-抗生素课件(英文)Antibiotics-and-Pain-

Examples

ofOperationalNeedStimulatingScientificInnovationAntibioticsandPainControlWWIIPoole,1944:“ThegreatestlessonlearnedfromWorldWarIImayhavebeenthebenefitoftheuseofpenicillinprophylacticallyinthesurgicalunitsclosetothefront.”KoreaScott,1954:“Inanytacticalsituationwherethecasualtycannotreachtheaidstationuntil4-5hoursorlongerafterwounding,antibiotictherapybytheaidmaninthefieldismostdesirable”VietnamKell,1991:“Asingleinjectionofabroad-spectrumantibioticwithalonghalf-lifeshouldbegivenprophylacticallytopersonnelonthebattlefieldtoprovidebactericidalcoveragefromtheearliestmomentafterinjuryoccurs.”SomaliaMabry,2000:4of5openfracturesofthetibiafromgunshotwoundsbecameinfected.2of2openfracturesofthefemurbecameinfected.Inall,15woundinfectionsin58casualties.15hourdelaytodefinitivecare,“CurrentUSArmydoctrineonprehospitalcaredoesnotcallforantibioticadministrationbymedicsinthefield…”.Whynot?!Antibioticsnotroutinelygiveninthefieldbycivilianpre-hospitalpersonnel (EMT/paramedicmodelformedictraining).Combatmedicsdon’ttypicallyseewoundinfectionsduringthetimetheycareforthem–maynotappreciatetheirdevastatingeffect.Nota“sexy”topic.IvoryTowerarrogance….IncreasedRiskofInfection

inTraumaPatientsDisruptionofMechanicalBarriersBacterialContaminationLocalWoundFactorsInvasiveInterventionsImpairedResistanceGeneralPreventiveMeasuresAdequateandTimelyResuscitationEarlyWoundCareAntibioticsTetanusImmuneProphylaxisAdequateandTimelyResuscitationA,B,C’s *Needtomaintaina“nearlynormal”arterialoxygentension.VolumeExpansionConsiderationsEarlyWoundCareEliminateDeadSpacefluid,bloodDelayedPrimaryClosure(DPC)4-6daysEarly ImmobilizationofFracturesSofttissuedamageSterileDressingcontamination,desiccationDebridementexcisedevitalizedtissueIrrigationhighpressure,solutionAntibioticsFiniteperiodoftimeinwhichinfectioncanbeprevented.Miles,Burke.Howearly,nothowlong.Fullen,etal.Boththetiming

andthechoice

areimportant.Thadepalli,etal.WhatBugs?YomKippurWarPseudomonas–25.6%isolatesGmNegbacilli–70%isolatesoverallUsedpenicillinsSomaliaPseudomonasandpolymicrobialRussianAfghanistanExperienceClostridialRecommendedPCN,Rifampin,Metronidazole,orCeftriaxoneWaterborneOpsSeaWater–VibrioOverwhelmingGmNegsepsis–50%mortalityFreshWater-AeromonasOurEnvironmentOurEnvironmentTacticalFieldCare

“WhatWeWantinanAntibiotic”Heat/ColdResistance“FireandForget”LongShelfLifeSingleAgentDurablePackagingEasyPreparationBroadSpectrumMultipleApplicationsTheEASTPracticeManagementGuidelinesTheJournalofTrauma-March2000Meta-analysis-MEDLINESearchfor1976-1997Afterdiscrimination-39articlesforreview32comparingoutcome,7comparingpharmacokinetics&cost.TheEASTPracticeManagementGuidelines(cont)LookingmostlyatClass1articles:Moresuccessfulregimentsincluded:cefoxinclindamycinwithgentamycintobramycinwithclindamycincefotetancefamandoleaztreonamgentamycinTheEASTPracticeManagementGuidelines(cont)Cefoxitinvs.Clinda.&Gent.Both24%

Nicholsetal.Cefoxitinvs.Tobra.&clinda.vs.CefamandoleCefox18%,T&C29%,Cefaman36%

Jonesetal.Cefoxitinvs.CefotetanNodifference

Fabianetal.Aztreonamvs.Gent.(bothwithClinda)Aztr3%,Gent13%

Fabianetal.WhataboutUS?

