常用抗菌药物在 MRSA HAP的临床应用

1、常用抗菌药物在 MRSA HAP的临床应用汕头大学医学院第一附属医院呼吸内科吴洁文HAP的流行病学 HAP发病率为0.5%1.0%， 居院内感染第二位，占所有院内感染的15%20%。在ICU，HAP发病率高达18%60%。Chest,2002,122:2115-2121.肺炎患病危险每日增加1% 在美国，HAP病死率达30%50%，入住ICU者HAP病死率超过50%（有报道达70%），为院内感染首要的死亡原因。不同人群HAP发病率主要研究人群论文数发病率(%)相对危险度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人工气道/机械通气460.5343.2738.8848.17其他123.062.192.022.3788篇论文总计8705例HAP的meta分析VAP的病原体: NNIS database86% 的医院内肺炎和机械通气相关革兰阳性金黄色葡萄球菌非常常见Richards et al. Crit Care Med 1999;27:887892EnterococciS. aureusP. aeruginosaEnterobacter spp.Frequency (%)01020305引起ICU内HAP的病原体NNIS（19862003年）病原菌肺炎(n = 4365)血流感染 (n = 2351

3、)革兰阴性大肠杆菌5.03.3肺炎克雷伯杆菌7.24.2肠杆菌属10.04.4粘质沙雷菌4.72.3铜绿假单胞菌18.13.4不动杆菌属6.92.4其他14.13.8革兰阳性凝固酶阴性葡萄球菌1.842.9金黄色葡萄球菌27.814.3肠球菌1.314.5其他3.24.5Clinical Infectious Diseases 2005; 41:84854MRSA引起的感染（2004-2005 美国）JAMA. 2007;298(15):1763-1771 ICU内耐药菌的增加 (NNIS, 2002 vs 19972001)Resistance (%)0102030405060708090万

4、古霉素/肠球菌甲氧西林/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病人与MRSAAccessed August 30, 2005.Lowy FD. J Clin Invest. 2003;111:1265-1273.63%MRSA 在中国不同时期甲氧西林耐药葡萄球菌的检出率检出率（%）中国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，几乎都是通过接触传播，通常感染年纪大、病情较严重、皮肤有伤口（例如褥疮）或有导管（如导尿管）的人，健康人很少

7、会感染CA-MRSA能够感染健康人拥挤的监狱中颇为流行近年在美国各地的城镇社区（包括洛杉矶、旧金山、纽约、波士顿、迈阿密等大城市）也出现了多次小规模爆发CA-MRSA：现状美国弗吉尼亚州贝德福德一名17岁高中生就因感染MRSA而死亡，21所学校停课 美国每年有逾9万人感染MRSA；每年致死人数可能超过艾滋病阿什顿邦兹，07年10月4日感到身体一侧疼痛，就到当地一家医院就诊。 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、围内社区获得性MRSA的发病率呈上升趋势社区获得性MRSA可从以下情况中隐匿获得 医疗保健 日常生活 过去一年中住院超过5天 社区获得性MRSA，表达Panton-Valentine leukocidin (p-v)潘顿-瓦伦丁杀白细胞素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的病原体构成主要影响因素住院的时间 早发 晚发肺炎本身的严重程度：重症 非重症基础疾病 先前的治疗（抗生素、免疫抑制）早期中期晚期1 3 5 10 15 20链球菌流感杆菌金葡菌 MRSA肠杆菌肺克，大肠绿脓杆菌不动杆菌嗜麦芽窄食单胞菌入院天数住院时间与HAP致病菌的关系早发性HAP和晚发性HAP的病原菌早发HAP晚发HAPPMS

13、SA13 (19.40) 22 (11.00) 0.063MRSA8 (11.94) 47 (23.50) 0.028肺炎链球菌8 (11.94) 7 (3.50) 0.015肠杆菌属2 (2.99) 6 (3.00) 0.639大肠杆菌1 (1.49) 7 (3.50) 0.361肺炎克雷伯菌3 (4.48) 12 (6.00) 0.454粘质沙雷菌2 (2.99) 3 (1.50) 0.369不动杆菌属2 (2.99) 7 (3.50) 0.598嗜麦芽窄食单胞菌1 (1.49) 2 (1.00) 0.581铜绿假单胞菌2 (2.99) 23 (11.50) 0.026莫他卡拉菌3 (4.

