DoseOptimizationofAntimicrobialAgentsinPatientswithSevereInfectionFirstAffiliatedHospitalofMedicalCollegeofXi’AnJiaoTongUniversity

DeptofCriticalCareMedicine

Wang,XueTherapeuticStrategyofAntibiotictoSevereInfectionTherapeuticStrategyofAntibiotictoPatientswithSevereInfectionInitialempiricaltherapyVS.TargetedtherapyDown-laddertherapeuticstrategy:isaanti-infectiveprotocolofempiricaltherapy

hastwocharacteristicsasfollowing:①useasingle,broad-spectrum,potentantibioticatthebeginningofanti-infectivetherapy,trytocoverthepathogenicbacteria;

②afterward(48to72hours),basedonmicrobiologicalandsusceptibilityteststoadjusttheantibiotics,letitmorespecific

AdaptedtoDown-laddertherapyprogram:

①severepneumonia

②presenceofriskfactors(receivedantibiotictreatment,lengthofhospitalstay,mechanicalventilation)

③drugselectionshouldaimtosuspectedpathogen

Appropriatetreatment:Bacterialsensitivitytoantibioticsmatchsselectedantimicrobialagents

ATS/IDSAGuidelines.AmJRespirCritCareMed.2005;171:388-416.

“S”=successSUSCEPTIBLETherapeuticStrategyofAntibiotictoPatientswithSevereInfectionTherapeuticStrategyofAntibiotictoPatientswithSevereInfectionInitialempiricaltherapyDown-laddertherapeuticstrategyTargetedtherapyAdequateantibiotictherapyInadequateantimicrobialtreatmentwascorrelatedwithhighmortalityinsevereinfection

三項(xiàng)對(duì)ICU感染患者起始抗菌治療的前瞻性研究，結(jié)果表明重癥患者感染起始不充分抗菌治療顯著增加患者住院死亡率BloodflowinfectionNP/VAPIbrahimEHetal.Chest.2000;118:146-155.Alvarez-LermaFetal.IntensiveCareMed.1996;22:387-394.RelloJetal.AmJRespirCritCareMed.1997;156:196-200.1P<0.001P=0.034P<0.05Mortality(%)InadequateadequateInadequateantimicrobialtreatmentsignificantlyaffectsthesurvivalrateofpatientswithsevereinfectionAretrospectivestudyanalyzedthedataof5715caseswithsepticshockfromthreecountriesandfoundthatearlyinadequateempiricalantimicrobialtherapysignificantlyreducedthesurvivalrateinpatientswithvariousseverebacterialinfectionStaphylococcusaureusStreptococcuspneumoniaeEnterococcusOtherStreptococcusE.coliKlebsiellaspp.EnterobacterPseudomonasaeruginosaCandidaalbicansNon-whiteyeastKumarAetal.Chest2009;136:1237-48.AllpatientsCulture（+）Culture（-）Bacteremia（+）Bacteremia（-）Community-acquiredinfectionsHospital-acquiredinfectionsEarlyinadequatetreatmentEarlyadequatetreatmentSurvivalrate（%）Oddsratio（OR）EarlyinadequatetreatmentEarlyadequatetreatmentSurvivalrate（%）Oddsratio（OR）上述決定因素取決于：體外效力（微生物特性）藥物暴露（藥物代謝動(dòng)力學(xué)特性）體內(nèi)效力（藥效學(xué)特性）AdequateAntibioticTherapy臨床和微生物學(xué)治療成功的決定因素Adequateantibiotictherapy

shouldregardpatientsasa“core”:

