抗生素英文课件-Antibiotic-dosage-regimen-based-on-PK-P

AntibioticdosageregimenbasedonPK-PDconceptsandthepossibleminimizationofresistancePLToutainUMR181PhysiopathologieetToxicologieExpérimentalesINRA/ENVTECOLENATIONALEVETERINAIRETOULOUSE24thWorldBuiatricCongress.France.15.October20061WhytooptimizedosageregimenforantibioticsTooptimizeefficacyReducetheemergenceandselectionofresistance2DosageregimenandantibioresistanceThedesignofappropriatedosageregimensmaybethesinglemostimportantcontributionofclinicalpharmacologytotheresistanceproblemSchentag,Annal.Pharm.1996Littleattentionhasbeenfocusedondelineatingthecorrectdrugdosetosuppresstheamplificationoflesssusceptiblemutantbacterialsub-populationsDrusano

etal(2005)3SelectingadosageregimenforaparticularanimalorgroupofanimalsIndividualanimal(orherd)issuesProbabilityof“cure”withoutsideeffectsPublichealthissuesProbabilityforavoidingenrichingaresistantbacterialsubpopulationTheprescribingveterinarianisthestewardofavaluableresourceandmustconsiderbothindividualhealthissuesaswellaspublichealthonesPossibleconflictofinterestbetweenthetwogoals

4WhytooptimizedosageregimenforantibioticsTooptimizeefficacyReducetheemergenceandselectionofresistanceTargetpathogen:efficacyissueNontargetpathogen:humansafetyissueZoonoticbacteria(foodbornepathogens)Commensalflora(resistancegenereservoir)5Biophases&antibiorésistanceG.I.TProximalDistal1-F%Résistance=lackofefficacyRésistance=publichealthconcernTargetbiophaseBugofvetinterestBloodFoodchainEnvironmentalexposureManGutfloraZoonotic(salmonella,campylobactercommensal(enterococcus)F%AB:oralroute6Biophases&antibiorésistanceG.I.TProximalDistalIntestinalsecretionBileRésistance=lackofefficacyRésistance=publichealthconcernBiophaseBugofvetinterestBloodFoodchainEnvironmentalexposureManGutfloraZoonotic(salmonella,campylobactercommensal(enterococcus)SystemicadministrationQuinolonesMacrolidesTétracyclines7PublicHealthConcerns:

HumanpathogenicbacteriaspreadingfromanimalreservoirsCurrentmainconcerns:ResistanceemergingtocommonlyusedempirictherapiesforacuteGItractinfectionsSalmonella

Fluoroquinolone-resistance3rdgen.Cephalosporin-resistanceCampylobacter

Fluoroquinolone-resistanceMacrolide-resistance8EmergenceofquinoloneresistanceinSalmonellatyphimuriumDT104inUKfollowinglicensingoffluoroquinolonesforuseinfoodanimalsStöhr&Wegener,DrugresistanceUpdates,2000,3:207-2099Dosageregimenandresistance:

Epidemiologicalevidences10DosageregimenandpreventionofresistanceManyfactors(e.g.;broadvs.narrowspectrum…)cancontributetothedevelopmentofbacteriaresistancethemostimportantriskfactorisrepeatedexposuretoinappropriateantibioticconcentrations(exposure)dosageregimenshouldminimizethelikelihoodofexposingpathogenstosublethaldruglevels11DrugfactorsinfluencingresistanceRegimenRouteofadministration,dose,intervalofadministration,durationoftreatment12EffectonPenicillinresistanceinpneumococcusisolates(n=465)ofdurationofb-lactamuse,6monthsbeforeswabcollectionNbofdaysofb-lactamuse1-78-14>14Oddratios0.861.52.595%CI0.37-2.020.73-3.061.3-4.82Nasrinetal.BMJ,200213DosageregimenandantibioticresistanceTreatmentswereinitiated7dayspostchallenge(E.coli)andcontinuedfor14daysTreatmentControlLabeluseGradientPulseRotationwithdissimilarantimicrobialsRotationwithsimilarantimicrobialsDosingschemeNoantibioticsApramycin,150g/tonoffeedfor14daysApramycin,50g/tonoffeedfor5days,then100g/tonfor5daysthen150g/tonfor4daysApramycin,150g/tonoffeedfor3days,then3dayswithoutantibiotics,sequencerepeatedthroughoutthe14-dayperiodApramycin,150g/tonoffeedfor5days,thensulfamethazineformulatedfor118g/kgBWindrinkingwaterfor5daysthencarbadox,50g/tonoffeedfor4daysApramycin,150g/tonoffeedfor5days,thengentamicin6.6mg/Lofdrinkingwaterfor5daysthenneomycinformulatedfor22mg/kgBWindrinkingwaterfor4daysMathew,200314Effectof14-dayantibioticdosingregimenonsensitivity(MIC,µg/mL)toapramycinbyE.colirecoveredABdosing daypostchallengeregimen 3 6 10 13 17 31Control(noAB) 4.3 3.9 3.5 3.1 2.3 2.6Label 5.9 41.1 56 49 50 6.6RotationSimilarAB 3.5 4.2 200 182 141 7.6RotationDissimilarAB 2.6 38.8 44 14 14.0 3.8Gradient50,100,150 3.5 3.5 3.5 68.5 109.9 2.8Pulse(3days) 5.2 4.3 3.6 4.0 7.0 3.7Mathew,200315Howtodetermineadosageregimenthatisbothefficaciousandthatminimizestherisktopromoteresistance16Howtofindandconfirmadose(dosageregimen)Dosetitration

