抗微生物药物（英文PPT）Antimicrobial Agents.ppt 126页

AntimicrobialAgentsMartinVotavaOlgaKroftová OverviewIfbacteriamakeitpastourimmunesystemandstartreproducinginsideourbodies,theycausedisease.Certainbacteriaproducechemicalsthatdamageordisablepartsofourbodies.Antibioticsworktokillbacteria.Antibioticsarespecifictocertainbacteriaanddisrupttheirfunction. WhatisanAntibiotic?Anantibioticisaselectivepoison.Ithasbeenchosensothatitwillkillthedesiredbacteria,butnotthecellsinyourbody.Eachdifferenttypeofantibioticaffectsdifferentbacteriaindifferentways.Forexample,anantibioticmightinhibitabacteria"sabilitytoturnglucoseintoenergy,orthebacteria"sabilitytoconstructitscellwall.Thereforethebacteriadiesinsteadofreproducing. AntibioticsSubstancesproducedbyvariousspeciesofmicroorganisms:bacteria,fungi,actinomycetes-tosuppressthegrowthofothermicroorganismsandtodestroythem.TodaythetermATBextendstoincludesyntheticantibacterialagents:sulfonamidesandquinolones. HistoryTheGermanchemistPaulEhrlichdevelopedtheideaofselectivetoxicity:thatcertainchemicalsthatwouldbetoxictosomeorganisms,e.g.,infectiousbacteria,wouldbeharmlesstootherorganisms,e.g.,humans.In1928,SirAlexanderFleming,aScottishbiologist,observedthatPenicilliumnotatum,acommonmold,haddestroyedstaphylococcusbacteriainculture. SirAlexanderFleming Fleming’sPetriDish ZoneofInhibitionAroundthefungalcolonyisaclearzonewherenobacteriaaregrowingZoneofinhibitionduetothediffusionofasubstancewithantibioticpropertiesfromthefungus HistoryPenicillinwasisolatedin1939,andin1944SelmanWaksmanandAlbertSchatz,Americanmicrobiologists,isolatedstreptomycinandanumberofotherantibioticsfromStreptomycesgriseus. Susceptibilityvs.ResistanceofmicroorganismstoAntimicrobialAgentsSuccessoftherapeuticoutcomedependson:AchievingconcentrationofATBatthesiteofinfectionthatissufficienttoinhibitbacterialgrowth.Hostdefensesmaximallyeffective–MIeffectissufficient–bacteriostaticagents(slowproteinsynthesis,preventbacterialdivision)Hostdefensesimpaired-bactericidalagentsCompleteATB-mediatedkillingisnecessary Susceptibilityvs.Resistance(cont.)Doseofdrughastobesufficienttoproduceeffectinhibitorkillthemicroorganism:Howeverconcentrationofthedrugmustremainbelowthosethataretoxictohumancells–Ifcanbeachieved–microorganismsusceptibletotheATBIfeffectiveconcentrationishigherthantoxic-microorganismisresistant Susceptibilityvs.Resistance(cont.)LimitationofinvitrotestsInvitrosensitivitytestsarebasedonnon-toxicplasmaconcentrations–cutoffDonotreflectconcentrationatthesiteofinfectionE.g.:G-aer.bacillilikePs.aeruginosainhibitedby2–4ug/mlofgentamycinortobramycin.Susceptible!? AntibioticSusceptibilityTesting84021Tetracycline(μg/ml)MIC=2μg/mlDeterminationofMICChlAmpEryStrTetDiskDiffusionTest Susceptibilityvs.Resistance(cont.)Plasmaconcentrationabove6-10ug/mlmayresultinototoxicityornephrotoxicityRationoftoxictotherapeuticconcentrationisverylow–agentsdifficulttouse.Concentrationincertaincompartments–vitreousfluidorcerebrospinalfluidmuchlowerthanthoseinplasma.Thereforecanbeonlymarginallyeffectiveorineffectiveeventhoseinvitroteststatessensitive. Susceptibilityvs.Resistance(cont.)Thereforecanbeonlymarginallyeffectiveorineffectiveeventhoseinvitroteststates„sensitive“.Conversely–concentrationofdruginurinemaybemuchhigherthaninplasma,so„resistant“agentscanbeeffectiveininfectionlimitedtourinetract ResistanceTobeeffectiveATBmustreachthetargetandbindtoit.Resistance:FailuretoreachthetargetThedrugisinactivatedThetargetisaltered