Consideringtherelationshipamongthe"patients-drugs-bacteria"comprehensivelyPATIENTPATHOGENICBACTERIAANTIMICROBIALAGENTSResistancetodisease(immunity)Pathogenicityinvivometabolism（PK）AdversereactionsDrugresistance(MIC)Antibacterialeffect(PD)AlterationofPharmacokineticsinSevereInfectionSevereinfection=Sepsis+acuteorgansdysfunctionCharacteristicsofSevereInfectionBasicstatus,complexanddangerousPresenceofmultiplediseasesororganfailureChangesofdrugdistributionandmetabolicprocessesinthebodyUseseveraldrugsandtherapeuticmeasuressimultaneouslyPronetooccurringdruginteractionsoradversereactionsDrugPlasmaProtein-bindingdrugsFreedrugMetabolitesRenalexcretionSiteofactionFreedrugReceptorbindingPharmacologicaleffectOrganstorageFreedrugTissuebindingLiverMetabolitesAbsorptionRe-absorptionMetabolicprocessofdruginvivoCapillaryleakageHypoproteinemiaTissueischemiaandhypoxiaOrgandysfunctionDrugintakeConcentrationofdruginbloodcirculationsystemDistributionofdrugintissueCConcentrationofdrugatactivesitePharmacologicaleffectClinicalreactiveeffectToxicityTherapeuticeffect（PK）（PD）absorptionDistributionClearanceMetabolismorexcretionofdrugCEffectofsevereinfectivepatienttoPK

Hypo-albuminemia:proteinbindingcapacityCLS:increasedvolumeofdistributionCRRT:clearanceincreaseMODS:toxic-sideeffectsEnhancementofdistributionvolume(Vd)ofantimicrobialdrugsinseverepatientAtotalof57itemsofPK/PDstudyforbeta-lactamantimicrobialagentsinICUpatientsduring1966-2010wassystematicreviewed;Resultsshowedthatthevolumeofdistribution(Vd)ofsixantimicrobialagentsincriticalpatientsweresignificantincreasedcomparedtothehealthyvolunteers.JoaoGoncalves-Pereira,etal.CriticalCare2011,15:R206healthyvolunteerICUpatientCefpiromeCefepimeCeftazidimePiperacillinImipenemMeropenemVolumeofDistributionf(L)Increasedvolumeofdistribution(Vd)incriticalpatient——

DrugconcentrationreducedinbloodandtissueThesystemicinflammatoryresponseandalterationofvascularpermeabilityinpatientswithsevereinfectionresultedtohypotensionandexudationofcapillaryfluidMeantime,aplentyofliquidinfusionforanti-hypotensionandanti-septicshockclinicallyalsoincreasedthevolumeofdistributionUlldemolinsM,RelloJ.CurrPharmBiotechnol.2011;12(12):1996-2001.Vp:volumeofdistributioninperipheralroom(organs);Vc:volumeofdistributionincentralcompartment(plasma)Healthyvolunteer

ICUpatient標(biāo)準(zhǔn)藥物劑量標(biāo)準(zhǔn)藥物劑量VolumeofdistributionofAmikacinin100ICUadultsandchildrenResultVdwasincreasedinaccordancewiththeseverityofdisease

Vdwasincreasedinallwater-solubleantibioticsinICU,theinitialdoseshouldbehigherthanthestandardone!MariketalJAC1991;27SuppC:81-9Volumeofdistribution(Vd)ofantibioticsvs.diseaseseverityAlterationofdifferentphysicalandchemicalpropertiesandPKinsevereinfectionCritCareMed2009;37(3):840-51CommonPKLowVdClearancebykidneymainlyLowcellpenetratingHighVdClearancebylivermainlyBettercellpenetratingChangeofICUPKDeterminedbyliverfunctionDeterminedbyrenalfunctionExampleBeta-LactamsAminoglycosidesGlycopeptidesLinezolidPolymxinFluroquinolonesMacrolidesLincosamidesTigecyclineWater-solubleantibioticsFat-solubleantibioticsDatasubmittedAntibioticsVd-proteinbindingcapacityinsevereinfectionHighbinding

Veryimportant!ModerateModerateCombinationverylowcombination

notsoimportantFordrugswithhighproteinbinding,hypoproteinemia-induceddeclineofbindingcapacityisveryimportant!