AnimalinfectiousmodelClinicaltrialPK/PD17Thedose-titration18Thedose-titration:

experimentalinfectiousmodelSeverenotrepresentativeoftherealworldProphylaxisvs.metaphylaxisvs.curativepowerofthedesigngenerallylowforlargespeciesinfluenceoftheendpoints19Howtofindandconfirmadose(dosageregimen)DosetitrationAnimalinfectiousmodelClinicaltrialPK/PD20Bacteriologicalvsclinicalsuccess:

thepollyannaphenomenon21ThePollyannaphenomenonIfefficacyismeasuredbysymptomaticresponse,drugswithexcellentantibacterialactivitywillappearlessefficaciousthantheyreallyareanddrugswithpoorantibacterialactivitywillappearmoreefficaciousthantheyreallyare.Theclinicalefficacydoesnotalwaysindicatebacteriologicalefficacymakingitdifficulttodistinguishbetweenantimicrobialsonclinicaloutcomesonly22ThePollyannaeffectDiscrepencybetweenclinicalandbacteriologicalresultsEfficacy(%)Merchantetal.Pediatrics1992AntibioticeffectPlaceboeffectBacteriologicalcureClinicalsuccessOtitismedia89%27%74%100%0%20%40%60%80%100%23ThePollyannaeffect

030609000.521664Dose(mg/kg)Response%MortalityBacterialsheddingCeftiofur–oralYanceyetal.1990Am.J.Vet.Res.24EFFICACYOFORALPRADOFLOXACINANDAMOXYCILLIN/CLAVULANATEINCANINECYSTITISANDPROSTATITISTreatmentNumberofdogsClinicalCure(%)ReductionofTotalClinicalScore(%)BacteriologicalcurePradofloxacin8589.396.885.3Amoxicillin/Clavulanate7783.993.448.0*P=0.002DatafromBayerAnimalHealth(VERAFLOXSYMPOSIUM)25ThePollyannaphenomenonTheclinicalefficacydoesnotalwaysindicatebacteriologicalefficacyandagoodclinicalefficacyisnotenoughtovalidateanappropriatedosageregimen26TheroleofantibioticsistoeradicatethecausativeorganismsfromthesiteofinfectionJacobs.Istambul,200127Howtofindandconfirmadose(dosageregimen)DosetitrationAnimalinfectiousmodelClinicaltrialPK/PD28ThemaingoalofaPK/PDtrialinveterinarypharmacologyTobeanalternativetodose-titrationstudiestodiscoveranoptimaldosageregimen29What

isPK/PD?30DosetitrationDoseResponseclinicalBlackboxPK/PDDoseResponsePKPDPlasmaconcentrationBodypathogen31MediumconcentrationTesttubeResponseMICInvitroMICisveryvariablefrompathogentopathogenandshouldbeacknowledgedTheideaatthebackofthePK/PDindicesweretodevelopsurrogatesabletopredictclinicalsuccessbyscalingaPKvariablebytheMICPK/PD:invitro32DosetitrationDoseResponseclinicalBlackboxPK/PDDoseResponsePKPDAplasmaconcentrationvariablescaledbyMICBodypathogen33Dosetitrationvs.PK/PD:theexplicativevariableEffectEffectDoseDOSE(externaldose)EXPOSURE(internaldose)effectAPK/PDSURROGATEAUCAUC/MIC,

