脑性瘫痪儿童的语言障碍(上)林馨一、脑性瘫痪的定义据2004年10月昆明全国小儿脑性瘫痪专题研讨会讨论通过脑瘫的定义是:出生前到生后1个月内各种原因所引起的脑损伤或发育缺陷所致的运动障碍及姿势异常。诊断条件(1)引起脑性瘫痪(简称脑瘫)的脑损伤为非进行性；(2)引起运动障碍的病变部位在脑部；(3)症状在婴儿期出现；(4)有时合并智力障碍、癫痫、感知觉障碍及其他异常；(5)除外进行性疾病所致的中枢性运动障碍及正常小儿暂时性的运动发育迟缓。临床分型(1)痉挛型:痉挛是肌肉僵硬和紧张的意思。肌肉的僵硬使运动缓慢和笨拙。痉挛型是以锥体系受损为主,来自受损部分脑的错误指令引起机体保持在典型的异常姿势，小儿感到难以从异常姿势中解脱出来。这就使运动缺乏多样性，逐渐地发生变形。痉挛型脑瘫是脑瘫中最常见的类型。临床分型(2)不随意运动型:以锥体外系受损为主,不随意运动增多,表现为手足徐动,舞蹈样动作,肌张力不全,震颤等;小儿下肢、上肢、手及颜面的痉挛样运动，或缓慢地扭动样运动。每天的大部分时间都出现这样的运动。这样的表现在小儿兴奋及不开心时加重，而在安静时减轻。这样的孩子很少发生变形。临床分型(3)共济失调型:失调是不稳定的摇晃运动的意思。以小脑受损为主。这种不稳定的运动只在小儿试图平衡、走路及手做事时见到。(4)肌张力低下型:往往是其他类型的过渡形式;(5)混合型。许多脑瘫儿呈现出不止一种类型的特征。例如，某些小儿为痉挛型脑瘫并伴有手足徐动。按瘫痪部位(指痉挛型)(1)单瘫:单个肢体受累;(2)双瘫:四肢受累,上肢轻,下肢重;(3)三肢瘫:三个肢体受累;(4)偏瘫:半侧肢体受累;(5)四肢瘫:四肢受累,上、下肢受累程度相似。二、脑瘫的伴发障碍脑瘫的生长发育较正常儿差，重症更明显，营养也较差。身体矮小，常有呼吸障碍和易患呼吸道感染疾病。牙齿多数发育不良，质地疏松、易折、易蛀，各种牙病的发生率较正常儿童高。并发智能低下者较多，还有多动，情绪不稳、自闭（孤独倾向）亦多。伴发癫痫者很多。伴发听力、视力、语言、行为障碍。一、脑瘫的家庭护理脑瘫孩子的家庭护理是脑瘫运动康复中非常重要的方面，家长必须引起足够的重视。家庭护理除了日常照顾外，更应注意随时矫治孩子的异常姿势和体位。一、脑瘫的家庭护理(一)如何正确地抱孩子抱起方法一、脑瘫的家庭护理二、脑瘫孩子训练的基础知识（一）头和躯干的控制：1、头的控制如果小儿不学会抬头，那么练习坐位将会很困难。竖直的姿势将帮助小儿使头竖起，环视周围和学习。开始在支持下坐，因为这样的姿势容易使小儿头部保持平衡。2、回旋头和躯干之间的扭转是正常回旋的一部分，这对以后的坐和步行是必须的。回旋时，首先头转向一侧，接着是肩部，然后是下肢。2、独坐为了在椅子上有良好的坐位，孩子必须学会保持两脚平放在地板上，分开双腿，向前靠并用双手抓握。当她坐得好时给予表扬。（三）立位当拉起站立时，小儿需要很好地向前靠。他们常常向后挺，这会使站立困难。（二）坐1、准备阶段1、拉向立位第一节概述脑瘫对每一个患儿的影响是不同的:轻度损伤小儿可学会步行，只是在步行时带有轻微的平衡障碍，不稳定。另外一些小儿可能有手的功能障碍。损害严重的小儿可能日常生活不能独立。脑瘫影响小儿的一生。脑的损伤不会增重，但随着小儿年龄的增长，其影响会变得更明显。虽然脑瘫是不能痊愈的疾病，但可以减少该病的影响，这取决于是否尽早地开始康复训练及脑损伤的程度。第二节脑瘫康复的基础知识平时抱孩子的姿势:采用既能纠正异常姿势，又能将他的双上肢向前放的方法抱他，且较直立的姿势有助于小儿竖头和环视。(二)保持良好的姿势1、卧位姿势2、坐位姿势良好的坐姿：头稍向前。背挺直，不弯向侧方。臀部顶靠椅背。双膝垂直。两腿轻轻分开。脚平放在地板上，或用脚垫支持如何纠正坐姿3、站立姿势良好的站立姿势是：身体呈直线，两脚放平，体重均等地放在两脚上，髋关节伸直。(三)如何喂养随着孩子能力的增加，在进食及喝水时减少支持，但要维持好的坐姿。教小儿自己进食和拿杯子。他可能需要帮助使下颌闭上。要从正前方给他喂食物和饮料，以使他保持头向前方。如果小儿已经学会了自己进食，可以让他抓住桌边的木棒，以避免上肢后缩。这时他应能以很好的姿势独坐在椅子或凳子上。ImipenemTheCarbapenemwithUnsurpassedExperienceandTime-TestedReliabilityImipenem:UnsurpassedExperienceandTime-TestedReliabilityAfter27yearsofresearchand18yearsofclinicalexperiencein22millionpatientsinover100countries,imipenem/cilastatinstillreliablydemonstratesbroad-spectrumactivity,lowpotentialforresistance,andfavorabletolerabilityTheNeedforInitialAppropriateTherapyintheTreatmentofSeriousInfectionInitialTherapyforSeriousNosocomialInfectionHAPandsepsisaretwoofthemostcommon,mostseriousinfectionsintheICU,andareassociatedwithhighmortalityrates.InadequatetherapyforHAPandseveresepsisincreasesmortality.Empiricbroad-spectrumtherapymustbeinitiatedatthefirstsuspicionofseriousinfectiontoensureadequatecoverageofalllikelypathogens.DE-ESCALATIONTHERAPY?Stage1Administeringthebroadest-spectrumantibiotictherapytoimproveoutcomes.Stage2Focusingonde-escalatingasameanstominimizeresistanceandimprovecost-effectivenessCarbapenems:AGoodChoiceforInitialAppropriateTherapyinICUPatientswithSeriousNosocomialInfectionThecarbapenemofchoiceforinitialappropriatetherapyshouldoffer:BroadspectrumactivityProvenefficacyLowpotentialforresistanceTimetestedtolerabilityImipenemProvidesBroad-SpectrumCoverageandProvenEfficacyforSeriousInfectionTheExcellentBroadSpectrumActivityofImipenemImipenemprovidescoverageof:AerobicandanaerobicbacteriaGram-negativeandGram-positivebacteriaEnterococcusfaecaliscoveredbyimipenembutnotmeropenemImipenem:ProvenEfficacyLowPotentialforResistanceWithImipenemPotentActivityvs.ESBL-ProducingStrainsImipenemhasshownpotentactivityagainstextended-spectrumb-lactamase-(ESBL)producingstrainsofE.coliandK.pneumoniae.199-100%ofEnterobacterspp.,K.pneumoniaeandE.coliICUisolatesweresusceptibletoimipenem.2“ClinicalmicrobiologylaboratoriesshouldtakeheedofcurrentrecommendationsfordetectionofESBLsinordertoavoidpotentialtreatmentfailurewhencephalosporinsareused.”3LowPotentialforResistanceinAcinetobacterConsistentCoverageofPseudomonasaeruginosa—U.S.DataStableCoverageofP.aeruginosa–GermanDataImipenemhasFewerMechanismsofResistanceinPseudomonasaeruginosaPorinOprDdeficiencyproducesresistancetocarbapenems.Decreasedvirulencedemonstratedinporin-deficientstrainsofPAresultsinrelativelyhighcurerates.ComparativePharmacodynamicsandPharmacokineticsLowEndotoxinReleasewithImipenemEndotoxinsenhancethereleaseofcytokines.Cytokinesmaybeassociatedwithdeteriorationinthesepticpatient.Imipeneminduces3to4timeslessendotoxinthanothercarbapenems.Imipenem:LowerPlasmaEndotoxinConcentrationsImipenemAssociatedwithLowerEndotoxinLevelsthanMeropeneminP.aeruginosaApprovedIndicationsforImipenemvs.MeropenemIndicationsImipenemIntra-abdominalinfectionLowerrespiratorytractinfectionUrinarytractinfectionGynecologicalinfectionBacterialsepticemiaBoneandjointinfectionSkinandskinstructureinfectionEndocarditisPolymicrobicinfectionMeropenemIntra-abdominalinfectionBacterialmeningitisImipenem:Time-TestedTolerabilityDispellingCNSAdverseEventswithCarbapenems:Label-to-LabelCNSAdverseExperiencesWithCarbapenemsOnly0.2%(4/1951)ofimipenem-treatedpatientsexperiencedseizuresinstudyof1951patients.4of1951patients(0.2%)experiencedseizures.Allattributedtoexcessivedoseswithrespecttocorrespondingrenalfunction.Noseizureswerereportedintwocomparativestudiesofimipenem(n=101;n=116)andmeropenem(n=100;n=116).SummaryBroadspectrumactivityReliableefficacyLowpotentialforresistanceFavorablepharmacokinetics/pharmacodynamicsLowendotoxinreleaseMultipleindicationsallowmaximumflexibilityFavorabletolerabilityReferencesReferences(cont.)References(cont.)TheincidenceofreportedCNSadverseexperiencessuchasseizureremainslowovertime.Inalabel-to-labelcomparison:DatafromU.S.LabelinPhysiciansDeskReference55thed.,2000.DatafromU.S.LabelinPhysiciansDeskReference56thed.,2002.DatafromU.S.LabelinPhysiciansDeskReference57thed.,2003. 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SchentagJJ,GillilandKK,PaladinoJA.Whathavewelearnedfrompharmacokineticandpharmacodynamictheories.ClinInfectDis2001;32(Suppl1):S39-S46.37. TurnridgeJD.Thepharmacodynamicsofb-lactams.ClinInfectDis1998;27:10-22.38. CraigWA.Pharmacokinetic/pharmacodynamicparameters:rationaleforantibacterialdosingofmiceandmen.ClinInfectDis1998;26:1-12.39. MoutonJWetal.Comparativepharmacokineticsofthecarbapenems.Clinicalimplications.ClinPhamacokinet2000;39:185-201.40. Physicians’DeskReference?57thed,MontvaleNJ:MedicalEconomics,2003.41. SaitoA.Pharmacokineticstudyonmeropenem.Chemotherapy(Tokyo)1992;40(Suppl1):276-282.42. MoutonJWetal.Meropenemclinicalpharmacokinetics.ClinPharmacokinet1995;28:275-286.43. DreetzM,HamacherJ,EllerJetal.Serumbactericidalactivitiesandcomparativepharmacokineticsofmeropenemandimipenem-cilastatin.AntimicrobAgentsChemother1996;40:105-109NorimatsuMetal.Correlationofantibiotic-inducedendotoxinreleaseandcytokineproductioninEscherichiacoli—inoculatedmousewholebloodexvivo.JInfectDis1998;177:1302-1307.HoriiTetal.Carbapenem-inducedendotoxinreleaseingram-negativebacterialsepsisratmodels.FEMSImmunolMedMicrobiol1998;21:297-302.YokochiTetal.Differentialreleaseofsmooth-typelipopolysaccharidefromPseudomonasaeruginosatreatedwithcarbapenemantibioticsanditsrelationtoproductionoftumornecrosisfactoralphaandnitricoxide.AntimicrobAgentsChemother1996;40:2410-2412.PrinsJMetal.Clinicalrelevanceofantibiotic-inducedendotoxinrelease.AntimicrobAgentsChemother1994;38:1211-1218.HoriiTetal.RelationshipbetweenmorphologicalchangesandendotoxinreleaseinducedbycarbapenemsinPseudomonasaeruginosa.JMedMicrobiol1999;48:309-315.PestotnikSetal.Prospectivesurveillanceofimipenem/cilastatinuseandassociatedseizuresusingahospitalinformationsystemAnnPharmacotherapy1993;27:497-501.GeroulanosSetal.Meropenemversusimipenem/cilastatininintra-abdominalinfectionsrequiringsurgery.JAntimicrobChemother1995;36(Suppl.A):191-205.Severesepsis,andhospital-acquiredpneumonia(HAP)aretwoofthemostcommon,mostseriousinfectionsinhospitalizedpatients.4SepsisandHAParemostfrequentlyobservedamongpatientswhorequireintensivemedicalcare.5HAPhasbeenassociatedwithcasefatalityrates>20%inmostreportedstudies.5,6Althoughtherehavebeenimportantadvancesincritical-caremedicine,includingtheavailabilityofmanyantibiotics,mortalityduetosepsisremainshigh.7Despiteadvancesincriticalcare,anexaminationoffourreferencespublishedbetween1990and2000foundthatmortalityratesfromseveresepsisrangedfrom30to50%.8Inadequatetherapycanincreasemortalityrates.3,9Inlightofthishighmortality,itisimportanttoadministerinitialappropriateantibiotictherapythatwillcoveralllikelypathogensatthefirstsuspicionofseriousinfection,evenifcultureresultsarenotyetavailable.3,10Ref3p472par2L11-14,3-25p470par2L1-3Ref4p891par1L3Ref5pS133par3L1Ref6p1711par1L1Ref7p172par4L1Ref8p699par1l1-4Ref9p2188parlastL1-4Ref10p1473parlastL16-21Imipenemisusedforthetreatmentofseriousinfectionsuchasnosocomial(hospital-acquired)infections.1Thisslidekitwillreviewthebroadantimicrobialspectrumandefficacyofimipenem,thelowpotentialfordevelopmentofantibioticresistance,andthefavorabletolerabilityprofileofimipenem.Ref1WPCTitleslide—tobecoveredinslidesetImipenemisabroad-spectrumantibiotic,providingcoverageofinfectionscausedbyaerobicandanaerobicgram-negativeandgram-positivebacteria.1OneimportantdifferencebetweenimipenemandmeropenemisthatinfectioncausedbyEnterococcusfaecalisiscoveredbyimipenembutnotbymeropenem.19Ref1WPCRef19p153TableIIparlastTheSENTRYAntimicrobialSurveillanceProgrammonitorsmajorpathogensandantimicrobialresistancepatternsamongnosocomialandcommunity-acquiredinfectionsworldwide.Aspartofthisstudy,theprevalenceofpathogensproducingextended-spectrumb-lactamases(ESBLs)wasstudied.22Standardbrothmicrodilutionmethodswereusedtomonitorantimicrobialsusceptibilityofpathogens.Atotalof19%ofK.pneumoniaeand5%ofE.coliisolatesproducedESBLs.Highratesofresistancewerefoundagainstaminoglycosides,tetracycline,trimethoprim-sulfamethoxazoleandthequinolones.However,theauthorsconcludedthat“ImipenemremainsalmostuniformlyactiveagainstK.pneumoniae,E.coli,Proteusmirabilis,andSalmonellaisolatesthatexpressanESBL.”22Neuhauseretal.(2003)foundthat99to100%ofallEnterobacterspp.,K.pneumoniae,andE.coli(n=13,903)testedfromparticipatingICUsintheU.S.weresusceptibletoimipenem.23Thiswasincontrastto63to84%ofspeciessusceptibletothecephalosporinscefepime,ceftazidime,ceftriaxone,andcefotaxime.ConcernaboutwidespreadESBLsleadPatersonetal.