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IntroductiontoAntibacterialTherapyClinicallyRelevantMicrobiologyandPharmacologyEdwardL.Goodman,MDJuly21,2003IntroductiontoAntibacterial1RationaleAntibioticuse(appropriateornot)leadstomicrobialresistanceResistanceresultsinincreasedmorbidity,mortality,andcostofhealthcareAppropriateantimicrobialstewardshipwillpreventorslowtheemergenceofresistanceamongorganisms(ClinicalInfectiousDiseases1997;25:584-99.)Antibioticsareusedas“drugsoffear”(KuninCMAnnals1973;79:555)Rationale2抗生素英文課件——Introduction-to-Antibacterial-Therapy3AntibioticMisuseSurveysrevealthat:25-33%ofhospitalizedpatientsreceiveantibiotics(ArchInternMed1997;157:1689-1694)22-65%ofantibioticuseinhospitalizedpatientsisinappropriate(InfectionControl1985;6:226-230)AntibioticMisuseSurveysrevea4ConsequencesofMisuseofAntibioticsContagiousRESISTANCENoequivalentdownsidetooveruseofendoscopy,calciumchannelblockers,etc.Morbidity-drugtoxicityMortalityCostConsequencesofMisuseofAnt5Outline

BasicClinicalBacteriologyCategoriesofAntibioticsPharmacologyofAntibioticsOutline

BasicClinicalBacter6Goodman’sSchemefortheMajorClassesofBacterialPathogens

GramPositiveCocciGramNegativeRodsFastidiousGNRAnaerobesGoodman’sSchemefortheMajor7GramPositiveCocciGramstain:clustersCatalasepos=StaphCoagpos=SaureusCoagneg=varietyofspeciesChainsandpairsCatalaseneg=streptococciClassifybyhemolysisTypebyspecificCHOGramPositiveCocciGramstain:8Staphylococcusaureus>95%producepenicillinase(betalactamase)=penicillinresistantAtPHD~50%ofSAarehetero(methicillin)resistant=MRSAGlycopeptide(vancomycin)intermediate(GISA)MIC8-16Eightnationwide(oneatPHD)VRSAreportedJuly5,2002MMWRMIC>128Staphylococcusaureus>95%prod9S.aureusPenicillin[1950s]Penicillin-resistantS.aureusEvolutionofDrugResistanceinS.aureusMethicillin[1970s]Methicillin-resistant

S.aureus(MRSA)Vancomycin-resistantenterococci(VRE)Vancomycin[1990s][1997]Vancomycinintermediate-resistantS.aureus

(VISA)

[2002]Vancomycin-resistantS.aureusS.aureusPenicillin[1950s]Peni10MSSAvs.MRSA

SurgicalSiteInfections

(1994-2000)MSSAvs.MRSA

SurgicalSiteI11CoagulaseNegativeStaphManyspecies–S.epidermidismostcommonMostlymethicillinresistant(65%)Oftencontaminantsorcolonizers–usespecificcriteriatodistinguishMajorcauseofoveruseofvancomycinCoagulaseNegativeStaphManys12NosocomialBloodstreamIsolatesSCOPEProjectOther(11%)Coagulase-negativestaphylococci(32%)Enterococci(11%)Allgram-negative(21%)Candida