Mayresultinincreasedtoxicityorclearance

TDMisnotuptostandardrangePK/PDischangedbysepsisExtracorporealcirculationChangeofdrugclearanceandenhancementofVdinARF?PlasmadrugconcentrationIfthedoseisnotadjustedcorrespondingly:itisNOTthebesttherapy(incompletetreatment)Non-optimalclinicaloutcomeCapillaryleakageand/orchangeofproteinbindingcapacitySepsisCardiacoutputincreasedIncreasedclearancerateincreasedapparentVdLowplasmadrugconcentrationNormalorganfunctionsunchangedapparentVdNormalplasmaconcentrationEnd-stageorganfunctionfailure(KidneyLiver)ReducedclearancerateHighplasmadrugconcentrationOptimizationofantibioticdosageinsevereinfectionTherelationshipofmedicine-timecurveanddrugconcentrationandtherapeuticeffectTime(h)CmaxPeakMinimalinhibitoryconcentration(MIC90

value)TimeofeffectiveconcentrationmaintainAUCAverageplasmaconcentration(mg/L)ToxicconcentratinTherapeuticscope(treatingwindowTimetomaximalconcentrationtmaxInteractionstrengthEvaluationparametersofPK/PDforantimicrobialagentsAUC：Theareaundertheconcentration-timecurve;Cmax:Peakplasmaconcentration;PAE:Post-antibioticeffect0AUC:MICT>MICCmax:MICDrugconcentrationTime

(h)MICConcentration-dependentTime-dependentPotentofantibioticeffectPharmacodynamics(PD)IndexofantibioticsConcentration-dependent(withprolongandconstantbactericidaleffect)Time-dependent(withoutprolongandconstantbactericidaleffect)Time-dependent(Moderateprolongandconstantbactericidaleffect)AminoglycosidesQuinolonesRelatetoAUC/MIC,Peak/MICBeta-LactamsRelatetotimeaboveMIC(T>MIC)Macrolides,Aza-lactone,glycopeptidesOxazolidinone,Tetrcyclines,ClindamycinRelatetoAUC/MICCritCareMed2009;37(3):840-51T>40-70%4-5xMICCmax:MIC=10Van:400Quinolone:G-:125G+:30Pharmacodynamics(PD)Indexofantibiotics14例入組ICU的VAP（臨床肺部感染評(píng)分【CPIS】≥6）患者

左氧氟沙星：第1天2×500mg；隨后連續(xù)7天1×500mg

通過中心靜脈管靜脈輸注，60分鐘內(nèi)輸完左氧氟沙星PK/PD指數(shù)：fCmax,ss/MIC;fAUC/MIC氟喹諾酮類：

格蘭陰性菌：fCmax,ss/MIC=10;fAUC/MIC≥100–125格蘭陽性菌：fCmax,ss/MIC=10;fAUC/MIC≥30CasesItemCase1Case2Age1972DiagnosisVAPVAPDiagnosisatadmissionMultipletraumaRespiratoryfailureBasicmedicalhistoryNOCOPDRealbodyweight105kg62kgSerumcreatinineconcentration5595AntibioticRxMeropenemMeropenemCase

(Meropenem1gq8h30minInfusion)fT>MIC2mg/LfT>MIC4mg/LCase159%40%Case295%69%ThePDofTigecyclineanddoseoptimization61例院內(nèi)獲得性肺炎患者使用替加環(huán)素靜脈輸注100mg負(fù)荷劑量

之前輸注劑量為50mgq12h

至少持續(xù)輸注7天結(jié)果：臨床成功率：

白蛋白每升高1g/dl，成功率升高13.0倍（P<0.001）

相比f

AUC0–24:MIC<0.9者，f

AUC0–24:MIC>0.9的患者則升高8.42倍（P=0.008）結(jié)果：

微生物學(xué)成功率白蛋白每升高1g/dl，成功率21.0倍（P<0.001）

非VAP相比VAP，前者成功率高8.59倍（P=0.003）

MIC：（P=0.006）

MIC50：VAPvs非VAP——0.5vs0.25mg/lMIC90：VAPvs非VAP——16vs1mg/l替加環(huán)素的MIC分布由是否VAP狀態(tài)來區(qū)分ClinicalandmicrobiologicalefficacyofTigecyclinetocIAIpatients:AUC/MIC≥6.96Combinedanalysisof3clinicalstudiesofTigecyclinetohospitalizedc1A1patientswasperformed,theresultsshowedthatinpatientswithE.coliandanaerobicinfection,theAUC/MIC>6.96canensurethehighcurativeratesbothinclinicalandmicrobiologicalaspectsPassarellJA,etal.AntimicrobAgentsChemother.2008;52(1):204-210.AmbrosePG,etal.DiagnMicrobiolInfectDis.2009;63(1):38-42.AUC/MIC>6.96canensurehehighcurerate1microbiologicalcure(P=0.0004)Clinicalrecovery(P=0.0399)AUC/MIC>6.96，

