH)對替考拉寧的耐藥率達38.5%2009年CLSI最新指南：葡萄球菌： 萬古霉素MIC 替考拉寧MIC 敏感菌株 0.5-2ug/ml 8ug/ml 耐藥菌株 16ug/ml 32ug/ml 低敏菌株 4-8ug/ml 萬古霉素與同為糖肽類替考拉寧相比：萬古霉素對葡萄球菌和腸球菌的MIC值比較中，萬古霉素仍然有明顯的優(yōu)勢 腸球菌： 萬古霉素MIC 替考拉寧MIC 敏感菌株 4ug/ml 8ug/ml 耐藥菌株 32ug/ml 32

34、ug/ml 萬古霉素在肺組織的濃度 在一項30例行肺葉次全切除術(shù)的患者研究中，靜脈給予萬古霉素1 g 之后，組織藥物濃度范圍為0-12.2 mg/kg，平均組織濃度為2.8 mg/kg，組織穿透率為41% Penetration of vancomycin into human lung tissueM. Cruciani, G. Gattr*, L. Lazzarini, G. Furlan, G. Broccali, M. Malena,C. Franchini and Ercole Concia萬古霉素的肺組織濃度健康志愿者給予萬古霉素1 g q12h 給藥后，12 h肺組織濃度為2.4

35、 mg/kg ， 總體穿透率為52% 。 Program and abstracts of the 14th European Congress of Clinical Microbiology and Infectious Diseases (Prague). Basel: European Society of Clinical Microbiology and Infectious Diseases, 2004:4431 MichaelJ.Rybak The Pharmacokinetic and Pharmacodynamic Properties of Vancomycin. Cli

36、nical Infectious Diseases 2006; 42(Suppl 1):S35S394-h12-h血漿濃度19.83.75.11.7上皮細胞襯液（ELF）5.31.52.40.7肺泡巨噬細胞（AM）32.08.545.223.3不同時間血漿和肺組織中萬古霉素的濃度1萬古霉素治療金葡菌菌血癥和心內(nèi)膜炎的臨床療效文獻來源疾病病例數(shù)有效率Levine9心內(nèi)膜炎3582.8%Esposito10心內(nèi)膜炎5080.0%Levine9心內(nèi)膜炎1782.4%Craven11菌血癥1973.6%Esposito12菌血癥9286.9%Kirby13敗血癥3372.7%Myers14菌血癥158

37、6.7%Coppens15菌血癥887.5%Sorrell16菌血癥1172.7%9 Ann Int Med 115:674 10 JAMA 238:1756 11 J Antimicrob Chemo 14:Suppl D:73 12 J Infect Dis 147:137 13 NEJM 262:49-55 14 Ann Int Med 97:330-338 15 Antimicro Agents and Chemo 23:36 16 Ann Int Med 97:344替考拉寧治療重癥感染的療效資料來源疾病劑量/天病例數(shù)有效率Calain P17金葡菌菌血癥3 mg/kg650%Ler

38、ner 18金葡菌菌血癥6 mg/kg9100%USA-1 18金葡菌菌血癥6 mg/kg6080.0%USA-2 18金葡菌菌血癥6 mg/kg1421.4%USA-3 18金葡菌菌血癥30 mg/kg4985.7%Liu 19金葡菌菌血癥6 mg/kg2085.0%17 J Infect Dis 1987;155(2):187-91 18 Int J Antimicrob Agents 1994;4(Suppl 1):S1-S30 19 Clin Drug Invest 1996;12:80-7替考拉寧治療金葡菌心內(nèi)膜炎的療效資料來源疾病劑量/天病例數(shù)有效率Davey20心內(nèi)膜炎6 mg/

39、kg1050%Rybak21心內(nèi)膜炎6 mg/kg520%Gilbert22心內(nèi)膜炎6 mg/kg825%Rybak23心內(nèi)膜炎6 mg/kg1421.4%Fortun24心內(nèi)膜炎6 mg/kg633.3%USA-323心內(nèi)膜炎30 mg/kg2176.2%20 J Antimicro Chemo 27(Suppl B):43 21 Antimicrob Agents & Chemo 35:696 22Antimicrob Agents & Chemo 35:7923 Int J Antimicrob Chemo 4(Suppl 1);S1 24 ICC 1993, Abstract 1223

40、萬古霉素和替考拉寧的療效比較 同屬于糖肽類抗生素，具有相似的化學結(jié)構(gòu)和抗菌譜 金葡菌和凝固酶陰性葡萄球菌對替考拉寧易產(chǎn)生耐藥 替考拉寧較高的蛋白結(jié)合率（90-97%) ,使感染部位無法達到有效 的藥物濃度，導致對嚴重感染療效不確切，需加大劑量 替考拉寧常規(guī)劑量臨床療效不理想（尤其在心內(nèi)膜炎），加大劑 量往往導致副反應(yīng)增加 研究表明，穩(wěn)可信與替考拉寧在引起皮疹，腎功能障礙等副反應(yīng) 方面無統(tǒng)計學差異；但替考拉寧引起的血小板減少癥的發(fā)生率顯 著高于穩(wěn)可信利奈唑胺抗菌機制利奈唑胺抗菌譜Gram-positive microorganisms: 屎腸球菌(包括VRE) 金黃色葡萄球菌(包括MRSA)肺炎