(8%)Viridansstreptococci(1%)Staphylococciaureus(16%)ClinInfectDis1999;29:239-244NosocomialBloodstreamIsolate13StreptococciBetahemolysis:GroupA,B,Cetc.Invasive–mimicstaphinvirulenceS.pyogenes(GroupA)Pharyngitis,SofttissueNonsuppurativesequellae:ARF,AGNStreptococciBetahemolysis:Gr14Betastrept-continuedS.agalactiae(GroupB)Peripartum/NeonatalDiabeticfootBacteremia/endocarditis/metastaticfociGroupD(nonenterococcal)=S.bovisAssociatedwithcarcinomaofcolonBetastrept-continuedS.agal15ViridansStreptococciManyspeciesStreptococcusintermediusgroupLiverabscessEndocarditisGIorpharyngealfloraMostotheraremouthflora–causeIEViridansStreptococciManyspec16EnterococciFormerlyconsideredGroupDStreptococci nowaseparategenusBacteremia/EndocarditisBacteriuriaPartofmixedabdominal/pelvicinfectionsIntrinsicallyresistanttocephalosporinsNobactericidalsingleagentEnterococciFormerlyconsidered17GramNegativeRodsFermentorsOxidasenegativeFacultativeanaerobesEntericfloraNumerousgeneraEscherischiaEnterobacterSerratia,etcNon-fermentorsOxidasepositivePureaerobesPseudomonasandAcinetobacterNosocomialOpportunisticInherentlyresistantGramNegativeRodsFermentorsNo18FastidiousGramNegativeRodsNeisseria,Hemophilus,Moraxella,HACEKRequireCO2forgrowthNeisseriamustbeplatedatbedsideChocolateagarwithCO2LigasechainreactionhasreducednumberofculturesforN.gonorrhea

FastidiousGramNegativeRodsN19AnaerobesGramnegativerodsBacteroidesFusobacteriaGrampositiverodsClostridiaProprionobacteriaGrampositivecocciPeptostreptococciandpeptococciAnaerobesGramnegativerods20AnaerobicGramNegativeRodsProducebetalactamaseEndogenousfloraPartofmixedinfectionsConferfoulodorHeterogeneousmorphologyFastidiousAnaerobicGramNegativeRodsPr21AntibioticClassification

accordingtoGoodmanNarrowSpectrumActiveagainstonlyoneofthefourclassesBroadSpectrumActiveagainstmorethanoneoftheclassesBoutiqueActiveagainstaselectnumberwithinaclassAntibioticClassification

acco22NarrowSpectrumActivemostlyagainstonlyoneoftheclassesofbacteriagrampositive:glycopeptides,linezolidaerobicgramnegative:aminoglycosides,aztreonamanaerobes:metronidazoleNarrowSpectrumActivemostlya23NarrowSpectrumGPCGNRFastidAnaerVanc++++----------onlyclostridiaLinezolid++++----------OnlygramposAG-----++++++-----Aztreon-----++++-----Metro---------------++++NarrowSpectrumGPCGNRFastidAna24BroadSpectrum ActiveagainstmorethanoneclassGPCandanaerobes:clindamycinGPCandGNR:cephalosporins,penicillins,T/S,newerFQGPC,GNRandanaerobes:ureidopenicillins±BLI,carbapenemsGPCandfastidious:macrolidesBroadSpectrum Activeagainst25PenicillinsStrepOSSAGNRFastidAnaerPen+++--+/----+/--Amp/amox+++--++/--+/--Ticar++--+++/--+Ureid+++--+++++++++BLI+++++++++++++++++Carba++++++++++++++++++PenicillinsStrepOSSAGNRFastidA26CephalosporinsGPCnon-MRSAGNRFASTIDANAERCeph1+++++----Ceph2+++++--Cepha-mycin++++++++Ceph3+++++++++--Ceph4++++++++++--CephalosporinsGPCnon-MRSAGNR27BoutiqueAntibioticsJustliketheMallspecialtystoresspecialtydrugsOftenliketheMall–storesinsearchofbusiness;drugsinsearchofdiseasesSynercid–forVREfaecium,notfaecalis,MRSALinezolid–VRE,MRSAIDconsultneededBoutiqueAntibioticsJustlike28Pharmacodynamics

MIC=lowestconcentrationtoinhibitgrowthMBC=thelowestconcentrationtokillPeak=highestserumlevelafteradoseAUC=areaundertheconcentrationtimecurvePAE=persistentsuppressionofgrowthfollowingexposuretoantimicrobialPharmacodynamics

