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IsResistanceFutile?
DonaldELowUniversityofTorontoOntarioAgencyforHealthProtectionandPromotion
IsResistanceFutile?
DonaldAchievementsinPublicHealthControlofinfectiousdiseasesSanitationandHygieneVaccinationAntibioticsAchievementsinPublicHealthC抗生素课件(英文)-Is-Resistance-Futile抗生素课件(英文)-Is-Resistance-FutileMMWR199948(29);621MMWR199948(29);621Antibiotics:theepitomeofa
wonderdrug
Theintroductionofantibioticsinthe1940sconvertedillnessintoastrictlytechnicalproblem:"virtualeliminationofinfectiousdiseaseasasignificantfactorinsociallife."BurnetFM.Naturalhistoryofinfectiousdisease.2nded.Cambridge:CambridgeUniversityPress,1953Antibiotics:theepitomeofaPrevalenceofIsolatesofMultidrug-ResistantGramNegativeRodsRecoveredWithinTheFirst48hAfterAdmissiontotheHospitalPop-VicasandD'AgataCID
2005;40:1792-8.PrevalenceofIsolatesofMult7MRSADeLeoandChambersJCI2009adaptedfromKlevensetal.JAMAI2007MRSADeLeoandChambersJCI2008NewemergingthreatsHospitalsettingCarbapenemases(KPCs)CommunityS.pneumoniaeCommunityAssociatedMRSAFluoroquinoloneresistantE.coliMulti-drugresistantGCNewemergingthreatsHospitalsClinicalCaseA73yoMwithnotravelhxLaparoscopicrightradicalnephrectomyforahypernephromawithpost-oppneumoniaEmpiricallytreatedwithvariousantimicrobialsincludingthecarbapenemsCulturesfoundMDRK.pneumoniae,initiallyreportedasAmpC-andESBL-containingDiedwithpneumoniaandrespiratoryfailureSKrajden,RobertoMelano,andDylanR.PillaiClinicalCaseA73yoMwithnoDrugMIC(mg/mL)CLSIbreakpointsAmpicillin>16RCephalothin>16RCefoxitin>16RTobramycin>8RAmikacin32ICeftriaxone>32RCiprofloxacin>2RMeropenem4SDrugCLSIbreakpointsAmpicillinCarbapenemasesAbilitytohydrolyzepenicillins,
cephalosporins,monobactams,andcarbapenemsResilientagainstinhibitionbyallcommerciallyviable
ß-lactamaseinhibitorsCarbapenemasesAbilitytohydrKPC(K.pneumoniaecarbapenemase)KPCsarethemostprevalentofthisgroupofenzymes,foundmostlyontransferableplasmidsinK.
pneumoniaeSubstratehydrolysisspectrumincludes
cephalosporins,suchascefotaxime.KPCshavetransferredtoEnterobacter
spp.andinSalmonellasppKPC(K.pneumoniaecarbapenemaStreptococcuspneumoniaeMostimportantpathogenin
mild-to-moderateRTIs1
Greatestmorbidity2Greatestmortality2Streptococcuspneumoniae1FileTMJr.Lancet.2003;362:1991-2001;2BartlettJG,etal.ClinInfectDis.2000;31:347-382;StreptococcuspneumoniaeMostiPercentageofPenicillinNon-Susceptible
S.pneumoniaeinCanada:1988-2008CanadianBacterialSurveillanceNetwork,Feb2009*OralbreakpointsusedPercentageofPenicillinNMacrolide-ResistantPneumococci:
CanadianBacterialSurveillanceNetwork,1988-2008CanadianBacterialSurveillanceNetwork,Feb2009Macrolide-ResistantPneumococcS.pneumoniaecolonisation:thekeytopneumococcaldiseaseNPcarriage15%<6mosto40%>19mos~10%afterageof10~3%inadultsInvasiveandmucosalinfectioninvolvesNPcolonizationwithconcurrentviralrespiratoryinfectionKadiogluA.,etal.NatRevMicro2008S.pneumoniaecolonisation:thPneumococcal