14、48) 4 (2.00) 0.244流感嗜血杆菌4 (5.97) 4 (2.00) 0.122所有病原体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不充分的抗生素治疗(n=169) 充分的抗生素治疗(n=486) 0102030405060总死亡率感染

18、相关死亡率2442*18住院死亡率 (%)52*P.001充分起始抗生素治疗降低ICU内肺炎死亡率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菌血症社区获得性-菌血症金葡菌菌血症呼吸机相关肺炎病死率(患者% )正确的抗菌治疗不恰当的抗菌治疗P .0011a3P 5 days)HAP或 MDR病原体的危险因素否是窄谱抗菌药物广谱抗菌药物针对MDR病原体HAP初始经验性抗菌药物治疗的流程图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.经验性治疗: 晚期发病或存在MDR病原菌感染联合抗

22、菌治疗铜绿假单胞菌有抗假单胞菌活性的头孢菌素(头孢吡肟 ，头孢他定)或肺炎克雷伯菌(ESBL阳性)有抗假单胞菌活性的碳青霉烯类(亚胺培南或美罗培南)不动杆菌或-内酰胺/-内酰胺酶抑制剂(哌拉西林-他唑巴坦)有抗绿脓杆菌活性的氟喹诺酮类(环丙沙星或左氧氟沙星)或氨基糖苷类(阿米卡星，庆大霉素或妥布霉素)甲氧西林耐药金葡菌(MRSA)万古霉素或利奈唑胺嗜肺军团菌2006年亚洲HAP工作组抗生素选择策略特殊耐药菌感染的抗生素方案病原菌等级推荐抗生素方案MRSA12万古霉素 或 替考拉宁利奈唑胺 或 替加环素MDR 铜绿假单胞菌12哌拉西林-他唑巴坦 或 碳青霉烯类+/-氨基糖苷类或氟喹诺酮 （环丙沙

23、星）多粘菌素B 或 多粘菌素E +/- 环丙沙星MDR 不动杆菌12头孢哌酮/舒巴坦和/或替加环素多粘菌素B 或 多粘菌素E 肺炎克雷伯菌(ESBL+)12碳青霉烯类 或 替加环素哌拉西林-他唑巴坦大肠埃细菌(ESBL+)12碳青霉烯类 或 替加环素哌拉西林-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岁，宫腔术后金葡菌Nosocomial Pneumonia due to MRSASputum and blood: MRSABetter 1st

24、-line Anti-MRSA Agents,Glycopeptide orLinezolid ?万古霉素、利奈唑胺和替考拉宁分子结构比较万古霉素是微生物发酵产生的天然抗生素,属糖肽类抗生素利奈唑胺是人工合成的抗菌药,属于噁唑烷酮类抗菌药物替考拉宁是微生物发酵产生的抗生素,属于糖肽类抗生素万古霉素、利奈唑胺和替考拉宁 抗菌谱比较万古霉素、替考拉宁和利奈唑胺的抗菌谱相似，都是窄谱抗生素，治疗革兰阳性菌感染 金葡菌，包括MRSA 肺炎链球菌，包括PRSP 凝固酶阴性葡萄球菌，包括MRCNS 肠球菌，有少数耐药菌株万古霉素、利奈唑胺和替考拉宁 适应证的比较35、稳可信、他格适和斯沃产品说明书适应证万

