CRRT抗生素劑量調(diào)整ICU臨床藥師孫浩contextContinuousrenalreplacementtherapy(CRRT)isnowcommonlyusedasameansofsupportforcriticallyillpatientswithrenalfailure.acuterenalfailureorchronicrenalfailure.NorecentcomprehensiveguidelinesexistthatprovideantibioticdosingrecommendationsforadultpatientsreceivingCRRT.Dosesusedinintermittenthemodialysiscannotbedirectlyappliedtothesepatientsantibioticpharmacokineticsaredifferentthanthoseinpatientswithnormalrenalfunction.目前現(xiàn)狀CRRT廣泛用于重癥病人腎臟衰竭治療缺乏此類人群抗生素劑量調(diào)整的指導(dǎo)（傳統(tǒng)的劑量調(diào)整方案不適用于CRRT患者）劑量調(diào)整難度大危重患者/ARF：Vd、PBCRRT:腎臟排泄率》25%有意義不同抗生素具有不同藥代、藥動(dòng)學(xué)患者—抗生素---CRRT三者關(guān)系DataSources1995~2004

DataSources:MEDLINEsearchfromFebruary1986to2008.DataSources1995~2004推薦依據(jù)1.有相關(guān)報(bào)道2.沒有相關(guān)報(bào)道：a化學(xué)性質(zhì)b其它臨床數(shù)據(jù)（分子量、蛋白結(jié)合率PB、間斷透析的清除率）幾點(diǎn)說明1.Inmostcases,therecommended“target”drugconcentrationcorrespondstotheupperlimitoftheMICrangeforsusceptibility.2.ThegoalofourdosingrecommendationsistokeeptheconcentrationabovethetargetMICforanoptimalproportionofthedosinginterval,reflectingknownpharmacodynamicproperties(timedependentvs.concentration-dependentkilling),3.whileminimizingtoxicityduetounnecessarilyhighconcentrations.ANTIBIOTICSFORDRUG-RESISTANTGRAM-POSITIVEBACTERIA

VancomycinThehalf-lifeofvancomycinincreasessignificantlyinpatientswithrenalinsufficiency.CVVH,CVVHD,andCVVHDFalleffectivelyremovevancomycin.avancomycinloadingdoseof15–20mg/kgiswarranted.VancomycinmaintenancedosingforpatientsreceivingCVVHvariesfrom500mgq24hto1500mgq48hreceivingCVVHDorCVVHDF,werecommendavancomycinmaintenancedosageof1–1.5gq24h.Monitoringofplasmavancomycinconcentrationsandsubsequentdoseadjustmentsarerecommendedtoachievedesiredtroughconcentrations.Atroughconcentrationof5–10mg/Lisadequateforinfectionsinwhichdrugpenetrationisoptimal,suchasskinandsoft-tissueinfectionsoruncomplicatedbacteremia.However,highertroughs(10–15mg/L)areindicatedforinfectionsinwhichpenetrationisdependentonpassivediffusionofdrugintoanavascularpartofthebody,suchasosteomyelitis,endocarditis,ormeningitis.Recentguidelinesalsorecommendhighertroughs(15–20mg/L)inthetreatmentofhealthcare–associatedpneumonia,becauseofsuboptimalpenetrationofvancomycinintolungtissueLinezolid.

Fiftypercentofalinezoliddoseismetabolizedintheliverto2inactivemetabolites,and30%ofthedoseisexcretedintheurineasunchangeddrug.Thereisnoadjustmentrecommendedforpatientswithrenalfailure;