Clinicalcurativerate94%AUC/MIC<6.96，Clinicalcurativerate60%（P=0.0399)2Queue1:E.coli;Queue2:singleormultipleE.coli;Queue3:atleastonekindE.coli+anaerobes;Queue4:atleastoneE.coil+G+-bacteriaCombinedanalysisofTigecyclinetocSSSIpatientsinoneclinicalPhaseIIandtwoPhaseIIIstudieswasconducted,theresultsdisclosedthatinpatientswithstaphylococcusaureusorstreptoco-ccusviridansinfection:MeagherAK,etal.AntimicrobAgentsChemother.2007;51(6):1939-1945.AmbrosePG,etal.DiagnMicrobiolInfectDis.2009;63(2):155-159.Queue1:Staphylococcusaureus;Queue2:singleStaph.aureusorviridansstrepto.;Queue3:TwoG+-bacteria;Queue4:Multiplebacterialinfection;Queue5:othersinglebacterialinfectionClinicalandmicrobiologicalefficacyofTigecyclinetocSSSIpatients:AUC/MIC≥17.9AUC/MIC>17.9

canensurethehighcurativerate1Microbiologicalcure(P=0.0001)clinicalrecovery

(P=0.0376)AUC/MIC>17.9，microbiologicalcure100%

AUC/MIC<17.9，clinicalrecovery50%

(P=0.0001)2TheAUC/MICofTigecyclineachievedtostandardlevel:BetterclinicalefficacyCombinedanalysisofTigecyclinetohospitalizedcIAIpatientsintwoPhaseIIIstudieswasperformed.TheresultsshowedthatintheE.coli-infectedpatients,whenMIC≤0.5mg/L,therateofPK/PDachievedtostandardlevelwasover90%In2009,asurveyofdrug-resistanceofpathogenicbacteriaamongpatientswithhospital-infectioninatotalof13teachinghospitalsinChinaindicatedthatE.colitoTigecycline:MIC50=0.25mg/LMIC90=0.5mg/LMIC=0.25mg/L:clinicalrecovery94%MIC=0.5mg/L:

clinicalrecovery84%AmbrosePG,etal.DiagnMicrobiolInfectDis.2009;63(2):155-159.Yangqiwen,etc..ChineseJournalofLaboratoryedicine.2011;05(34):422-430.PooledanalysisofTigecyclinetocSSSIpatientsinonephaseIIandtwoPhaseIIIclinicalstudieswasperformed.DatarevealedthatinpatientswithStaphylococcusaureusorStreptococcusviridansinfection,whenMIC≤0.25mg/L,therateofPK/PDachievedtostandardrangewas60to100%.AmbrosePG,etal.DiagnMicrobiolInfectDis.2009;63(2):155-159.Yangqiwen,etc..ChineseJournalofLaboratoryedicine.2011;05(34):422-430.In2009,asurveyofdrug-resistanceofpathogenicbacteria

amongpatientswithhospital-infectioninatotalof13teachinghospitalsinChinarevealedthatStaphylococcusaureustoTigecycline:MIC50=0.125mg/L，MIC90=0.25mg/LStreptococcusviridanstoTigecycline:MIC50=0.064mg/L，MIC90=0.25mg/LTheAUC/MICofTigecyclineachievedtostandardlevel:BetterclinicalefficacyMIC=0.125mg/L:clinicalcurerate99.9%MIC=0.5mg/L:clinicalcurerate94.2%TigecyclinevsImipenemHospital-acquiredpneumonia(HAP)phaseIIIregistrationstudyPhaseIII,internationalmulti-center,double-blind,randomized,controlled,non-inferiorityclinicalscreenedatotalof138researchcentersin31countrieswith979HAPorVAPpatients:945casesintherandomized(ITTpopulation),934casestreated(safetypopulation,mlTTpopulation)Attheendofstudy,531casesformicrobiologicevaluationand511patientsforclinicalassessmentTOCfollowupTigecyclinefirstdose