MIC=lowestco29ParametersofantibacterialefficacyTimeaboveMIC-betalactams,macrolides,clindamycin,glycopeptides24hourAUC/MIC-aminoglycosides,fluoroquinolones,azalides,tetracyclines,glycopeptides,quinupristin/dalfopristinPeak/MIC-aminoglycosides,fluoroquinolonesParametersofantibacterialef30TimeoverMIC ShouldexceedMICforatleast50%ofdoseintervalHigherdosesmayallowadequatetimeoverMICFormostbetalactams,optimaltimeoverMICcanbeachievedbycontinuousinfusion(exceptunstabledrugssuchasimipenem,ampicillin)TimeoverMIC ShouldexceedMI31HigherSerum/tissuelevelsareassociatedwithfasterkilling AminoglycosidesPeak/MICratioof>10-12optimalAchievedby“OnceDailyDosing”PAEhelpsFluoroquinolones10-12ratioachievedforentericGNRPAEhelpsnotachievedfor

PseudomonasnorStreptococcuspneumoniaeHigherSerum/tissuelevelsare32AUC/MIC=AUICForStreptococcuspneumoniae,FQshouldhaveAUIC>=30ForgramnegativerodswherePeak/MICratioof10-12notpossible,thenAUICshould>=125.AUC/MIC=AUICForStreptococcu33AntibioticUseandResistance-Strongepidemiologicalevidencethatantibioticuseinhumansandanimalsassociatedwithincreasingresistance-Subtherapeuticdosingencouragesresistantmutantstoemerge;conversely,rapidbactericidalactivitydiscourages-HospitalantibioticcontrolprogramshavebeendemonstratedtoreduceresistanceAntibioticUseandResistance-34TotalAntibiotic

Doses/DayTotalAntibiotic

Doses/Day35ChangesinBug/DrugSusceptibilityPatternsChangesinBug/DrugSusceptibi36FurtherActivitiesofCAMPDecreaseinappropriatefluoroquinoloneuseStaffeducationRestrictedreportingDecreaseinappropriatesputumculturesStaffeducationLaboratorydisclaimerDecreaseinappropriatevancomycinlevelsEducationaboutunnecessarypeaklevelsFurtherActivitiesofCAMPDecr37FurtherActivitiesofCAMPMonitorsurgicalsiteinfectionsandinterveneasnecessaryImprovedtimingandadministrationofpre-opantibioticsclippingnotshavingnasaldecolonizationchangingpathogens(MRSA,gram-rods)Automatedprotocol-drivenantibioticprescribingComputerizedphysicianorderentryFurtherActivitiesofCAMPMoni38AntibioticArmageddon“ThereisonlyathinredlineofIDpractitionerswhohavededicatedthemselvestorationaltherapyandcontrolofhospitalinfections”KuninCID1997;25:240AntibioticArmageddon“Thereis39Historicoverviewontreatmentofinfections2000BC:Eatthisroot1000AD:Saythisprayer1800’s:Takethispotion1940’s:Takepenicillin,itisamiracledrug1980’s:Takethisnewantibiotic,itisbetter?2003AD:EatthisrootHistoricoverviewontreatment40IntroductiontoAntibacterialTherapyClinicallyRelevantMicrobiologyandPharmacologyEdwardL.Goodman,MDJuly21,2003IntroductiontoAntibacterial41RationaleAntibioticuse(appropriateornot)leadstomicrobialresistanceResistanceresultsinincreasedmorbidity,mortality,andcostofhealthcareAppropriateantimicrobialstewardshipwillpreventorslowtheemergenceofresistanceamongorganisms(ClinicalInfectiousDiseases1997;25:584-99.)Antibioticsareusedas“drugsoffear”(KuninCMAnnals1973;79:555)Rationale42抗生素英文課件——Introduction-to-Antibacterial-Therapy43AntibioticMisuseSurveysrevealthat:25-33%ofhospitalizedpatientsreceiveantibiotics(ArchInternMed1997;157:1689-1694)22-65%ofantibioticuseinhospitalizedpatientsisinappropriate(InfectionControl1985;6:226-230)AntibioticMisuseSurveysrevea44ConsequencesofMisuseofAntibioticsContagiousRESISTANCENoequivalentdownsidetooveruseofendoscopy,calciumchannelblockers,etc.Morbidity-drugtoxicityMortalityCostConsequencesofMisuseofAnt45Outline