however,linezolidclearanceisincreasedby80%duringintermittenthemodialysis.ThereareveryfewdataonlinezolidclearanceduringCRRT.Onthebasisofstudies,alinezoliddosageof600mgq12hprovidesaserumtroughconcentrationof>4mg/L,whichistheupperlimitoftheMICrangefordrugs-susceptibleStaphylococcusspecies.TheupperlimitoftheMICrangefordrug-susceptibleEnterococcusandStreptococcusspeciesis2mg/L.Thus,nolinezoliddosageadjustmentisrecommendedforpatientsreceivinganyformofCRRT;however,insuchpatients,neitherthedispositionnortheclinicalrelevanceofinactivelinezolidmetabolitesareknown.Therefore,thereaderiscautionedtopayattentiontohematopoieticandneuropathicadverseeffectswhenadministeringlinezolidforextendedperiodstopatientsreceivingCRRTb-LACTAMSCarbapenems.Imipenemandcilastatinhavesimilarpharmacokineticpropertiesinpatientswithnormalrenalfunction;bothdrugsaccumulateinpatientswithrenalinsufficiency.Cilastatinmayaccumulatetoagreaterextent,becausenonrenalclearanceofcilastatinaccountsforalowerpercentageofitstotalclearance,comparedwithimipenem.Tomaintainanimipenemtroughconcentrationof2mg/LduringCRRT,adosageof250mgq6hor500mgq8hisrecommended.Ahigherdosage(500mgq6h)maybewarrantedincasesofrelativeresistancetoimipenem(MIC,_4mg/L).Cilastatinalsoaccumulatesinpatientswithhepaticdysfunction,andincreasingthedosingintervalmaybeneededtoavoidpotentialunknownadverseeffectsofcilastatinaccumulation.ThemeropenemMICformostsusceptiblebacteriais《4mg/L.Thisrepresentsanappropriatetroughconcentrationforcriticallyillpatients,especiallywhenthepathogenandMICarenotyetknown.ManystudieshaveanalyzedthepharmacokineticsofmeropeneminpatientsreceivingCRRT.Thereissignificantvariabilityinthedata,owingtodifferentequipment,flowrates,andtreatmentgoals.However,ameropenemdosageof1gq12hwillproduceatroughconcentrationof4mg/Linmostpatients,regardlessofCRRTmodality.Iftheorganismisfoundtobehighlysusceptibletomeropenem,alowerdosage(500mgq12h)maybeappropriate.b-Lactamase–inhibitorcombinations.Ofthe3b-lactamase–inhibitorcombinationsavailablecommercially,onlypiperacillin-tazobactamhasbeenextensivelystudiedinpatientsreceivingCRRT.Onthebasisofpublisheddata,piperacillinisclearedbyallmodalitiesofCRRT.ThetazobactamconcentrationhasbeenshowntoaccumulaterelativetothepiperacillinconcentrationduringCVVH.Thus,piperacillinisthelimitingfactortoconsiderwhenchoosinganoptimaldose.Onthebasisofresultsof4studiesevaluatingpiperacillinorthefixedcombinationofpiperacillin-tazobactaminpatientsreceivingCRRT,adosageof2g/0.25gq6hpiperacillin-tazobactamisexpectedtoproducetroughconcentrationsoftheseagentsinexcessoftheMICformostdrugsusceptiblebacteriaduringthemajorityofthedosinginterval.ForpatientsreceivingCVVHDorCVVHDF,oneshouldconsiderincreasingthedoseto3g/0.375gpiperacillin-tazobactamiftreatingarelativelydrug-resistantpathogen,suchasPseudomonasaeruginosaforpatientswithnoresidualrenalfunctionwhoareundergoingCVVHandreceivingprolongedtherapywithpiperacillin-tazobactam,itisnotknownwhethertazobactamaccumulates.Moreover,thetoxicitiesoftazobactamarenotknown,andithasbeenrecommendedthatalternatingdosesofpiperacillinaloneinthesepatientsmayavoidthepotentialtoxicityassociatedwithtazobactamaccumulationAlthoughfewdataexistwithampicillin-sulbactamandticarcillin-clavulanate[35],extrapolationsarepossiblebetweenpiperacillin-tazobactamandampicillin-sulbactam.Piperacillin,tazobactam,ampicillin,andsulbactamprimarilyareexcretedbythekidneys,andall4drugsaccumulateinpersonswithrenaldysfunction.theratioofb-lactamtob-lactamaseinhibitorispreservedinpersonswithvaryingdegreesofrenalinsufficiency,becauseeachpairhassimilarpharmacokinetics.Thisisnottrueforticarcillin-clavulanate.Althoughticarcillinwillalsoaccumulatewithrenaldysfunction,clavulanateisnotaffected;itismetabolizedbytheliver.Ifthedosingintervalisextended,onlyticarcillinwillremaininplasmaattheendoftheintervalForthisreason,aninterval18hisnotrecommendedwithticarcillin-clavulanateduringCRRT.BecauseCVVHDandCVVHDFaremoreefficientatremovingb-lactamssuchasticarcillin,thedosingintervalwiththeseCRRTmodalitiesshouldnotexceed6hforticarcillin-clavulanate.Cephalosporinsandaztreonam.Withtheexceptionofceftriaxone,theseb-lactamsarerenallyexcretedandaccumulateinpersonswithrenaldysfunction.therateofeliminationisdirectlyproportionaltorenalfunction,patientsrequiringintermittenthemodialysismayreceivedosesmuchlessoften.Insomeinstances,3timesweeklydosingafterhemodialysisisadequate.However,clearancebyCRRTisgreaterformostoftheseagents,necessitatingmore-frequentdosingtomaintaintherapeuticconcentrationsgreaterthantheMICforanoptimalproportionofthedosinginterval.Ceftriaxoneistheexceptioninthisgroupofb-lactams,primarilybecauseofitsextensiveprotein-bindingcapacity,whichpreventsitfrombeingfiltered,anditshepaticmetabolismandbiliaryexcretion.CeftriaxoneclearanceinpatientsreceivingCVVHhasbeenshowntobeequivalenttoclearanceinsubjectswithnormalrenalfunction,andtherefore,nodoseadjustmentisnecessaryforpatientsreceivingCRRT。Theothercephalosporinsandaztreonamareclearedatarateequivalenttoacreatinineclearancerateof30–50mL/minduringCVVHDorCVVHDF,whereastherateofclearancebyCVVHislower.Ifthegoalincriticallyillpatientsistomaintainatherapeuticconcentrationfortheentiredosinginterval,anormal,unadjusteddosemayberequired.ThisisthecasewithcefepimeOnthebasisof2well-donestudiesinvolvingcriticallyillpatients,acefepimedosageof1gq12hisappropriateformostpatientsreceivingCVVH,andupto2gq12hisappropriateforpatientsreceivingCVVHDorCVVHDFCefepimeandceftazidimepharmacokineticsarealmostidentical,andsimilardosesareadvocated.OlderrecommendationsforCVVHdosing(1–2gq24–48h)arebasedonCAVHdataItisnotclearwhetherCAVHdatacanbeextrapolatedtoCVVH,CVVHD,andCVVHDF.Aceftazidimedosageof2gq12hisneededtomaintainconcentrationsabovetheMICformostnosocomialgram-negativebacteriaincriticallyillpatientsreceivingCVVHDandCVVHDF.Ceftazidime1gq12hisappropriateduringCVVH.Studieshavenotbeenperformedwithcefazolin,cefotaxime,oraztreonamduringCRRT.However,theirpharmacokineticandmolecularpropertiesaresimilarenoughsuchthatextrapolationsareappropriate.Dosingrecommendationsfortheseb-lactamsarelistedintable2.FLUOROQUINOLONESFewantibioticclasseshavemoredatasupportingtheinfluenceofpharmacodynamicsonclinicaloutcomesthanfluoroquinolones.AUC/MICevidenceexiststhatmanufacturer-recommendeddosingforciprofloxacinwillnotalwaysachieveatargetAUC/MICratioincriticallyillpatientsAciprofloxacindosageof400mgq.d.isrecommendedbythemanufacturerforpatientswithacreatinineclearancerateof_30mL/minIncriticallyillpatientsreceivingCRRT,adosageof600–800mgperdaymaybemorelikelytoachieveanoptimalAUC/MICratio,andfororganismswithaciprofloxacinMICof_1mg/mL,standarddosesarelesslikelytoachieveatargetratio.Levofloxacinisexcretedlargelyunchangedintheurine,andsignificantdosageadjustmentsarenecessaryforpatientswithrenalfailure.Intermittenthemodialysisdoesnoteffectivelyremovelevofloxacin,andtherefore,supplementaldosesarenotrequiredafterhemodialysisLevofloxaciniseliminatedbyCVVHandCVVHDFAlevofloxacindosageof250mgq24hprovidedCmax/MICandAUC24/MICvaluesthatwerecomparabletothevaluesfoundinpatientswithnormalrenalfunctionafteradosageof500mgq24h.Levofloxacindosagesof250mgq24h,aftera500mgloadingdose,areappropriateforpatientsreceivingCVVH,CVVHD,orCVVHDFThepharmacokineticsofmoxifloxacinhavebeenrecentlystudiedincriticallyillpatientsreceivingCVVHDF[50].Thesedata,aswellasknownpharmacokineticsdata,indicatenoneedtoadjustthemoxifloxacindosageforpatientsreceivingCRRTAMINOGLYCOSIDES

