ICU阳性菌感染规范化治疗.ppt

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.VincentJL,RelloJ,MarshallJ,etal.InternationalStudyofthePrevalenceandOutcomesofInfectioninIntensiveCareUnits.JAMA2009;302(21):2323-2329.2.VincentJL,BihariDJ,SuterPM,etal.TheprevalenceofnosocomialinfectioninintensivecareunitsinEurope.ResultsoftheEuropeanPrevalenceofInfectioninIntensiveCare(EPIC)Study.EPICInternationalAdvisoryCommittee.JAMA1995;274(8):639-644.,重症感染抗生素治疗的三大原则1,1.ThisofficialstatementoftheAmericanThoracicSocietyandtheInfectiousDiseasesSocietyofAmericawasapprovedbytheATSBoardofDirectors,December2004andtheIDSAGuidelineCommitteeGuidelinesfortheManagementofAdultswithHospital-acquired,Ventilator-associated,andHealthcare-associatedPneumoniaAmJRespirCritCareMed2005;171:388-416.2.DellingerRP,LevyMM,RhodesA,etal.SurvivingSepsisCampaign:InternationalGuidelinesforManagementofSevereSepsisandSepticShock,2012.IntensiveCareMed2013;39:165228,主要内容,ICU感染的分布,VincentJL,RelloJ,MarshallJ,etal.InternationalStudyofthePrevalenceandOutcomesofInfectioninIntensiveCareUnits.JAMA2009;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,VincentJL,RelloJ,MarshallJ,etal.InternationalStudyofthePrevalenceandOutcomesofInfectioninIntensiveCareUnits.JAMA2009;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2008;3(5):347-350.,MRSA检出率(%),MRSA所致ICU病死率显著高于MSSA,HanbergerH,WaltherS,LeoneM,etal.Increasedmortalityassociatedwithmethicillin-resistantStaphylococcusaureus(MRSA)infectionintheintensivecareunit:resultsfromtheEPICIIstudy.IntJAntimicrobAgents2011;38(4):331-335.,革兰阳性菌国内监测结果与全球一致，金葡菌持续增高,检出菌株数,1.JonesRn,etal.DiagnMicrobiolInfectDis.2009Jun;64(2):191-201.2.JonesRN,etal.DiagnMicrobiolInfectDis.2009Dec;65(4):404-13.3.BiedenbachDJ,etal.DiagnMicrobiolInfectDis.2010Dec;68(4):459-67.4.FlammRK,etal.JChemother.2012Dec;24(6):328-37.5.FlammRK,etal.DiagnMicrobiolInfectDis.2013Jun;76(2):206-13.6.MendesRE,etal.JAntimicrobChemother.2014Jun;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):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.PeaF,VialeP.Theantimicrobialtherapypuzzle:couldphamacokinetic-phamacodynamicrelationshipsbehelpfulinaddressingtheissueofappropriatepneumoniatreatmentincriticallyIIIpatients?ClinInfectDis2006;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,2011IDSAMRSA肺炎感染的治疗推荐,LiuC,BayerA,CosgroveSE,etal.ClinicalPracticeGuidelinesbytheInfectiousDiseasesSocietyofAmericafortheTreatmentofMethicillin-ResistantStaphylococcusAureusInfectionsinAdultsandChildren.CID2011:52.,2011IDSAMRSA菌血症与感染性心内膜炎中的治疗推荐,LiuC,BayerA,CosgroveSE,etal.ClinicalPracticeGuidelinesbytheInfectiousDiseasesSocietyofAmericafortheTreatmentofMethicillin-ResistantStaphylococcusAureusInfectionsinAdultsandChildren.CID2011:52.,主要内容,ZEPHyR研究引发了广泛的学术关注,1.TacconeFS,etal.ClinInfectDis.2012;55(1):161-163.2.LaheyT.ClinInfectDis.2012;55(1):159-160.3.WolffM,MourvillierB.ClinInfectDis.2012;55(1):160-161.4.MasutaK,etal.ClinInfectDis.2012;55(1):161.5.GraysonML,etal.ClinInfectDis.2012;55(1):165.6.RichardGW,etal.ClinInfectDis.2012;55(1):163-165.7.BrianBlackburn.InfectiousDiseaseAlert.2012;31(9):100-102.8.AlanizC,PogueJM.AnnPharmacother.2012;46(10):1432-1435.,利奈唑胺治疗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),KalilAC,KlompasM,HaynatzkiG,etal.Treatmentofhospital-acquiredpneumoniawithlinezolidorvancomycin:asystematicreviewandmeta-analysis.BMJOpen2013;3(10):e003912.,利奈唑胺或万古霉素治疗阳性菌HAP：系统回顾和荟萃分析,KalilAC,KlompasM,HaynatzkiG,etal.Treatmentofhospital-acquiredpneumoniawithlinezolidorvancomycin:asystematicreviewandmeta-analysis.BMJOpen2013;3(10):e003912.,临床反应率,随机双盲研究(RD5.0%)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,-0.38,0.00,0.38,0.75,49/193,61/302,100/587,23/301,2/71,235/1454,33/220,3/101,7/51,6/74,49/445,284/1900,71/107,114/168,95/165,19/23,19/26,318/489,12/23,9/10,11/51,15/23,47/107,365/596,0.790,0.566,0.041,0.731,0.131,0.114,0.907,0.409,0.881,0.406,0.820,0.192,0.113,0.130,0.216,0.191,0.426,0.112,0.263,0.137,0.182,0.423,0.108,0.092,-0.149,-0.071,0.005,-0.272,-0.055,-0.012,-0.297,-0.337,-0.212,-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唑胺,KalilAC,KlompasM,HaynatzkiG,etal.Treatmentofhospital-acquiredpneumoniawithlinezolidorvancomycin:asystematicreviewandmeta-analysis.BMJOpen2013;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(RD8.4%)和随机开放标签研究(RD3.0%)之间无统计学差异,医院获得性肺炎：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,-0.033,-0.095,-0.324,-0.267,-0.211,-0.140,-0.041,-0.126,0.197,0.084,0.254,0.044,0.000