VaccinesAlthoughthe23-valentvaccineisimmunogenicinadultsandchildrenolderthan5years,youngchildren(<2years)haveaseverelyimpairedantibodyresponsetopolysaccharidevaccinationPPV23426B89V9N1410A18C11A19F12F23F15B117F5207F22F333F19APneumococcal
VaccinesAlthoughIntroductionofpneumococcalvaccines,OntarioOct1996–PPV23programforadultsIncreasedcoveragefrom?2%to35%inadultsIntroductionofpneumococcalvInvasivepneumococcaldisease,elderly
MetropolitanToronto,1995-2000Invasivepneumococcaldisease,Pediatricinvasivepneumococcaldisease
MetropolitanToronto,1995-2000PediatricinvasivepneumococcaPCV7PPV234426B6B89V9V9N141410A18C18C11A19F19F12F23F23F15B117F522F7F33F319APneumococcalvaccinesPCV7PPV234426B6B89V9V9N141410AMMWRFeb2008InvasivePneumococcalDiseaseinChildren5YearsAfterConjugateVaccineIntroduction,1998--2005TheoverallincidenceofIPDamongchildrenaged<5yearsdeclinedfrom99cases/100,000during1998--1999to23cases/100,000in2005MMWRFeb2008InvasivePneumocoIntroductionofpneumococcalvaccines,OntarioOct1996–PPV23programforadultsIncreasedcoveragefrom?2%to35%inadultsDec2001–PCV7licensedGradualincreaseinuseinchildren(toabout1doseperchild,or4dosesfor20%ofchildren)Jan2005–provincialPCV7programNocatch-up;startwithbirthcohortIntroductionofpneumococcalvPediatricinvasivepneumococcaldisease
MetropolitanToronto,1995-2007PediatricinvasivepneumococcaInvasivepneumococcaldisease,elderly
MetropolitanToronto,1995-2001Invasivepneumococcaldisease,RatesofpenicillinandamoxicillinresistanceCanada:1988-2008CanadianBacterialSurveillanceNetwork,March2008RatesofpenicillinandamoxicMostCommonMDRSPNSerotypesVSMostCommonMDRSPNSerotypesV28MostCommonMDRSPNSerotypesP<0.0001P=0.0009P<0.0001P<0.0001VSMostCommonMDRSPNSerotypes29WorldwidePrevalanceofMRSA
AmongS.aureusIsolatesGrundmannHetal.Lancet2006;368:874.WorldwidePrevalanceofMRSA
A30MRSAinCanada,1995-2005Source:CNISPMRSAinCanada,1995-2005Sourc31Community-Associated
MRSASportsparticipantsInmatesincorrectionalfacilitiesMilitaryrecruitsChildrenindaycareNativeAmericans,AlaskanNatives,PacificIslandersMenwhohavesexwithmenHurricaneevacueesinsheltersFoalwatchersRuralcrystalmethamphetamineusersCommunity-Associated
MRSASpor32FirstOutbreaksofCA-MRSAAustralia(1993)UdoEEetal.Geneticanalysisofcommunityisolatesofmethicillin-resistantStaphylococcusaureusinWesternAustralia.J.Hosp.Infect.1993US(1999)CDC.Fourpediatricdeathsfromcommunity-acquiredmethicillin-resistantStaphylococcusaureus—MinnesotaandNorthDakota,MMWR1999Canada(2000)MulveyMRetal.Community-associatedMethicillin-resistantStaphylococcusaureus,CanadaEID2005Worldwide(2000)VandeneschFetal.Community-AcquiredMethicillin-ResistantStaphylococcusaureusCarryingPanton-ValentineLeukocidinGenes:WorldwideEmergenceEID2003FirstOutbreaksofCA-MRSAAust33EmergenceofCA-MRSACanadaSimoreAetal.CanadianNosocomialInfectionSurveillanceProgramCMRSA7(USA400)CMRSA10(USA300)EmergenceofCA-MRSACanadaSim34CurrentTreatmentOptionsforCA-MRSAInfectionMoelleringRCCID2008CurrentTreatmentOptionsfor35Community-acquiredantibioticresistanceinurinaryisolatesfromadultwomeninCanada