Resistance(cont.)Bacteriaproduceenzymesatorwithinthecellsurface–inactivatedrugBacteriapossessimpermeablecellmembranepreventinfluxofdrug.Transportmechanismforcertaindrugisenergydependent-noteffectiveinanaerobicenvironment.ATBasorganicacidspenetrationispH–dependent. Resistance(cont.)Acquiredbymutationandpassedverticallybyselectiontodaughtercells.Morecommonly–horizontaltransferofresistancedeterminantfromdonorcell,oftenanotherbacterialspecies,bytransformation,transduction,orconjugation.HorizontaltransfercanberapidlydisseminatedByclonalspreadorresistantstrainitselfOrgeneticexchangebetweenresistantandfurthersusceptiblestrains. Resistance(cont.)MethicilinresistantstrainsofStaphylococcusaureusclonallyderivedfromfewancestralstrainswithmecAgeneEncodeslow-affinitypenicillin-bindingproteinthatconfersmethicillinresistance.Staphylococcalbeta-lactamasegene,whichisplasmidencoded,presumamblytransferredonnumerousoccasions.Becauseiswidelydistributedamongunrelatedstrains,identifiedalsoinenterococci SelectionoftheATBRequiresclinicaljudgment,detailedknowledgeofpharmacologicalandmicrobiologicalfactors.Empiricaltherapy–initial–infectingorganismnotidentified–singlebroadspectrumagentDefinitivetherapy-microorganismidentified–anarrow–spectrumlowtoxicityregimenttocompletethecourseoftreatment EmpiricalandDefiniteTherapyKnowledgeofthemostlikelyinfectingmicroorganismanditssusceptibilityGramstainPendingisolationandidentificationofthepathogenSpecimenforculturefromsiteofinfectionshouldbeobtainbeforeinitiationoftherapyDefinitetherapy PenicillinsPenicillinscontainab-lactamringwhichinhibitstheformationofpeptidoglycancrosslinksinbacterialcellwalls(especiallyinGram-possitiveorganisms)PenicillinsarebactericidalbutcanactonlyondividingcellsTheyarenottoxictoanimalcellswhichhavenocellwall SynthesisofPenicillinb-Lactamsproducedbyfungi,someascomycetes,andseveralactinomycetebacteriab-Lactamsaresynthesizedfromaminoacidsvalineandcysteine bLactamBasicStructure Penicillins(cont.)ClinicalPharmacokineticsPenicillinsarepoorlylipidsolubleanddonotcrosstheblood-brainbarrierinappreciableconcentrationsunlessitisinflamed(sotheyareeffectiveinmeningitis)Theyareactivelyexcretedunchangedbythekidney,butthedoseshouldbereducedinsevererenalfailure Penicillins(cont.)ResistanceThisistheresultofproductionofb-lactamaseinthebacteriawhichdestroystheb-lactamringItoccursine.g.Staphylococcusaureus,HaemophilusinfluenzaeandNeisseriagonorrhoea Penicillins(cont.)ExamplesTherearenowawidevarietyofpenicillins,whichmaybeacidlabile(i.e.brokendownbythestomachacidandsoinactivewhengivenorally)oracidstable,ormaybenarroworbroadspectruminaction Penicillins(cont.)ExamplesBenzylpenicillin(PenicillinG)isacidlabileandb-lactamasesensitiveandisgivenonlyparenterallyItisthemostpotentpenicillinbuthasarelativelynarrowspectrumcoveringStrepptococcuspyogenes,S.pneumoniae,NeisseriameningitisorN.gonorrhoeae,treponemes,Listeria,Actinomycetes,Clostridia Penicillins(cont.)ExamplesPhenoxymethylpenicillin(PenicillinV)isacidstableandisgivenorallyforminorinfectionsitisotherwisesimilartobenzylpenicillin Penicillins(cont.)ExamplesAmpicillinislessactivethanbenzylpenicillinagainstGram-possitivebacteriabuthasawiderspectrumincluding(inadditioninthoseabove)Strept.faecalis,Haemophilusinfluenza,andsomeE.coli,KlebsiellaandProteusstrainsItisacidstable,isgivenorallyorparenterally,butisb-laclamasesensitive