100mg，

followedby50mgq12hi.v.IfpseudomonasaeruginosaorMRSAinfectioncannotbeexcluded:Inordertocoverpseudomonasaeruginosa,allgroupsofTigecyclinetreatmentreceivedadjuvanttherapy:ceftazidime2gq8hInordertocoverMRSA,thegroupofimipenem/cilastatintreatmentreceivedadjuvanttherapy:vancomycin1gq12hEOT:

Endofthetreatment；TOC：CurethecheckFreireAT,etal.DiagnMicrobiolInfectDis.2010;68(2):140-151.Therapeuticcourse7-14dayEOTafter10-21day1:1RandomizedImipenem/cilastatin1gq8hi.v.InTOC,thecurerateoftigecyclinegroupinnon-VAPpatientswasfulfilledtogetherwithimipenem/cilastatinnon-inferiorityresistance;non-inferiorityisnotreachedinpatientswithVAP

35/73147/195Curerate（%）Differencebetween-22.295%CI(-37.8,-4.9)FreireAT,etal.DiagnMicrobiolInfectDis.2010;68(2):140-151.Clinicalevaluablepopulationc-mITTpopulationDifferencebetween-5.995%CI(-14.5,3.0)Differencebetween-11.395%CI(-24.6,2.0)Differencebetween-1.995%CI(-9.4,5.6)47/67143/17659/127217/31367/116223/313Non-inferiorityisnotreachedNon-inferiorityreachedc-Mittpopulation:IntentionaltreatingpopulationbyclinicalcorrectionTigecyclinevs.ImipenemHospital-acquiredpneumonia(HAP)phaseIIIregistrationstudyTigecycline50mgq12hNon-VAPNon-VAPNon-inferiorityreachedNon-inferiorityisnotreachedTheprominentdifferentofPDinNon-VAPandVAPpatientsFreireAT,etal.DiagnMicrobiolInfectDis.2010;68(2):140-151.Non-VAPpatientsAUC0-12h=3.198VAPpatientsAUC0-12h=2.72615%significantlydecline（P=0.041）顯著降低60%（P=0.002）AUC0-12hAUC0-24h/MICAUC0-24h/MIC（n=38）（n=22）Tigecyclinevs.ImipenemHospital-acquiredpneumonia(HAP)phaseIIIregistrationstudyNon-VAPpatientsAUC0-12h=3.198Non-VAPBhavnaniSM,etal.AntimicrobAgentsChemother.2012;56(2):1065-1072.Non-VAPVAPPrescribeddosePDofTigecyclineaffectedefficacyinpatientswithVAPThemicrobiologicalcurerateinNon-VAPpatientsmaybe8.59timeshigherthanthoseinVAPpatients（P=0.003）BhavnaniSM,etal.AntimicrobAgentsChemother.2012;56(2):1065-1072.Enhancementofclinicalcurerateof

Tigecycline：

PD：AUC/MIC≥0.90/Serumalbuminconcentration≥26g/LAUC0-24h/MIC≥0.90較<0.9clinicalcureratemayincrease8.42times（P=0.008）AUC0-24h/MIC≥0.90AUC0-24h/MIC<0.90Serumalbuminconcentrationelevates1g/dL,clinicalcureratemayincrease13.0times（P<0.001）ClinicalcurerateAlbuminTreatmentofHAPbyTigecycline,revelationfromPhaseIIIstudy

