非beta内酰胺类抗生素（英文）nonbetalactam

Assoc Prof IvanLambeve mail itlambev mail bg NONBETA LACTAMANTIBIOTICS MedicalUniversityofSofia FacultyofMedicineDepartmentofPharmacologyandToxicology lactamsGlycopeptides AminoglycosidesTetracyclinesChloramphenicolMacrolidesLincosamides Rifampicin Polymyxins ANTIBIOTICS mechanismofaction Aminoglycosideshaveahexosering eitherstreptidine instreptomycin or2 deoxystreptamine otheraminoglycosides towhichvariousaminosugarsareattachedbyglycosidiclinkages Theyarewater soluble stableinsolution andmoreactiveatalkalinethanatacidpH I AMINOGLYCOSIDES Streptomycin Streptomycinisanaminoglycosideantibiotic Itsantibacterialactivityisduetoitbindingtothe30Ssubunitofthebacterialribosomeandinhibitingofproteinsynthesis Ithasawidespectrumofanti bacterialactivitybutisprimarilyusetotreatmycobacterialinfections i m Themainproblemsareeighthnervetoxi city vestibulotoxicitymorethandeaf ness nephrotoxicity allergicreactions Gentamicin Tobramycin Mechanismsofaction Aminoglycosidesareirreversibleinhibitorsofproteinsynthesis buttheprecisemechanismforbactericidalactivityisnotknown Theinitialeventispassivediffusionviaporinchannelsacrossthecellwall Drugisthenactivelytransportedacrossthecellmembraneintothecytoplasm Thetransmembraneelectrochemicalgradientsuppliestheenergyforthisprocess LowextracellularpHandanaerobicconditionsinhibittransportbyreducingthegradient Transportmaybeenhancedbycellwall activedrugssuchaspenicillinorvancomycin thisenhancementmaybethebasisofthesynergismoftheseantibioticswithaminoglycosides Insidethecell aminoglycosidesbindtospecific30S subunitribosomalproteins Proteinsynthesisisinhibitedbyaminoglycosidesinatleastthreeways interferencewiththeinitiationcomplexofpeptideformation 2 misreadingofmRNA whichcausesincorporationofincorrectaminoacidsintothepeptide resultinginanonfunctionalortoxicprotein 3 breakupofpolysomesintononfunctionalmonosomes Theseactivitiesoccurmoreorlesssimultaneously andtheoveralleffectisirrever sibleandlethalforthecell Aminoglycosidesactbactericidalondividingandnodividingmicroorganisms TheyareingeneralactiveagainststaphylococciandaerobicGram negativeorganismsincludingP aeruginosaandalmostalltheEnterobacteriaceae ClinicalusesAminoglycosidesaremostlyusedagainstGram negativeentericbacteria especiallywhentheisolatemaybedrug resistantandwhenthereissuspicionofsepsis Theyarealmostalwaysusedincombinationwitha lactamantibiotictoextendcoveragetoincludepotentialGram positivepathogensandtotakeadvantageofthesynergismbetweenthesetwoclassesofdrugs Penicillin aminoglycosidecombinationsalsoareusedtoachievebactericidalactivityintreatmentofenterococcalendocarditisandtoshortendurationoftherapyforviridansstreptococcalandstaphy lococcalendocarditis AmikacinGentamicin sol 80mg 2ml 80mg 8hi m KanamycinNeomycin Bivacin sprayderm fl150ml neomycin bacitracin Nemybacin ung ophth 2 5g neomycin bacitracin StreptomycinTobramycin Spectinomycinisstructurallyrelatedtoaminoglycosides Itlacksaminosugarsandglycosidesbonds SpectinomycinisactiveagainstmanyGram positiveandGram negativeorganisms butitisusedasanalternativetreatmentfordrug resistantgonorrheaorgonorrheainpenicillin allergicpatients Strainsofgonococcimayberesistanttospectinomycin butthereisnocross resistancewithotherdrugs Spectinomycinisrapidlyabsorbedafteri m injection Asingledoseof40mg kguptoamaximumof2gisgiven Thereispainattheinjectionsite Nephrotoxicityandanemiahavebeenobservedrarely AdverseeffectsAllaminoglycosidesareototoxicandnephrotoxic Ototoxicityandnephrotoxicityaremorelikelytobeencounteredwhentherapyiscontinuedformorethan5days athigherdoses intheelderly andinthesettingofrenalinsufficiency Concurrentusewithloopdiuretics eg furosemide ethacrynicacid orothernephrotoxicantimicrobialagents vancomycin amphotericin canpotentiatenephro toxicityandshouldbeavoided