41、鏈球菌(包括PRSP)無乳鏈球菌化膿性鏈球菌糞腸球菌(包括VRE)表皮葡萄球菌(包括MRSE)溶血葡萄球菌草綠色鏈球菌Some anaerobic bacteria:萬古霉素和利奈唑胺治療院內(nèi)肺炎療效相當在利奈唑胺提交給FDA的臨床報告中,治療醫(yī)院內(nèi)肺炎的臨床研究.用萬古霉素和利奈唑胺進行對照,顯示萬古霉素可評價臨床療效為60%,利奈唑胺可評價臨床療效57%0102030405060利奈唑胺萬古霉素利奈唑胺萬古霉素25 ZYVOX 產(chǎn)品說明書信息 Distributed by Pfizer Pharmacia&Upjohn Company Divison of Pfizer Inc,NY,NY

42、10017 LAB-0319-16.0 % Linezolid versus Vancomycin or TeicoplaninFor Nosocomial Pneumonia: A Meta-AnalysisAC. KALIL, M. H. MURTHY, E. HERMSEN, et al.Methods: Prospective, randomized trails which tested linezolid vs. vancomycin or teicoplanin of NP were included. Heterogenneity was analyzed by I2 and

43、Q statistics. Relative Risks(RR) were base on the Mantel-Haenszel method. Outcomes analysed included clinical cure (CC), microbiologic eradication (ME), and side effects. Results: 8 linezolid trials (6 vancomycin, 2 teicoplanin) were included (N=853). The linezolid vs glycopeptide analysis shows: CC

44、 RR= 1.01(95% CI 0.93, 1.10, p=0.80; I2=0%; N=853); ME RR=1.10(CI 0.97, 1.23; p=0.11; I2=0%; N=597); and MRSA population RR=1.14(CI 0.82, 1.58; p=0.44; I2=47%; N=191). If linezolid is compared to vancomycin only, the CC RR remains 1.01 (CI 0,73, 1.47), respectively. The risk of thrombocytopenia(RR=1

45、.92CI 1.29, 2.86; p=0.001) and GI event (RR=1.90CI 1.04, 3.48; p=0.03) were significantly higher with linezolid, but no differences were seen for renal dysfunction (RR=0.82CI 0.52, 1.27; p=0.37, or all cause deaths(RR=0.95CI 0.76, 1.18; P=0.63).2008 ICAAC K-533Conclusions: Meta-analysis did not dete

46、ct clinical superiority of linezolid vs. glycopeptides for treatment of NP. Compared to linezolid, Vancomycin was not associated with more renal dysfunction. Linezolid shows a significant increase in the risk of thrombocytopenia an GI events. Available data dose not support the claim that linezolid

47、is superior to vancomycin for the treatment of NP.利奈唑胺耐藥性抗菌機制:50S亞基中23S rRNA V區(qū)結(jié)合耐藥機制: 23S rRNA V區(qū)點突變, G2576T疊加性: 5-6個23S rRNA 基因逐步變異交叉耐藥:氯霉素,鏈陽霉素,林可霉素Enterocccus, Staphylococcus臨床菌株已有報道實驗室篩選萬古霉素和替考拉寧安全性的比較不良事件替考拉寧（N=238）萬古霉素（N=239）過敏反應(yīng)7.6%8.8% 發(fā)熱3.4%2.5% 皮疹4.6%3.8%腹瀉3.4%4.6%惡心/嘔吐3.4%3.3%聽力/平衡功能障礙1.

48、3%1.3%肝功能損害1.3%1.3%腎毒性1.7%2.1%血液系統(tǒng)3.8%0.8%血小板減少a3.4%0.0%26、a p = 0.007, Fishers test27、Source: Wilson, Grunberg, Neu, Int. J. Antimicrob Agents, Suppl 1:S1 (1994)萬古霉素和利奈唑胺安全性比較由于萬古霉素制劑的純度顯著提高，目前臨床大量應(yīng)用萬古霉素，證實其腎毒性很少見,包括調(diào)整劑量后用于腎功能受損的病人，同時萬古霉素的腎毒性具有可逆性28。而有數(shù)據(jù)表明，利奈唑胺引起的嚴重不良反應(yīng)血小板減少的病例高達35%,在腎功能損傷的病人應(yīng)用利奈唑胺引起的血小板減少達到65%,29。高純度的萬古霉素具有良好的安全性28 Wakefield DS, Pfaller M, Massanari RM, Hammons GT. Variat