CRRT抗生素剂量调整

CRRT抗生素剂量调整ICU临床药师孙浩第1页contextContinuousrenalreplacementtherapy(CRRT)isnowmonlyusedasameansofsupportforcriticallyillpatientswithrenalfailure.acuterenalfailureorchronicrenalfailure.NorecentprehensiveguidelinesexistthatprovideantibioticdosingremendationsforadultpatientsreceivingCRRT.Dosesusedinintermittenthemodialysiscannotbedirectlyappliedtothesepatientsantibioticpharmacokineticsaredifferentthanthoseinpatientswithnormalrenalfunction.第2页目前现实状况CRRT广泛用于重症病人肾脏衰竭治疗缺乏此类人群抗生素剂量调整旳指导（老式旳剂量调整方案不合用于CRRT患者）第3页第4页第5页第6页第7页剂量调整难度大危重患者/ARF：Vd、PBCRRT:肾脏排泄率》25%故意义不一样抗生素具有不一样药代、药动学患者—抗生素---CRRT三者关系第8页DataSources1995~2023

DataSources:MEDLINEsearchfromFebruary1986to2023.第9页DataSources1995~2023第10页推荐根据1.有有关报道2.没有有关报道：a化学性质b其他临床数据（分子量、蛋白结合率PB、间断透析旳清除率）第11页几点阐明1.Inmostcases,theremended“target”drugconcentrationcorrespondstotheupperlimitoftheMICrangeforsusceptibility.2.ThegoalofourdosingremendationsistokeeptheconcentrationabovethetargetMICforanoptimalproportionofthedosinginterval,reflectingknownpharmacodynamicproperties(timedependentvs.concentration-dependentkilling),3.whileminimizingtoxicityduetounnecessarilyhighconcentrations.第12页第13页第14页ANTIBIOTICSFORDRUG-RESISTANTGRAM-POSITIVEBACTERIA