Penicillins(cont.)ExamplesAmoxycillinissimilarbutbetterabsorbedorallyItissometimescombinedwithclavulanicacid,whichisab-lactamwithlittleantibacterialeffectbutwhichbindsstronglytob-lactamaseandblockstheactionofb-lactamaseinthiswayItextendsthespectrumofamoxycillin Penicillins(cont.)ExamplesFlucloxacillinisacidstableandisgivenorallyorparenterallyItisb-lactamaseresistantItisusedasanarrowspectrumdrugforStaphylococcusaureusinfections Penicillins(cont.)ExamplesAzlocillinisacidlabileandisonlyusedparenterallyItisb-lactamasesensitiveandhasabroadspectrum,whichincludesPseudomonasaeruginosaandProteusspeciesItisusedintravenouslyforlife-threateninginfections,i.e.inimmunocompromisedpatientstogetherwithanaminoglycoside Penicillins(cont.)AdverseeffectsAllergy(in0.7%to1.0%patients).PatientshouldbealwaysaskedaboutahistoryofpreviousexposureandadverseeffectsSuperinfections(e.g.causedbyCandida)Diarrhoea:especiallywithampicillin,lesscommonwithamoxycillinRare:haemolysis,nephritis Penicillins(cont.)DruginteractionsTheuseofampicillin(orotherbroad-spectrumantibiotics)maydecreasetheeffectivenessoforalconraceptivesbydiminishingenterohepaticcirculation AntistaphylococcuspenicillinsOxacillin,cloxacillinResistantagainststaphylococcuspenicillinasis CephalosporinsTheyalsoowetheiractivitytob-lactamringandarebactericidal.Goodalternativestopenicillinswhenabroad-spectrumdrugisrequiredshouldnotbeusedasfirstchoiceunlesstheorganismisknowntobesensitive CephalosporinsBACTERICIDAL-modifycellwallsynthesisCLASSIFICATION-firstgenerationareearlycompoundsSecondgeneration-resistanttoβ-lactamasesThirdgeneration-resistanttoβ-lactamases&increasedspectrumofactivityFourthgeneration-increasedspectrumofactivity CephalosporinsFIRSTGENERATION-egcefadroxil,cefalexin,Cefadrine-mostactivevsgram+vecocci.Analternativetopenicillinsforstaphandstrepinfections;usefulinUTIsSECONDGENERATION-egcefaclorandcefuroxime.ActivevsenerobacteriaceaeegE.coli,Klebsiellaspp,proteusspp.MaybeactivevsHinfluenzaeandNmeningtidis CephalosporinsTHIRDGENERATION-egcefiximeandotherI.V.scefotaxime,ceftriaxone,ceftazidine.Verybroadspectrumofactivityincgram-verods,lessactivityvsgram+veorganisms.FOURTHGENERATION-cefpiromebettervsgram+vethan3rdgeneration.Alsobettervsgram-veespenterobacteriaceae&pseudomonasaerugenosa.I.V.routeonly Cephalosporins(cont.)AdverseeffectsAllergy(10-20%ofpatientswitpenicillinallergyarealsoallergictocephalosporins)NephritisandacuterenalfailureSuperinfectionsGastrointestinalupsetswhengivenorally Aminoglycosides(bactericidal)streptomycin,kanamycin,gentamicin,tobramycin,amikacin,netilmicin,neomycin(topical)Modeofaction-Theaminoglycosidesirreversiblybindtothe16SribosomalRNAandfreezethe30Sinitiationcomplex(30S-mRNA-tRNA)sothatnofurtherinitiationcanoccur.TheyalsoslowdownproteinsynthesisthathasalreadyinitiatedandinducemisreadingofthemRNA.Bybindingtothe16Sr-RNAtheaminoglycosidesincreasetheaffinityoftheAsitefort-RNAregardlessoftheanticodonspecificity.Mayalsodestabilizebacterialmembranes.SpectrumofActivity-Manygram-negativeandsomegram-positivebacteriaResistance-CommonSynergy-Theaminoglycosidessynergizewithβ-lactamantibiotics.Theβ-lactamsinhibitcellwallsynthesisandtherebyincreasethepermeabilityoftheaminoglycosides. AminoglycosidesClinicalpharmacokineticsThesearepoorlylipidsolubleand,therefore,notabsorbedorallyParenteraladministrationisrequiredforsystemiceffect.TheydonotentertheCNSevenwhenthemeningesareinflamed.Theyarenotmetabolized. Aminoglycosides(cont.)ClinicalpharmacokineticsTheyareexcretedunchangedbythekidney(wherehighconcentrationmayoccur,perhapscausingtoxictubulardemage)byglomerularfiltration(noactivesecretion).Theirclearanceismarkedlyreducedinrenalimpairmentandtoxicconcentrationsaremorelikely. Aminoglycosides(cont.)ResistanceResistanceresultsfrombacterialenzymeswhichbreakdownaminoglycosidesortotheirdecreasedtransportintothecells. Aminoglycosides(cont.)ExamplesGentamicinisthemostcommonlyused,coveringGram-negativeaerobes,e.g.Entericorganisms(E.coli,Klebsiella,S.faecalis,PseudomonasandProteusspp.)ItisalsousedinantibioticcombinationagainstStaphylococcusaureus.ItisnotactiveagainstaerobicStreptococci. Aminoglycosides(cont.)ExamplesInadditiontotreatingknownsensitiveorganisms,itisusedoftenblindlywithotherantibioticsinsevereinfectionsofunknowncause.Streptomycinwasformerlythemainstayofantituberculoustherapybutisnowrarelyusedinthedevelopedworld. Aminoglycosides(cont.)ExamplesTobramycin:usedforpseudomonasandforsomegentamicin-resistantorganisms.Someaminoglycosides,e.g.Gentamicin,mayalsobeappliedtopicallyforlocaleffect,e.g.Inearandeyeointments.NeomycinisusedorallyfordecontaminationofGItract. Aminoglycosides(cont.)AdverseeffectsAlthougheffective,aminoglycosidesaretoxic,andthisisplasmaconcentrationrelated.Itisessentialtomonitorplasmaconcentrations(shortlybeforeandafteradministrationofadose)toensureadequateconcentrationsforbactericidaleffects,whileminimisingadverseeffects,every2-3days. Aminoglycosides(cont.)AdverseeffectsThemainadverseeffectsare:NephrotoxicityToxictothe8thcranialnerve(ototoxic),especiallythevestibulardivision.Otheradverseeffectsarenotdoserelated,andarerelativelyrare,e.g.Allergies,eosinophilia. Macrolides(bacteriostatic)erythromycin,clarithromycin,azithromycin,spiramycinModeofaction-Themacrolidesinhibittranslocationbybindingto50SribosomalsubunitSpectrumofactivity-Gram-positivebacteria,Mycoplasma,Legionella(intracellularbacterias)Resistance-Common Macrolides(cont.)ExamplesandclinicalpharmacokineticsErythromycinisacidlabilebutisgivenasanentericallycoatedtabletAbsorptioniserraticandpoor.Itisexcretedunchangedinbileandisreabsorbedlowerdownthegastrointestinaltract(enterohepaticcirculation).Itmaybegivenorallyorparenterally Macrolides(cont.)ExamplesandclinicalpharmacokineticsMacrolidesarewidelydistributedinthebodyexcepttothebrainandcerebrospinalfluidThespectrumincludesStaphylococcusaureus,Streptococcusspyogenes,S.pneumoniae,MycoplasmapneumoniaeandChlamydiainfections. Macrolides(cont.)ExamplesandclinicalpharmacokineticsNewermacrolidessuchasclarithromycinandazithromycinmayhavefeweradverseeffects. Macrolides–sideeffectsNauzea,vomitusAllergyHepatitis,ototoxicityInteractionwithcytochromeP4503A4(inhibition) Chloramphenicol,Lincomycin,Clindamycin(bacteriostatic)Modeofaction-Theseantimicrobialsbindtothe50Sribosomeandinhibitpeptidyltransferaseactivity.Spectrumofactivity-Chloramphenicol-Broadrange;Lincomycinandclindamycin-RestrictedrangeResistance-CommonAdverseeffects-Chloramphenicolistoxic(bonemarrowsuppression)butisusedinthetreatmentofbacterialmeningitis. ClindamycinClindamycin,althoughchemicallydistinct,issimilartoerythromycininmodeofactionandspectrum.Itisrapidlyabsorbedandpenetratesmosttissueswell,exceptCNS.ItisparticularlyusefulsystematicallyforS.aureus(e.g.osteomyelitisasitpenetratesbonewell)andanaerobicinfections. ClindamycinAdverseeffectsDiarrhoeaiscommon.SuperinfectionwithastrainofClostridiumdifficilewhichcausesseriousinflammationofthelargebowel(Pseudomembranouscolitis) ChloramphenicolThisinhibitsbacterialproteinsynthesis.Itiswellabsorbedandwidelydistributed,includingtotheCNS.Itismetabolizedbyglucoronidationintheliver.Althoughaneffectivebroad-spectrumantibiotics,itsusesarelimitidbyitsserioustoxicity. Chloramphenicol(cont.)ThemajorindicationistotreatbacterialmeningitiscausedbyHaemophilusinfluenzae,ortoNeisseriamenigitidisoriforganismisunknown.ItisalsospeciallyusedforRikettsia(typhus). Chloramphenicol(cont.)AdverseeffectsArareanemia,probablyimmunologicalinoriginbutoftenfatalReversiblebonemarrowdepressioncausedbyitseffectonproteinsynthesisinhumansLiverenzymeinhibition SulfonamidesandtrimethoprimSulfonamidesarerarelyusedalonetoday.Trimethoprimisnotchemicallyrelatedbutisconsideredherebecausetheirmodesofactionarecomplementary. Sulfonamides,Sulfones(bacteriostatic)Modeofaction-Theseantimicrobialsareanaloguesofpara-aminobenzoicacidandcompetitivelyinhibitformationofdihydropteroicacid.Spectrumofactivity-Broadrangeactivityagainstgram-positiveandgram-negativebacteria;usedprimarilyinurinarytractandNocardiainfections.Resistance-CommonCombinationtherapy-Thesulfonamidesareusedincombinationwithtrimethoprim;thiscombinationblockstwodistinctstepsinfolicacidmetabolismandpreventstheemergenceofresistantstrains. Trimethoprim,Methotrexate,(bacteriostatic)Modeofaction-Theseantimicrobialsbindstodihydrofolatereductaseandinhibitformationoftetrahydrofolicacid.Spectrumofactivity-Broadrangeactivityagainstgram-positiveandgram-negativebacteria;usedprimarilyinurinarytractandNocardiainfections.Resistance-CommonCombinationtherapy-Theseantimicrobialsareusedincombinationwiththesulfonamides;thiscombinationblockstwodistinctstepsinfolicacidmetabolismandpreventstheemergenceofresistantstrains. p-aminobenzoicacid+PteridineDihydropteroicacidDihydrofolicacidTetrahydrofolicacidPteridinesynthetaseDihydrofolatesynthetaseDihydrofolatereductaseThymidinePurinesMethionineTrimethoprimSulfonamides SulfonamidesandtrimethoprimModeofactionFolateismetabolizedbyenzymedihydrofolatereductasetotheactivetetrahydrofolicacid.Trimethopriminhibitsthisenzymeinbacteriaandtoalesserdegreeinanimals,astheanimalenzymeisfarlesssensitivethanthatinbacteria. SulfonamidesandtrimethoprimClinicalpharmacokineticsMostsulfonamidesarewellabsorbedorallyandtheyarewidelydistributedincludingtotheCNS.Mostareexcretedbythekidneyunchanged.TheyareeffectiveagainstGram-positiveandmanyGram-negativeorganismbutarerarelyusedalonenow. SulfonamidesandtrimethoprimClinicalpharmacokineticsTrimethoprimisalsowellabsorbedandexcretedbythekidneys,withsimilarspectrum.Cotrimoxazoleiswidelyusedforurinaryandupperrespiratorytractinfectionsbutshouldnotbethedrugofchoicebecauseofitsadverseeffects. SulfonamidesandtrimethoprimClinicalpharmacokineticsItisthedrugofchoiceforthetreatmentandpreventionofpneumoniacausedbyPneumocystiscariniiinimmunosupressedpatients.Trimethoprimisincreasinglyusedaloneforurinarytractandupperrespiratorytractinfections,asitislesstoxicthanthecombinationandequallyeffective. SulfonamidesandtrimethoprimAdverseeffectsGastrointestinalupsetsLesscommonbutmoreserious:-sulfonamides:allergy,rash,fever,agranulocytosis,renaltoxicity-trimethoprim:macrocytisanemia,thrombocytopenia-cotrimoxazole:aplasticanemia SulfonamidesandtrimethoprimDrugintereactionsSulfonamidescandecreasemetabolismofphenytoin,warfarinandsomeoralhypoglycaemics,increasingtheireffects. Quinolones(bactericidal)nalidixicacid,ciprofloxacin,ofloxacin,norfloxacin,levofloxacin,lomefloxacin,sparfloxacinModeofaction-TheseantimicrobialsbindtotheAsubunitofDNAgyrase(topoisomerase)andpreventsupercoilingofDNA,therebyinhibitingDNAsynthesis.Spectrumofactivity-Gram-positivecocciandurinarytractinfectionsResistance-Commonfornalidixicacid;developingforciprofloxacin