RecommendationsConsideringspecialneeds:Mostapplications-Cefoxitin/Cefotetancancoverbothorthoandguttrauma,fast,stable.CefoxingetsedgewithstorageCefotetanlongerhalf-lifeonsetsameForPCN-Allergic:Cipro&ClindacoversbothBUT…Whynotorals?Nopowdertoreconstitute.Cancarryalotmore.BroadSpectrum/RapidAbsorptionnowavailable.Onlyhesitationwouldbe:PenetratingAbd.Trauma.Unconsciousness.Shock.BodyArmorhasprofoundlylessenedtorsoinjuries.Therefore,oralsareappropriateforvastmajorityofcasualties.WhichOrals?Penicillins.Toomanyseriousallergicreactions.Dosingrequirementstoofrequent.MissmostGramNegs.WhichOrals?(cont.)Flouroquinolones–BloodlevelsviaPOroutesimilartoIVdosing.Ciprofloxacin.Goodvs.Pseudomonas,butnotvs.anaerobes.Levafloxacin.BetterGmPosthanCipro,butstillnotgoodforanaerobes.Okayforpseudomonas.WhichOrals?(cont.)Flouroquinolones(cont.).Trovafloxacin.CoversGmpos,neg,andanaerobes.Hepatotoxicitywithprolongeduse.Absorptiondelayedbymorphine.Moxifloxacin.CoversGmpos,neg,andanaerobes.Goodvs.ClostridiumandBacteroides–samerangeasmetronidazole,andsuperiortoclindamycin.QDdosing.Gatifloxicin.CoversGmpos,neg,andanaerobes.Verysimilartomoxifloxacin,butlessexpensive.QDdosing.Recommendationfor

OralDosingGatifloxacin.400mgPOQDforallpenetratinginjurieswhocantakeoralmeds.Alternative–Moxifloxacin400mgPOQD.FinalRecommendationsinTacticalArena(2002)Forallopencombatwounds:Gatifloxacin400mgbymouthonceaday.Ifunabletotakeoralmedications(shock,unconsciousness,penetratingabd.Injury):Cefotetan2gmIV(slowpushover3-5min.)orIMevery12hours.ReviewofOralAntibioticChoicestoReplaceGatifloxacinKevinC.O’Connor,D.O.LTC,MC,USACommitteeonTacticalCombatCasualtyCareTampa,FL29June2006CurrentSituationSafety

OverviewSeriousAdverseDrugEffectshaveledtowithdrawaloffourquinolones:Temafloxacin(immunologicalreactions),Grepafloxacin(cardiotoxicity),Trovafloxacin(hepatotoxicity),Sparfloxacin(cardiotoxicity).Gatifloxacinassociatedwithdysglycemia.Tosufluxacinassociatedwithimmunologicalreactions.Gemifloxacinassociatedwithhighrateofrashes(esp.women<40yo).*Morethan100millionprescriptionswerewrittenforterfenadineandastemizolewerewrittenbeforetheywerewithdrawnforTdPandsuddendeath.FrothinghamR:QuinoloneSafetyandEfficacyMoreImportantthanPotency.EmergingInfectiousDiseases2004;10:156-57.IanniniPB,KubinR,ReiterC,TillotsonG:ReassuringSafetyProfileofMoxifloxacin.ClinicalInfectiousDiseases2001;32(4):1112-4.2002Recommendation“Ingeneral,moxifloxacinwasthemostpotentfluoroquinoloneforGram-positivebacteriawhileciprofloxacin,moxifloxacin,gatifloxacin,andlevofloxacindemonstratedequivalentpotencytoGram-negativebacteria.”MatherR,KarenchakLM,RomanowskiEG,KowalskiRP:Fourthgenerationflouroquinolones:newweaponsinthearsenalofopthalmicantibiotics.AmJOphthalmol2002;133:463-466O’ConnorK,ButlerF:AntibioticsinTacticalCombatCasualtyCare2002.MilitaryMedicine2002;168(11):911-914.2002RecommendationAnotherstudyMoxifloxacinwasalmostasactiveastrovafloxacin,asactiveasgatifloxacin,andmoreactivethanlevofloxacinandciprofloxacinagainsttheanaerobestested(includingClostridiumspecies)AckermanG,SchaumannR,PlessB,ClarosMC,GoldsteinEF,Rodloff:Comparativeactivityofmoxifloxacininvitroagainstobligatelyanaerobicbacteria.EurJClinMicrobiolInfDis2000;19:228-232.O’ConnorK,ButlerF:AntibioticsinTacticalCombatCasualtyCare2002.MilitaryMedicine2002;168(11):911-914.2002Recommendation“Gatifloxacinisagoodchoiceforsingle-agenttherapybasedonitsexcellentspectrumofcoverage,goodsafetyprofile,andonce-a-daydosing.Moxifloxacinwouldbeanacceptablesecondchoice.Athirdchoicemightbelevofloxacin,butbecauselevofloxacinhasonlylimitedactivityagainstanaerobes,anotherdrugmustbeaddedtoachievecoverageagainsttheseorganisms.”O’ConnorK,ButlerF:AntibioticsinTacticalCombatCasualtyCare2002.MilitaryMedicine2002;168(11):911-914.2002Recommendation