25、古霉素利奈唑胺替考拉宁皮肤感染肺炎感染性心内膜炎？骨髓炎关节炎肺脓肿脓胸腹膜炎导管相关感染？脑膜炎万古霉素抗菌素作用机制万古霉素属快效杀菌剂具有三重作用机制1.抑制细菌细胞壁的合成抑制细菌细胞壁粘肽链合成的第二步 与五肽末端氨基酸分子结合，阻断转肽交叉连接 转糖作用发生障碍2. 影响细菌细胞膜的通透性3. 抑制细菌孢浆中RNA的合成MGMGMGMG糖肽类糖肽类抗菌机制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)万古霉素对金葡菌的MIC值呈逐年上升趋势Wang G et al. J Clin Microbiol. 2006;44:3883-3886*一项自2000年1月至2004年12月UCLA医学中心对6003例临床分离金黄色葡萄球菌菌株进行的分析监测结果近年来，万古霉素对70%金黄色葡萄球菌的MIC值1g/mL*分离菌株的百分比(%)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以上时间应40%万古霉素PK与PD 以t1/2 6hr 1g 滴注 1hr 滴注结束，即刻峰浓60ug/ml ；2hr后峰浓 25ug/ml计用药剂量：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%万古霉素PK与PD 以t1/2 6hr 0.5g 滴注 30分滴注,结束即刻峰浓33ug/ml; 6hr后峰浓 计用药剂量： 0.5g q8h MIC值TMICT3MIC0.5100%100%1.0100

29、% 62.5%1.5100%50%2.0100%万古霉素小鼠 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):S35万古霉素疗效与 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: 143万古霉素MIC与MRSA败血症/肺炎感染治疗Wilhelm KL. 2008 ICAAC abstract A-1905参数MIC1MIC1病例数2018万古霉素谷浓度(mg/L)18.618.7AUIC50327726795AUIC400(%)6011Clinical response,

31、length of stay, mortality and nephrotoxicity were equal .万古霉素MIC与MRSA 败血症疗效 OutcomeLow MIC(7 days9/104 (8.65%)11/54 (20.4%)0.03Kaur I. 2008 ICAAC abstract K-564 国内葡萄球菌对万古霉素始终保持100%敏感率 葡萄球菌菌株数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全国细菌耐药监测结果1、李家泰, Allan J Weinstein, 杨敏等. 中国细菌耐药监测研究. 中华医学杂志 2001;81(1):8-162-7. 国家细菌耐药性监测中心监测数据总结RESIST研究中3100株耐甲氧西林葡萄球菌对12种抗生素的耐药率耐药率%RESIST研究中207株甲氧西林敏感葡萄球菌对12种抗生素的耐药率耐药率%RESIST研究的结论3307株葡萄球菌中：除一株MRCNS，所有菌株对万古霉素保持100%敏感无论对甲氧西林耐药还是对甲氧西林敏感的葡萄球菌对替考拉宁存在不同程度耐药，尤

33、其是凝固酶阴性葡萄球菌MRCNS对替考拉宁的耐药性高，其中耐甲氧西林溶血性葡萄球菌(MRSH)对替考拉宁的耐药率高达48.2%对甲氧西林敏感的溶血性葡萄球菌(MSSH)对替考拉宁的耐药率达38.5%2009年CLSI最新指南：葡萄球菌： 万古霉素MIC 替考拉宁MIC 敏感菌株 0.5-2ug/ml 8ug/ml 耐药菌株 16ug/ml 32ug/ml 低敏菌株 4-8ug/ml 万古霉素与同为糖肽类替考拉宁相比：万古霉素对葡萄球菌和肠球菌的MIC值比较中，万古霉素仍然有明显的优势 肠球菌： 万古霉素MIC 替考拉宁MIC 敏感菌株 4ug/ml 8ug/ml 耐药菌株 32ug/ml 32

34、ug/ml 万古霉素在肺组织的浓度 在一项30例行肺叶次全切除术的患者研究中，静脉给予万古霉素1 g 之后，组织药物浓度范围为0-12.2 mg/kg，平均组织浓度为2.8 mg/kg，组织穿透率为41% Penetration of vancomycin into human lung tissueM. Cruciani, G. Gattr*, L. Lazzarini, G. Furlan, G. Broccali, M. Malena,C. Franchini and Ercole Concia万古霉素的肺组织浓度健康志愿者给予万古霉素1 g q12h 给药后，12 h肺组织浓度为2.4

35、 mg/kg ， 总体穿透率为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血浆浓度19.83.75.11.7上皮细胞衬液（ELF）5.31.52.40.7肺泡巨噬细胞（AM）32.08.545.223.3不同时间血浆和肺组织中万古霉素的浓度1万古霉素治疗金葡菌菌血症和心内膜炎的临床疗效文献来源疾病病例数有效率Levine9心内膜炎3582.8%Esposito10心内膜炎5080.0%Levine9心内膜炎1782.4%Craven11菌血症1973.6%Esposito12菌血症9286.9%Kirby13败血症3372.7%Myers14菌血症158