ExposurescaledbyMIC34PK/PDindicesasindicatorofantibioticefficacy35Thesurrogates(predictors)ofantibioticefficacyAUC/MIC,T>MIC,Cmax/MIC36PK/PDpredictorsofefficacyMICCmaxConcentrations24hTimeCmax/MICCmax/MIC:aminoglycosidesAUIC=AUCMICAUC/MIC:quinolones,tetracyclines,azithromycins,T>MIC:penicillins,cephalosporins,macrolides,T>CMI37WhytheseindicesaretermedPK/PDAUIC#=

AUCCMIDose/ClearanceCMI50(90)PKPDDualdosageregimenadaptation38RelationshipbetweendoseandPK/PDpredictorsofefficacyBreakpointvaluee.g.125PDPKFreefractionBioavailability39Whyplasmaconcentration

ThesiteofinfectionUpdate:22July202340Onlythefree(non-bound)fraction(concentration)ofthedrugcaninteractwithbacterialreceptorsOnlytheconcentrationoffreedrugthatisofconcernforitsPK/PDrelationship41MICisareasonableapproximateoftheconcentrationoffreedrugneededatthesiteofinfection42Mostinfectionsofinterestarelocatedextra-cellularlyanddirectcomparisonstototaltissueconcentrationwithPDparametersaremeaninglessCars,199143WherearelocatedthepathogensECFMostbacteriaofclinicalinterest-respiratoryinfection-woundinfection-digestivetractinf.Cell(inphagocyticcellmostoften)Legionnella

sppmycoplasma(some)chlamydiaeBrucellaCryptosporidiosisListeria

monocytogeneSalmonellaMycobacteriaMeningococciRhodococcusequi44Whenthereisnobarriertopenetration,theleveloffreedruginserumisanadequatesurrogatemarkerforbiophaseconcentrationCars,199145PlasmaInterstitial

fluidCellSurrogatemarker(T>MIC,AUIC,Cmax/MIC)Biophaseformost

bacteriaofveterinary

therapeutical

interestBiophaseforfacultativeandobligatory

intracellular

pathogensTotalconcentrationMannhemia,PasteurellaHaemophilus,Streptococcus,Staphylococcus,Coli,KlebsiellaBoundFBoundFCytosol(Listeria,Shigella)Phagosome(Chlamydiae)Phagolysosome(S.aureus,Brucella,Salmonella)ObligatoryorfacultativebacteriaBBrain,retina,prostateEffluxpumpBCellmembraneTissularbarrierBBBarrier,effluxpumpFBoundFPorous

capillarieslipophilicityBoundBBF46TissueconcentrationsAccordingtoEMEA"unreliableinformationisgeneratedfromassaysofdrugconcentrationsinwholetissues(e.g.homogenates)"EMEA200047MagnitudeofPK/PDparameterrequiredforefficacyIstambul,200148RelationshipBetweenT>MICandEfficacyforCarbapenems(Red),Penicillins(Aqua)andCephalosporins(Yellow)49RelationshipbetweenPK/PDparametersandefficacyforcefotaximeagainstKlebsiellapneumoniaeinapneumoniamodel310301003001000300024hAUC/MICratio5678910020406080100TimeaboveMIC(%)5678910R²=94%PeakMICratio01110100100010000Log10CFUperlungat24hCraigCID,1998567891050Efficacyindex:clinicalvalidationFreeserumconcentrationneedtoexceedtheMICofthepathogenfor40-50%ofthedosingintervaltoobtainbacteriologicalcurein80%ofpatientsBacteriologicalcureversustimeaboveMICinotitismedia(fromCraigandAndes1996)S.pneumoniaePenicillincephalosporinsH.influenzaePenicillincephalosporinsTimeaboveMIC(%)Bacteriologiccure(%)10050005010051PK/PDparameters:-lactamsTimeaboveMICistheimportantparameterdeterminingefficacyofthe-lactamsT>MICrequiredforstaticdosevaryfrom25-40%ofdosingintervalforpenicillinsandcephalosporins.Freedrug

