对糖肽类抗生素临床应用的再认识课件

对糖肽类抗生素临床应用的再认识浙江大学医学院附属二院呼吸科院感科王选锭2FolliculitisAbscessCellulitisStaphylococcusaureus

SkinorSoft-TissueInfections

NecrotizingpneumoniaEndocarditisOsteomyelitisStaphylococcusaureus

Deep-SeatedInfectionsIntracranialinfection真的王牌——

经得起时间的考验抗G+球菌：万古霉素替考拉宁抗G-杆菌：多粘菌素抗真菌：两性霉素B替考拉宁

对葡萄球菌属的抗菌活性细菌菌株数替考拉宁MIC90万古霉素

MIC90MSSA12500.52.0MRSA10830.52.0MSCNS8852.04.0MRCNS4284.04.0溶血葡萄球菌27916.04.0*替考拉宁对金葡菌的抗菌活性比万古霉素强2～4倍*替考拉宁对凝固酶阴性葡萄球菌的抗菌活性与万古霉素相似,但对溶血葡萄球菌的抗菌作用较万古霉素差SpencerRC,GoeringR,IntJAntimicrobAgents1995;5:169-177替考拉宁

对链球菌属的抗菌活性细菌菌株数他格适

MIC90万古霉素

MIC90肺炎链球菌6500.1250.5化脓性链球菌3580.1250.5无乳链球菌2280.1251.0C组链球菌420.250.5F组链球菌190.50.5G组链球菌540.50.5α-溶血性链球菌1281.01.0*替考拉宁对肺炎链球菌和化脓性链球菌等的抗菌活性较万古霉素稍强或相仿SpencerRC,GoeringR,IntJAntimicrobAgents1995;5:169-177替考拉宁

对肠球菌属的抗菌活性细菌菌株数替考拉宁MIC90万古霉素MIC90粪肠球菌21230.54.0屎肠球菌2471.02.0SpencerRC,GoeringR,IntJAntimicrobAgents1995;5:169-177替考拉宁

对厌氧菌的抗菌活性细菌菌株数他格适MIC90万古霉素MIC90消化链球菌190.251.0梭菌属580.251.0艰难梭菌2820.52.0产气荚膜杆菌1300.50.5丙酸杆菌1650.250.5Glupczynskietal.EurJClinMicrobiol1984;3:50-51MRSA菌血症、自体瓣膜感染性心内膜炎

——糖肽类首选MRSA菌血症：非复杂性（迅速转阴，迅速退热，无心内膜炎、迁涉灶、假体）：万古霉素或达托霉素2周复杂性：万古霉素或达托霉素4~6周心内膜炎：万古霉素或达托霉素6周评估、处理菌血症的来源！菌血症者常规行心超检查！MRSA儿童菌血症、感染性心内膜炎

——首选糖肽类万古霉素：15mg/kgq6h，2~6周鉴于替代药物疗效和安全性有限数据的考虑，不推荐利奈唑胺、克林霉素；达托霉素等选择也需慎重2011IDSA糖肽类治疗MRSA