Recommendationfor

OralDosingGatifloxacin.400mgPOQDforallpenetratinginjurieswhocantakeoralmeds.(USGovt.costAugust2002$1.86)Alternative–Moxifloxacin400mgPOQD.(USGovt.costAugust2002$5.09)O’ConnorK,ButlerF:AntibioticsinTacticalCombatCasualtyCare2002.MilitaryMedicine2002;168(11):911-914.Re-lookSafety

TorsadesdePointesProlongedQTinterval.GrepafloxacinandSparfloxacin-withdrawn…1996-2001cruderatesforTdPGatifloxacin90xciproLevofloxacin18xciproGatifloxacin5xrateforlevoMoxifloxacin–noUScases.(3foreigncases)??ConfidenceIntervalGatifloxacinassociatedwithhighestrateofTdP,Moxifloxacinassociatedwithlowest.BUT…-Preclinicalandclinicaltrialsindicatethatlevofloxacin,moxifloxacin,andgatifloxacin

allprolongQTinterval.Smallcrossoverstudy,asingleoraldoseofmoxifloxacin800mgassociatedwithgreaterQTintervalprolongation(16-18milliseconds)thanciprofloxacin1500mg(2-5milliseconds)orlevofloxacin1000mg(4-5milliseconds).FrothinghamR:Ratesoftorsadesdepointesassociatedwithciprofloxacin,ofloxacin,levofloxacin,gatifloxacin,andmoxifloxacin.Pharmacotherapy2001:21:1468-72.OwensR.,AmproseP:Torsadesdepointesassociatedwithfluoroquinolones.Pharmacotherapy2002;22(5):663-672.NoelGJ,NatarajanJ,ChienS,HuntTL,GoodmanDB,AbelsR:EffectsofthreefluoroquinolonesonQTintervalinhealthyadultsaftersingledoses.ClinicalPharmacologicalTherapeutics2003;73:292-303.Safety

Dysglycemia–OutpatientstudyGatifloxacinhasbeenassociatedwithbothhypoglycemiaandhyperglycemia.Ascomparedtomacrolides–gatifloxacinwasassociatedwithanincreaseriskofhypoglycemia(AdjustedOddsRatio4.3,95%ConfidenceInterval).Levofloxacinwasalsoassociatedwithslightlyincreasedrisk(AOR=1.5,95%CI)Noincreasedriskwithmoxifloxacin,ciprofloxacin,orcephalosporins.Park-WyllieLYJuurlinkDN,KoppA,ShahBR,StukelTA,StumpoC,DresserL,LowDE,MamdaniMM:Outpatientgatifloxacintherapyanddysglycemiainolderadults.NewEnglandJournalofMedicine2006;354(13):1352-61.Safety

