第44章四环素类氯霉素

1Tetracyclinesand

Chloramphenicol

Chapter442objectivesUnderstandthemeaningofbroad-spectrumantibiotics,themechanismofactionandadversereactionsoftetracyclinesandchloramphenicol.Bewareofthemajorsensitivebacteria,drugresistanceandclinicalapplicationsoftheseantibiotics.3broad-spectrumantibiotics:tetracyclinesandchloramphenicolareactiveagainstbothaerobicandanaerobicG+andG-,rickettsia,mycoplasmaandchlamydia.4tetracyclinesNaturaltetracyclinesTetracycline,tetramycin,chlortetracycline,demeclocyclineSemisyntheticaltetracyclinesmetacycline、doxycycline、minocycline5Strutureoftetracyclines6AntibacterialpropertyTheirbasicstructures,activities,antibacterialspectrum,antibacterialmechanismandtherapeuticapplicationsaresimilar.7MechanismofactionTetracyclinesinhibitbacterialproteinsynthesisbybindingtothe30SbacterialribosomeandpreventingaccessofaminoacyltRNA(aa-tRNA)totheacceptor(A)siteonthemRNA-ribosomecomplexbindingtothe30Ssubunitofbacterialribosomeandinhibitingaa-tRNAintoAsite.8P50S亚基30S亚基AminoacidmRNA核糖体移动方向tRNATetracyclinesTargetChloramphenicolTargetA9PharmacokineticsabsorptionOralabsorptionofmosttetracyclinesisplete;Absorptionmostlytakesplaceinthestomachanduppersmallintestineandisgreaterinthefastingstate;Oraldosesofoxycyclineandminocyclinearewellabsorbed(90%to100%)andhavehalf-livesof16to18hours.10PharmacokineticsabsorptionAbsorptionoftetracyclinesisimpairedbytheconcurrentingestionofdairyproducts;aluminumhydroxidegels;calcium,magnesium,andironorzincsalts;andbismuthsubsalicylate.Thedecreasedabsorptionapparentlyresultsfromchelationofdivalentandtrivalentcations.11PharmacokineticsDistributionTetracyclinesdistributewidelythroughoutthebodyandintotissuesandsecretions,includingurineandprostate.Tetracyclinesaredepositedingrowingbonesandteeth,causingstainingandsometimesdentalhypoplasiaandbonedeformities.12Adverseeffect1)GastrointestinaladverseeffectsAlltetracyclinescanproducegastrointestinalirritation,mostcommonlyafteroraladministration2)LiverandkidneytoxicityTetracyclinescanimpairhepaticfunctionandcauserenalinjury.13Adverseeffect3)PhotosensitivityDemeclocycline,doxycycline,andothertetracyclinestoalesserextentmayproducemild-to-severephotosensitivityreactionsintheskinoftreatedindividualsexposedtosunlight.14Adverseeffect4)BoneandteethTeeth:discolorationandenameldysplasiaBone:deformityorgrowthinhibitionTetracyclinesaredepositedintheskeletonorteethinchildrenasthedrugbindtocalcium.15Adverseeffect5)SuperinfectionsMycoticinfectionAntifungaldrugsPseudomembranouscolitisycinandmetronidazole16Resistance(1)decreasedaccumulationoftetracyclineasaresultofeitherdecreasedantibioticinfluxoracquisitionofanenergy-dependenteffluxpathway;(2)productionofaribosomalprotectionproteinthatdisplacestetracyclinefromitstarget,a"protection"thatalsomayoccurbymutation;(3)enzymaticinactivationoftetracyclines.1730S50S30S50S外膜胞质膜细胞内正常情况tertracycline四环素经(T)由外膜蛋白或穿过脂质壁进入细胞tertracycline肽聚糖18外膜胞质膜细胞内抗药性经由需能系统的流出作用移除药物的主动运送系统ProteininducedbyT排出排出肽聚糖tertracycline19tetracyclineAntibacterialproperty：TetracyclineactonG-morepotentlythanonG+.AntibacterialactivitytoG+islessthanβ-lactamanbiotics.AntibacterialactivitytoG-islessthanaminoglycosidesandchloramphenicol.S.typhi,S.paratyphi,P.aeruginosa,M.tuberculosis,virus20TherapeuticapplicationInfectionofRickettsiaInfectionofmycoplasma(mycoplasmapneumonia,infection

of

the

genitourinary

system）Infectionofchlamydia（psittacosis,trachomaandLymphogranulomaVenereum

）andsomespirochetes（recurrentfever）Plague,brucellosis,cholera,digestibilitycankercausedbyHelicobacterpylori,

groingranulomacausedbygranulomabacilli21SemisyntheticaltetracyclinesDoxycyclineandminocyclineAlmostcompletelyabsorbedLong-acting:t1/2>14hHigheractivitythantetracyclineEffectiveagainsttetracycline-resistantbacteriaLowtoxicityMinocycline:thestrongestactivity/vestibulardisturbance22DoxycyclineTheAntibacterialspectrumisthesametotetracycline.Theeffectisstrongerthantetracycline.ResistantStaphylococcusaureustotetracyclineoroxytetracyclineisstillsensitivetodoxycylineCross-resistance