levelsofpenicillinsand

cephalosporinsneedtoexceedtheMICfor40-50%ofthedosingintervaltoproducemaximumsurvivalGraig52BetalactamGoal:tomaximizethedurationofexposureoverwhichfreedruglevelsinbiophaseexceedtheMICnofurthersignificantreductioninbacteriacountwhenconcentrationexceed4MIC53Comparisonofrelationshipsbetween24-hrAUC/MICandefficacyagainstPneumococciforfluoroquinolonesinanimalsandpatientsPatientswithCAPandAECB58patientsenrolledinacomparativetrialoflevofloxacinvs.gatifloxacinFree-drug24-hrAUC/MIC<33.7,theprobabilityofamicrobiologiccurewas64%Free-drug24-hrAUC/MIC>33.7,theprobabilityofamicrobiologiccurewas100%Andes&CraigInt.J.Antimicrob.Agents,2002,19:25954AUIC=125hasaconsensusdescriptorofantibioticactionRoughlyspeakingAUIC=125hisequivalenttosaythatthemeanconcentrationshouldbe5timestheMICover80%ofthedosageinterval(24h)Schentagetal.199055Efficacyindex:clinicalvalidation246810126080100RelationshipbetweenthemaximalpeakplasmaleveltoMICratioandtherateofclinicalresponsein236patientswithGram-negativebacterialinfectionstreatedwithaminoglycosides(gentamicin,tobramycin,amikacin)Mooretal.1984J.Infect.Dis.Maximumpeak/MICratioResponserate(%)56ModerninterestsinpharmacodynamicsEstablishthePK/PDtargetrequiredforeffectiveantimicrobialtherapyIdentifywhichPK/PDparameter(T>MIC,AUC/MIC,peak/MIC)bestpredictsinvivoantimicrobialactivityDeterminethemagnitudeofthePK/PDparameterrequiredforinvivoefficacy(staticeffect,1or2logkill)Defineresistanceforthosesituationswhereonecannotattainthetargetrequiredforefficacy57MagnitudeofPK/PDparameterrequiredforefficacy:

thecaseofquinolonesforcalf58Bacterialgrowthinserumcontainingdanofloxacinforincubationperiodsof0.25to6hLogcfu/ml00.020.040.060.080.120.160.200.240.280.321.E+001.E+031.E+061.E+090123456Incubationtime(h)P.LeesConc.59SigmoidalEmaxrelationshipforbacterialcountvsexvivoAUIC24hingoat1serumP.Lees-7-6-5-4-3-2-101050100150200250300AUIC24hObservedPredictedBacteriostaticAUIC24h=18hBactericidalAUIC24h=39hEliminationAUIC24h=90hLogcfu/mldifference60ExvivoAUC24h/MIC(h)valuesfordanofloxacinandmarbofloxacinincalfserumParameter Danofloxacin MarbofloxacinBacteriostatic 15.9±2.0 37.3±6.9Bactericidal 18.1±1.9 46.5±6.8Elimination 33.5±3.5 119.6±10.9Slope 17.3±4.2 11.5±3.3Valuesaremean±sem(n=6)P.Lees61PK/PDindices

DeterminationofbreakpointvaluesTooptimizeefficacyTominimizeresistanceUpdate:17/05/200462EffectivenessofPK/PDindicesaspredictorforthedevelopmentofantimicrobialresistance63ThereisevidencethatthelikelihoodfortheselectionofbacteriawithmutationconferringresistancecanbepredictedonbasisofPK/PDrelationship64Impactofdosageregimenontheemergenceofresistance:

Experimentalevidences65AUICandbacterialeradicationNosocomialpneumoniatreatedwithIVciprofloxacinAUICwashighlypredictiveoftimetobacterialeradication

IfAUIC>250h/day:

eradicationoforganismonday1oftherapygoodtargetfornosocomialpneumoniaandcompromisedhostdefense1005004812Daysafterstartoftherapy%patientsremainingculturepositiveSchentagSymposium,1999AUIC<125AUIC125-250AUIC>25066Suboptimalantibioticdosageasariskfactorforselectionofpenicillin-resistantStreptococcuspneumoniae:invitrokineticmodelOdenholtetal.(2003)AntimicrobialAgentsand

