-抗微生物藥物(英文)課件

Chapter21:

Antimicrobial

MedicationsImportantPoint:Ifyouarehavingtroubleunderstandinglecturematerial:Tryreadingyourtextbeforeattendinglectures.AntimicrobialChemotherapeutics“Theprognosisforpeoplewithcommondiseasessuchasbacterialpneumoniaandseverestaphylococcalinfectionwasgrimbeforethediscoveryandwidespreadavailabilityofpenicillininthe1940s.”“Physicianswereabletoidentifythecauseofthedisease,buttheyweregenerallyunabletorecommendtreatmentsotherthanbedrest.”EarlyhistoryofAntimicrobialChemotherapeuticAgents:1910:Salvarsan(anarseniccompound)byPaulEhlrich1928:Penicillin(amoldproduct--firstantibioticdiscovered)byAlexanderFleming1932:Sulfanilamide(sulfadrug)byGerhardDomagk1941:PurificationofPenicillinbyErnstChainandHowardFloreypost-WWII:WidespreadavailabilityPenicillinGAntibioticDiscoveryItiseasytoidentifyantibiotic-producingmicroorganism,thehardpartisfindingantibioticsthataresufficientlySelectivelyToxic.Post-microbemodifiedantibioticsarecalledSemisyntheticantibiotics.SelectiveToxicitymeansthattheagentismoretoxicagainstbacteriathanagainst,e.g.,humans.AntimicrobalChemotherapyTermsDistinguishingAntibioticsAntibiotics(aswellassyntheticantimicrobials)differintermsof…Theorganismtheyareorwereisolatedfrom.Theirchemicalstructure.Their(chemo)Therapeuticindex.Bacteriostasisversusbacteriostatic.Theirspectrumofactivity.Their

pharmacokinetics

(tissuedistribution,metabolism,andexcretion).Theirsiteofactioninbacterialcells.Interactionwithotherchemotherapeutics.Potentialforevolutiontoresistance.Mechanismoftoxicitytothehost.Cost.DistinguishingAntibioticsAntibiotics(aswellassyntheticantimicrobials)differintermsof…Theorganismtheyareorwereisolatedfrom.Theirchemicalstructure.Their(chemo)Therapeuticindex.Bacteriostasisversusbacteriostatic.Theirspectrumofactivity.Their

pharmacokinetics

(tissuedistribution,metabolism,andexcretion).Theirsiteofactioninbacterialcells.Interactionwithotherchemotherapeutics.Potentialforevolutiontoresistance.Mechanismoftoxicitytothehost.Cost.AntibioticsSourcesDistinguishingAntibioticsAntibiotics(aswellassyntheticantimicrobials)differintermsof…Theorganismtheyareorwereisolatedfrom.Theirchemicalstructure.Their(chemo)Therapeuticindex.Bacteriostasisversusbacteriostatic.Theirspectrumofactivity.Their

pharmacokinetics

(tissuedistribution,metabolism,andexcretion).Theirsiteofactioninbacterialcells.Interactionwithotherchemotherapeutics.Potentialforevolutiontoresistance.Mechanismoftoxicitytothehost.Cost.FamilyTreeofPenicillinsAntibioticsarechemotherapeuticantimicrobialsthatareisolatedfrommicroorganisms.Compare:“Syntheticdrug.”SomePenicillinDerivativesMethicillin-InducedLysisVancomycinCell-WallSynthesisInhibitorsDistinguishingAntibioticsAntibiotics(aswellassyntheticantimicrobials)differintermsof…Theorganismtheyareorwereisolatedfrom.Theirchemicalstructure.Their(chemo)Therapeuticindex.Bacteriostasisversusbacteriostatic.Theirspectrumofactivity.Their

pharmacokinetics

(tissuedistribution,metabolism,andexcretion).Theirsiteofactioninbacterialcells.Interactionwithotherchemotherapeutics.Potentialforevolutiontoresistance.Mechanismoftoxicitytothehost.Cost.TherapeuticIndexItisrelativelytrivialtoidentifyantibiotics.Thetrickistoidentifyantibioticsthatareselectivelytoxic—harmingthepathogenbutnotthehost.WeemployaconceptcalledtheTherapeuticIndexasameasureofthedegreeofselectivetoxicity.Thetherapeuticindexistheratioofthetoxicdosagetothetherapeuticdosage.Thatis,(Lowestdosetoxictopatient)(Dosenormallyusedfortherapy).Thegreatertheratio(ordifference)ofthesetwonumbers,theeasieritistofindadosagethatkillsthepathogenwithoutharmingthehost.TherapeuticIndexTherapeuticIndexTherapeuticIndex=ToxicDose/TherapeuticDoseDrugDosage(perKgBodyWeight)ToxicTherapeuticToxicTherapeuticToxicTherapeuticSmallRatio(dangerous)ModerateRatioHighRatio(safe)Mostdesirable.DistinguishingAntibioticsAntibiotics(aswellassyntheticantimicrobials)differintermsof…Theorganismtheyareorwereisolatedfrom.Theirchemicalstructure.Their(chemo)Therapeuticindex.Bacteriostaticversusbactericidal.Theirspectrumofactivity.Their