TreatmentofpatientswithVAPneedtoincreasethedose1.FreireATetal.DMicrobioloInfectDis.2010;68(2):1402.BrinkAJetal.SAMJ,2010,100(6):3883.CrandonJLetal.AntimicrobAgentsChemother.2009;53:5060TigecyclinehasfasterclearancerateinVAP.ApparentlydecreaseofAUCresultedtothedeclineofAUC/MIC,whichmadeusunabletogettheidealtherapeuticeffect.Inthepresentstudy,pseudomonasoccupied39.6%inthegroupofTigecyclinetreatment.ComparedwiththegroupsofCephalosporinandImipenem,itdemonstratedthatthetherapeuticeffectsofImipenemtopseudomonaswerebetterthanCephalosporintreatment.Tigecyclineisatime-dependentandPAEanti-microbiologicagentwiththecharacteristicsoflinearpharmacokinetics.IncreasingthedoseofTigecyclineiscapabletoelevatethebeneficialeffectsofVAP.EtiologyFurtherstudyTigecyclineshowslinearpharmacokineticpropertiesPharmacokineticstudiesshowthatinasingledoseof12.5-300mgrange,theCmax,AUCofTigecyclineareproportionaltothedosage.MuralidharanG,etal.AntimicrobAgentsChemother.2005;49(1):220-229.DoseincreasingstudyofTigecycline:StudyDesignPhaseII,internationalmulti-centers,double-blind,randomized,controlled,non-inferiorityclinicaltrialscreeningtotal114patientswithHAPorVAPin75researchcenters(Europe,Asia,LatinAmerica,USAS,CanadaandAustralia):108casesintorandom(ITTpopulation),105patientsreceivedtreatment(safety,Mittpopulation)Attheendofthestudy,65patientstakingmicrobiologicalevaluation,67patientstakingclinicalevaluation1:1:1RandomizedTOCfollowupTigecyclinefirstdose

150mgfollowedby75mgq12hi.v.Imipenem/cilastatin1gq8hi.v.IfpseudomonasaeruginosaorMRSAinfectioncannotbeexcluded:Twogroupsoftigecyclinetreatmentreceivedadjuvanttherapy:ceftazidime2gq8h+aminoglycoside(tobramycin7mg/kgqdoramikacin20mg/kgqd)+vancomycinplaceboGroupofimipenem/cilastatintreatmentreceivedadjuvanttherapy:vancomycin15mg/kg+aminoglycoside(thetobramycin7mg/kgqdoramikacin20mg/kgqd)+ceftazidimeplaceboRamirezJ,etal.AntimicrobAgentsChemother.2013;57(4):1756-1762.Tigecyclinefirstdose

200mgfollowedby100mgq12hi.v.Therapeuticalcourse14daysEOTafter10-21dayEOT:

Endofthetreatment；TOC：CurethecheckDoseincreasingstudyofTigecycline:PatientCharacteristicsBaselinedemographiccharacteristics,diseaseconditionandcourseoftreatmentweresimilaramongthestudygroupsRamirezJ,etal.AntimicrobAgentsChemother.2013;57(4):1756-1762.RamirezJ,etal.AntimicrobAgentsChemother.2013;57(4):1756-1762.ParametersTigecycline（75mgq12h）Tigecycline（100mgq12h）Imipenem/Cilastatin（1gq8h）PvaluePatientnumber363534Age60.3±14.861.5±16.164.9±15.30.445Bodyweight71.8±16.270.6±20.373.7±17.00.770Diagnosis0.501Non-VAP23(63.9)23(65.7)18(52.9)VAP13(36.1)12(34.3)16(47.1)APACHEIIscore，n（%）0.752≤1524(66.7)26(74.3)23(67.7)>1512(33.3)9(25.7)11(32.4)AverageCPISscore(minimalandmaximalvalues)6.2(3.0,9.0)5.3(2.0,9.0)6.1(2.0,10.0)0.077DelayedonsetofHAP(≥5daysafteradmission,n(%)31(86.1)28(80.0)25(73.5)0.421Averagetherapeuticcourse0.245Averagecourseofceftazidime/vancomycintreatment4.8(22)5.7(19)6.1(22)0.430Averagecourseofaminoglycosidestreatment4.7(17)3.9(16)3.0(10)0.222AtTOC,inclinicalevaluablepopulation,thecurerateinthegroupofTigecycline100mgq12hwasnumericallyhigherthanthatofimipenem/cilastatingroupDoseincreasingstudyofTigecycline:Efficacyresultsofsubgroup16/2317/2018/249/138/1012/15Curerate（%）Differencebetweengroups10.070%CI(-6.1,24.8)Differencebetweengroups-5.470%CI(-21.6,10.9)Differencebetweengroups0.070%CI(-23.8,20.9)Differencebetweengroups-10.870%CI(-32.0,10.9)RamirezJ,etal.AntimicrobAgentsChemother.2013;57(4):1756-1762.RamirezJ,etal.AntimicrobAgentsChemother.2013;57(4):1756-1762.ClinicalevaluablepopulationMicrobiologicalevaluablepopulationTigecycline75mgq12hTigecycline100mgq12hImipenem/Cilastatin