15%ofE.coliisolatesfromadultwomenresistanttoTMP-SMXFluoroquinolone-resistantEcoliwas7%10%ofEcoliisolateswerefluoroquinolone-resistantinwomenolderthan65yearsofageMcIsaacWJetal.CanJInfectDisMedMicrobiol.2006Community-acquiredantibiotic36Quinolone-resistantNeisseriagonorrhoeaeinfectionsinOntarioIsolatesreferredtotheOPHLbetween2002and2006FQ-Rincreasedfrom4.0%in2002to27.8%in2006FQ-Rstrainsweremoreresistanttopenicillin(p<0.001);tetracycline(p<0.001)anderythromycin(p<0.001)Allisolatesweresusceptibletocefixime,ceftriaxone,azithromycinandspectinomycinOtaKetal.CanMedAssJInPressQuinolone-resistantNeisseria37ControllingantimicrobialresistanceReducingcolonizationandinfectionReducingvolumeofantimicrobialuseWhendecisionmadetotreatUserightdrugRightdoseRightdurationControllingantimicrobialresiControllingantimicrobialresistanceReducinginfectionReducingvolumeofantimicrobialuseWhendecisionmadetotreatUserightdrugRightdoseRightdurationControllingantimicrobialresiTheaverageexcessage-specificnumbersofoutpatientvisitsandcoursesofantibioticsper100childrenperyearNeuzilKMetal.NEJM2000TheEffectofInfluenzaonHospitalizations,OutpatientVisits,andCoursesofAntibioticsinChildrenTheaverageexcessage-specifiControllingantimicrobialresistanceReducingcolonizationandinfectionReducingvolumeofantimicrobialuseWhendecisionmadetotreatUserightdrugRightdoseRightdurationControllingantimicrobialresiRespiratoryInfectionsarethe#1ReasonforOfficeVisitsSource:VerispanPDDA2004Numberofcommonofficevisits(millions)RespiratoryInfectionsaretheNearlyTwo-thirdsofallOralSolidAntibioticPrescriptionsareforSinusitisandBronchitisSource:SDI,FANDxRx.Basedonalltablets/capsuleantibioticsforthe52weeksendingApril6,2005Telithromycin(Ketek®)isindicatedforacuteexacerbationsofchronicbronchitis,acutebacterialsinusitisandmild-to-moderate
community-acquiredpneumoniaNearlyTwo-thirdsofallOralUsageofantibioticsinEuropevs.pneumococcalpenicillinI/R1997Felminghametal.
JAntimicrobChemother2000;45:191–201Carsetal.Lancet2001;357:1851–185338.532.528.826.7241813.58.90102030405060FranceSpainPortugalBelgiumItalyUKGermanyNetherlandsDDD/1000/dayDI/RSP%**1996dataUsageofantibioticsinEuropeControllingantimicrobialresistanceReducingcolonizationandinfectionReducingvolumeofantimicrobialuseWhendecisionmadetotreatUserightdrugRightdoseRightdurationControllingantimicrobialresiMultivariateAnalysisofRiskFactors0123456β-lactamw/in3monthsAlcoholismNoninvasivedisease<5y≥65yOddsRatio
OtherConsiderationsImmunosuppressionIncludingsteroidsMultiplemedical
comorbiditiesExposuretodaycarechildExposuretoanyantibioticClavo-SanchezAJetal.ClinInfectDis.1997;24:1052-1059.HarwellJI,BrownRB.Chest.2000;117:530-541.VanderkooiOGetal.ClinInfectDis.2005;40:1288-1297.
