脑性瘫痪儿童的语言障碍(下)一、言语方面的评价有人对脑瘫患儿的构音运动进行了分析，结果发现运动性构音障碍发生率为80.4%，其中失调型、痉挛型四肢瘫患儿构音障碍发生率高且程度较严重，痉挛型双瘫次之.偏瘫型则较少发生异常构音障碍。提示运动性构音障碍是影响脑瘫患儿言语的主要问题，参照构音障碍的评价。一、言语方面的评价检查时必须注意：1、脑瘫儿童的构音问题，除辅音障碍外，大部分患者同时伴有元音障碍，因此在检查类似构音运动时，必须注意检查元音构音时下颌、口唇、舌的协调运动。2、检查脑瘫儿童的构音时，必须在抑制异常姿势或反射的基础上进行。还要将患儿日常生活中说话时的姿势类型记录下来。3、在音质方面的评价时还要结合患儿的年龄、性别，以免引起认为的误差。二、语言方面的检查参照语言发育迟缓检查评价方法。CRRC版语言发育迟缓检查法即S-S法三、智力方面的评价智力检查分两种：1、诊断性智力检查；常用方法：如WISC一R韦氏学龄儿童智力检查—修订版，适应年龄为6-16岁。WPPSI韦氏学龄前儿童智力量表，适用年龄为4-6.5岁。2、筛选性智力检查：如：皮博迪图片词汇检查，适用于2.5-18岁的儿童及青少年。DDST，适用于出生到6岁。一、日常生活交流能力的训练在新生儿期，主要用Bobth法开发儿童的随意运动，既是提高主动性又是促进语言发育更是为了不把表达的手段只限定在言语上，充分利用手势语，表情等可能利用的随意运动。将其作为日常生活交流的手段也作为语言发育的基础。随着主动地使用随意运动进行日常生活交流能力的提高，会大大地促进语言的发育。请看实际操作照片（略）二、言语训练1、进食训练进食训练可以提高口腔诸器官的协调运动功能，这对构音运动有很大的促进作用。进食训练可以说是发音训练的基础，尤其是在有意义发音之前，通过进食训练可以提高口腔诸器官的功能。(四)蹲和膝立蹲对伸展紧张的跟键是一个好的姿势。很多小儿蹲位时需要支持来平衡。蹲位对上厕所和游戏是重要的。良好的膝立位平衡使站立更容易。为改善膝立平衡：(五)步行 为了步行，小儿抬一只脚时，需要将体重移到另一只脚上。很多小儿需要很长时间才学会独步。他们可能需要矫形托或器械的帮助。通过进一步改善平衡来帮助小儿更稳定地步行。小儿还需学会迈上迈下。有些小儿可能需要步行辅助器的帮助。为使脚放平，还需要用矫形托。第三节脑瘫儿童语言障碍的特点脑瘫儿童约有80%都具有不同程度的语言障碍。脑瘫儿童的语言障碍主要是脑损伤所致，大部分言语输入系统与输出系统均有不同程度的障碍。从脑瘫的语言发生机制来看，除了运动性构音障碍之外，还有听觉、视觉等感觉系统异常，智能异常、发育性语言迟缓、行为异常等。有研究文章统计963例脑瘫患儿听神经通路损伤发生率为24.5%(236/963),听神经通路损伤在脑瘫的手足徐动型与混合型中发生率最高(P<0.01),而病理性黄疸是造成脑瘫合并听神经通路损伤的高危因素。其发生率与性别无关,与脑瘫分型有关。约有2∕3的脑瘫儿童伴有智能低下，一些有多重性障碍的脑瘫儿童，还有视觉中枢的损伤，许多痉挛型脑瘫伴有斜视，共济失调型的儿童伴有眼震。还有些脑瘫儿伴有行为异常如有固执、任性、情绪脆弱、自闭、强迫等表现。第四节脑瘫儿童语言障碍的检查与评价■在实际工作中选择量表和注意点：根据脑瘫儿童所表现的障碍不同，针对其特点，采用不同的方法进行评估:1、语言好、操作也不受限制的患儿，主要是在理解、反应并回答问题的准确性上有差距。主要采用诊断性智力检查，并在每题限制的时间上稍微给予宽限，一般比正常孩子测试时间再多1∕2倍。一旦检查不能顺利进行，可以使用筛查性的检查方法，结果供参考。2、语言好，操作受限的患儿，一般是手功能障碍，使得诊断性智力检查中操作性课题无法完成或完成起来有困难。遇到这类患者可以采取只测试其语言部分，得出语言的IQ分数。再根据手功能障碍的程度，适当作一些操作性课题并酌情给分。3、语言功能受限，手功能较好的患儿，检查时可只作操作部分的检查。对于手功能障碍较轻，能理解他人的言语，但自己不能说的患儿，检查者可多做演示，以便让患儿更好地理解操作意图；对多次理解操作意图或操作不正确，严重超时者。可放弃该项检查，继续下面的项目。对有部分语言功能的患儿，可做言语检查时，对其回答的时间与分数可稍放宽。如患儿有方言，可请家长在旁协助提问（但要防止暗示提问）4、语言功能受限、手功能受限患儿，在接受智力检查时，测试者要考虑其功能受限的程度。以上是根据语言功能和手功能的不同情况灵活选择采用不同的方法进行评估。第五节脑瘫儿童的语言训练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. PestotnikSetal.AnnPharmacotherapy1993;27:497-501. BasoliAetal.ScandJInfectDis1997;29:503-508;andGeroulanosSetal.JAntimicrobChemother1995;36(Suppl.A):191-205.Imipenemisacarbapenemofchoiceforpatientswithseriousnosocomialinfections:1. Dataonfile.2. NeuHC.?Clinicalperspectivesonimipenem.?JAntimicrobChemother1983;12(SupplD):149-153.3. KollefMH,ShermanG,WardS,FraserV.Inadequateantimicrobialtreatmentofinfections.Ariskfactorforhospitalmortalityamongcriticallyillpatients.Chest1999;115:462-474.4. RichardsMJ,EdwardsJR,CulverDHetal.NosocomialinfectionsinmedicalintensivecareunitsintheUnitedStates.CritCareMed1999;27:887-892. 