對糖肽類抗生素臨床應(yīng)用的再認(rèn)識課件

對糖肽類抗生素臨床應(yīng)用的再認(rèn)識浙江大學(xué)醫(yī)學(xué)院附屬二院呼吸科院感科王選錠2FolliculitisAbscessCellulitisStaphylococcusaureus

SkinorSoft-TissueInfections

NecrotizingpneumoniaEndocarditisOsteomyelitisStaphylococcusaureus

Deep-SeatedInfectionsIntracranialinfection真的王牌——

經(jīng)得起時間的考驗抗G+球菌：萬古霉素替考拉寧抗G-桿菌：多粘菌素抗真菌：兩性霉素B替考拉寧

對葡萄球菌屬的抗菌活性細(xì)菌菌株數(shù)替考拉寧MIC90萬古霉素

MIC90MSSA12500.52.0MRSA10830.52.0MSCNS8852.04.0MRCNS4284.04.0溶血葡萄球菌27916.04.0*替考拉寧對金葡菌的抗菌活性比萬古霉素強(qiáng)2～4倍*替考拉寧對凝固酶陰性葡萄球菌的抗菌活性與萬古霉素相似,但對溶血葡萄球菌的抗菌作用較萬古霉素差SpencerRC,GoeringR,IntJAntimicrobAgents1995;5:169-177替考拉寧

對鏈球菌屬的抗菌活性細(xì)菌菌株數(shù)他格適

MIC90萬古霉素

MIC90肺炎鏈球菌6500.1250.5化膿性鏈球菌3580.1250.5無乳鏈球菌2280.1251.0C組鏈球菌420.250.5F組鏈球菌190.50.5G組鏈球菌540.50.5α-溶血性鏈球菌1281.01.0*替考拉寧對肺炎鏈球菌和化膿性鏈球菌等的抗菌活性較萬古霉素稍強(qiáng)或相仿SpencerRC,GoeringR,IntJAntimicrobAgents1995;5:169-177替考拉寧

對腸球菌屬的抗菌活性細(xì)菌菌株數(shù)替考拉寧MIC90萬古霉素MIC90糞腸球菌21230.54.0屎腸球菌2471.02.0SpencerRC,GoeringR,IntJAntimicrobAgents1995;5:169-177替考拉寧

對厭氧菌的抗菌活性細(xì)菌菌株數(shù)他格適MIC90萬古霉素MIC90消化鏈球菌190.251.0梭菌屬580.251.0艱難梭菌2820.52.0產(chǎn)氣莢膜桿菌1300.50.5丙酸桿菌1650.250.5Glupczynskietal.EurJClinMicrobiol1984;3:50-51MRSA菌血癥、自體瓣膜感染性心內(nèi)膜炎

——糖肽類首選MRSA菌血癥：非復(fù)雜性（迅速轉(zhuǎn)陰，迅速退熱，無心內(nèi)膜炎、遷涉灶、假體）：萬古霉素或達(dá)托霉素2周復(fù)雜性：萬古霉素或達(dá)托霉素4~6周心內(nèi)膜炎：萬古霉素或達(dá)托霉素6周評估、處理菌血癥的來源！菌血癥者常規(guī)行心超檢查！MRSA兒童菌血癥、感染性心內(nèi)膜炎

——首選糖肽類萬古霉素：15mg/kgq6h，2~6周鑒于替代藥物療效和安全性有限數(shù)據(jù)的考慮，不推薦利奈唑胺、克林霉素；達(dá)托霉素等選擇也需慎重2011IDSA糖肽類治療MRSA