Dysglycemia–In-patientstudySerumglucose>200or<50within72hrsofreceivingthedrug.Levofloxacin,Gatifloxacin,CiprofloxacinorCeftriaxoneDysglycemiarates:Gatifloxacin76of7540pts.(1.01%)Levofloxacin11of1179pts.(0.93%)Ceftriaxone14of7844pts.(0.18%)Ciprofloxacin0of545pts.(0%)Ofthe101patientswithdysglycemia,hypoglycemiaoccurredin9(9%)andhyperglycemiain92(91%).Inthe17,108patientsreceivingafluoroquinoloneorceftriaxone,therateofdysglycemiawasgreaterinthosereceivinglevofloxacinorgatifloxacin,thaninthosereceivingCeftriaxone.However,therewasnostatisticallysignificantdifferencebetween

levofloxacinandgatifloxacin.MohrJF,McKinnonPS,PeymannPJ,KentonI,SeptimusE,OkhuysenPC:Aretrospectivecomparativeevaluationofdysglycemiasinhospitalizedpatientsreceivinggatifloxacin,levofloxacin,ciprofloxacinorceftriaxone.Pharmacotherapy2005;25(10):1303-9.Safety

DysglycemiaPhaseII/IIIclinicaltrialsdatabase14,731patients(8474moxifloxacin,6257comparators).Nodrug-relatedhypoglycemiceventsinmoxifloxacingroup.Twodrug-relatedhypoglycemiceventswithlevofloxacin.Onewithtrovafloxacin.Sevenhyperglycemiceventsinmoxifloxacingroup(<.1%).Onehyperglycemiceventswithcomparators(<0.1%).Datafromfivemoxifloxacinpostmarketingstudies(46,130subjects)reportednoepisodesofhypoglycemiaandtwonon-drug-relatedhyperglycemicepisodes.Conclusion:ComprehensiveanalysisofdatapoolformoxifloxacinPhaseII/IIItrialsandpost-marketingstudiessuggestthatmoxifloxacinadministrationhasnorelevanteffectonbloodglucosehomeostasis.GavinJR3rd,KublinR,ChoudhriS,KubitzaD,HimmelH,GrossR,MeyerJM:Moxifloxacinandglucosehomeostasis:apooled-analysisoftheevidencefromclinicalandpostmarketingstudies.DrugSafety2004;27(9):671-86.Efficacy

PseudomonasScheldfavorsciprofloxacinforknownorsuspectedPseudomonasaeruginosainfections.FavorsmoxifloxacinforinfectionsinwhichStreptococcuspneumoniaeislikely.ScheldWM:Maintainingfluoroquinoloneclassefficacy:reviewofinfluencingfactors.EmergingInfectiousDiseases2003;9:1-9.Efficacy

RespiratoryandAbdominalPathogensMoxifloxacin,gatifloxacin,levofloxacin,andazithromycincompared.in-vitrosusceptibilityofcommonpathogensthatcauserespiratorytractandabdominalwoundinfections.50isolateseachMRSA,E.faecalis,E.faecium,S.pneumoniae,S.pyogenes,E.coli,P.aeruginosa,&H.influenzae.Results:Moxifloxacin

wasmostactivesubstancevs.Gram-positive

pathogens.Gatifloxacinmostactivevs.Pseudomonas.Moxifloxacin&Gatifloxacincomparablevs.E.coliandH.influenzae.Conclusions:Moxifloxacinandgatifloxacindisplayexcellentactivityvs.respiratorypathogensaswellasnosocomialpathogenscausingabdominalwoundinfections.WhentreatingPseudomonasaeruginosa,theearlierfluoroquinolonessuchasciprofloxacinorofloxacinarethesubstancesofchoice.WenzlerS,Schmidt-EisenlohrE,DaschnerF:Comparativeinvitroactivitiesofthreenewquinolonesandazithromycinagainstaerobicpathogenscausingrespiratorytractandabdominalwoundinfections.Chemotherapy2004;50(1):40-2.Efficacy