RisksforPenicillinResistance
inPneumococcusMultivariateAnalysisofRiskPrevalenceofErythromycinResistanceAmongPneumococcibyPriorMacrolideUseP=.02P=.004VanderkooiOGetal.ClinInfectDis.2005;40:1288-1297.P<.0010102030405060NoAntibioticErythromycinClarithromycinAzithromycinRateofMacrolideResistanceinInfectingIsolates(%)PrevalenceofErythromycinResRelativeRiskforInfectionWithFluoroquinolone-ResistantPneumococcibyPriorAntibioticUseVanderkooiOGetal.ClinInfectDis.2005;40:1288-1297.02468101214161820NoPriorAntibioticPriorAntibiotic
(notfluoroquinolone)Prior
FluoroquinoloneLevoofloxacinresistant(%)***P<.001RelativeRiskforInfectionWiFluoroquinolonePDProfileFreeAUC/MICLevofloxacin500mgLevofloxacin750mgGemifloxacin320mgMoxifloxacin400mg40(13-21)(24-40)(72-120)ResistancePrevention~AUC/MIC≥100Efficacy~AUC/MIC≥350206080100120140(41-69)MoranG.JEmergMed.2006;30:377-387.
10035FluoroquinolonePDProfileFreeWHOstatement2000Themosteffectivestrategyagainstantibioticresistanceis:“tounequivocallydestroymicrobes”“therebydefeatingresistancebeforeitstarts”WHOOvercomingAntimicrobialResistance,2000WHOstatement2000WHOOvercomiFluoroquinolone-ResistantPneumococci:
CanadianBacterialSurveillanceNetwork,1997-2008CanadianBacterialSurveillanceNetwork,Jan2009%ResistantFluoroquinolone-ResistantPneuResistanceIsn’tFutileResistanceIsn’tFutile
IsResistanceFutile?
DonaldELowUniversityofTorontoOntarioAgencyforHealthProtectionandPromotion
IsResistanceFutile?
DonaldAchievementsinPublicHealthControlofinfectiousdiseasesSanitationandHygieneVaccinationAntibioticsAchievementsinPublicHealthC抗生素课件(英文)-Is-Resistance-Futile抗生素课件(英文)-Is-Resistance-FutileMMWR199948(29);621MMWR199948(29);621Antibiotics:theepitomeofa
wonderdrug
Theintroductionofantibioticsinthe1940sconvertedillnessintoastrictlytechnicalproblem:"virtualeliminationofinfectiousdiseaseasasignificantfactorinsociallife."BurnetFM.Naturalhistoryofinfectiousdisease.2nded.Cambridge:CambridgeUniversityPress,1953Antibiotics:theepitomeofaPrevalenceofIsolatesofMultidrug-ResistantGramNegativeRodsRecoveredWithinTheFirst48hAfterAdmissiontotheHospitalPop-VicasandD'AgataCID
2005;40:1792-8.PrevalenceofIsolatesofMult59MRSADeLeoandChambersJCI2009adaptedfromKlevensetal.JAMAI2007MRSADeLeoandChambersJCI20060NewemergingthreatsHospitalsettingCarbapenemases(KPCs)CommunityS.pneumoniaeCommunityAssociatedMRSAFluoroquinoloneresistantE.coliMulti-drugresistantGCNewemergingthreatsHospitalsClinicalCaseA73yoMwithnotravelhxLaparoscopicrightradicalnephrectomyforahypernephromawithpost-oppneumoniaEmpiricallytreatedwithvariousantimicrobialsincludingthecarbapenemsCulturesfoundMDRK.pneumoniae,initiallyreportedasAmpC-andESBL-containingDiedwithpneumoniaandrespiratoryfailureSKrajden,RobertoMelano,andDylanR.PillaiClinicalCaseA73yoMwithnoDrugMIC(mg/mL)CLSIbreakpointsAmpicillin>16RCephalothin>16RCefoxitin>16RTobramycin>8RAmikacin32ICeftriaxone>32RCiprofloxacin>2RMeropenem4SDrugCLSIbreakpointsAmpicillinCarbapenemasesAbilitytohydrolyzepenicillins,
cephalosporins,monobactams,andcarbapenemsResilientagainstinhibitionbyallcommerciallyviable
ß-lactamaseinhibitorsCarbapenemasesAbilitytohydrKPC(K.pneumoniaecarbapenemase)KPCsarethemostprevalentofthisgroupofenzymes,foundmostlyontransferableplasmidsinK.
