針對(duì)四環(huán)素類(lèi)抗生素常見(jiàn)耐藥機(jī)制設(shè)計(jì)的新型甘酰胺類(lèi)抗生素替加環(huán)素不受核糖體保護(hù)耐藥機(jī)制的影響：與核糖體的親和力比四環(huán)素類(lèi)抗生素大5倍新的結(jié)合方式和結(jié)合區(qū)域可能會(huì)干擾核糖體保護(hù)蛋白的作用機(jī)制替加環(huán)素不受獲得性外排耐藥機(jī)制的影響：可能是無(wú)法將替加環(huán)素排出胞外、排出蛋白無(wú)法識(shí)別或是排出蛋白誘導(dǎo)不足。JAntimicrobChemother(2005)56,611–614替加環(huán)素與其他抗菌藥物的抗菌譜比較ClassMRSAGram-FermentersESBLsP.aeruginosaAnaerobesAPPip/Tazo-++-++++++-++++++-Imipenem/MEPM-++-+++++++-+++++-Ertapanem-++-++++++-+++-FQs-+-+++++-++++-++++-+++ESC(Extended-spectrumceph)-++-+++-+-+++-Tygacil+++++-++++++-+++++-+++替加環(huán)素的藥代動(dòng)力學(xué)特點(diǎn)濃度依賴(lài)性抗菌藥物L(fēng)inearpharmacokineticsCmax=0.87μg/mLCmin=0.13μg/mLAUC0-24h=4.7μg?h/mLt?=42hoursVss=639L,significanttissueuptake主要經(jīng)膽道排泄腎功能減退者無(wú)需調(diào)整劑量透析無(wú)法清除輕中度肝功能異常無(wú)需調(diào)整劑量重度肝功能損害維持劑量減半不經(jīng)過(guò)CYP450代謝，很少藥物相互作用Steady-StateSerumConcentrations0.010.1110024681012TimePost-Dose(hr)Concentrationlogscale(μg/mL)替加環(huán)素的組織分布

(組織濃度/血清濃度)aPatientsreceivedasingle100-mgIVdoseoftigecyclinepriortosurgery.bHealthysubjectsreceivedasingle100-mgIVdoseoftigecyclinefollowedby50mgIVq12h.Tissue/FluidConcentrationIncreaseinTissuevsSerumGallbladdera38-foldColona2.1-foldSkinBlisterfluida26%lowerthanserumAlveolarcellsb78-foldEpithelialliningfluidb32%greaterthanserumLunga8.6-foldSynovialfluidb0.58-foldBonea0.35-fold替加環(huán)素的肺組織分布ClinicalMedicine:Therapeutics2009:11275–1289替加環(huán)素的臨床應(yīng)用范圍FDA批準(zhǔn)的適應(yīng)癥復(fù)雜皮膚軟組織感染復(fù)雜腹腔感染社區(qū)獲得性細(xì)菌性肺炎適應(yīng)癥外使用：特殊MDR菌感染的靶向治療MDR非發(fā)酵菌：鮑曼不動(dòng)桿菌、嗜麥芽窄食單胞菌MDR腸桿菌科細(xì)菌：碳青霉烯耐藥的克雷伯菌MRSAVRE替加環(huán)素治療下呼吸道感染的研究現(xiàn)狀社區(qū)獲得性細(xì)菌性肺炎FDA批準(zhǔn)的適應(yīng)癥之一醫(yī)院獲得性肺炎現(xiàn)有的研究不支持標(biāo)準(zhǔn)劑量的替加環(huán)素做為HAP（尤其是VAP）的常規(guī)治療選擇最近的研究顯示高劑量替加環(huán)素治療非銅綠假單胞菌HAP（尤其是重癥HAP或VAP）的療效優(yōu)于亞胺培南替加環(huán)素在社區(qū)獲得性肺炎治療中的應(yīng)用替加環(huán)素對(duì)CAP常見(jiàn)致病原的體外抗菌活性InfectionandDrugResistance2011:4:77-86替加環(huán)素治療CAP的3期臨床試驗(yàn)multicenter,randomized,double-blindstudies308Study：conductedbetweenJune2003andJuly2005at54centersin8countriesinNorthAmerica,SouthAmerica,andMexico/CentralAmerica313Study：conductedfromJanuary2004toJanuary2005at62centersin20countriesinEurope,Africa,andtheAsiaPacificregion隨機(jī)分組治療組：IVTGC(100mginitiallyfollowedby50mgbid)對(duì)照組：IVlevofloxacin(500mgevery24hor500mgbid）durationofstudytherapy：7to14days療效判定：TOC:7and23daysafteradministrationofthelastdoseofstudymedicationDiagnosticMicrobiologyandInfectiousDisease61(2008)329–338308and313Study