Chemotherapy,47:518-52367Material

and

Methods

MixedcultureofStretococcus

pneumoniaecontainingca.90%susceptible,9%intermediateand1%resistantbacteriaInvitrokineticmodelExposuretoPenicillin:T>MICvariedfromS=46to100%I=6to100%R=0to48%Odenholt,200368SelectionbypenicillinofresistantbacteriainamixedpopulationofS.pneumoniae:controlAOdenholt,200369SelectionbypenicillinofresistantbacteriainamixedpopulationofS.pneumoniaeBOdenholt,200370SelectionbypenicillinofresistantbacteriainamixedpopulationofS.pneumoniaeCOdenholt,200371SelectionbypenicillinofresistantbacteriainamixedpopulationofS.pneumoniaeDOdenholt,200372SelectionbypenicillinofresistantbacteriainamixedpopulationofS.pneumoniaeEOdenholt,200373SelectionbypenicillinofresistantbacteriainamixedpopulationofS.pneumoniaeFOdenholt,200374OptimisationofMeropenemminimumconcentration/MICratiotosuppressinvitroresistanceofPseudomonasaeruginosaDeterminedbactericidalactivityofMeropenemandabilitytosuppressP.aeruginosaresistanceInvitrohollowfibreinfectionmodel(HFIM)inoculatedwithdenseinoculum(1x108cfu/mL)andsubjectedtovariousMeropenemexposuresover5days

Dosesadministeredevery8htoachievethesameCmaxbutescalatingunboundCminconcentrationsTam,V.H.etal(2005)Antimicrob.Agents

Chemother.49,492075OptimisationofMeropenemminimumconcentration/micratiotosuppressinvitroresistanceofPseudomonasaeruginosaPlaceboT>MIC84%T>MIC100%&Cmin/MIC=1.7T>MIC100%&Cmin/MIC=6T>MIC100%&Cmin/MIC=10T>MIC100%&Cmin/MIC=1.7+tobramycin01234512840Time(days)Log10cfu/mL01234510840Time(days)Log10cfu/mL0510840Log10cfu/mLTime(days)2341012345108406201234510840620123451084062Time(days)Time(days)Time(days)Log10cfu/mLLog10cfu/mLLog10cfu/mL76OptimisationofMeropenemminimumconcentration/MICratiotosuppressinvitroresistanceofpseudomonasaeruginosa

resultsResistanceemergedwhen(a)T>MIC=84%(b)T>MIC=100%andCmin/MIC=1.7Resistanceavoidancewhen(a)T>MIC=100%andCmin/MIC=6.0or(b)T>MIC=100%andCmin/MIC=1.7plustobramycin77OptimisationofMeropenemminimumconcentration/MICratiotosuppressinvitroresistanceofPseudomonasaeruginosa

conclusionsBreakpointtopreventresistancedifferentofthoseselectedforclinicalefficacyBecauseoftheceilingeffectforT>MICthisvariablemaynotbesatisfactorywhenthebreakpointexceeds100%Cmin/MICofMeropenemcanbeoptimizedtosuppresstheemergenceofnon-plasmid-mediatedPaeruginosaresistanceMeropenemexposurenecessarytoavoidresistancemaynotbeachievablewithconventionaldosesNOTE:Theexperimentalconditionsrepresentaveryconservativesituationinaclinicalsetting(neutropeniaandhighbacterialburden)78Surrogateindicesandemergenceofresistance:Ceftizoxime

invivoInvivo

murinestudyusingmixedinfectionmodelrelatedmutationfrequencytoT>MIC(aspercentageofdosinginterval)forceftizoximeNoresistancewhenT>MICwas<40%or=100%MutationfrequencyverylowwhenT>MIC87%PeakmutationfrequencyforT>MIC=70%ForoptimalefficacytheusualvaluequotedisT>MIC=40-60%Stearne

etal(2002)79PredictivevalueofPK/PDindicesforemergenceofresistance:

timedependentantibioticT>MICshouldbe40-60%ofthedosingintervalforclinicalefficacyBUTPlasmaconcentrationsshouldbe3-4timestheMICtooptimallypreventresistance80T>MICfor40-50%ofthedosinginterval:

Dailydosingvs.long-actingdrugMICBothtreatmentsensureplasmaconcentrationsaboveMICfor50%ofthedosinginterval(1or14days)buttheyarenotequivalentDailyformulationLong-actingdrug/formulation81Impactofdosageregimenontheemergenceofresistance:

Experimentalevidencesforquinolones82AUIC(AUC/MIC)andbacterialresistanceCiprofloxacinAUICpredictsbacterialresistanceinnosocomial

pneumoniaeAUIC<100=suboptimalResistanceforAUIC<100day %4 5020 93Schentag-Symposium1999No.DaysafterstartoftherapyProbabilityofremainingsusceptibleAUC/MIC>101AUC/MIC<10005101520025507510083PK/PDandresistancedevelopmentDatadrawnfromstudiesoffivedifferenttreatmentregimensfornosocomialpneumoniahavesuggestedthattheprobabilityofselectingforresistantorganismsincreasewhenAUIC<100(ciprofloxacin)EMEA200084Bacterialpopulationresponsestodrugselectivepressure:examinationofGarenoxacin’seffectonPseudomonasaeruginosa(1)DeterminedinfluenceofGarenoxacinonabilitytosuppressG

P.aeruginosaresistanceInvitrohollowfibreinfectionmodelinoculatedwithdenseinoculum(2.4x108cfu/ml)andsubjecttovariousGarenoxacinexposuresof2-3daysDosesadministeredoncedailyover1hperiodtoachieveconstanttargettedCmaxat1,25and49handAUC24/MICratiosof0,10,50,75,100and200h.Tam,V.H.etal.J.Infect.Dis.2005192,42085Bacterialpopulationresponsestodrugselectivepressure:examinationofGarenoxacin’seffectonPseudomonasaeruginosaControlAUC/MIC=48AUC/MIC=108AUC/MIC=10AUC/MIC=89AUC/MIC=20186AUC24/MICratiosused(10to200h)basedonsteadystatekineticsofunboundgarenoxacininhumansMICofresistantmutantsat48h4-16xgreaterthanwildtypeReplacementof(a)majorityofsusceptibleorganismsbyresistantmutantswhenAUC/MIC=10,48and89h(b)allsusceptibleorganismsbymutantswhenAUC/MIC=108and137hNoincreaseinresistantmutantswhenAUC/MIC=201hModellingdatagaveAUC24/MICratioof190htoavoidamplificationofresistantsub-populations

Theresistancesuppressionbreakpoint

Bacterialpopulationresponsestodrugselectivepressure:examinationofgarenoxacin’seffectonPseudomonasaeruginosa(2)87Invitromodeltosimulatehumanpharmacokineticsof4fluoroquinolones(monoexponentialdecline)Inoculumof108cfu/mlCmax (a)=MIC

(b)>MIC<MPC(withinMSW) (c)>MPCResultingAUC24/MICvalues=13to244hDeterminationofMICat0and72hAbsenceofWBCsFirsov

etal.(2003)Antimicrob.Agents

Chemother.47,1604.InvitropharmacodynamicevaluationofthemutantselectionwindowhypothesisusingfourfluoroquinolonesagainstStaph.aureus88TheMPChypothesisfor4QuinolonesagainstSaureusAsatestofthewindowideaFirsovandZinnercarriedoutapharmacodynamicstudyinwhichmoxifloxacinconcentrationwasvariedsothatitwaseitherabove,within,orbelowtheselectionwindowthroughouttreatmentusinganinvitromodelThedynamicmodelcontainedStaphylococcusaureus,andatthetimesindicatedbythearrowsmoxifloxacinwasaddedandsamplesweretakenforanalysis.DeterminationofMICshowedthatresistantmutantswereenrichedonlywhenthemoxifloxacinconcentrationwasinsidetheselectionwindowforatleast20%ofthetime.89Firsov

etal(2003).Antimicrob.AgentsChemother.47,1604DRUGSCmaxAUC24/MIC(h)ChangeinMICGatifloxacin&Ciprofloxacin>MIC15to16SlightincreaseMoxifloxacin&LevofloxacinMIC13to17NoneAll4drugs>MIC24to62*GreatestincreaseAll4drugs>MIC107to123SmallincreaseAlldrugs>>MIC201to244**None*ConcentrationswithinMSWovermostofdoseinterval**Concentrations>MPCovermostofdoseintervalTheMPChypothesisfor4QuinolonesagainstSaureus90TheMPChypothesisfor4QuinolonesagainstSaureus