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

80%ofthefluconazoledoseiseliminatedunchangedviathekidneys.azole-resistantCandidaadailydoseof800mgforcriticallyillpatientsreceivingCVVHDorCVVHDFwithacombinedultrafiltrationanddialysateflowrateof2L/hadailydoseof400mgforpatientsreceivingCVVH400mg(CVVHDandCVVHDF)orto200mg(CVVH)ifthespeciesisnotCandidakruseiorCandidaglabrataandthefluconazoleMICis_8mg/L.ItraconazoleandvoriconazoleTheparenteralformulationsaresolubilizedinacyclodextrindiluent,whichiseliminatedbythekidneysandwillaccumulateinpatientswithrenalinsufficiencyUseofintravenousitraconazoleandvoriconazoleisnotrecommendedforpatientswithcreatinineclearanceratesof<30and50mL/minAlthoughoralformulationsarenotcontraindicated（禁忌）,therearefewdataabouttriazoledosingforpatientsreceivingCRRTOnthebasisofpharmacokineticsdata,nodosereductionisrecommendedforpatientsreceivingCRRT.AmphotericinB.doseadjustmentsforCRRTarenotrecommended.DataSources:MEDLINEsearchfromFebruary1986to2008.PharmacokineticFactorsInfluencingInitialDosesofAntibacterialsVolumeofdistributionAlthoughbothcriticalillnessandacuterenalfailuremayaffectvolumeofdistribution,CRRTitselfgenerallyhasnoeffect.Althoughantibacterialvolumeofdistributionwouldbeexpectedtoincreaseinthecriticallyilandthosewithacuterenalfailure,thisisonlythecaseforcertainagents.PharmacokineticFactorsInfluencingMaintenanceDosesMaintenancedosesaredeterminedbyantibacterialclearance.Totalclearance=non-CRRT

clearance(renalclearanceduetoresidualrenalfunctionplusnonrenalclearance)andCRRTclearanceNonrenalclearancemaybeaffectedbycriticalillness,forexample,becauseofhepaticdysfunction.ItmayalsobeincreasedinthepresenceofacuterenalfailureCRRTclearance

isaffectedbyPB,adsorption,andGibbs-DonnaneffectPB影響因素Diseasestates,suchasuremia,cirrhosis,nephroticsyndrome,epilepsy,hepatitis,pregnancy,andsevereburnssystemicpH,heparin,freefattyacids,anddrugssuchassalicylateandsulfonamideOptimaldosingofantibacterialsisdependentonachievingpharmacokinetictargetsassociatedwithmaximalkillingofbacteriaandimprovedoutcomes.Theinitialdoseisdependentonthevolumeofdistribution.Maintenancedosesa