病例入選情況DiagnosticMicrobiologyandInfectiousDisease61(2008)329–338替加環(huán)素治療CAP的3期臨床試驗(yàn)：mITT基線特征DiagnosticMicrobiologyandInfectiousDisease61(2008)329–338替加環(huán)素治療CAP的3期臨床試驗(yàn)：

mITT人群基線病情嚴(yán)重程度DiagnosticMicrobiologyandInfectiousDisease61(2008)329–338替加環(huán)素治療CAP的3期臨床試驗(yàn)：TOC療效DiagnosticMicrobiologyandInfectiousDisease61(2008)329–338替加環(huán)素治療CAP的3期臨床試驗(yàn)：

基于基線致病原的臨床治愈率（ME人群）DiagnosticMicrobiologyandInfectiousDisease61(2008)329–338替加環(huán)素治療CAP的3期臨床試驗(yàn)：SAEs(mITT人群)DiagnosticMicrobiologyandInfectiousDisease61(2008)329–338替加環(huán)素在CAP中的應(yīng)用ClinicalMedicine:Therapeutics2009:11275–1289TGC治療CAP等三類(lèi)感染的薈萃分析：CE人群成功率Antimicrob.AgentsChemother.2011,55(3):1162TGC治療CAP等三類(lèi)感染的薈萃分析：MITT人群成功率Antimicrob.AgentsChemother.2011,55(3):1162TGC治療CAP等三類(lèi)感染的薈萃分析：安全性Antimicrob.AgentsChemother.2011,55(3):1162哪些CAP患者可能從替加環(huán)素治療中獲益？存在MDR菌（PA除外）感染危險(xiǎn)因素的CAP患者:優(yōu)于氟喹諾酮類(lèi)藥物CA-MRSA腸球菌多藥耐藥革蘭氏陰性腸道桿菌PA之外的其他非發(fā)酵菌細(xì)菌與非典型致病原的混合感染無(wú)法使用呼吸喹諾酮類(lèi)藥物的成人CAP患者合并腎功能不全的CAP患者或有潛在腎功能減退的高齡CAP患者需要同時(shí)使用經(jīng)P450酶代謝的藥物的CAP患者長(zhǎng)期口服華法令抗凝的患者長(zhǎng)期口服免疫抑制劑（他克莫司、西羅莫司、環(huán)孢素等）的患者替加環(huán)素在醫(yī)院獲得性肺炎治療中的應(yīng)用TGC對(duì)HAP常見(jiàn)致病菌的體外抗菌活性ClinicalTherapeutics/2006；28：1079,中國(guó)大型教學(xué)醫(yī)院呼吸科HAP臨床調(diào)查