CONCLUSIONSResistantmutantsselectivityenrichedwhenantibioticconcentrationsfallwithinMSWMIC72/MIC0peakatAUC24/MICof43Onlymoxifloxacinmayprotectagainstresistanceatnormalclinicaldoses91PredictivevalueofPK/PDindicesforemergenceofresistance:concentrationdependentantibioticMoreclearlyestablishedthanfortimedependentantibioticsForquinolones,thedevelopmentofresistanceismostlyattributabletotheprimaryresistancepathway(mutation)ConceptsofselectionwindowandAUICareconvergent92ConditionsforcounterselectivedosingtoavoidemergenceofresistanceThetotalorganismburdensubstantiallyexceedstheinverseofthemutationalfrequencytoresistanceThereisahighprobabilityofaresistantclonebeingpresentatbaselineThestepsizeofchangeinMICofthemutatedpopulationisrelativelysmall(<10-fold) Appropriatedosingthenabletosuppresstheparent/sensitivepopulationandalsosufficestoinhibitthemutantsub-populationDrusanoG.L.(2003)CID,36Suppl1.342-35093Cmax/MICandresistanceEnoxacinStaphylococcusaureus,Klebsiellapneumoniae,E.coli,P.aeruginosaCmax=3MIC>99%reductionofinitialinoculousregrowthat24hunlessCmax/MIC>8ifregrowth,MICfortheregrowingbacteriawas4-8foldthatofparentstrainConclusion:therewasselectionofaresistantsubpopulationCmaxcorrelateswithsuppressionofemergenceofresistanceoforganismsBlaseretal.1987Antimicrob.AgentChemother.94PK/PDparametersvs.emergenceofresistanceforfluoroquinolones24-hrAUC/MICP.aeruginosaOtherGNB<100–monotherapy80%100%>100–monotherapy33%10%Combinations11%0%25%12%Thomasetal.AAC,1998,42:521Resistancedeveloped95AUIC>250hBacterialkillingisextremelyfastwitheradicationaveraging1.9daysregardlessthespeciesofbacteriaVeterinaryapplication:one

shot96Whatistheconcentrationneededtopreventmutationand/orselectionofbacteriawithreducedsusceptibility?Beta-lactams:stayalwaysabovethe4xMICAminoglycosides:achieveapeakof8xtheMICatleastFluoroquinolones:AUC/MIC>200andpeak/MIC>897MutantPreventionConcentration(MPC)

andtheSelectionWindow(SW)hypothesis98SelectivePressureMICTimeConcentrationTraditionalexplanationforenrichmentofmutants99TraditionalExplanationforEnrichmentofMutantsPlacingMICnearthelowerboundaryoftheselectionwindowcontradictstraditionalmedicalteachinginwhichresistantmutantsarethoughttobeselectedprimarilywhendrugconcentrationsarebelowMICThisdistinctionisimportantbecausetraditionaldosingrecommendationstoexceedMICarelikelytoplacedrugconcentrationsinsidetheselectionwindowwheretheywillenrichresistantmutantsubpopulations.Whilelowdrugconcentrationsdonotenrichresistantmutants,theydoallowpathogenpopulationexpansion;consequently,lowdrugdosesindirectlyfosterthegenerationofnewmutantsthatwillbeenrichedbysubsequentantimicrobialchallenge100TheselectionwindowhypothesisMutantpreventionconcentration(MPC)(toinhibitgrowthoftheleastsusceptible,singlestepmutant)MICSelectiveconcentration(SC)toblockwild-typebacteriaPlasmaconcentrationsAllbacteriainhibitedGrowthofonlythemostresistantsubpopulationGrowthofallbacteriaMutantSelectionwindow101WithoutantibioticsBlockingGrowthofSingleMutantsForcesCellstoHaveaDoubleMutationtoOvercomeDrugWithantibiotics10-810-810-8Wildpopulation

éradicationsensiblesinglemutant

DoublemutantWildpopsinglemutantpopulationsinglemutantpopulation102Mutantsarenotselected

atconcentrationsbelowMICorabovetheMPC103wildtypesinglemutantdoublemutantfrequency~10-7frequency