pneumoniaeSubstratehydrolysisspectrumincludes
cephalosporins,suchascefotaxime.KPCshavetransferredtoEnterobacter
spp.andinSalmonellasppKPC(K.pneumoniaecarbapenemaStreptococcuspneumoniaeMostimportantpathogenin
mild-to-moderateRTIs1
Greatestmorbidity2Greatestmortality2Streptococcuspneumoniae1FileTMJr.Lancet.2003;362:1991-2001;2BartlettJG,etal.ClinInfectDis.2000;31:347-382;StreptococcuspneumoniaeMostiPercentageofPenicillinNon-Susceptible
S.pneumoniaeinCanada:1988-2008CanadianBacterialSurveillanceNetwork,Feb2009*OralbreakpointsusedPercentageofPenicillinNMacrolide-ResistantPneumococci:
CanadianBacterialSurveillanceNetwork,1988-2008CanadianBacterialSurveillanceNetwork,Feb2009Macrolide-ResistantPneumococcS.pneumoniaecolonisation:thekeytopneumococcaldiseaseNPcarriage15%<6mosto40%>19mos~10%afterageof10~3%inadultsInvasiveandmucosalinfectioninvolvesNPcolonizationwithconcurrentviralrespiratoryinfectionKadiogluA.,etal.NatRevMicro2008S.pneumoniaecolonisation:thPneumococcal
VaccinesAlthoughthe23-valentvaccineisimmunogenicinadultsandchildrenolderthan5years,youngchildren(<2years)haveaseverelyimpairedantibodyresponsetopolysaccharidevaccinationPPV23426B89V9N1410A18C11A19F12F23F15B117F5207F22F333F19APneumococcal
VaccinesAlthoughIntroductionofpneumococcalvaccines,OntarioOct1996–PPV23programforadultsIncreasedcoveragefrom?2%to35%inadultsIntroductionofpneumococcalvInvasivepneumococcaldisease,elderly
MetropolitanToronto,1995-2000Invasivepneumococcaldisease,Pediatricinvasivepneumococcaldisease
MetropolitanToronto,1995-2000PediatricinvasivepneumococcaPCV7PPV234426B6B89V9V9N141410A18C18C11A19F19F12F23F23F15B117F522F7F33F319APneumococcalvaccinesPCV7PPV234426B6B89V9V9N141410AMMWRFeb2008InvasivePneumococcalDiseaseinChildren5YearsAfterConjugateVaccineIntroduction,1998--2005TheoverallincidenceofIPDamongchildrenaged<5yearsdeclinedfrom99cases/100,000during1998--1999to23cases/100,000in2005MMWRFeb2008InvasivePneumocoIntroductionofpneumococcalvaccines,OntarioOct1996–PPV23programforadultsIncreasedcoveragefrom?2%to35%inadultsDec2001–PCV7licensedGradualincreaseinuseinchildren(toabout1doseperchild,or4dosesfor20%ofchildren)Jan2005–provincialPCV7programNocatch-up;startwithbirthcohortIntroductionofpneumococcalvPediatricinvasivepneumococcaldisease
MetropolitanToronto,1995-2007PediatricinvasivepneumococcaInvasivepneumococcaldisease,elderly
MetropolitanToronto,1995-2001Invasivepneumococcaldisease,RatesofpenicillinandamoxicillinresistanceCanada:1988-2008CanadianBacterialSurveillanceNetwork,March2008RatesofpenicillinandamoxicMostCommonMDRSPNSerotypesVSMostCommonMDRSPNSerotypesV80MostCommonMDRSPNSerotypesP<0.0001P=0.0009P<0.0001P<0.0001VSMostCommonMDRSPNSerotypes81WorldwidePrevalanceofMRSA
AmongS.aureusIsolatesGrundmannHetal.Lancet2006;368:874.WorldwidePrevalanceofMRSA
A82MRSAinCanada,1995-2005Source:CNISPMRSAinCanada,1995-2005Sourc83Community-Associated
MRSASportsparticipantsInmatesincorrectionalfacilitiesMilitaryrecruitsChildrenindaycareNativeAmericans,AlaskanNatives,PacificIslandersMenwhohavesexwithmenHurricaneevacueesinsheltersFoalwatchersRuralcrystalmethamphetamineusersCommunity-Associated