Ototoxicitycanmanifestasauditorydamage resultingintinnitusandhigh frequencyhearinglossinitially orasvestibulardamage evidentbyvertigo ataxia andlossofbalance Streptomycinandgentamicinarethemostvestibulotoxic Nephrotoxicityresultsinrisingserumcreatininelevelsorreducedcreatinineclearance Neomycin kanamycin andamikacinarethemostototoxicagents Neomycin tobramycin andgentamicinarethemostnephrotoxic Inveryhighdoses aminoglycosidescanproduceacurare likeeffectwithneuromuscularblockadethatresultsinrespiratoryparalysis Thisparalysisisusuallyreversiblebycalciumgluconate givenpromptly orneostigmine Hypersensitivityoccursinfrequently Mechanismsofresistance1 Productionofatransferaseenzymeorenzymesinactivatestheaminoglycosidebyadenylylation acetylation orphosphorylation Thisistheprin cipaltypeofresistanceencounteredclinically 2 Impairedentryofaminoglycosideintothecell Thismaybegenotypic resultingfrommutationorphenotypic resultingfromgrowthconditions 3 Thereceptorproteinonthe30Sribosomalsubunitmaybedeletedoralteredasaresultofamutation II TETRACYCLINES Tetracyclinesentermicroorganismsinpartbypassivediffusionandinpartbyanenergy dependentprocessofactivetransport Susceptiblecellsconcentratethedrugintracellularly Onceinsidethecell tetracyclinesbindreversiblytothe30Ssubunitofthebacterialribosome blockingthebindingofaminoacyl tRNAtotheacceptorsiteonthemRNA ribosomecomplexThispreventsadditionofaminoacidstothegrowingpeptide Tetracyclinesarebroad spectrumbacteriostaticantibioticsthatinhibitproteinsynthesis TetracyclinesareactiveagainstmanyGram positiveandGram negativebacteria includinganaerobes rickettsiae chlamydiae mycoplasmas andL forms andagainstsomeprotozoa eg amebas Theantibacterialactivitiesofmosttetracyclinesaresimilarexceptthattetracycline resistantstrainsmaybesusceptibletodoxycyclineandminocycline allofwhicharepoorsubstratesfortheeffluxpumpthatmediatesresistance Differencesinclinicalefficacyforsusceptibleorganismsareminorandattributablelargelytofeaturesofabsorption distribution andexcretionofindividualdrugs AntimicrobialActivity PharmacokineticsTetracyclinesmainlydifferintheirabsorptionafteroraladministrationandtheirelimination Absorptionafteroraladministrationisapproximately60 70 fortetracycline oxytetracycline andmethacycline and95 100 fordoxycyclineandminocycline Aportionofanorallyadministereddoseoftetracyclineremainsinthegutlumen modifiesintestinalflora andisexcretedinthefeces Absorptionoccursmainlyintheuppersmallintestineandisimpairedbyfood exceptdoxycyclineandminocycline bydivalentcations Ca2 Mg2 Fe2 orAl3 bydairyproductsandantacids whichcontainmultivalentcations andbyalkalinepH Tetracyclinesare40 80 boundbyserumproteins TetracyclinesaredistributedwidelytotissuesandbodyfluidsexceptforCSF whereconcentrationsare10 25 ofthoseinserum Minocyclinereachesveryhighconcentrationsintearsandsaliva whichmakesitusefulforeradicationofthemeningococcalcarrierstate Tetracyclinescrosstheplacentatoreachthefetusandarealsoexcretedinmilk Asaresultofchelationwithcalcium tetracyclinesareboundtoanddamage growingbonesandteeth Carbamazepine phenytoin barbiturates andchronicalcoholingestionmayshortenthehalf lifeofdoxycycline50 byinductionofhepaticenzymesthatmetabolizethedrug Tetracyclinesareexcretedmainlyinbileandurine Concentrationsinbileexceedthoseinserumtenfold Someofthedrugexcretedinbileisreabsorbedfromtheintestine enterohepaticcirculation andmaycontributetomaintenanceofserumlevels From10to50 ofvarioustetracyclinesisexcretedintotheurine mainlybyglomerularfiltration Tento40 ofthedrugisexcretedinfeces Doxycycline incontrasttoothertetracyclines iseliminatedbynonrenalmechanisms donotaccumulatesignificantlyandrequirenodosageadjustmentinrenalfailure Tetracyclinesareclassifiedas short acting chlortetracycline tetracycline oxytetracycline