5. KollefMH.Inadequateantimicrobialtreatment:Animportantdeterminantofoutcomeforhospitalizedpatients.ClinInfectDis2000;31(Suppl4):S131-S138.6. CampbellGDJr.,NiedermanMS,BroughtonWAetal.Hospital-acquiredpneumoniainadults:Diagnosis,assessmentofseverity,initialantimicrobialtherapy,andpreventativestrategies.Aconsensusstatement.AmJRespirCritCareMed1996;153:1711-1725.7. vanderPollT.Immunotherapyofsepsis.LancetInfectiousDiseases2001;1:165-174.8. BernardGR,VincentL-L,LaterreP-Fetal.EfficacyandsafetyofrecombinanthumanactivatedproteinCforseveresepsis.NEnglJMed2001;344:699-709.9. H?ffkenG,NiedermanMS.Nosocomialpneumonia.Theimportanceofade-escalatingstrategyforantibiotictreatmentofpneumoniaintheICU.Chest2002;122:2183-2196.10. KollefMH.Hospital-acquiredpneumoniaandde-escalationofantimicrobialtreatment.CritCareMed2001;29:1473-1475.11. AounM,CrokaertF,PaesmansMetal.Imipenemversustargetedtherapyincancerpatients.IntJAntimicrobAgents1998;10:263-270.12. EvansRS,PestotnikSL,ClassenDEetal.Acomputer-assistedmanagementprogramforantibioticsandotheranti-infectiveagents.NEnglJMed1998;338:232-238. 13. Alvarez-LermaFandtheICU-AcquiredPneumoniaStudyGroup.Modificationofempiricantibiotictreatmentinpatientswithpneumoniaacquiredintheintensivecareunit.IntensiveCareMed1996;22:387-394.14. LunaCM,VujacichP,NiedermanMSetal.ImpactofBALdataonthetherapyandoutcomeofventilator-associatedpneumonia.Chest1997;111:676-685.15. RelloJ,GallegoM,MariscalDetal.Thevalueofroutinemicrobialinvestigationinventilator-associatedpneumonia.AmJRespirCritCareMed1997;156:196-200.16. LunaCM,FamigliettiA,AbsiRetal.Community-acquiredpneumonia.Etiology,epidemiology,andoutcomeatateachinghospitalinArgentina.Chest2000;118:1344-1354.17. Sanchez-NietoJMetal.Impactofinvasiveandnoninvasivequantitativeculturesamplingonoutcomeofventilator-associatedpneumonia:Apilotstudy.AmJRespirCritCareMed1998;157:371-376.18. KollefMH,WardS.Theinfluenceofmini-BALculturesonpatientoutcomes:Implicationsfortheantibioticmanagementofventilator-associatedpneumonia.Chest1998;113:412-420.19. EndtzHP,vanDijkWC,VerbrughHAetal.Comparativein-vitroactivityofmeropenemagainstselectedpathogensfromhospitalizedpatientsintheNetherlands.JAntimicrobChemother1997;39:149-156.20. BasoliA,ZarbaEZ,MazzocchiPetal.Imipenem/cilastatin(1.5gdaily)versusmeropenem(3.0gdaily)inpatientswithintra-abdominalinfections:Resultsofaprospective,randomized,multicentretrial.ScandJInfectDis1997;29:503-508.ChanWCetal.Markedlydifferentratesandresistanceprofilesexhibitedbysevencommonlyusedandnewerb-lactamsontheselectionofresistantvariantsofEnterobactercloacae.JAntimicrobChemother1999;43:55-60.WinokurPLetal.Variationsintheprevalenceofstrainsexpressinganextended-spectrumb-lactamasephenotypeandcharacterizationofisolatesfromEurope,theAmericas,andtheWesternPacificRegion.ClinInfectDis2001;32:S94:S103.23. NeuhauserMMetal.Antibioticresistanceamonggram-negativebacilliinUSintensivecareunits.Implicationsforfluoroquinoloneuse.JAMA2003;289:885-888.24. PatersonDLetal.Outcomeofcephalosporintreatmentforseriousinfectionsduetoapparentlysusceptibleorganismsproducingextended-spectrumb-lactamases:Implicationsofrtheclinicalmicrobiologylaboratory.JClinMicrobiol2001;39:2206-2212.25. NunezMLetal.AppearanceofresistancetomeropenemduringthetreatmentofapatientwithmeningitisbyAcinetobacter.ScandJInfDis1998;30:421-423.FridkinSK,GaynesRP.Antimicrobialresistanceinintensivecareunits.ClinChestMed1999;20:303-316.27. MuellerXetal.Invitroactivityofimipenem±aminoglycosidesagainstPseudomonasaeruginosaandAcinetobactercalcoaceticus/baumaniisolatedfrompatientsinICUsinGermanyhospitals(1999-2002).22ndInternationalSymposiumonIntensiveCareandEmergencyRoomMedicine,Brussels,Belgium,19-22March2002[abstract].28. LivermoreDM.MultiplemechanismsofantimicrobialresistanceinPseudomonasaeruginosa:Ourworstnightmare?ClinInfectDis2002;34:634-640.29. KrasinskiKM.Virulenceversusresistance.BullNYAcadMed1987;63:237-250.30. HarrisAetal.EpidemiologyandclinicaloutcomesofpatientswithmultiresistantPseudomonasaeruginosa.ClinInfectDis1999;28:1128-1133.31. MasudaNetal.SubstratespecificitiesofMexAB-OprM,MexCD-OprJ,andMexXY-OprMeffluxpumpsinPseudomonasaeruginosa.AntimicrobAgentsChemother2000;44:3322-3327.32. KohlerTetal.CarbapenemactivitiesagainstPseudomonasaeruginosa:RespectivecontributionsofOprDandeffluxsystems.AntimicrobAgentsChemother1999;43:424-427.33. Ziha-ZarifiIetal.Invivoemergenceofmultidrug-resistantmutantsofPseudomonasaeruginosaoverexpressingtheactiveeffluxsystemMexA-MexB-OprM.AntimicrobAgentsChemother1999;43:287-291.34. GuineaJetal.PrevalenceofeffluxpumpsamongclinicalisolatesofmultipleantibioticresistantPseudomonasaeruginosa.40thInterscienceConferenceonAntimicrobialAgentsandChemotherapy,September2000,SanDiego,CA.Abstract1034.35. PooleK.MultidrugeffluxpumpsandantimicrobialresistanceinPseudomonasaeruginosaandrelatedorganisms.JMolMicrobiolBiotechnol2001;3:255-264.36. 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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