BasicClinicalBacteriologyCategoriesofAntibioticsPharmacologyofAntibioticsOutline

BasicClinicalBacter46Goodman’sSchemefortheMajorClassesofBacterialPathogens

GramPositiveCocciGramNegativeRodsFastidiousGNRAnaerobesGoodman’sSchemefortheMajor47GramPositiveCocciGramstain:clustersCatalasepos=StaphCoagpos=SaureusCoagneg=varietyofspeciesChainsandpairsCatalaseneg=streptococciClassifybyhemolysisTypebyspecificCHOGramPositiveCocciGramstain:48Staphylococcusaureus>95%producepenicillinase(betalactamase)=penicillinresistantAtPHD~50%ofSAarehetero(methicillin)resistant=MRSAGlycopeptide(vancomycin)intermediate(GISA)MIC8-16Eightnationwide(oneatPHD)VRSAreportedJuly5,2002MMWRMIC>128Staphylococcusaureus>95%prod49S.aureusPenicillin[1950s]Penicillin-resistantS.aureusEvolutionofDrugResistanceinS.aureusMethicillin[1970s]Methicillin-resistant

S.aureus(MRSA)Vancomycin-resistantenterococci(VRE)Vancomycin[1990s][1997]Vancomycinintermediate-resistantS.aureus

(VISA)

[2002]Vancomycin-resistantS.aureusS.aureusPenicillin[1950s]Peni50MSSAvs.MRSA

SurgicalSiteInfections

(1994-2000)MSSAvs.MRSA

SurgicalSiteI51CoagulaseNegativeStaphManyspecies–S.epidermidismostcommonMostlymethicillinresistant(65%)Oftencontaminantsorcolonizers–usespecificcriteriatodistinguishMajorcauseofoveruseofvancomycinCoagulaseNegativeStaphManys52NosocomialBloodstreamIsolatesSCOPEProjectOther(11%)Coagulase-negativestaphylococci(32%)Enterococci(11%)Allgram-negative(21%)Candida

(8%)Viridansstreptococci(1%)Staphylococciaureus(16%)ClinInfectDis1999;29:239-244NosocomialBloodstreamIsolate53StreptococciBetahemolysis:GroupA,B,Cetc.Invasive–mimicstaphinvirulenceS.pyogenes(GroupA)Pharyngitis,SofttissueNonsuppurativesequellae:ARF,AGNStreptococciBetahemolysis:Gr54Betastrept-continuedS.agalactiae(GroupB)Peripartum/NeonatalDiabeticfootBacteremia/endocarditis/metastaticfociGroupD(nonenterococcal)=S.bovisAssociatedwithcarcinomaofcolonBetastrept-continuedS.agal55ViridansStreptococciManyspeciesStreptococcusintermediusgroupLiverabscessEndocarditisGIorpharyngealfloraMostotheraremouthflora–causeIEViridansStreptococciManyspec56EnterococciFormerlyconsideredGroupDStreptococci nowaseparategenusBacteremia/EndocarditisBacteriuriaPartofmixedabdominal/pelvicinfectionsIntrinsicallyresistanttocephalosporinsNobactericidalsingleagentEnterococciFormerlyconsidered57GramNegativeRodsFermentorsOxidasenegativeFacultativeanaerobesEntericfloraNumerousgeneraEscherischiaEnterobacterSerratia,etcNon-fermentorsOxidasepositivePureaerobesPseudomonasandAcinetobacterNosocomialOpportunisticInherentlyresistantGramNegativeRodsFermentorsNo58FastidiousGramNegativeRodsNeisseria,Hemophilus,Moraxella,HACEKRequireCO2forgrowthNeisseriamustbeplatedatbedsideChocolateagarwithCO2LigasechainreactionhasreducednumberofculturesforN.gonorrhea