(2001)totheconclusion“ClinicalmicrobiologylaboratoriesshouldtakeheedofcurrentrecommendationsfordetectionofESBLsinordertoavoidpotentialtreatmentfailurewhencephalosporinsareused.”24Ref22pS95par1par6L1-3PS97Table2PS99Par1PS101Table7PS102Par1L4-6Ref23p886par2L1-4Table1Ref24p2211par3L5-7InacasereportconcerningapatientwithAcinetobactermeningitisassociatedwithanintraventricularcatheter,ninestrainsofAcinetobacterwererecoveredfromcerebrospinalfluids.25Allofthestrainsisolatedweremultidrug-resistant,retainingsusceptibilitytoimipenem,ampicillinplussulbactam,andcolistin.Itwasfoundthatresistancetomeropenemdevelopedfollowingtreatmentwithmeropenem.Allstrainsweresusceptibletoimipenem.OnestrainhadanMIC>32g/Lagainstmeropenem,indicatingthatthisstrainwasresistanttomeropenem.Ref14p422par1par2L1-3;33-34par6L2-7Effluxpumpsareproteinsthatremovecertainchemicalsfromthebacterialcell.TheyplayamajorroleintheintrinsicandacquiredresistanceofP.aeruginosatoantimicrobialdrugs.31Unlikeothercarbapenems,suchasmeropenem,Imipenemisnotasubstrateofeffluxpumps.31,32TheMexAB-OprMsystem,themostprevalenteffluxsystem,hasbeenfoundtocauseresistancetomeropenem,butnotimipenem,invitro.28,31,32-34Invivoemergenceofmultidrug-resistantmutantsofPAoverexpressingtheactiveMexAB-OprMeffluxsystemduringantibiotictherapyresultsinantibiotictreatmentfailure.29,35TheMexAB-OprMsysteminducescross-resistancetootherantimicrobialssuchasfluoroquinolones,penicillins,cephalosporins,macrolides,andsulphonamides.28,31-34Ref31p3322par1L1p3325par3p3326table4Ref32p424par5Ref28p634par1Ref32p424par5Ref33p288par10Ref31p3322par1Ref34table2parlastRef33p288par10p290par3L1Ref29p241par2Llastp248par1L1par2L2Ref35par4Ref33p290par3L10Ref34p424par5Porinsareproteinchannelsontheoutermembranesofsomegram-negativebacteriasuchasP.aeruginosa.Carbapenemscrossthroughthesechannels,asshownonnextslide.28-Mutationsthatresultinimpermeabilitycanproduceresistancetoallcarbapenems.Thismutationalimpermeabilityoccursasaresultofthelossofaporin.29-Antibioticresistanceandincreasedvirulencemaybelinked.Thedecreasedvirulencedemonstratedinporin-deficientstrainsofP.aeruginosaresultsinrelativelyhighcurerates,andmaybelinkedtothelossofaporin.29,30Ref28p635table1par2L1-6p634par1par3L12-14Ref29p241par2Llastp248par1L1par2L2Ref30p1132par1L1-7par4L3-6Thefollowingslideswillillustratethelowpotentialforresistancedevelopmentwithimipenemin:EnterobacterEscherichiacoliKlebsiellapneumoniaeAcinetobacterPseudomonasaeruginosaThereisaneedtoadministerempiricantibiotictherapyappropriatethatwillcoveralllikelypathogensatthefirstsuspicionofseriousinfection.3Ref3Thefollowingslideswillpresentsomeoftheimportantpharmacokineticandpharmacodynamicdifferencesbetweenimipenemandmeropenemwillbepresentedinthefollowingslides.Itshouldbenotedthattheclinicalsignificanceoftheseparametersisnotknown.Thepeakconcentration(Cmax)toMICratiohastraditionallybeenusedtodescribethepharmacodynamicresponseofantibioticswithconcentration-dependentpharmacokinetics.36Areaundertheinhibitorycurve(AUIC)representstheratiooftheantibioticareaunderconcentration-timecurve(AUC24)totheMIC,andisanewwaytointegratepharmacokineticandpharmacodynamic(PKandPD)principles.TheMICistheonlysatisfactoryinvitrosurrogateforantimicrobialactivity.37RegrowthoforganismscanbeginonceserumdruglevelsfallbelowtheMIC.TimeaboveMICisanimportantconcept,representingthepercentageoftimeovera24hourperiodthatthedrugconcentrationexceedstheMICandcorrelateswiththetherapeuticefficacyofmanyb-lactamantibiotics.38Inthefigureabove,thisisrepresentedwheretheMIClineintersectstheAUC.Ref36pS39par1L8-11Par2L1-6Ref37p10par3L1-2Ref381998p2par6L7-9p5par2L1-3ThisslideshowsCmaxrangesforimipenemandmeanCmaxandformeropenemaspresentedintheprescribinginformation.40Theinfusionrateforimipenemwas20minutesandformeropenemwas30minutes.Atequivalentdosages,thepeakconcentrationrangesforimipenemarehigherthanthoseofmeropenem.Ref1WPCRef40meropenemPIThistableshowsthecalculatedpercentagetimeaboveMICofimipenemandmeropenemat4and1?g/ml.Becauseoftherelativelylowproteinbindingofthesecarbapenems,proteinbindingwasnottakenintoaccountinthecalculations.39Aregimenofimipenem500mg4timesdailyyieldsthesamepercentagetimeabovetheMICasdoesmeropenem1000mg3timesdaily.Ref39Ref39p196TableVIAnopen,randomizedcrossoverstudyof12healthymalevolunteerswhoreceivedasingledoseof1gofimipenemor1gofmeropenem,thentheotherdrugfollowinga9-weekwashoutperiod.43Plasmalevelsofimipenemandmeropenemattheendofinfusion,1hour,6hours,and8hoursfollowingadoseof1gadministeredasa30minuteinfusionareshownabove.Plasmalevelsofimipenemwereconsistentlyhigherateachtimepointwhencomparedwithmeropenem.Ref43p105par1L1-2par2L1-5par3L1-3Atthesamedose,pharmacokineticstudieshavesuggestedthatimipenemandmeropenemarenotdoseequivalent.ThistablecontainsthemeanplasmaderivedpharmacokineticparametersforimipenemandmeropeneminhealthymalevolunteersafterIVadministrationfromthreehead-to-headstudies.Saitoetal.conductedacrossoverstudyof6healthymalevolunteerswhoreceived500mgofimipenemand500mgmeropenem.41,42Plasmasampleswerecollectedeveryhourfor6hoursafterintravenousinfusion.Dreetzetal.conductedanopen,randomizedcrossoverstudyof12healthymalevolunteerswhoreceivedasingledoseof1gofimipenemor1gofmeropenem,thentheotherdrugfollowinga9-weekwashoutperiod.43Plasmasampleswereobtainedforpharmacokineticassaysbeforedosingandatregularintervalsupto8hoursafterintravenousinfusion.Imipenemandmeropenemhadsimilarpharmacokinetics,althoughimipenemhadagreaterAUC,perhapsduetoaslowerclearancerate(Cl).Ref41p278Table3,4p282Ref42p279Par1L4-9p280TableVRef43p105par1L1-2par2L1-5par3L1-3p107Table3Imipenemandmeropenemarebothindicatedforuseinpatientswithintra-abdominalinfection.1,40Meropenemcanalsobeusedinpatientswithbacterialmeningitis.Imipenemisindicatedforuseinlowerrespiratorytract,urinarytract,gynecological,boneandjoint,andskinandskinstructureinfectionsaswellasinpatientswithbacterialsepticemia.Ref1WPCRef40meropenemPCBetweenMay1,1987andJune30,1991,1951patientsweretreatedwithimipenem.Atotalof42%ofpatients(n=816)withabnormalrenalfunctionwerereceivingexcessiveimipenemdoses.Fourseizures(0.20%)weredetected,allofthesepatientswerereceivingdosesthatwereexcessivefortheirrenalfunction.49Aprospective,open-label,multicenter,parallelgroupstudyofpatientswithserious,complicatedintra-abdominalinfectionofmildtomoderateseverityrandomizedpatientstoeitherimipenem(500mg,q8h)ormeropenem(1000mg,q8h)foratleast5days.20Atotalof98%(99of101)ofevaluableimipenem-treatedpatientsexperiencedclinicalcure,and96%experiencedbacteriologicaleradication.Atotalof95(95of100)evaluablemeropenem-treatedpatientsexperiencedclinicalcure,and98%experiencedbacteriologicaleradication.Therewerenobetween-groupdifferencesintheincidenceofadverseevents.Onepatientintheimipenemgroupexperiencedafacial“butterfly”erythema.Onepatientinthemeropenemgroupexperiencedanerythematouswhealthatwasprobablydrug-related;andthreepatientsinthemeropenemgroupexperiencedepigastralgia,pyrosisandsweating;hyperbilirubinemia;andsurgicalwoundsuppuration,respectively,thatwerepossiblydrug-related.Noseizureswerereportedinthisstudy.Amulticenter,open-label,parallel-groupstudyrandomizedpatientswithserious,complicatedintra-abdominalinfectiontoimipenem(n=116;88evaluable)ormeropenem(n=116;82evaluable)(1g,q8h).Cureorimprovementwasobservedin94%ofimipenemgroupand96%ofmeropenemgrouppatients(p=NS).Bacteriologicsuccessorpresumedsuccesswasobservedin81%ofimipenemgroupand84%ofmeropenemgrouppatients(p=NS).Atotalof25%ofimipenemgroupand28%ofmeropenemgrouppatientsexperienceddrug-relatedadverseevents,mostcommonlyinjectionsiteinflammation,elevatedASTorALT.Therewerenoclinicallysignificantdifferencesinthesafetyprofile.50???Ref49P498Par4L1Par7L1Ref33P504Par9L1Par10L1P505Par5L1Par8L1P506Par2L1Par7L4Ref50P192Par6L1Par7L1P193Par2L1P194Par4L1P195ParContL1P198Par1L1P200Par3L1P201Par1L1P202Par7L1P203Par2L3Asdetailedinthepreviousslides,imipenemhasbroadspectrumactivityandmultipleclinicalindications.Imipenemhasproventobeeffectiveandwelltoleratedoverthecourseofnearlytwodecades.Inaddition,imipenemhasbeenshowntohavealowpotentialforresistanceoverthiscourseoftime.Ref1DOFRef2p149par1L5Ref21p56par1par2Par3par4L4-9Ref23p886par2L1-4Table1Ref14p422par1par2L1-3;33-34par6L2-7Ref41p278Table3,4p282Ref42p279Par1L4-9p280TableVRef43p105par1L1-2par2L1-5par3L1-3p107Table3Ref44pa1303par1par2par4par6par7parLastp1304Fig1BP1305par4L5-11Ref46p2411Table1Alabel-to-labelcomparisonshowedverylowseizurerateswithimipenemandmeropenem.1,40Thesedatadispelthelongstandingmisperceptionthatcarbapenemsareassociatedwithhighseizurerates.[Note:IfcountrycanuseaUSlabel-to-labelcomparison,pleaseusecopyaswritten.Ifcountrycanusealocallabel-to-labelcomparison,pleasechangenumbersaccordingtolocallabels.Ineitheroftheseoptionsisavailable,usedatafromNorrbySRetal.ScanJInfectDis1999;31:3-10.]Ref1WPCRef40meropenemPIThereareseveralimportantdifferencesbetweenimipenem/cilastatin(TIENAM?)?andmeropenem.1,2Thefollowingslideswillexaminethespectrumofactivity,potentialforresistance,thetolerability,andthepharmacokineticsoftheseagents.?TrademarkofMerck&Co.,WhitehouseStation,NJ,USARef1DOFRef2p149par1L5SourcingisforslidesandnotesunlessotherwiseindicatedTherearetwostagesintheprocessofDE-ESCALATIONTHERAPY?.Thefirststageinvolvesadministeringthebroadest-spectrumantibiotic.Thisisdonetodecreasemorbidity,mortality,andpotentiallydecreasehospitallengthofstay.DE-ESCALATIONTHERAPY?worksontheprinciplethatthebestpossibleregimenforcriticallyillpatientsisempirictherapywithabroad-spectrumagentthatprovidesfullcoverageofallidentifiedpathogens.Theconceptisthatabroad-spectrumantimicrobialthatiseffectiveagainstbothGram-negativeandGram-positivebacterianeedstobeadministeredassoonasinfectionissuspected.10Thisisdonetoavoidthehighmortalityassociatedwithinadequateantibiotictherapy.10Ofcourse,itisveryimportantforeveryinstitutiontohavelocal,currentmicrobiologicaldatainordertoassessthelikelyinfectingpathogensandthesusceptibilitypatterns.3,10Intheearlyandmid-1990s,severalstudieswerepublishedwhichsuggestedthattheappropriatenessofinitialantibiotictherapywasamajorfactorinhospitalmortalityrates.12-17Thesestudiesfoundthatpatientswhodidnotreceiveappropriateinitialtherapyhadhigherhospitalmortalityratesthanthosepatientswhoreceivedempirictherapythatprovidedfullantimicrobialcoverage.Moreover,oncetherapywasinitiated,switchingfrominadequatetoappropriatetherapydidnotlowermortalityrates.13,15,18,19Inotherwords,theconsequencesofinitialinadequatetherapywereirreversible.Laterpublicationsconfirmedthesefindings.10,18Ref12p236par2L3-9Ref13p392par1Table6p393parlastL12-13Ref14p680par1L6-11par2l3-11p682parlastL22-25p684parlastL13-17Ref15p198par1L11-endpar2table5p199par1L10-12Ref16p1353par2l7-8Ref17p374par7L1-8Ref18p416parlastL1-6p417par1L1-6p418fig2Ref19p149par1l11-15p150fig1p152par1L1-6Ref18p469fig2KollefMH.ClinInfectDis2000;31(Suppl4):S131-S138.KollefMH.Chest1999;115:462-474.RichardsMJetal.CritCareMed1999;27:887-892.VanderPollT.LancetInfectiousDiseases2001;1:165-174.BernardGRetal.NEnglJMed2001;344:699-709.InitialAppropriateTherapyEmpiricbroad-spectrumtherapyinitiatedatthefirstsuspicionofseriousinfection.Selectionofantibiotictoensureadequatecoverageofalllikelypathogens.Factorstoconsiderwhendefiningappropriatetherapy:MicrobiologicdataMonotherapyvs.combinationtherapyDoseanddosingfrequencyPenetrationTimingToxicityRiskofinfluencingresistancePriorantibioticuseKollefMHetal.Chest1999;115:462-474.KollefMH.ClinInfectDis2000;31(Suppl4):S131-S138.Slidedevelopedbyopinionleadersforde-escalationslidekitRef5pS131par3L6-12pS132par1L1-6pS135par5L6-11Ref10p473par1DE-ESCALATIONTHERAPY?Stage1Administeringthebroadest-spectrumantibiotictherapytoimproveoutcomes(decreasemortality,preventorgandysfunction,anddecreaselengthofstay)Stage2Focusingonde-escalatingasameanstominimizeresistanceandimprovecost-effectivenessns98%96%Bacteriologiceradicationns95%98%Clinicalcure0.0197.2days6.7daysTreatmentDuration0.0462.46days1.83daysTimetodefervescenceP-valueMeropenem(n=100)Imipenem(n=101)OutcomeOpen-label,prospective,randomized,comparativestudyofimipenem(1.5g/day)vs.meropenem(3g/day)inpatientswithseriousintra-abdominalinfectionfoundsignificantlyshortertimetodefervescenceandtherapyduration.BasoliAetal.ScandJInfectDis1997;29:503-508.LowPotentialforEnterobacterResistanceChanWCetal.JAntimicrobChemother1999;43:55-60.Imipenemdidnotselectforresistance,whilemeropenemandthird-andfourth-generationcephalosporinsallselectedforresistance1NeuhauserMM.JAMA2003;289:885-888.2WinokurPLetal.ClinInfectDis2001;32(Suppl.2):S94-103.3PatersonDLetal.JClinMicrobiol29:2206-2211.NunezMLetal.ScandJInfectDis1998;30:421-423.0.25->32Meropenem0.5-1.5ImipenemMIC(g/L)RangeAntibioticImipenemremainedactiveagainstninestrainsofAcinetobacterisolatedfromonepatient,whilemeropenemdidnot.“WebelievethatthiscaseshouldserveasaremindertoustobecautiouswhentreatingseriousinfectionscausedbyAcinetobacterwithmeropenemandtobealerttothepossibleappearanceofresistance.”NOTE:IfcountrycanuseUSdatapleaseusecopyaswritten.Ifnot,pleaseuseNPRSdata.198919901991199219931994199519961997Year1008060PercentsusceptibilityofPaeruginosaSustainedSusceptibilityPercentFridkinSKetal.ClinChestMed1999;20:303-316.P.aeruginosasusceptibilitywasseenwithimipenemaloneandimipenem/amikacinorimipenem/gentamicinwhere86.3%and93.8%ofisolatesweresusceptible,respectively.Muelleretal.2002