QuinolonesThequinolonesareeffectivebutexpensiveantibiotics.Withincreaseduse,resistancetothesedrugsisbecomingmorecommon.Theyshouldingeneralbereversedrugsandnotfirst-linetreatment. Quinolones(cont.)ExamplesandclinicalpharmacokineticsNalidixicacid,thefirstquinolone,isusedasaurinaryantisepticandforlowerurinarytractinfections,asithasnosystemicantibacterialeffect.CiprofloxacinisafluoroquinolonewithabroadspectrumagainstGram-negativebacilliandPseudomonas, Quinolones(cont.)ExamplesandclinicalpharmacokineticsItcanbegivenorallyori.v.totreatawiderangeofinfections,includingrespiratoryandurinarytractinfectionsaswellasmoreseriousinfections,suchasperitonitisandSalmonella.Activityagainstanaerobicorganismispooranditshouldnotbefirstchoiceforrespiratorytractinfections. Quinolones(cont.)AdverseeffectsGastrointestinalupsetsFluoroquinolonesmayblocktheinhibitoryneurotransmitterGABA,andthismaycauseconfusionintheelderlyandlowerthefittingthreshold.Theyarealsocontraindicatedinepileptics.Allergyandanaphylaxis Quinolones(cont.)AdverseeffectsPossiblydamagetogrowingcartilage:notrecommendedforpregnantwomenandchildrenDruginteractionCiprofloxacinisaliverenzymeinhibitorandmaycauselife-threateninginteractionwiththeophylline. Tetracyclines(bacteriostatic)tetracycline,minocyclineanddoxycyclineModeofaction-Thetetracyclinesreversiblybindtothe30Sribosomeandinhibitbindingofaminoacyl-t-RNAtotheacceptorsiteonthe70Sribosome.Spectrumofactivity-Broadspectrum;UsefulagainstintracellularbacteriaResistance-CommonAdverseeffects-Destructionofnormalintestinalfloraresultinginincreasedsecondaryinfections;stainingandimpairmentofthestructureofboneandteeth. Tetracyclines(cont.)ExamplesandclinicalpharmacokineticsTetracycline,oxytetracyclinehaveshorthalf-lives.Doxycyclinehasalongerhalf-lifeandcanbegivenonceperday.Thesedrugsareonlyportlyabsorbed.Theybindavidlytoheavymetalionsandsoabsorptionisgreatlyreducediftakenwithfood,milk,antacidsorirontablets. Tetracyclines(cont.)ExamplesandclinicalpharmacokineticsTheyshouldbetakenatleasthalfanhourbeforefood.Tetracyclinesconcentrateinbonesandteeth.Theyareexcretedmostlyinurine,partlyinbile.Theyarebroadspectrumantibiotics,activeagainstmostbacteriaexceptProteusorPseudomonas. Tetracyclines(cont.)ExamplesandclinicalpharmacokineticsResistanceisfrequent.TheyarespeciallyindicatedforMycoplasma,Rikettsia,ChlamydiaandBrucellainfections.Theirmostcommonusetodayisforacne,giveneitherorallyortopically. Tetracyclines(cont.)AdverseeffectsGastrointestinalupsetsSuperinfectionDiscolourationanddeformityingrowingteethandbones(contraindicatedinpregnancyandinchildren<12years)Renalimpairment(shouldbealsoavoidedinrenaldisease) MetronidazoleMetronidazolebindstoDNAandblocksreplication.PharmacokineticsItiswellabsorbedafteroralorrectaladministrationandcanbealsogiveni.v.Itiswidelydistributedinthebody(includingintoabscesscavities)Itismetabolizedbytheliver. Metronidazole(cont.)UsesMetronidazoleisactiveagainstanaerobicorganisms(e.g.Bacteroides,Clostridia),whichareencounteredparticularlyinabdominalsurgery.ItisalsousedagainstTrichomonas,GiardiaandEntamoebainfectionsandcanbeusedtotreatpseudomembranouscolitis. Metronidazole(cont.)UsesIncreasingly,itisusedaspartoftreatmentofHelicobacterpylorisinfestionofthestomachandduodenumassociatedwithpepticulcerdisease.Itisusedalsototreatavarietyofdentalinfections,particularlydentalabscess. Metronidazole(cont.)AdverseeffectsNausea,anorexiaandmetallictasteAtaxiaInpatients,whodrinkalcohol,mayoccurunpleasantreactions.Theyshouldbeadvisednottodrinkalcoholduringatreatment.Possiblyteratogeniciftakeninthefirsttrimesterofpregnancy