VanycinThehalf-lifeofvanycinincreasessignificantlyinpatientswithrenalinsufficiency.CVVH,CVVHD,andCVVHDFalleffectivelyremovevanycin.avanycinloadingdoseof15–20mg/kgiswarranted.VanycinmaintenancedosingforpatientsreceivingCVVHvariesfrom500mgq24hto1500mgq48hreceivingCVVHDorCVVHDF,weremendavanycinmaintenancedosageof1–1.5gq24h.Monitoringofplasmavanycinconcentrationsandsubsequentdoseadjustmentsareremendedtoachievedesiredtroughconcentrations.Atroughconcentrationof5–10mg/Lisadequateforinfectionsinwhichdrugpenetrationisoptimal,suchasskinandsoft-tissueinfectionsorunplicatedbacteremia.However,highertroughs(10–15mg/L)areindicatedforinfectionsinwhichpenetrationisdependentonpassivediffusionofdrugintoanavascularpartofthebody,suchasosteomyelitis,endocarditis,ormeningitis.Recentguidelinesalsoremendhighertroughs(15–20mg/L)inthetreatmentofhealthcare–associatedpneumonia,becauseofsuboptimalpenetrationofvanycinintolungtissue第15页Linezolid.Fiftypercentofalinezoliddoseismetabolizedintheliverto2inactivemetabolites,and30%ofthedoseisexcretedintheurineasunchangeddrug.Thereisnoadjustmentremendedforpatientswithrenalfailure;however,linezolidclearanceisincreasedby80%duringintermittenthemodialysis.ThereareveryfewdataonlinezolidclearanceduringCRRT.Onthebasisofstudies,alinezoliddosageof600mgq12hprovidesaserumtroughconcentrationof>4mg/L,whichistheupperlimitoftheMICrangefordrugs-susceptibleStaphylococcusspecies.TheupperlimitoftheMICrangefordrug-susceptibleEnterococcusandStreptococcusspeciesis2mg/L.Thus,nolinezoliddosageadjustmentisremendedforpatientsreceivinganyformofCRRT;however,insuchpatients,neitherthedispositionnortheclinicalrelevanceofinactivelinezolidmetabolitesareknown.Therefore,thereaderiscautionedtopayattentiontohematopoieticandneuropathicadverseeffectswhenadministeringlinezolidforextendedperiodstopatientsreceivingCRRT第16页b-LACTAMSCarbapenems.Imipenemandcilastatinhavesimilarpharmacokineticpropertiesinpatientswithnormalrenalfunction;bothdrugsaccumulateinpatientswithrenalinsufficiency.Cilastatinmayaccumulatetoagreaterextent,becausenonrenalclearanceofcilastatinaccountsforalowerpercentageofitstotalclearance,paredwithimipenem.Tomaintainanimipenemtroughconcentrationof2mg/LduringCRRT,adosageof250mgq6hor500mgq8hisremended.Ahigherdosage(500mgq6h)maybewarrantedincasesofrelativeresistancetoimipenem(MIC,_4mg/L).Cilastatinalsoaccumulatesinpatientswithhepaticdysfunction,andincreasingthedosingintervalmaybeneededtoavoidpotentialunknownadverseeffectsofcilastatinaccumulation.第17页ThemeropenemMICformostsusceptiblebacteriais《4mg/L.Thisrepresentsanappropriatetroughconcentrationforcriticallyillpatients,especiallywhenthepathogenandMICarenotyetknown.ManystudieshaveanalyzedthepharmacokineticsofmeropeneminpatientsreceivingCRRT.Thereissignificantvariabilityinthedata,owingtodifferentequipment,flowrates,andtreatmentgoals.However,ameropenemdosageof1gq12hwillproduceatroughconcentrationof4mg/Linmostpatients,regardlessofCRRTmodality.Iftheorganismisfoundtobehighlysusceptibletomeropenem,alowerdosage(500mgq12h)maybeappropriate.第18页b-Lactamase–inhibitorbinations.Ofthe3b-lactamase–inhibitorbinationsavailablemercially,onlypiperacillin-tazobactamhasbeenextensivelystudiedinpatientsreceivingCRRT.Onthebasisofpublisheddata,piperacillinisclearedbyallmodalitiesofCRRT.ThetazobactamconcentrationhasbeenshowntoaccumulaterelativetothepiperacillinconcentrationduringCVVH.Thus,piperacillinisthelimitingfactortoconsiderwhenchoosinganoptimaldose.Onthebasisofresultsof4studiesevaluatingpiperacillinorthefixedbinationofpiperacillin-tazobactaminpatientsreceivingCRRT,adosageof2g/0.25gq6hpiperacillin-tazobactamisexpectedtoproducetroughconcentrationsoftheseagentsinexcessoftheMICformostdrugsusceptiblebacteriaduringthemajorityofthedosinginterval.ForpatientsreceivingCVVHDorCVVHDF,oneshouldconsiderincreasingthedoseto3g/0.375gpiperacillin-tazobactamiftreatingarelativelydrug-resistantpathogen,suchasPseudomonasaeruginosaforpatientswithnoresidualrenalfunctionwhoareundergoingCVVHandreceivingprolongedtherapywithpiperacillin-tazobactam,itisnotknownwhethertazobactamaccumulates.Moreover,thetoxicitiesoftazobactamarenotknown,andithasbeenremendedthatalternatingdosesofpiperacillinaloneinthesepatientsmayavoidthepotentialtoxicityassociatedwithtazobactamaccumulation第19页Althoughfewdataexistwithampicillin-sulbactamandticarcillin-clavulanate[35],extrapolationsarepossiblebetweenpiperacillin-tazobactamandampicillin-sulbactam.Piperacillin,tazobactam,ampicillin,andsulbactamprimarilyareexcretedbythekidneys,andall4drugsaccumulateinpersonswithrenaldysfunction.theratioofb-lactamtob-lactamaseinhibitorispreservedinpersonswithvaryingdegreesofrenalinsufficiency,becauseeachpairhassimilarpharmacokinetics.Thisisnottrueforticarcillin-clavulanate.Althoughticarcillinwillalsoaccumulatewithrenaldysfunction,clavulanateisnotaffected;itismetabolizedbytheliver.Ifthedosingintervalisextended,onlyticarcillinwillremaininplasmaattheendoftheintervalForthisreason,aninterval18hisnotremendedwithticarcillin-clavulanateduringCRRT.BecauseCVVHDandCVVHDFaremoreefficientatremovingb-lactamssuchasticarcillin,thedosingintervalwiththeseCRRTmodalitiesshouldnotexceed6hforticarcillin-clavulanate.第20页Cephalosporinsandaztreonam.Withtheexceptionofceftriaxone,theseb-lactamsarerenallyexcretedandaccumulateinpersonswithrenaldysfunction.therateofeliminationisdirectlyproportionaltorenalfunction,patientsrequiringintermittenthemodialysismayreceivedosesmuchlessoften.Insomeinstances,3timesweeklydosingafterhemodialysisisadequate.However,clearancebyCRRTisgreaterformostoftheseagents,necessitatingmore-frequentdosingtomaintaintherapeuticconcentrationsgreaterthantheMICforanoptimalproportionofthedosinginterval.第21页Ceftriaxoneistheexceptioninthisgroupofb-lactams,primarilybecauseofitsextensiveprotein-bindingcapacity,whichpreventsitfrombeingfiltered,anditshepaticmetabolismandbiliaryexcretion.CeftriaxoneclearanceinpatientsreceivingCVVHhasbeenshowntobeequivalenttoclearanceinsubjectswithnormalrenalfunction,andtherefore,nodoseadjustmentisnecessaryforpatientsreceivingCRRT。第22页Theothercephalosporinsandaztreonamareclearedatarateequivalenttoacreatinineclearancerateof30–50mL/minduringCVVHDorCVVHDF,whereastherateofclearancebyCVVHislower.Ifthegoalincriticallyillpatientsistomaintainatherapeuticconcentrationfortheentiredosinginterval,anormal,unadjusteddosemayberequired.ThisisthecasewithcefepimeOnthebasisof2well-donestudiesinvolvingcriticallyillpatients,acefepimedosageof1gq12hisappropriateformostpatientsreceivingCVVH,andupto2gq12hisappropriateforpatientsreceivingCVVHDorCVVHDF第23页Cefepimeandceftazidimepharmacokineticsarealmostidentical,andsimilardosesareadvocated.OlderremendationsforCVVHdosing(1–2gq24–48h)arebasedonCAVHdataItisnotclearwhetherCAVHdatacanbeextrapolatedtoCVVH,CVVHD,andCVVHDF.Aceftazidimedosageof2gq12hisneededtomaintainconcentrationsabovetheMICformostnosoialgram-negativebacteriaincriticallyillpatientsreceivingCVVHDandCVVHDF.Ceftazidime1gq12hisappropriateduringCVVH.Studieshavenotbeenperformedwithcefazolin,cefotaxime,oraztreonamduringCRRT.However,theirpharmacokineticandmolecularpropertiesaresimilarenoughsuchthatextrapolationsareappropriate.Dosingremendationsfortheseb-lactamsarelistedintable2.第24页FLUOROQUINOLONESFewantibioticclasseshavemoredatasupportingtheinfluenceofpharmacodynamicsonclinicaloutesthanfluoroquinolones.AUC/MICevidenceexiststhatmanufacturer-remendeddosingforciprofloxacinwillnotalwaysachieveatargetAUC/MICratioincriticallyillpatientsAciprofloxacindosageof400mgq.d.isremendedbythemanufacturerforpatientswithacreatinineclearancerateof_30mL/minIncriticallyillpatientsreceivingCRRT,adosageof600–800mgperdaymaybemorelikelytoachieveanoptimalAUC/MICratio,andfororganismswithaciprofloxacinMICof_1mg/mL,standarddosesarelesslikelytoachieveatargetratio.第25页Levofloxacinisexcretedlargelyunchangedintheurine,andsignificantdosageadjustmentsarenecessaryforpatientswithrenalfailure.Intermittenthemodialysisdoesnoteffectivelyremovelevofloxacin,andtherefore,supplementaldosesarenotrequiredafterhemodialysisLevofloxaciniseliminatedbyCVVHandCVVHDFAlevofloxacindosageof250mgq24hprovidedCmax/MICandAUC24/MICvaluesthatwereparabletothevaluesfoundinpatientswithnormalrenalfunctionafteradosageof500mgq24h.Levofloxacindosagesof250mgq24h,aftera500mgloadingdose,areappropriateforpatientsreceivingCVVH,CVVHD,orCVVHDF第26页ThepharmacokineticsofmoxifloxacinhavebeenrecentlystudiedincriticallyillpatientsreceivingCVVHDF[50].Thesedata,aswellasknownpharmacokineticsdata,indicatenoneedtoadjustthemoxifloxacindosageforpatientsreceivingCRRT第27页AMINOGLYCOSIDES