鮑曼不動(dòng)桿菌的抗生素敏感性中國(guó)大型教學(xué)醫(yī)院呼吸科HAP臨床調(diào)查

腸桿菌科細(xì)菌的抗生素敏感性中國(guó)大型教學(xué)醫(yī)院呼吸科HAP臨床調(diào)查

金黃色葡萄球菌的抗生素敏感性替加環(huán)素與亞胺培南/西司他丁治療HAP對(duì)照研究311研究311注冊(cè)研究設(shè)計(jì)方案(N=945)研究目的：比較替加環(huán)素與亞胺培南治療HAP的療效與安全性研究設(shè)計(jì)：多中心，雙盲，隨機(jī)對(duì)照，Ⅲ期臨床研究（2004.3-2006.12）替加環(huán)素首劑100mg；維持50mgq12h若懷疑銅綠：加用頭孢他定2gQ8h1:1隨機(jī)分組亞胺培南-西司他丁500mg～1gIVq6h*若懷疑MRSA：加用萬(wàn)古霉素1gQ12h或5-14天亞胺培南-西司他丁劑量取決于體重和肌酐清除率及對(duì)病情的判斷療效判定人群CE人：臨床可評(píng)估人群mITT：修正意向治療人群FreireATetal.DMicrobioloInfectDis.2010;68(2):14031個(gè)國(guó)家138個(gè)研究機(jī)構(gòu)參與TOC臨床療效：替加環(huán)素VS亞胺培南CE人群未達(dá)到預(yù)期試驗(yàn)終點(diǎn)mITT人群達(dá)到非劣性終點(diǎn)TOC臨床療效：替加環(huán)素VS亞胺培南VAP治愈率：CE人群及mITT人群均未達(dá)到非劣性終點(diǎn)Non-VAP治愈率：CE人群及mITT人群均達(dá)到了非劣性終點(diǎn)VAP未獲得預(yù)期療效的原因分析：病原學(xué)因素體外敏感性并非治療失敗唯一原因??！治愈率常常顯著低于體外敏感率，部分體外敏感菌株感染并未獲得理想療效??！VAP未獲得預(yù)期療效的原因分析：PK/PD因素VAP中替加環(huán)素清除較快，雖然Cmax變化不大，但AUC明顯降低，導(dǎo)致AUC/MIC下降，無(wú)法獲得理想療效1.PKPD2.病原學(xué)3.進(jìn)一步研究方向VAP致病菌的敏感性較低（更高的MIC），AUC/MIC下降，從而導(dǎo)致治療失敗。但部分敏感菌株感染未能獲得理想療效提示致病菌敏感性降低非唯一的治療失敗因素替加環(huán)素為濃度依賴(lài)性抗菌藥物，具備線性藥代動(dòng)力學(xué)特性，增加劑量可能改變VAP的療效

HAP2000研究311研究結(jié)果的啟示：VAP治療中增加TGC劑量的必要性1.FreireATetal.DMicrobioloInfectDis.2010;68(2):1402.BrinkAJetal.SAMJ,2010,100(6):3883.CrandonJLetal.AntimicrobAgentsChemother.2009;53:5060替加環(huán)素AUC隨劑量呈線性增加

MuralidharanG,etal.AntimicrobAgentsChemother.2005;49:220-229.

ECCMIDAbstract:2757ClinicalEfficacyofTwoHighTigecyclineDosageRegimensVersusImipenem-CilastatininHospital-AcquiredPneumonia:ResultsofaRandomizedPhaseIIClinicalTrial(2000Study)

HassanGandjini,PaulMcGovern,M.D.,JeanLiYan,NataileDartois,M.D.2000HAPSTUDY2000HAPSTUDYDESIGNGlobalphase2,multicenter,randomized,double-blind(third-partyunblinded)study210subjectsin3cohorts70%VAP;30%non-VAPSubjectswithPseudomonasaeruginosapathogenfromthebaselineculturewerewithdrawnfromthestudyTheprimaryefficacyendpointistheclinicalresponseintheCEpopulationattheTOCassessment,10to21daysposttherapy2000HAPINCLUSIONCRITERIAHAPinthistrialisdefinedaspneumoniawithonsetofsymptoms≥48hoursafteradmissionor≤7daysafterdischargefromhospital(≥3daysduration)VAPinthistrialisdefinedaspneumoniawithonsetofsymptoms≥48hoursafterendotrachealintubationor≤48hoursafterextubationPresenceofaneworevolvinginfiltrateonachestx-rayfilmPresenceoffeverorleukocytosis2ofthefollowingclinicalsignsandsymptoms:cough,dyspnea,ortachypnea,pleuriticchestpain,ausculatatoryfindings,hypoxemia,purulentsputumsecretionorchangeinsputumcharacter