菌血症与感染性心内膜炎推荐剂量LiuC,etal.ClinicalPracticeGuidelinesbytheInfectiousDiseasesSocietyofAmericafortheTreatmentofMethicillin-ResistantStaphylococcusAureusInfectionsinAdultsandChildren.CID2011:52.推荐药物成人剂量儿童剂量证据级别补充说明菌血症万古霉素15-20mg/kg/剂IV每8-12h15mg/kg/剂IV每6hAII常规不推荐将庆大霉素(AII)或利福平(AI)加入万古霉素达托霉素6mg/kg/剂IVQD6-10mg/kg/剂IVQDAI/CIII对于成人患者，部分专家推荐较高剂量(8-10mg/kgIVQD)给药(BIII)孕期分级B感染性心内膜炎自体瓣膜感染同菌血症感染性心内膜炎人工瓣膜感染万古霉素15-20mg/kg/剂IV每8-12h15mg/kg/剂IV每6hBIII庆大霉素1mg/kg/剂IV每8h1mg/kg/剂IV每8h利福平300mg/kgPO/IV每8h5mg/kg/剂PO/IV每8hMRSA肺炎的推荐抗菌治疗重症CAP（进入ICU/坏死或空洞浸润/脓胸）经验性治疗MRSA感染HA-MRSACA-MRSA伴脓胸MRSA肺炎，抗生素+引流儿童MRSA肺炎：万古霉素（克林霉素，替代—利奈唑胺）万古霉素利奈唑胺克林霉素7~21天LiuC,etal.ClinicalPracticeGuidelinesbytheInfectiousDiseasesSocietyofAmericafortheTreatmentofMethicillin-ResistantStaphylococcusAureusInfectionsinAdultsandChildren.CID2011:52.2011IDSA糖肽类治疗MRSA肺炎推荐剂量LiuC,etal.ClinicalPracticeGuidelinesbytheInfectiousDiseasesSocietyofAmericafortheTreatmentofMethicillin-ResistantStaphylococcusAureusInfectionsinAdultsandChildren.CID2011:52.推荐药物成人剂量儿童剂量证据级别补充说明万古霉素15-20mg/kg/剂IV每8-12小时15mg/kg/剂IV每6小时AII利奈唑胺600mgPO/IVBID10mg/kg/剂PO/IV每8小时不超过600mg/剂AII12岁及以上儿童600mgPO/IVBID孕期分级C克林霉素600mgPO/IVTID10-13mg/kg/剂PO/IV每6-8小时不超过40mg/kg/dBIII/AII孕期分级BMRSA骨关节感染骨髓炎：清创引流+万古霉素或达托霉素、利奈唑胺、克林霉素（+利福平），﹥8周化脓性关节炎：同骨髓炎，3~4周骨关节、脊柱植入物术后感染：早发：同骨髓炎（+2周利福平）迟发：取出植入物儿童：万古霉素（克林霉素，达托霉素，利奈唑胺）万古霉素治疗失败怎么办？万古霉素治疗失败怎么办？清创引流替代一：达托霉素+（庆大霉素，利福平，利奈唑胺，SMZco）替代二：奎奴普丁/达福普丁，SMZco，利奈唑胺，特拉万星台湾传染病协会推荐

替考拉宁为MRSA-HAP的经验性治疗GuidelinesonantimicrobialtherapyofpneumoniainadultsinTaiwan,revised2006.JMicrobiolImmunolInfect.2007;40(3):279-283.推荐替考拉宁作为MRSA感染的迟发性HAP和VAP的经验性治疗用药对于存在多重耐药危险因素和任何严重疾病的迟发性HAP(肺炎发生于入院第5天或以后)，推荐替考拉宁联合其他抗生素作为MRSA感染的经验性治疗用药对于VAP，推荐替考拉宁联合其他抗生素作为MRSA感染的经验性治疗用药台湾成人肺炎抗生素治疗指南

(2007)台湾传染病协会(IDST)英国MRSA感染预防和治疗指南

推荐MRSA感染选用糖肽类治疗GouldFK,etal.JournalofAntimicrobialChemotherapy.2009;63:849–861.英国MRSA感染预防和治疗指南(2008)无并发症的菌血症推荐使用糖肽类抗生素，疗程至少14d[证据级别Ⅱ]严重皮肤软组织感染和/或菌血症高危因素的住院患者，可考虑使用使用糖肽类抗生素[证据级别ⅠA]糖肽类分子结构万古霉素替考拉宁组织浓度

(%ofserumconcentration)TissueVancomycinTeicoplaninLinezolidBone,%7–1350–6060CSF,%0–181071LF,%11–1748-332450Muscle,%304094Vancomycin

Teicoplanin

-64%p＜0.05Hahn-AstCetal.Infection2008;36:54–8.替考拉宁肾毒性发生率低于万古霉素NephrotoxicityofglycopeptidesDoseandDuration(loading)NephrotoxicityTeicoplaninVancomycinTeicoplaninVancomycin200-400mg/24hrs,loading400mg.4-30d0.75-1g12-hourly,1-19d1/28(3.5%)5/28(18%)400mg/24hrs,loading400mg/12hrs,3doses.5-31d500mg/8hrs,3-42d6/24(25%)17/32(53%)Definations:>50%riseincreatinineJChemother2000;12(supp5):21-529/4932/42Hahn-AstCetal.Infection2008;36:54–8.2/1111/19%OverallOverallPneumoniaPneumonia替考拉宁vs万古霉素--肺部感染OverallvsPneumoniaClinicalEfficacy