Today’sfiltersarecapableofremovingaminoglycosidesatarateequivalenttoacreatinineclearancerateof10–40mL/minThisequatestoanaminoglycosidehalf-lifeof6–20h.Thetypicaldosingintervalwithaminoglycosideswillbe3halflives;therefore,thetypicaldosingintervalduringCRRTwillbe18–60h.Indeed,mostpatientsundergoingCRRTwillrequireanintervalof24,36,or48h.第28页第29页ANTIFUNGALS

80%ofthefluconazoledoseiseliminatedunchangedviathekidneys.azole-resistantCandidaadailydoseof800mgforcriticallyillpatientsreceivingCVVHDorCVVHDFwithabinedultrafiltrationanddialysateflowrateof2L/hadailydoseof400mgforpatientsreceivingCVVH400mg(CVVHDandCVVHDF)orto200mg(CVVH)ifthespeciesisnotCandidakruseiorCandidaglabrataandthefluconazoleMICis_8mg/L.第30页ItraconazoleandvoriconazoleTheparenteralformulationsaresolubilizedinacyclodextrindiluent,whichiseliminatedbythekidneysandwillaccumulateinpatientswithrenalinsufficiencyUseofintravenousitraconazoleandvoriconazoleisnotremendedforpatientswithcreatinineclearanceratesof<30and50mL/minAlthoughoralformulationsarenotcontraindicated（禁忌）,therearefewdataabouttriazoledosingforpatientsreceivingCRRTOnthebasisofpharmacokineticsdata,nodosereductionisremendedforpatientsreceivingCRRT.第31页AmphotericinB.doseadjustmentsforCRRTarenotremended.第32页DataSources:MEDLINEsearchfromFebruary1986to2023.第33页PharmacokineticFactorsInfluencingInitialDosesofAntibacterialsVolumeofdistributionAlthoughbothcriticalillnessandacuterenalfailuremayaffectvolumeofdistribution,CRRTitselfgenerallyhasnoeffect.Althoughantibacterialvolumeofdistributionwouldbeexpectedtoincreaseinthecriticallyilandthosewithacuterenalfailure,thisisonlythecaseforcertainagents.第34页PharmacokineticFactorsInfluencingMaintenanceDosesMaintenancedosesaredeterminedbyantibacterialclearance.Totalclearance=non-CRRT

clearance(renalclearanceduetoresidualrenalfunctionplusnonrenalclearance)andCRRTclearance第35页Nonrenalclearancemaybeaffectedbycriticalillness,forexample,becauseofhepaticdysfunction.ItmayalsobeincreasedinthepresenceofacuterenalfailureCRRTclearanceisaffectedbyPB,adsorption,andGibbs-DonnaneffectPB影响原因Diseasestates,suchasuremia,cirrhosis,nephroticsyndrome,epilepsy,hepatitis,pregnancy,andsevereburnssystemicpH,heparin,freefattyacids,anddrugssuchassalicylateandsulfonamide第36页Optimaldosingofantibacterialsisdependentonachievingpharmacokinetictargetsassociatedwithmaximalkillingofbacteriaandimprovedoutes.Theinitialdoseisdependentonthevolumeofdistribution.Maintenancedosesaredependentonclearance.Bothshouldbeadjustedaccordingtothepharmacokinetictargetassociatedwithoptimalbacterialkilling,whenknown.Thevolumeofdistributionofsomeantibacterialsisalteredbycriticalillnessoracuterenalfailureorboth.ClearancebyCRRTisdependentonthedoseandmodeofCRRTandthesievingorsaturationcoefficientofthedrug.Bothsievingandsaturationcoefficientarerelatedtotheplasmaproteinbindingandthusmaybealteredinrenalfailure.第37页Conclusions:Appropriatedosecalculationrequiresknowledgeofthepharmacokinetictargetandtheusualminimuminhibitoryconcentrationofthesuspectedorganisminthepatient’slocality(orifunavailable,thebreakpointfortheorganism),publishedpharmacokineticdata(volumeofdistribution,non-CRRTclearance)oncriticallyillpatientsreceivingCRRT(whichmaydiffersubstantiallyfromnoncriticallyillpatientsorthosewithoutrenalfailure),thesievingorsaturationcoefficientoftherelevantdrugincriticallyillpatients,thedoseandmodeofCRRTbeingused,andtheactualdoseofCRRTthatisdelivered.Thislargenumberofvariablesresultsinconsiderableinter-andintrapatientheterogeneityindoserequirements.

第38页Theabilityofadrugtopassthroughthemembraneisexpressedasthesievingcoefficient(Sc):theratioofdrugconcentrationintheultrafiltratetoplasma.Sc=1-PBPBinthecriticallyillisvariableandforsomedrugs(e.g.,levofloxacin)Scvarieswidely

第39页CICVVH(pre)=Qf×Sc×CF,whereCF=Qb/(Qb+Qrep)第40页InpostdilutionmodeCICVVH(post)=Qf×Sc第41页Severalaspectsofthisremendationrequireelaboration.需要阐明旳几种问题：1.First,forthesakeofsimplicity,ravenousinfusionofantibacterialswithtime-dependentkillingcharacteristicsisremendedbecausedoseestimationismuchsimpler第42页2.intermittentbolusdoseswherek=CL/VdT=dosinginterval(mins)andCth_targetthresholdconcentration.第43页3.forpatientswithresidualrenalfunction,totalclearanceneedstobeadjustedforrenalclearance.Inthiscontext,itisimportanttounderstand