37、6.7%Coppens15菌血症887.5%Sorrell16菌血症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替考拉宁治疗重症感染的疗效资料来源疾病剂量/天病例数有效率Calain P17金葡菌菌血症3 mg/kg650%Ler

38、ner 18金葡菌菌血症6 mg/kg9100%USA-1 18金葡菌菌血症6 mg/kg6080.0%USA-2 18金葡菌菌血症6 mg/kg1421.4%USA-3 18金葡菌菌血症30 mg/kg4985.7%Liu 19金葡菌菌血症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替考拉宁治疗金葡菌心内膜炎的疗效资料来源疾病剂量/天病例数有效率Davey20心内膜炎6 mg/

39、kg1050%Rybak21心内膜炎6 mg/kg520%Gilbert22心内膜炎6 mg/kg825%Rybak23心内膜炎6 mg/kg1421.4%Fortun24心内膜炎6 mg/kg633.3%USA-323心内膜炎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、万古霉素和替考拉宁的疗效比较 同属于糖肽类抗生素，具有相似的化学结构和抗菌谱 金葡菌和凝固酶阴性葡萄球菌对替考拉宁易产生耐药 替考拉宁较高的蛋白结合率（90-97%) ,使感染部位无法达到有效 的药物浓度，导致对严重感染疗效不确切，需加大剂量 替考拉宁常规剂量临床疗效不理想（尤其在心内膜炎），加大剂 量往往导致副反应增加 研究表明，稳可信与替考拉宁在引起皮疹，肾功能障碍等副反应 方面无统计学差异；但替考拉宁引起的血小板减少症的发生率显 著高于稳可信利奈唑胺抗菌机制利奈唑胺抗菌谱Gram-positive microorganisms: 屎肠球菌(包括VRE) 金黄色葡萄球菌(包括MRSA)肺炎

41、链球菌(包括PRSP)无乳链球菌化脓性链球菌粪肠球菌(包括VRE)表皮葡萄球菌(包括MRSE)溶血葡萄球菌草绿色链球菌Some anaerobic bacteria:万古霉素和利奈唑胺治疗院内肺炎疗效相当在利奈唑胺提交给FDA的临床报告中,治疗医院内肺炎的临床研究.用万古霉素和利奈唑胺进行对照,显示万古霉素可评价临床疗效为60%,利奈唑胺可评价临床疗效57%0102030405060利奈唑胺万古霉素利奈唑胺万古霉素25 ZYVOX 产品说明书信息 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.利奈唑胺耐药性抗菌机制:50S亚基中23S rRNA V区结合耐药机制: 23S rRNA V区点突变, G2576T叠加性: 5-6个23S rRNA 基因逐步变异交叉耐药:氯霉素,链阳霉素,林可霉素Enterocccus, Staphylococcus临床菌株已有报道实验室筛选万古霉素和替考拉宁安全性的比较不良事件替考拉宁（N=238）万古霉素（N=239）过敏反应7.6%8.8% 发热3.4%2.5% 皮疹4.6%3.8%腹泻3.4%4.6%恶心/呕吐3.4%3.3%听力/平衡功能障碍1.

48、3%1.3%肝功能损害1.3%1.3%肾毒性1.7%2.1%血液系统3.8%0.8%血小板减少a3.4%0.0%26、a p = 0.007, Fishers test27、Source: Wilson, Grunberg, Neu, Int. J. Antimicrob Agents, Suppl 1:S1 (1994)万古霉素和利奈唑胺安全性比较由于万古霉素制剂的纯度显著提高，目前临床大量应用万古霉素，证实其肾毒性很少见,包括调整剂量后用于肾功能受损的病人，同时万古霉素的肾毒性具有可逆性28。而有数据表明，利奈唑胺引起的严重不良反应血小板减少的病例高达35%,在肾功能损伤的病人应用利奈唑胺引起的血小板减少达到65%,29。高纯度的万古霉素具有良好的安全性28 Wakefield DS, Pfaller M, Massanari RM, Hammons GT. Variat