TigecyclineIV*150mgloadthen75mgq12h

TigecyclineIV*200mgloadthen100q12hImipenem-cilastatinIV**1gq8h

1:1:1Randomization

*TigecyclineAdjunctiveRx:ceftazidime2gIVq8handaminoglycoside(tobramycin7mg/kgdailyoramikacin20mg/kgdaily)**Imipenem-cilastatinAdjunctiveRx:vancomycin15mg/kgIVq12andaminoglycoside(tobramycin7mg/kgdailyoramikacin20mg/kgdaily)7-14days10-21daysafterLDOTLDOTVisitTOCVisitTGC75MG(N=36)n(%)TGC100MG(N=35)n(%)IMIPENEM(N=34)n(%)Age(MeanYears)60.3161.4664.85Sex(Male)23(63.89)19(54.29)29(85.29)Race(White)20(55.56)25(71.43)17(50.00)Weight(Meankg)71.8170.6273.61Diagnosis-VAP13(36.11)12(34.29)16(47.06)APACHEII>1512(33.33)9(25.71)11(32.35)PriorAbxFailure4(11.11)12(34.29)5(14.71)Rx(MeanDays)7.478.948.562000HAPEFFICACY(TOC)Tigecyclinen/N(%)Imipenemn/N(%)Difference(70%CI)CEPopulationTGC7516/23(69.6)18/24(75.0)-5.4(-21.6,10.9)TGC10017/20(85.0)10.0(-6.1,24.8)c-mlTTPopulationTGC7519/36(52.8)18/34(52.9)-0.2(-14.3,14.0)TGC10025/35(71.4)18.5(4.3,31,8)2000HAPVS.311HAPEFFICACY

ClinicalResponseswith70%ConfidenceIntervalsCureRate(%)311Study2000StudyTGC75mgn/N(%)TGC100mgn/N(%)IMIPENEMn/N(%)Non-VAP11/16(68.8)11/13(84.6)11/15(73.3)VAP5/7(71.4)6/7(85.7)7/9(77.8)APACHE≤1514/17(82.4)13/16(81.3)14/17(82.4)APACHE>152/6(33.3)4/4(100)4/7(57.1)替加環(huán)素大劑量組具有較高的治愈率n=20n=23n=24n=35n=36n=34大劑量替加環(huán)素治療重癥HAP的優(yōu)勢(shì)尤其明顯131615779161717467大劑量組的不良反應(yīng)并未隨著劑量上升而增加TGC75MG(N=36)n(%)TGC100MG(N=35)n(%)IMIPENEM(N=34)n(%)TEAEs31(86.1)27(77.1)28(82.4)Nausea2(5.6)4(11.4)1(2.9)Vomiting4(11.1)2(5.7)4(11.8)SAEs12(33.3)9(25.7)10(29.4)Discontinued4(11.1)3(8.6)3(8.8)Deaths7(19.4)3(8.6)7(20.6)2000HAPCONCLUSIONS替加環(huán)素在治療特殊耐藥菌感染中的應(yīng)用替加環(huán)素對(duì)多藥耐藥腸桿菌科細(xì)菌的累積敏感率JournalofAntimicrobialChemotherapy(2008)62,895–904替加環(huán)素治療MDR腸桿菌科細(xì)菌肺部感染的臨床報(bào)道JournalofAntimicrobialChemotherapy(2008)62,895–904替加環(huán)素對(duì)MDR-AB的體外抗菌活性AuthorCountry;collectionperiod;Numberofisolates%susceptibleMICdistribution(mg/L)MIC90(mg/L)MezzatestaItaly;2003–2004107A.baumanniMDR>90%;(meropenem-resistant:58)930.25–42InsaUSA;2003–200677AB;resistanttob-lactams(includingcarbapenems),sulbactam,aminoglycosides,fluoroquinolones800.094–8NRCurcioglobalisolatesArgentina;631A.baumannii;resistanttoAminoglycosidescephalosporins,95NRNRSongKorea;2002–200643A.baumannii;carbapen