,0.003,0.092,0.030,0.064,-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,KalilAC,KlompasM,HaynatzkiG,etal.Treatmentofhospital-acquiredpneumoniawithlinezolidorvancomycin:asystematicreviewandmeta-analysis.BMJOpen2013;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(RD1.9%)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,-1.25,0.00,0.25,0.50,49/193,61/302,100/587,23/301,2/71,235/1454,33/220,3/101,7/51,6/74,49/445,284/1900,36/203,64/321,94/597,17/304,5/71,216/1496,44/240,13/215,14/100,4/75,75/630,291/2126,0.063,0.935,0.549,0.310,0.243,0.342,0.337,0.189,0.963,0.498,0.253,0.992,0.004,0.060,0.029,0.019,0.113,0.014,0.101,0.077,0.119,0.053,0.052,0.021,-0.157,-0.066,-0.055,-0.060,-0.029,-0.040,-0.035,-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,KalilAC,KlompasM,HaynatzkiG,etal.Treatmentofhospital-acquiredpneumoniawithlinezolidorvancomycin:asystematicreviewandmeta-analysis.BMJOpen2013;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,KalilAC,KlompasM,HaynatzkiG,etal.Treatmentofhospital-acquiredpneumoniawithlinezolidorvancomycin:asystematicreviewandmeta-analysis.BMJOpen2013;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,KalilAC,KlompasM,HaynatzkiG,etal.Treatmentofhospital-acquiredpneumoniawithlinezolidorvancomycin:asystematicreviewandmeta-analysis.BMJOpen2013;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,KalilAC,KlompasM,HaynatzkiG,etal.Treatmentofhospital-acquiredpneumoniawithlinezolidorvancomycin:asystematicreviewandmeta-analysis.BMJOpen2013;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MRSANP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。,ConsensusstatementonMRSANPinAsia.ClinRespirJ2014;:.,AntibiotictreatmentalgorithmforMRSANP,稳可信说明书用法用量,肾功能正常患者：成人：2g/天，500mgq6h或1gq12h，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：1015mg/kg/次出生1周内，q12h给药出生1周到1月，q8h给药老年人：500mgq12h或1gqd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，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.RybakMJetal.Vancomycintherapeuticguidelines:asummaryofconsensusrecommendationsfromtheinfectiousdiseasesSocietyofAmerica,theAmericanSocietyofHealth-SystemPharmacists,andtheSocietyofInfectiousDiseasesPharmacists.ClinInfectDis.2009Aug1;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,RybakM,LomaestroB,RotschaferJC,etal.Vancomycintherapeuticguidelines:asummaryofconsensusrecommendationsfromtheinfectiousdiseasesSocietyofAmerica,theAmericanSocietyofHealth-SystemPharmacists,andtheSocietyofInfectiousDiseasesPharmacists.ClinInfectDis2009;49(3):325-327.,Reviewofcontinuous-infusionvancomycin,OBJECTIVE:Toevaluatetheefficacyandsafetyofadministeringvancomycinasacontinuousinfusion.DATASOURCES:LiteraturewasaccessedthroughMEDLINE(1977-September2012),Embase(1977-September2012),andGoogleScholar,usingthetermsvancomycin,continuous,discontinuous,infusion,pharmacokinetics,pharmacodynamics,andnephrotoxicity.Inaddition,referencecitationsfrompublicationsidentifiedwerereviewed.Fourteenclinicaltrialswerereviewed(2prospective,1meta-analysis,11retrospective).Continuous-infusiontherapydidnotsignificantlyimprovetheefficacyofvancomycininthetreatmentofinvasiveMRSAinfections.Conflictingresultsexistregardingthesafetyprofileofcontinuous-infusioncomparedwithintermittent-infusionvancomycin.Theonlypublishedprospectiverandomizedclinicaltrialcomparingcontinuousinfusionwithintermittenttherapyfoundnosignificantdifferenceintheratesofnephrotoxicity.Thedatafromretrospectivestudiesareheterogeneousandshowvariableratesofnephrotoxicity.,36,AnnPharmacother.2013Feb;47(2):219-27,CONCLUSIONS:Currentlyavailableevidenceisinsufficienttoconcludewhetheranimprovementinvancomycinefficacyexistswhenitisadministeredasacontinuousinfusion.Theriskofnephrotoxicityassociatedwithcontinuous-infusionvancomycinrequiresfurtherinvestigationinprospectiverandomizedtrials.,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2005-2010年GPRS监测项目金葡菌对万古霉素MIC值稳定,ZhaoC,SunH,WangH,etal.Antimicrobialresistancetrendsamong5608clinicalGram-positiveisolatesinChina:resultsfromtheGram-PositiveCocciResistanceSurveillanceprogram(2005-2010).DiagnMicrobiolInfectDis2012;73(2):174-81.,2005-2010年在中国为期4年的GPRS细菌耐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：VISAvancomycinintermediatelysusceptibleS.aureus万古霉素中介的金黄色葡萄球菌RybakM,LomaestroB,RotschaferJC,etal.Vancomycintherapeuticguidelines:asummaryofconsensusrecommendationsfromtheinfectiousdiseasesSocietyofAmerica,theAmericanSocietyofHealth-SystemPharmacists,an