AgainstGram-PositivesOlderflouroquinolones(i.e.ciprofloxacin)–limitedabilitytocoverGram-positivebacteria.CiproMIC90forS.pneumoniais1-4mg/L,whilethemaximumconcentrationsinserumare2-3mg/L.Moxifloxacinhadthehighestin-vitroactivityvs.S.pneumonia(MIC90=0.25mg/L;MICrange0.06-0.25mg/L)TheMIC90valueswereonedilutionlowerthanthoseobtainedwithsparfloxacinandgrepafloxacin.Threedilutionslowerthanthoseobtainedwithlevofloxacin.Fourdilutionslowerthanthoseofofloxacinandciprofloxacin.Moxifloxacin>grepafloxacin=sparfloxacin>levofloxacin>ofloxacin=ciprofloxacin.ReinertR.,SchlaegerJ.,LuttickenR:Moxifloxacin:acomparisonwithotherantimicrobialagentsofin-vitroactivityagainstStreptococcuspneumoniae.JournalofAntimicrobialChemotherapy1998;42:803-806.FrothinghamR:[letter,inresponsetoBellomoS:QuinoloneSafetyandefficacy(letter).EmergingInfectiousDiseases2005;11(6)985-6.]EmergingInfectiousDiseases2005;11(6)986-7.Efficacy

RespiratoryPathogens/Gram-PositivesComparisonofinvitroactivityofmoxifloxacin,levofloxacinandsixotherantibioticsfrequentlyusedforURIs.1563isolatesS.pneumonia,S.pyogenes,S.aureus,H.influenzae,andM.catarrhalis.21centersin10LatinAmericancountriesFindings:Moxifloxacinwasthemostactivecompoundvs.allthespeciesincluded.Moxifloxacinwas2–4foldmoreactivethanlevofloxacinvs.grampositivebacteria.LopezH,SaderH,AmabileC,PedreiraW,MunozBellidoJL,GarciaRodriquezJA,GrupoMSP-LA:[InvitroactivityofmoxifloxacinagainstrespiratorypathogensinLatinAmerica][ArticleinSpanish].RevEspQuimioter2002;15(4):325-34.ComparisonofAntibioticSpectrum

Notabledifferences

(otherwiseratedequally)MoxifloxacinE.faecium(Gm+)Clinicaltrialslackingor30-60%susc.S.aureus(MRSA)(Gm+)

Usuallyeffectiveclinicallyor>60%susc.S.(X.)maltophilia(Gm-)

Usuallyeffectiveclinicallyor>60%susc.Actinomycetes(anaerobe)Usuallyeffectiveclinicallyor>60%susc.B.fragilis(anaerobe)Clinicaltrialslackingor30-60%susc.C.difficile(anaerobe)Clinicaltrialslackingor30-60%susc.LevofloxacinE.faecium(Gm+)Noteffectiveclinicallyor<30%susc.S.aureus(MRSA)(Gm+)Noteffectiveclinicallyor<30%susc.S.(X.)maltophilia(Gm-)Clinicaltrialslackingor30-60%susc.Actinomycetes(anaerobe)(Nodataavailable)B.fragilis(anaerobe)Noteffectiveclinicallyor<30%susc.C.difficile(anaerobe)Noteffectiveclinicallyor<30%susc.GilbertDN,MoelleringRC,EliopoulosGM,SandeMA:TheSanfordGuidetoAntimicrobialTherapy2004,Thirty-fourthEdition;34:p.52.CostsLevofloxacin(Levoquin®)500mg$1.95perdose–DoDpricingMoxifloxacin(Avelox®)400mg$1.22perdose–DoDpricingSource:Ms.DonnaKelly,PharmacyPurchasingOfficer,EvansArmyCommunityHospital,Ft.Carson,Colorado(719)526-7869(26June2006)RecommendationReplaceGatifloxacin400mgx1withMoxifloxacin400mgx1takenorallyforallcombatwounds.TacticalFieldCare-AntibioticsRecommendedforallopenwoundsUsePOmoxifloxacin400mgadayifableIf