FastidiousGramNegativeRodsN59AnaerobesGramnegativerodsBacteroidesFusobacteriaGrampositiverodsClostridiaProprionobacteriaGrampositivecocciPeptostreptococciandpeptococciAnaerobesGramnegativerods60AnaerobicGramNegativeRodsProducebetalactamaseEndogenousfloraPartofmixedinfectionsConferfoulodorHeterogeneousmorphologyFastidiousAnaerobicGramNegativeRodsPr61AntibioticClassification

accordingtoGoodmanNarrowSpectrumActiveagainstonlyoneofthefourclassesBroadSpectrumActiveagainstmorethanoneoftheclassesBoutiqueActiveagainstaselectnumberwithinaclassAntibioticClassification

acco62NarrowSpectrumActivemostlyagainstonlyoneoftheclassesofbacteriagrampositive:glycopeptides,linezolidaerobicgramnegative:aminoglycosides,aztreonamanaerobes:metronidazoleNarrowSpectrumActivemostlya63NarrowSpectrumGPCGNRFastidAnaerVanc++++----------onlyclostridiaLinezolid++++----------OnlygramposAG-----++++++-----Aztreon-----++++-----Metro---------------++++NarrowSpectrumGPCGNRFastidAna64BroadSpectrum ActiveagainstmorethanoneclassGPCandanaerobes:clindamycinGPCandGNR:cephalosporins,penicillins,T/S,newerFQGPC,GNRandanaerobes:ureidopenicillins±BLI,carbapenemsGPCandfastidious:macrolidesBroadSpectrum Activeagainst65PenicillinsStrepOSSAGNRFastidAnaerPen+++--+/----+/--Amp/amox+++--++/--+/--Ticar++--+++/--+Ureid+++--+++++++++BLI+++++++++++++++++Carba++++++++++++++++++PenicillinsStrepOSSAGNRFastidA66CephalosporinsGPCnon-MRSAGNRFASTIDANAERCeph1+++++----Ceph2+++++--Cepha-mycin++++++++Ceph3+++++++++--Ceph4++++++++++--CephalosporinsGPCnon-MRSAGNR67BoutiqueAntibioticsJustliketheMallspecialtystoresspecialtydrugsOftenliketheMall–storesinsearchofbusiness;drugsinsearchofdiseasesSynercid–forVREfaecium,notfaecalis,MRSALinezolid–VRE,MRSAIDconsultneededBoutiqueAntibioticsJustlike68Pharmacodynamics

MIC=lowestconcentrationtoinhibitgrowthMBC=thelowestconcentrationtokillPeak=highestserumlevelafteradoseAUC=areaundertheconcentrationtimecurvePAE=persistentsuppressionofgrowthfollowingexposuretoantimicrobialPharmacodynamics

MIC=lowestco69ParametersofantibacterialefficacyTimeaboveMIC-betalactams,macrolides,clindamycin,glycopeptides24hourAUC/MIC-aminoglycosides,fluoroquinolones,azalides,tetracyclines,glycopeptides,quinupristin/dalfopristinPeak/MIC-aminoglycosides,fluoroquinolonesParametersofantibacterialef70TimeoverMIC ShouldexceedMICforatleast50%ofdoseintervalHigherdosesmayallowadequatetimeoverMICFormostbetalactams,optimaltimeoverMICcanbeachievedbycontinuousinfusion(exceptunstabledrugssuchasimipenem,ampicillin)TimeoverMIC ShouldexceedMI71HigherSerum/tissuelevelsareassociatedwithfasterkilling AminoglycosidesPeak/MICratioof>10-12optimalAchievedby“OnceDailyDosing”PAEhelpsFluoroquinolones10-12ratioachievedforentericGNRPAEhelpsnotachievedfor

PseudomonasnorStreptococcuspneumoniaeHig

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