basedonplasmat1 2of6 8h 2 intermediateacting demeclocyclineandmethacycline t1 212h 3 long acting doxycyclineandminocycline withplasmat1 216 18h Thealmostcompleteabsorptionandslowexcretionofdoxycyclineandminocyclineallowforonce dailydosing ClinicalUsesAtetracyclineisthedrugofchoiceininfectionswithM pneumoniae chlamydiae rickettsiae andsomespirochetes TheyareusedincombinationregimenstotreatgastricandduodenalulcerdiseasecausedbyH pylori TheymaybeusedinvariousGram positiveandGram negativebacterialinfections includingVibrioinfections Incholera tetracyclineresistancehasappearedduringepidemics Tetracyclinesremaineffectiveinmostchlamydialinfections includingsexuallytransmitteddiseases Tetracyclinesarenolongerrecommendedingonococcaldiseasebecauseofresistance Atetracyclineusuallyincombinationwithanaminog lycosideisindicatedforplague tularemia andbru cellosis Tetracyclinesaresometimesusedinthetreatmentofprotozoalinfections eg thoseduetoE histolyticaorP falciparum Otherusesincludetreatmentofacne exacerbationsofbronchitis community acquiredpneumonia Lymedisease relapsingfever leptospirosis andsomenontuber culousmycobacterialinfections eg M marinum Anewlyapprovedtetracyclineanalog tigecycline isasemisyntheticderivativeofminocycline Itispoorlyabsorbedorallyandmustbeadministeredintravenously t1 236h Manytetracycline resistantstrainsaresusceptibletotigecycline Itsspectrumisverybroad Coagulase negativestaphylococciandS aureus includingMRS vancomycin intermediate andvancomycin resistantstrains streptococci penicillin susceptibleand resistant enterococci includingvancomycin resistantstrains Gram positiverods Enterobacteriaceae multidrug resistantstrainsofAcinetobacterspp anaerobes bothGram positiveandGram negative atypicalagents rickettsiae chlamydia andlegionella andrapidlygrowingmycobacteriaallaresusceptible ProteusandP aeruginosa however areresistant AdverseReactionsHypersensitivityreactions drugfever skinrashes totetracyclinesareuncommon Nausea vomiting anddiarrheaarethemostcommonreasonsfordisconti nuingtetracyclinemedication Theseeffectsareattri butabletodirectlocalirritationoftheintestinaltract Nausea anorexia anddiarrheacanusuallybecon trolledbyadministeringthedrugwithfoodorcarboxy methylcellulose reducingdrugdosage ordiscont inuingthedrug Tetracyclinesmodifythenormalflora withsuppressionofsusceptiblecoliformorganismsandovergrowthofpseudomonas proteus staphylococci resistantcoliforms clostridia andcandida Thiscanresultinintestinalfunctionaldisturbances analpruritus vaginalororalcandidiasis orenterocolitiswithshockanddeath Tetracyclinesarereadilyboundtocalciumdepositedinnewlyformedboneorteethinyoungchildren Whenatetracyclineisgivenduringpregnancy itcanbedepositedinthefetalteeth leadingtofluorescence discoloration andenameldysplasia itcanbedepositedinbone whereitmaycausedeformityorgrowthinhibition Ifthedrugisgivenforlongperiodstochildrenunder8yearsofage similarchangescanresult Tetracyclinescanprobablyimpairhepaticfunction especiallyduringpregnancy inpatientswithpreexistinghepaticinsufficiencyandwhenhighdosesaregivenintravenously Hepaticnecrosishasbeenreportedwithdailydosesof 4gi v Renaltubularacidosisandotherrenalinjuryresul tinginnitrogenretentionisaconraindicationtotheadministrationofoutdatedtetracyclinepreparations Tetracyclinesgivenwithdiureticsmayproducenitrogenretention Tetracyclinesotherthandoxycyclinemayaccumulatetotoxiclevelsinpatientswithimpairedkidneyfunction Intravenousinjectioncanleadtovenousthrombosis Intramuscularinjectionproducespainfullocalirritationandshouldbeavoided Systemicallyadministeredtetracycline especiallydemeclocycline caninducesensitivitytosunlightorultravioletlight particularlyinfair skinnedpersons Dizziness vertigo nausea andvomitinghavebeennotedparticularlywithdoxycyclineandMinocyclineathighdoses