23ClinicalapplicationDoxycylineisthefirstchoiceoftetracyclines.Itsclinicalapplicationisthesametotetracycline.ItisspeciallyadaptedfortheinfectionofBiliarysystemorpanyingtorenalfailure.24chloramphenicol25ChloramphenicolItisaantibioticsgeneratedfromvenezuelaStreptothrix.Itcanbegeneratedalotbychemosynthesis.Thefirstsyntheticalantibiotics.ItsL-isomerisusedinclinic.26AntibacterialspectrumBroad-spectrumandbacteriostaticStrongeffecttoG-ItisgermicidetoDiplococcusintracellularisandStreptococcuspneumoniae.TheeffecttoG+isnotasgoodaspenicilinandtetracycline.ItcanrepressRickett’sorganism,chlamydiaandmycoplasma.27MechanismofactionApotentinhibitorofmicrobialproteinsynthesisItactsprimarilybybindingreversiblytothe50ssubunitofthebacterialribosome,andinterfereswithpeptidyltransferaseinthestepofproteinsynthesis.Abacteriostaticantibiotic28P50S亚基30S亚基肽链mRNA核糖体移动方向tRNATetracyclinesTargetChloramphenicolTargetA29ResistanceAlmostallmicroorganismscoulddevelopresistancetochloramphenicol.Theresistanceusuallyiscausedbyaplasmid-encodedacetyltransferasethatinactivatesthedrug.Afterchloramphenicolisacetylated,itfailstobindtobacterialribosomes.30PharmacokineticsLiposolubilityHighconcentrationincerebrospinalfluidMostofthedrugbindingwithglucuronicacidinvivoeliminatebyurine.31AdverseeffectsBonemarrowdisturbancesReversibleanemiaisapparentlydose-relatedandoccursitantlywithperiodoftreatment.Irreversibleaplasticanemiaisidiosyncraticandusuallyfatal,whichisnotrelatedtodoseandtherapy.32GraysyndromeInthenewborn,especiallytheprematurenewborn,forlackofaneffectiveglucuronicacidconjugationmechanism,asyndromeduetoxicityofChloramphenicolaccumulatesinthebaby,causinghypotension,cyanosis(bluecoloringoflips,nailbeds,andskinfromlackofoxygenintheblood.)Adverseeffects33Adverseeffectsothers:superinfection,gastrointestinaladverseeffects(nausea,vomiting,diarrhea),allergicresponse34ClinicalapplicationDuetoitssevereadverseeffects,chloramphenicolisseldomusedinclinic.Itisusedonlywhenthebenefitsoftherapyoutweightherisksofthepotentialtoxicityandtherearenootherantimicrobialagentstoselect.35ClinicalapplicationTyphoidandparatyphoidfeverSeriousrickettsialinfectionsTopicalusefortreatmentofeyeinfectionsBacterialmenigitiscausedbypenicillin-resistantbacteriaorpenicillin-allergicpatients36DrugInteractionsChloramphenicolinhibitshepaticcytochromeP450isozymes(CYPs)andtherebyprolongsthehalf-livesofdrugsthataremetabolizedbythissystem,includingwarfarin,dicumarol,phenytoin,chlorpropamide,antiretroviralproteaseinhibitors,rifabutin,andtolbutamide.Severetoxicityanddeathhaveoccurredbecauseoffailuretorecognizesucheffects.37Tetracyclinesinhibitproteinsynthesistoblockgrowthmicroorganisms.TetracyclinesactonG+organismsmorepotentlythanonG-organisms.ChloramphenicolinhibitsproteinsynthesisinbothaerobicandanaerobicG+andG-organisms.Chloramphenicolisseldomusedinclinicduetoitstoxicitysuchasbonemarrowdisturbances.summary38practiceBonemarrowdisturbancebychloramphenicolisrelatedtodoseandtherapy.Minocyclinehastheabilitytotreatinfectionscausedbytetracyclin-resistanxestrains.FT39QuestionsBothofchloramphenicolandtetracyclinesarebroad-spectrumantibiotics,whataredifferencesbetweentheiranti-bacterialspectra?Whatarethefataladversereactionofchloramphenicol?40Pseudomembranouscoli