casualtyisunconscious,hasanabdominalwound,orisinshock:Cefotetan2gmslowIVpush

(over3-5minutes)orIMevery12hoursO’ConnorK,ButlerF.“AntibioticsinTacticalCombatCasualtyCare2003.”MilitaryMedicine168/11(November2003):911-914.NOW-Ertapenam1gmIV/IMqD(recentchange)Introduction“Painisamoreterriblelordofmankindthanevendeathitself.” -AlbertSchweitzer.“Oligoanalgesia”Termcoinedin1989byWilsonandPendleton.Thephenomenathatcare-giversoftenfailtoeitherrecognizeorappropriatelytreatpain.PainAsInterpreted

bytheCasualty“Itis,ofcourse,acompletemyththatastandardcauseproducesastandardpain…” -PatrickWallWallPD.Pain:TheScienceofSuffering.London:Weidenfeld&Nicolson;1999FundamentalsReassuranceDistractionImmobilizationTypesofMedicationsNon-OpioidsAcetaminophenNSAIDsOtherSedativeHypnoticsDissociativesOpioidsFullagonistsPartialagonistsMixedOpioids

General1680A.D.“…amongtheremediesithaspleasedAlmightyGodtogivemantorelievehissufferings,noneissouniversalandsoefficaciousasopium.” -SyndenhamJaffeeJH,MartinWR:Opioidanalgesicsandantagonists.InGilmanAG.WallTW,NeisAS,etal(eds):Thepharmacologicbasisoftherapeutics,ed8,NewYork,1993,McGraw-Hill.Opioids

General2002A.D.“…amongtheremediesithaspleasedAlmightyGodtogivetomantorelievehissufferings,noneissouniversalandsoefficaciousasopioidderivatives…”

-O’ConnorToday,SOMA,2002Opioids

GeneralDrugsofchoiceforseverepainAdverseeffectsRespiratorydepressionSedation/lightheadednessNausea/vomitingConstipationToleranceDependenceOpioids

FullAgonistsMorphinerelatedMorphineHydromorphoneOxymorphoneHeroinCodeinerelatedCodeineOxycodoneHydrocodoneDihydrocodeineSyntheticMeperidineFentanylMethadoneProproxypheneLevorphanolTramadolOpioids

FullAgonists–LongActingMorphineStandardofcomparisonOnset:IV:4-6minDuration:2-3hoursOnset:IM:20-60minDuration:4-5hoursPatientControlledAnalgesiaPatientTitrationElementofControlLesstotalmedicationusedMuchimprovedpatientsatisfaction/senseofpainreliefprovidedOralPainMedicationsProvidepainreliefwithoutalteredmentalstatusManycombatwoundswithoutbonyinjuriesonlymild-moderatepainNon-narcoticsmedspreservecombatantabilityofcasualtyTacticalFieldCare-PAIN:AnalgesiaasNecessaryIfAbletoFight

-UseoralmedsMeloxicam(Mobic®)

–15mgPOQDRofecoxib(Vioxx®)(originalrecommendation)-50mgperdayNoplateletinhibitionNosulfareactionsAcetaminophen–(Tylenol®8hrBi-layer)1300mgNOdecreaseinmentalstatusasaresultofthesemedicationsCombatPillPackTacticalFieldCare-AnalgesiaasNecessaryIfUnabletoFightMorphine5mgIV/IOReassessin10minutesRepeatdoseq10minasnecessarytocontrolseverepainMonitorforrespiratorydepression

Promethazine25mg

IV/IO/IMq4h (forpainandnausea)(NewRec–onlyPRN…)OralTransmucosalFentanylCitrateFentanylTransmucosalLozengeFENTANYLSynthesizedinBelgiuminthelate1950sHighlylipophilicsyntheticphenylpiperidinederivative80-100timesmorepotentthanmorphineSelectivelybindstomu-1andmu-2receptorsOTFCOTFCManufacturedin1980sFDAapproval:Oralet®,1993;Actiq®,1998Crystallineformoffentanylcitrate(raspberrylozengeonaplasticstick)Only50%absorbed