MRSASpor84FirstOutbreaksofCA-MRSAAustralia(1993)UdoEEetal.Geneticanalysisofcommunityisolatesofmethicillin-resistantStaphylococcusaureusinWesternAustralia.J.Hosp.Infect.1993US(1999)CDC.Fourpediatricdeathsfromcommunity-acquiredmethicillin-resistantStaphylococcusaureus—MinnesotaandNorthDakota,MMWR1999Canada(2000)MulveyMRetal.Community-associatedMethicillin-resistantStaphylococcusaureus,CanadaEID2005Worldwide(2000)VandeneschFetal.Community-AcquiredMethicillin-ResistantStaphylococcusaureusCarryingPanton-ValentineLeukocidinGenes:WorldwideEmergenceEID2003FirstOutbreaksofCA-MRSAAust85EmergenceofCA-MRSACanadaSimoreAetal.CanadianNosocomialInfectionSurveillanceProgramCMRSA7(USA400)CMRSA10(USA300)EmergenceofCA-MRSACanadaSim86CurrentTreatmentOptionsforCA-MRSAInfectionMoelleringRCCID2008CurrentTreatmentOptionsfor87Community-acquiredantibioticresistanceinurinaryisolatesfromadultwomeninCanada
15%ofE.coliisolatesfromadultwomenresistanttoTMP-SMXFluoroquinolone-resistantEcoliwas7%10%ofEcoliisolateswerefluoroquinolone-resistantinwomenolderthan65yearsofageMcIsaacWJetal.CanJInfectDisMedMicrobiol.2006Community-acquiredantibiotic88Quinolone-resistantNeisseriagonorrhoeaeinfectionsinOntarioIsolatesreferredtotheOPHLbetween2002and2006FQ-Rincreasedfrom4.0%in2002to27.8%in2006FQ-Rstrainsweremoreresistanttopenicillin(p<0.001);tetracycline(p<0.001)anderythromycin(p<0.001)Allisolatesweresusceptibletocefixime,ceftriaxone,azithromycinandspectinomycinOtaKetal.CanMedAssJInPressQuinolone-resistantNeisseria89ControllingantimicrobialresistanceReducingcolonizationandinfectionReducingvolumeofantimicrobialuseWhendecisionmadetotreatUserightdrugRightdoseRightdurationControllingantimicrobialresiControllingantimicrobialresistanceReducinginfectionReducingvolumeofantimicrobialuseWhendecisionmadetotreatUserightdrugRightdoseRightdurationControllingantimicrobialresiTheaverageexcessage-specificnumbersofoutpatientvisitsandcoursesofantibioticsper100childrenperyearNeuzilKMetal.NEJM2000TheEffectofInfluenzaonHospitalizations,OutpatientVisits,andCoursesofAntibioticsinChildrenTheaverageexcessage-specifiControllingantimicrobialresistanceReducingcolonizationandinfectionReducingvolumeofantimicrobialuseWhendecisionmadetotreatUserightdrugRightdoseRightdurationControllingantimicrobialresiRespiratoryInfectionsarethe#1ReasonforOfficeVisitsSource:VerispanPDDA2004Numberofcommonofficevisits(millions)RespiratoryInfectionsaretheNearlyTwo-thirdsofallOralSolidAntibioticPrescriptionsareforSinusitisandBronchitisSource:SDI,FANDxRx.Basedonalltablets/capsuleantibioticsforthe52weeksendingApril6,2005Telithromycin(Ketek®)isindicatedforacuteexacerbationsofchronicbronchitis,acutebacterialsinusitisandmild-to-moderate
community-acquiredpneumoniaNearlyTwo-thirdsofallOralUsageofantibioticsinEuropevs.pneumococcalpenicillinI/R1997Felminghametal.
JAntimicrobChemother2000;45:191–201Carsetal.Lancet2001;357:1851–185338.532.528.826.7241813.58.90102030405060FranceSpa
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