菌血癥與感染性心內(nèi)膜炎推薦劑量LiuC,etal.ClinicalPracticeGuidelinesbytheInfectiousDiseasesSocietyofAmericafortheTreatmentofMethicillin-ResistantStaphylococcusAureusInfectionsinAdultsandChildren.CID2011:52.推薦藥物成人劑量兒童劑量證據(jù)級別補充說明菌血癥萬古霉素15-20mg/kg/劑IV每8-12h15mg/kg/劑IV每6hAII常規(guī)不推薦將慶大霉素(AII)或利福平(AI)加入萬古霉素達(dá)托霉素6mg/kg/劑IVQD6-10mg/kg/劑IVQDAI/CIII對于成人患者，部分專家推薦較高劑量(8-10mg/kgIVQD)給藥(BIII)孕期分級B感染性心內(nèi)膜炎自體瓣膜感染同菌血癥感染性心內(nèi)膜炎人工瓣膜感染萬古霉素15-20mg/kg/劑IV每8-12h15mg/kg/劑IV每6hBIII慶大霉素1mg/kg/劑IV每8h1mg/kg/劑IV每8h利福平300mg/kgPO/IV每8h5mg/kg/劑PO/IV每8hMRSA肺炎的推薦抗菌治療重癥CAP（進(jìn)入ICU/壞死或空洞浸潤/膿胸）經(jīng)驗性治療MRSA感染HA-MRSACA-MRSA伴膿胸MRSA肺炎，抗生素+引流兒童MRSA肺炎：萬古霉素（克林霉素，替代—利奈唑胺）萬古霉素利奈唑胺克林霉素7~21天LiuC,etal.ClinicalPracticeGuidelinesbytheInfectiousDiseasesSocietyofAmericafortheTreatmentofMethicillin-ResistantStaphylococcusAureusInfectionsinAdultsandChildren.CID2011:52.2011IDSA糖肽類治療MRSA肺炎推薦劑量LiuC,etal.ClinicalPracticeGuidelinesbytheInfectiousDiseasesSocietyofAmericafortheTreatmentofMethicillin-ResistantStaphylococcusAureusInfectionsinAdultsandChildren.CID2011:52.推薦藥物成人劑量兒童劑量證據(jù)級別補充說明萬古霉素15-20mg/kg/劑IV每8-12小時15mg/kg/劑IV每6小時AII利奈唑胺600mgPO/IVBID10mg/kg/劑PO/IV每8小時不超過600mg/劑AII12歲及以上兒童600mgPO/IVBID孕期分級C克林霉素600mgPO/IVTID10-13mg/kg/劑PO/IV每6-8小時不超過40mg/kg/dBIII/AII孕期分級BMRSA骨關(guān)節(jié)感染骨髓炎：清創(chuàng)引流+萬古霉素或達(dá)托霉素、利奈唑胺、克林霉素（+利福平），﹥8周化膿性關(guān)節(jié)炎：同骨髓炎，3~4周骨關(guān)節(jié)、脊柱植入物術(shù)后感染：早發(fā)：同骨髓炎（+2周利福平）遲發(fā)：取出植入物兒童：萬古霉素（克林霉素，達(dá)托霉素，利奈唑胺）萬古霉素治療失敗怎么辦？萬古霉素治療失敗怎么辦？清創(chuàng)引流替代一：達(dá)托霉素+（慶大霉素，利福平，利奈唑胺，SMZco）替代二：奎奴普丁/達(dá)福普丁，SMZco，利奈唑胺，特拉萬星臺灣傳染病協(xié)會推薦

替考拉寧為MRSA-HAP的經(jīng)驗性治療GuidelinesonantimicrobialtherapyofpneumoniainadultsinTaiwan,revised2006.JMicrobiolImmunolInfect.2007;40(3):279-283.推薦替考拉寧作為MRSA感染的遲發(fā)性HAP和VAP的經(jīng)驗性治療用藥對于存在多重耐藥危險因素和任何嚴(yán)重疾病的遲發(fā)性HAP(肺炎發(fā)生于入院第5天或以后)，推薦替考拉寧聯(lián)合其他抗生素作為MRSA感染的經(jīng)驗性治療用藥對于VAP，推薦替考拉寧聯(lián)合其他抗生素作為MRSA感染的經(jīng)驗性治療用藥臺灣成人肺炎抗生素治療指南

(2007)臺灣傳染病協(xié)會(IDST)英國MRSA感染預(yù)防和治療指南

推薦MRSA感染選用糖肽類治療GouldFK,etal.JournalofAntimicrobialChemotherapy.2009;63:849–861.英國MRSA感染預(yù)防和治療指南(2008)無并發(fā)癥的菌血癥推薦使用糖肽類抗生素，療程至少14d[證據(jù)級別Ⅱ]嚴(yán)重皮膚軟組織感染和/或菌血癥高危因素的住院患者，可考慮使用使用糖肽類抗生素[證據(jù)級別ⅠA]糖肽類分子結(jié)構(gòu)萬古霉素替考拉寧組織濃度

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

Teicoplanin

-64%p＜0.05Hahn-AstCetal.Infection2008;36:54–8.替考拉寧腎毒性發(fā)生率低于萬古霉素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替考拉寧vs萬古霉素--肺部感染OverallvsPneumoniaClinicalEfficacy

inFebrileNeutropeniaC.Tascini.et.al.JournalofChemotherapy.2009;21:311-316.利奈唑胺與替考拉寧治療G+菌感染的回顧性研究利奈唑胺組（169例）替考拉寧組（91例）菌血癥患者占25%肺炎患者占19.5%其中22名患者為VAP，且均由MRSA引起，3例為早發(fā)性菌血癥患者占16%肺炎患者占20%其中10名患者為VAP，亦均由MRSA引起，7例為早發(fā)性菌血癥及肺炎是兩組患者最常見的感染類型C.Tascini.etal.JournalofChemotherapy.2009;21:311-316.臨床有效率(%)32/3712/1515/227/1015/1611/1413/169/1413/148/13利奈唑胺治療各部位感染的臨床有效率與替考拉寧無統(tǒng)計學(xué)差異C.Tascini.etal.JournalofChemotherapy.2009;21:311-316.

研究結(jié)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說明書對于劑量的規(guī)定：腎功能正常的