大环内酯类药物

Chapter38Macrolides,LincomycinsandPolymycins大环内酯类药物14元大环内酯类：红霉素、罗红霉素、克拉霉素、地红霉素15元大环内酯类：阿奇霉素16元大环内酯类：螺旋霉素、乙酰螺旋霉素、麦迪霉素、麦白霉素、罗他霉素、柱晶白霉素、交沙霉素、米欧卡霉素MacrolidesFirstgeneration：1950’s—erythromycinSecondgeneration：1970’s—claithromycinazithromycinThirdgeneration：CommonpropertiesofMacrolidesAntibacterialactivityFirstgenerationMostG+organisms:pneumococci,streptococci,staphylococci,diphtheriaeetcPartG-organisms:legionella（军团菌）,bacilluspertussis(百日咳),brucella(布氏)etcOthers:mycoplasma(支原体),chlamydiatrachomatis(沙眼衣原体),rickettsia(立克次体),spirochete,anaerobesetc.SecondgenerationMoreactiveonG-organismsMechanismofactionTarget50sribosomalRNAMechanisminhibitionoftranslocationofmRNAMechanismofresistanceProductionofinactivatingenzymesModificationoftheribosomalbindingsiteActiveeffluxsystemMLSRPharmokineticsAbsorptionErythromycin:notstableatacidpHNewmacrolides:stablepoDistributionMetabolism:Erythromycin&clarithromycin:inliverExcretionErythromycin&azithromycin:bileClarithromycin:kidneyCommomlyusedmacrolidesErythromycinAntimicrobialactivityGram-positiveorganisms:pneumococci,streptococci,staphylococci,diphtheriaeetcGram-negativeorganisms:legionella（军团菌）,bacilluspertussis(百日咳),brucella(布氏),meningococci,diplococcusgonorrhoeaeetcOthers:mycoplasma(支原体),chlamydiatrachomatis(沙眼衣原体),rickettsia(立克次体),spirochete,anaerobesetc.ErythromycinClinicalusesAspenicillinsubstituteinpenicillin-allergicorresistantpatientswithinfectionscausedbystaphylococci,streptococciandpneumococciPertussis，diphtheriaeLegionellaandmycoplasmapneumoniaH.pinfectionErythromycinAdversereactionsGastrointestinaleffectsLivertoxicityCardiotoxicityErythromycinErythromycinlactobionate(乳糖酸红霉素）erythromycinestolate（无味红霉素)erythromycinstearate(硬脂酸红霉素）erythromycinethylsuccinate（琥乙红霉素，利君沙）NewmacrolidesantibioticsAdvantage:Broaderspectrum,higheractivityOrallyeffectiveHighbloodconcentrationLongert1/2LesstoxicityMainlyusedinrespiratorytractinfectionClarithromycin（甲红霉素,克拉霉素）HasthestrongestactivityonGram-positivebacteria,legionellapneumophila,chlamydiapneumoniaeandH.pGoodpharmacokineticpropertyLowtoxicityAzithromycin(阿齐霉素,丽珠奇乐）Hasthestrongestactivityagainstmycoplasmapneumoniae（肺炎支原体）MoreeffectiveonGram-negativebacteriaWelltoleratedT1/2:35~48honcedailyMainlyusedinrespitorytractinfectionRoxithromycin（罗红霉素，严迪）1987FranceThehighestbloodconcentrationF72%~85%RespiratorytractinfectionandsofttissueinfectionLowadverseeffectsLincomycinandClindamycinAntimicrobialactivityGram-positiveorganismsBacteroidefragilisandotheranaerobesMechanismBindingto50sribosomesubunitandinhibitingproteinsynthesisPharmacokineticsAbsorbedwellPenetratewellintomosttissuesincludingboneClindaycinClinicalusesSevereanaerobicinfectionAcuteorchronicalsuppurativeosteomylitis,arthritiscausedbysusceptiveorganismsespeciallyStaphylococciaureusAdversereactionsGastrointestinaleffects:severediarrheaandpseudomembranousenterocolitiscausedbyClostridiumdifficile:vancomycin&metronidazoleOther:Impairedliverfunction,neutropeniaPolypeptideantibioticsVancomycin&TeicoplaninPolymyxinsbactitracinVancomycinMechanismofactionInhibitcellwallsynthesisAntimicrobialspectrum:Narrowspectrum,activeonlyagainstgram-positivebacteriapaticularlystaphylococciPharmacokineticsPoorlyabsorbedfromintestinaltract,ivExcretedfromglomerularfiltration90%VancomycinClinicalusesInfectioncausedbyMRSA,MRSEandpenicillin-resistantpneumococcusTreatmentofantibiotic-associatedenterocolitiscausedbyclostridiumdifficilepoAdversereactionOtotoxicity&nephrotoxicityRed-mansyndromeTeicoplaninSimilartovancomycininmechanismandantimicrobialspectrumCanbegivenimaswellasivLessadversereactionsPolymyxinsActiveonlyagainstgram-negativerods,particularlyP.aeruginosaMechanism:increasepermeabilityofcellmembraneMainlyusedinP.aeruginosainfectionwhenotherdrugsareresistantToxicity:nephrotoxicity&neurotoxicityBaciteracinActiveagainstgram-positivebacteriaInhibitcellwallformationNocross-resistancewithotheragentsTopicaluseonlybecauseofnephrotoxicity