NitrofurantoinThisisusedasaurinaryantisepticandtotreatGram-negativeinfectionsinthelowerurinarytract.Itistakenorallyandiswellabsorbedandisexcretedunchangedintheurine.Itonlyexertsitsantimicrobialeffectwhenitisconcentratedintheurineandsohasnosystemicantibacterialeffect. Nitrofurantoin(cont.)Itisineffectiveinrenalfailurebecauseoffailuretoconcentrate.Resistancedevelopsrelativelyquickly. Nitrofurantoin(cont.)AdverseeffectsGastrointestinalupsetsAllergyPolyneuritis FucidinFucidinisactiveonlyagainstStaphylococcusaureus(byinhibitingbacterialproteinsynthesis)andisnotaffectedb-lactamase.Itisusuallyonlyusedwithflucloxacillintoreducethedevelopmentofresistance.Itiswellabsorbedandwidelydistributed,includingtobone Fucidin(cont.)Itcanbegivenorallyorparenterally.Itismetabolizedintheliver.AdverseeffectsGastrointestinalupsetsHepatitisandjaundice VancomycinThisinterfereswithbacterialcellwallformationandisnotabsorbedafteroraladministrationandmustbegivenparenterally.Itisexcretedbythekidney.Itisusedi.v.totreatseriousorresistantStaph.aureusinfectionsandforprophylaxisofendocarditisinpenicillin-allergicpeople. Vancomycin(cont.)Itisgivenorallytotreatpseudomembranouscolitisteicoplaninissimilarbutlesstoxic Vancomycin(cont.)AdverseeffectsItstoxicityissimilartoaminoglycosideandlikewisemonitoringofplasmaconcentrationsisessential.NephrotoxicityOtotoxicityAllergy AntibioticsforleprosyLeprosyiscausedbyinfectionwithMycobacterialeprae.Amixtureofdrugsareusedtotreatleprosy,dependingonthetypeandseverityoftheinfectionandthelocalresistancepatterns. AntibioticsforleprosyRifampicinisusedanddapsone,whichisrelatedtothesulphoamides.Itsadverseeffectsincludehaemolysis,gastrointestinalupsetsandrashes. Chemotherapyforviruses AntiviraldrugsAntiviralchemotherapyisstillinitsinfancy.Virusesaremoredifficult‘targets’thanbacteria:theyaremostvulnerableduringreproduction,butallusehostcellorganellesandenzymestodothis,sothatantiviralcompoundsareoftenastoxictohostcellsastovirus. Antiviraldrugs(cont.)Viruseshaveassumedincreasingimportanceinthesettingofimmunosuppression-bothdruginducedandAIDS. Antiviraldrugs(cont.)Currentantiviraldrugsarethoughttoworkinoneofthefollowingways:-inhibitionofviral‘uncoating’shortlyafterpenetrationintothecell;theyarebestforprophylaxisorveryearlyinthediseasecourse(e.g.amantadine)-interferencewithviralRNAsynthesisandfunction(e.g.ribavirin) Antiviraldrugs(cont.)interferencewithDNAsynthesis(e.g.cytarabine)inhibitionofviralDNApolymerase(e.g.aciclovirandgancyclovir)inhibitionofreversetranscriptaseatretrovirusessuchasHIV(e.g.zidovudine)useofcomplexnaturalantiviraldefencesbyemployinginterferon AciclovirModeofactionItisactiveagainstHerpessimplexandHerpeszoster.Aciclovirtargetsvirus-infectedcellsquitespecifically,andthisexplainsthedrug`srelativelylowtoxicity. Aciclovir(cont.)ClinicalpharmacokineticsThedrugisusedtopically,orallyandi.v.Littledrugisabsorbedfromtopicalformulations,andthebioavailabilityoftheoraldrugislow(about20%).Itiswidelydistributedandcrossestheblood-brainbarrier.Itisexcretedintheurineandinlactatingwomeninthebreastmilk. Aciclovir(cont.)TherapeuticusesItisthedrugoffirstchoiceforHerpessimplexandzosterinfections,becauseofthegreatefficacyandlowertoxicitythanthealternatives.ThedrughaslittleactivityagainstcytomegalovirusorEpstein-Barrvirus. Aciclovir(cont.)TherapeuticusesHerpessimplexinfectionsofskin,mucousmembranesandcorneaLife-threateningHerpessimplexinfections;acicloviri.v.reducesmortalityHerpeszosterthatislesssensitivetoaciclovirthanH.simplex.Itisusedforearlytopicororaltreatmentofzoster;acicloviri.v.isusedforlife-threateningzosterinfectionsaspneumonia