1gq8hDoseincreasingstudyofTigecycline:PrimaryendpointresultsCurerate（%）RamirezJ,etal.AntimicrobAgentsChemother.2013;57(4):1756-1762.AtTOC,inclinicalevaluablepopulation,thecurerateineachsubgroupwithtigecycline100mgq12htreatmentisnumericallyhigherthanthatofimipenem/cilastatingroup,especiallyincriticalpatientsRamirezJ,etal.AntimicrobAgentsChemother.2013;57(4):1756-1762.Tigecycline75mgq12hTigecycline100mgq12hImipenem/Cilastatin

1gq8hNon-VAPDoseincreasingstudyofTigecycline:PK/PDparametersElevationofserumconcentrationandAUCingroupofTigecycline100mgtreatmentTheAUC/MICvaluewashigherinclinicalcurepatientsthanthatinclinicalfailurepatients,itmayrelatetomoredrugPDachievedtostandardrange.*SerumconcentrationsofTigecycline（ng/mL）IVinfusiontime（h）AUC/MIC（n=17）（n=8）RamirezJ,etal.AntimicrobAgentsChemother.2013;57(4):1756-1762.*DuetothesmallsamplesizeofPKPDdata,theconclusioncannotbemadeyet.RamirezJ,etal.AntimicrobAgentsChemother.2013;57(4):1756-1762.ClinicalcureFailureoruncertainTigecycline100mgq12h(n=19)Tigecycline75mgq12h(n=20)DoseincreasingstudyofTigecycline:SafetyresultsIncidenceofdrug-relatedAEwas29.5%Drug-relatedgastrointestinalAE(incidence12.4%)isoneofthemostcommonillness,themajoritywereonlymildtomoderate.IncidenceofSAEwas29.5%,itwassimilaramongthethreegroups(P=0.801)duetothecomparablenumbersofpatientswithdrawalAEDuringtheperiodofstudy,atotalof17patientshaddiedwithouttherelevanttotherapeuticagents.RamirezJ,etal.AntimicrobAgentsChemother.2013;57(4):1756-1762.Patientratio（%）RamirezJ,etal.AntimicrobAgentsChemother.2013;57(4):1756-1762.Tigecycline100mgq12hImipenem/Cilastatin

1gq8hTigecycline75mgq12hAllcausesmortalityAdjustingprocessofantibioticsdosageinseverepatientsSevereinfectedpatientIncreasedVdInitialhigh-loaddosage

LiverorKidneyfailure大容量液體復(fù)蘇有創(chuàng)通氣外科手術(shù)操作NoIncreasedclearancerate(EvaluationbyCcr)YesAdjustingdosebasedonorganfunctionpreservinghigh-doseRe-assessmentafter48-72hAnyofthefollowingoccurs:PathogenicbacteriaMIClowNormalcreatinineclearanceSepsiscontrolledAdjustingdosage↑Vasopressors↑c(diǎn)ardiacoutput↑diureticGoncalves-PereiraJ,PaivaJA.JCritCare.Jan182013.DoseoptimizationbasedonPK/PDofantimicrobialagents

Water-solubleantibioticsVd↑CL↑CL↓Cmin↓Cmin↑Toincreasethefrequencyofadministration(increasingtotaldailydose)Continuousinfusionorlonge