pharmacokinetics

(tissuedistribution,metabolism,andexcretion).Theirsiteofactioninbacterialcells.Interactionwithotherchemotherapeutics.Potentialforevolutiontoresistance.Mechanismoftoxicitytothehost.Cost.Bactericidalagentsoutrightkillbacteria.Bacteriostaticagentsinhibitgrowthbutdon’tkill.Theyrelyonbodydefensestocleartheinfection.Removalofagentresultsinreturnofgrowthofanyremainingbacteria.Bactericidalagentsarepreferableparticularlyifthebodyotherwisehastroubleclearingthebacteria.DistinguishingAntibioticsAntibiotics(aswellassyntheticantimicrobials)differintermsof…Theorganismtheyareorwereisolatedfrom.Theirchemicalstructure.Their(chemo)Therapeuticindex.Bacteriostasisversusbacteriostatic.Theirspectrumofactivity.Their

pharmacokinetics

(tissuedistribution,metabolism,andexcretion).Theirsiteofactioninbacterialcells.Interactionwithotherchemotherapeutics.Potentialforevolutiontoresistance.Mechanismoftoxicitytothehost.Cost.SpectrumofActivityNarrow-SpectrumAntimicrobialWide-SpectrumAntimicrobialSpectrumofActivityWide-SpectrumAntimicrobialBroad-spectrumantibioticsareusefulifonemustbegintreatmentbeforeidentifyingeitherapathogenoritsantibioticsusceptibility.However,broad-spectrumantibioticsaremorelikelytodestroynormalflora,resultinginsuperinfections.

DistinguishingAntibioticsAntibiotics(aswellassyntheticantimicrobials)differintermsof…Theorganismtheyareorwereisolatedfrom.Theirchemicalstructure.Their(chemo)Therapeuticindex.Bacteriostasisversusbacteriostatic.Theirspectrumofactivity.Their

pharmacokinetics

(tissuedistribution,metabolism,andexcretion).Theirsiteofactioninbacterialcells.Interactionwithotherchemotherapeutics.Potentialforevolutiontoresistance.Mechanismoftoxicitytothehost.Cost.Penetrationoftheantibiotictoinfectedtissuesiskindofimportant,andantibioticsdifferinwhereandtowhatdegreetheypenetrate.Anitibioticsdifferintermsofhowthebodymodifiesordestroysthem,e.g.,livervs.kidneys.Ultimately,antibioticsarenotretainedwithinthebodyindefinitely,andthedosageandrateofadministrationallowsabalanceofuptakeandexcretion.Concentrationsatthesiteofactionshouldremainhighthroughoutthetreatmentperiod,thoughnotsohighthatthehostispoisoned.FluctuationofAntibioticLevelswithTimeTimeofingestionofdose#3.DistinguishingAntibioticsAntibiotics(aswellassyntheticantimicrobials)differintermsof…Theorganismtheyareorwereisolatedfrom.Theirchemicalstructure.Their(chemo)Therapeuticindex.Bacteriostasisversusbacteriostatic.Theirspectrumofactivity.Their

pharmacokinetics

(tissuedistribution,metabolism,andexcretion).Theirsiteofactioninbacterialcells.Interactionwithotherchemotherapeutics.Potentialforevolutiontoresistance.Mechanismoftoxicitytothehost.Cost.FindingTargetsDrug-FindingAbilityasFunctionofHost-PathogenSimilarityBacteriaFungi,Helminths,Viruses,#BiochemicalDifferencesfromMammalianHostNumberDrugTargetsorDrugswithHighChemotherapeuticIndexToo-FewGenes&sharehostMetabolismTooBiochemicallysimilarasfellowEukaryotesBasicallytheyareUs!DifferentdomainfromUs!TargetsofAntibacterialDrugsTargetsofAntibacterialDrugsYes,doknowthefiveindicatedsitesofaction.No,donotmemorizethespecificantibioticsfromthisfigure.RibosomalTargetsTetracyclinesTetracyclineDistinguishingAntibioticsAntibiotics(aswellassyntheticantimicrobials)differintermsof…Theorganismtheyareorwereisolatedfrom.Theirchemicalstructure.Their(chemo)Therapeuticindex.Bacteriostasisversusbacteriostatic.Theirspectrumofactivity.Their