Aciclovir(cont.)AdverseeffectsRenalimpairment:mainlyinhighi.v.dosesindehydratedpatientsLocalinflammationfollowingextravascularadministrationEncephalopathy:mainlyinhighi.v.doses Zidovudine(AZT)ModeofactionHIVvirusisanRNAviruscapableofincludingthesynthesisofaDNAtranscriptofitsgenome,whichcanthenbecomeintegratedintothehostcell`sDNA,therebyallowingviralreplication.SynthesisoftheinitialDNAtranscriptinvolvestheenzymereversetranscriptase. Zidovudine(AZT)cont.ModeofactionZidovudineisapotentinhibitorofreversetranscriptase.Ithasrelativelyspecifictoxicityforthevirus. Zidovudine(AZT)cont.ClinicalpharmacokineticsItiswellabsorbedfromthegutbutsubjecttofirst-passmetabolismBioavailabilityisabout70%Thedrugiswidelydistributedandcrossestheblood-brainbarrierMostofthedrugiseliminatedbyhepaticmetabolism,unchangedzidovudineaccountingforabout10%ofthedose Zidovudine(AZT)cont.ClinicalpharmacokineticsInpatientswithrenalorliverimpairment,thedrugmayaccumulate,anddosesareusuallyadjustedinthesediseasestates Zidovudine(AZT)cont.TherapeuticusesItisusedtoprolonglifepatientswithAIDSandAIDS-relatedcomplex(ACR);itprobablydoesnotdelaytheonsetofAIDSinHIV-positivepatientsThedrugusuallyproducesariseinCD4cellcounts,buteventualdeteriorationisusualinspiteofzidovudineInpatientswithlateAIDSitisoflittleuse. Zidovudine(AZT)cont.AdverseeffectsBonemarrowtoxicityPolymyositisHeadacheandinsomnia Zidovudine(AZT)cont.DruginteractionsParacetamol:theriskofbonemarrowsuppressionmayincreasedProbenecid PurineandpyrimidineanaloguesModeofactionThesedrugsareeffectiveagainstDNAvirusesThecompoundsstructurallyresemblepurineandpyrimidinenucleosidesTheresultingDNAmoleculeismoreeasilyfragmented,leadingtotranscriptionerrors.TheyalsoinhibitviralDNApolymerase. PurineandpyrimidineanaloguesExamplesandclinicalpharmacokineticsIdoxuridine:itisnotabsorbedfromthegut,andisusedtopicallyVidarabine:cannotbegivenorallybecauseitismetabolizedinthegut-itisusuallygiveni.v.ortopically PurineandpyrimidineanaloguesTherapeuticusesIdoxuridine:maybeusedtopicallyforHerpessimplexandzosterbutistootoxicforsystemicuseandhaslargelybeensupplantedbyaciclovirVidarabine:maybeusedforlife-threateningsystemicHerpesinfections PurineandpyrimidineanaloguesAdverseeffectsIdoxuridine:becauseitisusedonlytopically,severeadverseeffectsareunusualVidarabine:anorexia,nausea,vomiting,diarroeaandbonemarrowsuppression PurineandpyrimidineanaloguesDruginteractionsThemetabolismofvidarabineisinhibitedbythexanthineoxidaseinhibitorallopurinol,andtoxicitymayresult RibavirinItiseffectiveagainstawiderangeofDNAandRNAvirusesThedrugmaybegivenbyaerosolinhalation,orallyori.v.Oralbiavailabityisabout40%Itreadilycrossestheblood-brainbarrierandhasaverylargevolumeofdistribution,mainlybecauseofcellularuptake. Ribavirin(cont.)Thedrugiseliminatedbybothmetabolismandrenalexcretion,withaterminalhalf-lifeofabout2weeks Ribavirin(cont.)TherapeuticusesRespiratorysyncytialvirus(RSV)infections:bronchiolitisandpneumoniaatyoungchildrenInfluenzaAandBLassafever