icu危重感染抗菌药应用

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

三项对ICU感染患者起始抗菌治疗的前瞻性研究，结果表明重症患者感染起始不充分抗菌治疗显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）上述决定因素取决于：体外效力（微生物特性）药物暴露（药物代谢动力学特性）体内效力（药效学特性）AdequateAntibioticTherapy临床和微生物学治疗成功的决定因素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标准药物剂量标准药物剂量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例入组ICU的VAP（临床肺部感染评分【CPIS】≥6）患者

左氧氟沙星：第1天2×500mg；随后连续7天1×500mg

通过中心静脉管静脉输注，60分钟内输完左氧氟沙星PK/PD指数：fCmax,ss/MIC;fAUC/MIC氟喹诺酮类：

格兰阴性菌：fCmax,ss/MIC=10;fAUC/MIC≥100–125格兰阳性菌：fCmax,ss/MIC=10;fAUC/MIC≥30CasesItemCase1Case2Age1972DiagnosisVAPVAPDiagnosisatadmissionMultipletraumaRespiratoryfailureBasicmedicalhistoryNOCOPDRealbodyweight105kg62kgSerumcreatinineconcentration5595AntibioticRxMeropenemMeropenemCase

(Meropenem1gq8h30minInfusion)fT>MIC2mg/LfT>MIC4mg/LCase159%40%Case295%69%ThePDofTigecyclineanddoseoptimization61例院内获得性肺炎患者使用替加环素静脉输注100mg负荷剂量

之前输注剂量为50mgq12h

至少持续输注7天结果：临床成功率：

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的患者则升高8.42倍（P=0.008）结果：

微生物学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替加环素的MIC分布由是否VAP状态来区分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）显著降低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较<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大容量液体复苏有创通气外科手术操作NoIncreasedclearancerate(EvaluationbyCcr)YesAdjustingdosebasedonorganfunctionpreservinghigh-doseRe-assessmentafter48-72hAnyofthefollowingoccurs:PathogenicbacteriaMIClowNormalcreatinineclearanceSepsiscontrolledAdjustingdosage↑Vasopressors↑cardiacoutput↑diureticGoncalves-PereiraJ,PaivaJA.JCritCare.Jan182013.DoseoptimizationbasedonPK/PDofantimicrobialagents

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