ISICEMabstract.LivermoreDM.ClinInfectDis2002;34:634-640.KrasinskiKM.BullNYAcadMed1987;63:237-250.HarrisAetal.ClinInfectDis1999;28:1128-1133.PorinsareproteinchannelsontheoutermembranesofP.aeruginosa.Carbapenemscrossthroughthesechannels.MechanismsofResistance:PseudomonasandEffluxPumpsAdaptedwithpermissionfromLivermoreDM.ClinInfectDis2002;34:634-640.ImipenemandmeropenementerhereMeropenemispumpedoutwhileimipenemisnotEffluxSystemExitPortal(OprM)OuterMembranePeriplasmLinkerLipoprotein(MexA)CytoplasmicMembraneEffluxSystemPump(MexB)PorinPK/PDMarkersforClinicalEfficacyReprintedwithpermissionfromSchentagJJetal.ClinInfectDis2001;32(Suppl.1):S39-S46.Cmin(trough)Half-lifeAUCTimeaboveMICTimeSerumConcentrationCmax(peak)AUC24MICComparativePharmacodynamics:Imipenemvs.MeropenemCalculatedpercentagetimeaboveMICof4?g/mland1?g/mlforimipenemandmeropenemDosageRegimen Percentageoftime >4?g/ml >1?g/mlImipenem500mgq6 h 45% 78%Meropenem1gmq8h 46% 71%MoutonJWetal.ClinPharmacokinet2000;39(3):185-201.ComparativePharmacokinetics:Imipenemvs.MeropenemPhysicians’DeskReference?57thed,MontvaleNJ:MedicalEconomics,2003.Imipenem Cmaxrange250mg 14-24?g/mL 500mg 21-58?g/mL1gm 41-83?g/Ml20minuteinfusionMeropenem Cmaxrange500mg 14-26?g/mL1gm 39-58?g/mL30minuteinfusionImipenem500mgisnotequivalenttomeropenem500mg:Imipenemachieveshigherpeakconcentrations.1AdaptedfromMoutonJWetal.ClinPharmacokinet1995;28(4):275-286.;2SaitoA.Chemotherapy(Tokyo)1992;40Suppl.1:276-282.;3DreetzMetal.AntimicrobAgentsChemother1996;40(1):105-109.Imipenemandmeropenemarenotdoseequivalent,asevidencedbyhigherpeakconcentrations,AUC,halflifeandfasterclearanceratesofimipenem.ComparativePharmacokinetics:Imipenemvs.MeropenemaCalculatedasCmax=Dose/Volumeofdistribution;bDosecorrected;cP?0.05 Cmax=peakconcentration;AUC=areaunderthetime-concentrationcurve;t1/2=eliminationhalflife;Vss=volumeofdistributionatsteadystate;Cl=totalclearanceComparativePharmacokinetics:Imipenemvs.MeropenemSerumLevels(?g/mL)1gminfusionover30minutesDreetzMetal.AntimicrobAgentsChemother1996;40(1):105-109.Endotoxin(EU/ml)100075050025005xMICMEROCEFControlIPM0481000750500250050xMIC048MEROCEFControlIPMNorimatsuMetal.JInfectDis1998;177:1302-1307.HoriiTetal.FEMSImmunolMedMicrobiol1998;21:297-302.050100150200250300123456EscherichiacoliPlasmaendotoxinconcentration(ngml-1)123456Serratiamarcescens123456Klebsiellapneumoniae123456Pseudomonasaeruginosa123456Proteusvulgaris123456Proteusmirabilis49.3±2.01341.4±50.3311Control42.4±3.21430.9±49.5337Ceftazidime54.3±3.81079.1±39.4314Meropenem19.1±1.2c18.7±7.5c34ImipenemNOConcentrationb(mM/ml)TNF-aConcentrationb(pg/ml)EndotoxinReleased(ng/ml)AntibioticaaConcentration=2timesMICbMean+/-standarddeviationtestdoneintriplicateCp<0.01versusmeropenemandceftazidimeAdaptedfromYokochiTetal.AntimicrobAgentsChemother1996;177:2410-2412.Notindicatedfortherapywiththeintramuscularformulation.DatafromU.S.LabelinPhysiciansDeskReference57thed.,2003.Note:Countriesshoulduselocallabelforindications. 0hr 1hr 6hr 8hr Imipenem 61.2 21.0 0.82 0.24 Meropenem 51.6 15.0 0.42 0.15
Dose Cmax
((g/mL) AUC
((g(h/mL) t1/2
(h) Vss
(L) Cl
(mL/min) Saito Meropenem500mg1,2 26.0a 33.6 0.88 19.2 252 Imipenem500mg1,2 31.4a 41.7 0.90 15.9 203 Dreetz Meropenem1gm3 51.6 70.5 1.07 18.6c 240 Imipenem1gm3 61.2c 96.1 1.11 15.3 175
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