pharmacokinetics

(tissuedistribution,metabolism,andexcretion).Theirsiteofactioninbacterialcells.Interactionwithotherchemotherapeutics.Potentialforevolutiontoresistance.Mechanismoftoxicitytothehost.Cost.CombinationofDrugsForantibiotics“A”and“B”usedincombination:Actualkillingrate=A+BAdditiveActualkillingrate>A+BSynergisticActualkillingrate<A+BAntagonisticTypicallybacteriostaticagentsareantagonistictobactericidalagents.Bacteriocidalagentscanbesynergistic(thinkofthelatterasoneantibioticweakensmorebacteriathanitkills,makingthenot-killedbacteriamoresusceptibletoadditionalinsultbythesecondantibiotic).Additivemeansthatthetwo(ormore)antibioticsneitherhindernorhelpeachother’sabilitytokill.Alsorelevanttoratesofmutationtoresistance.CombinationofDrugsForantibiotics“A”and“B”usedincombination:Actualkillingrate=A+BAdditiveActualkillingrate>A+BSynergisticActualkillingrate<A+BAntagonisticTypicallybacteriostaticagentsareantagonistictobactericidalagents.Bacteriocidalagentscanbesynergistic(thinkofthelatterasoneantibioticweakensmorebacteriathanitkills,makingthenot-killedbacteriamoresusceptibletoadditionalinsultbythesecondantibiotic).Additivemeansthatthetwo(ormore)antibioticsneitherhindernorhelpeachother’sabilitytokill.Alsorelevanttoratesofmutationtoresistance.Synergisticmeansgreaterthanthesumoftheparts.Antagonisticmeanslessthanthesumoftheparts.MutationtoResistanceThenumberofresistantbacteriaisdependentontherateofmutationtoresistance.RationalforCombiningDrugsWhatyouwantisarateofmutationtomultipledrugresistancethatislessthanthanthereciprocalofthepathogenpopulationsize(andthensomeaccountingforlackofenvironmentalhomogeneity).ConsequenceofNotCombiningIfthiswerecancerthaneach“bump”wouldrepresenttheendofremission.Inahomogeneouspopulationthiswouldbethelastcancercell/virus/pathogenalive.ConsequenceofNotCombiningSo,hence,multi-druganti-cancerchemotherapyorcombinationtherapyagainstHIVorTB.NotMaintainingCourseObviouslythisisnotwhatyouwanttohappen.DistinguishingAntibioticsAntibiotics(aswellassyntheticantimicrobials)differintermsof…Theorganismtheyareorwereisolatedfrom.Theirchemicalstructure.Their(chemo)Therapeuticindex.Bacteriostasisversusbacteriostatic.Theirspectrumofactivity.Theirpharmacokinetics

(tissuedistribution,metabolism,andexcretion).Theirsiteofactioninbacterialcells.Interactionwithotherchemotherapeutics.Potentialforevolutiontoresistance.Mechanismoftoxicitytothehost.Cost.AcquiredAntibioticResistanceInnateorIntrinsicResistancemeansthattheantibiotictargetssimplyaremissingfromabacterium,e.g.,lackofcellwall=penicillinresistance.Alternativelythereexistanumberofnon-intrinsic(acquired)mechanismsthatcanleadtoantibioticresistance.AcquiredAntibioticResistanceAcquiredresistancecanoccurbyalterationoftargetbychromosomalmutation.Oracquisitiononplasmidencodingresistancegenes.ResistanceinSimplerTerms…BABy-passAlteredtargetEffluxImpermeabilityInactivationChromosomalvs.RPlasmidEncodedBABy-passAlteredtargetEffluxImpermeabilityInactivationChromosomalmutationRplasmidRplasmidDistinguishingAntibioticsAntibiotics(aswellassyntheticantimicrobials)differintermsof…Theorganismtheyareorwereisolatedfrom.Theirchemicalstructure.Their(chemo)Therapeuticindex.Bacteriostasisversusbacteriostatic