inFebrileNeutropeniaC.Tascini.et.al.JournalofChemotherapy.2009;21:311-316.利奈唑胺与替考拉宁治疗G+菌感染的回顾性研究利奈唑胺组（169例）替考拉宁组（91例）菌血症患者占25%肺炎患者占19.5%其中22名患者为VAP，且均由MRSA引起，3例为早发性菌血症患者占16%肺炎患者占20%其中10名患者为VAP，亦均由MRSA引起，7例为早发性菌血症及肺炎是两组患者最常见的感染类型C.Tascini.etal.JournalofChemotherapy.2009;21:311-316.临床有效率(%)32/3712/1515/227/1015/1611/1413/169/1413/148/13利奈唑胺治疗各部位感染的临床有效率与替考拉宁无统计学差异C.Tascini.etal.JournalofChemotherapy.2009;21:311-316.

研究结果TimeMIC90LogConcentration24h-AUCTroughlevel:15-20mg/L24h-AUC:>800gh/mL(teicolanin)24h-AUIC(AUC24/MIC):AtleastanAUC24/MIC>125，BetteranAUC24/MIC>345or400

GlycopeptidesTime-dependentBacterialKillingMICDoseDoseCmaxT>MICTeicoplaninPharmacokineticsTeicoplanincanbegivenbytheIVorIMrouteLongserumhalflife(88~182hrs)90%boundtoserumalbuminExcretedthroughthekidneys,80%ofthedosebeingrecoveredinurineand3%instoolin16days4.987.649.4一一TeicoplaninLevelsinCriticallyIllPatients

202PatientsJAntimicrobChemother2003;51:971–5.Anappropriateloadingdoseofteicoplanin(6mg/kgevery12hforatleastthreedoses)wasadministeredonlyin38.6%ofcases41.2%withnormalrenalfunction8.7%withmoderatelyimpairedrenalfunction2.2%ofpatientswithtotallyimpairedrenalfunctionHypoalbuminaemicin74.5%MorerapiddistributionandhigherclearanceJAntimicrobChemother2003;51:971–710.86.1111.228.66TeicoplaninLevelsinCriticallyIllPatients

LoadingDoseIsNeeded6mg/kgevery12hforthreedoses4.987.649.4一一TeicoplaninLevelsinCriticallyIllPatients

202PatientsJAntimicrobChemother2003;51:971–5.NiwaTetal.IntJAntimicrobAgents2010;35:507-10.KanazawaNetal.JInfectChemother2011;17:297-300.MatsumotoKetal.JInfectChemother2010;16:193-9.AhnBJ,etal.YonseiMedJ2011;52:616-23.ClinicalResponsevs.TroughTeicoplaninLevels

Ctrough

13mg/Lon4thDay(N=69)MatsumotoKetal.JInfectChemother2010;16:193-9.83%20%TeicoplaninDosingforMRSAInfectionsTeicoplaninatotaldoseof36mg/kgduringthefirst3daysandatroughconcentrationof13mg/Lonthefourthday9%88%36mg/kgwasrecommendedtoachieveCtrough>13mg/LMatsumotoKetal.JInfectChemother2010;16:193-9.13SerumLevelofTeicoplanin12mg/kgq12hx3doses,followedby12mg/kg24hx1dose6mg/kgq12hx3doses,followedby6mg/kg24hx1doseMaintenancedose:both6mg/kg.dayWangJT,etal.ManuscriptpreparedRecommendedTeicoplaninLoadingDosesAloadingdoseof400mgq12hforthreedosesfollowedby400mgoncedaily:Noneachievedtheoptimalteicoplanintroughconcentrationwithin3days800mgand400mg12hapartonDay1and600mgand400mg12hapartonDay2,followedbyahighmaintenancedoseof400mg95%ofpatients(21/22)showedtheoptimalconcentration800mgonDay1followedby400mgonDays2and3isrecommendedastheinitialloadingdosestoachievetheoptimaltroughconcentrationpromptlyNiwaTetal.IntJAntimicrobAgents2010;35:507-10.

Slide43of45RecommendedTeicoplaninLoadingDoses说明书对于剂量的规定：肾功能正常的