Themainmechanismsofresistancetotetracyclineanditsanaloguesare impairedinfluxorincreasedeffluxbyanactivetransportproteinpump 2 ribosomeprotectionduetoproductionofproteinsthatinterferewithtetracyclinebindingtotheribosome 3 enzymaticinactivation III CHLORAMPHENICOL Chloramphenicolandmacrolidesbindtothe50Ssubunitandblocktranspeptidationandproteinsynthesis Ithasbacteriostaticaction Becauseofpotentialtoxicity bacterialresistance andtheavailabilityofmanyothereffectivealternatives chloramphenicolisrarelyused ItmaybeconsideredfortreatmentofseriousrickettsialinfectionssuchastyphusandRockyMountainspottedfever Itisanalternativetoabeta lactamsfortreatmentofmeningococcalmeningitisoccurringinpatientswhohavemajorhypersensitivityreactionstopenicillinorbacterialmeningitiscausedbypenicillin resistantstrainsofpneumococci AdverseReactionsofChloramphenicolAdultsoccasionallydevelopnausea vomiting anddiarrhea Thisisrareinchildren Oralorvaginalcandidiasismayoccurasaresultofalterationofnormalmicrobialflora Chloramphenicolcausesadose relatedreversiblesuppressionofredcellproductionatdosagesexceeding50mg kg dafter1 2weeks Aplasticanaemia arareconsequence 1in24000to40000coursesoftherapy ofchloramphenicoladministrationbyanyroute Ittendstobeirreversibleandcanbefatal Newborninfantslackaneffectiveglucuronicacidconjugationmechanismforthedegradationanddetoxificationofchloramphenicol Consequently wheninfantsaregivendosagesabove50mg kg d thedrugmayaccumulate resultinginthegraybabysyndrome withvomiting flaccidity hypothermia graycolor shock andcollapse Toavoidthistoxiceffect chloramphenicolshouldbeusedwithcautionininfantsandthedosagelimitedto50mg kg dorless duringthefirstweekoflife infull terminfants Chloramphenicolinhibitshepaticmicrosomalenzymesthatmetabolizephenytoinandwarfarin IV MACROLIDESandKETOLIDES Azithromycin t1 240 68h tab 500mg ErythromycinClarithromycin antihelicobacteractivity Josamycin salivaexcretion MidecamycinOleandomycin salivaexcretion RoxithromycinSpiramycin salivaexcretion Rodogyl spiramicin metronidazole withsignificantsalivaexcretion Ketolides Telithromycin Inhibitionofbacterialproteinsynthesisbymacrolides listeria andcertainmycobacteria Gram negativeorganismssuchasNeisseriaspp Bordetellapertussis Bartonellahenselae andB quintana etiologicagentsofcat scratchdiseaseandbacillaryangiomatosis somerickettsiaspp T pallidum andcampylobacterspp aresusceptible ErythromyciniseffectiveagainstGram positivemicroorganisms pneumococci streptococci staphylococci andcoryne bacteria Mycoplasma legionella Chlamydiatrachomatis AdverseReactionsofErythromycinAnorexia nausea vomiting anddiarrheaaccompanyoraladministration GIintolerance whichisduetoadirectstimulationofgutmotility isthemostcommonreasonfordiscontinuingerythromycinandsubstitutinganotherantibiotic Erythromycincanproduceacutecholestatichepatitis fever jaundice impairedliverfunction probablyasahypersensitivityreaction Mostpatientsrecoverfromthis buthepatitisrecursifthedrugisreadministered ErythromycinmetabolitescaninhibitcytochromeP450enzymesandthusincreasetheserumconcen trationsoftheophylline oralanticoagulants cyclos porine methylprednisolone anddigoxin Resistancetoerythromycinisusuallyplasmid encoded Threemechanismshavebeenidentified 1 reducedpermeabilityofthecellmembraneoractiveefflux 2 production byEnterobacteriaceae ofesterasesthathydrolyzemacrolides 3 modificationoftheribosomalbindingsite so calledribosomalprotection bychromosomalmutationorbyamacrolide inducibleorconstitutivemethylase Cross resistanceiscompletebetweenerythromycinandtheothermacrolides Clarithromycinisderivedfromerythromycinbyadditionofamethylgroupandhasimprovedacidstabilityandoralabsorptioncomparedwitherythromycin ClarithromycinanderythromycinarevirtuallyidenticalwithrespecttoantibacterialactivityexceptthatclarithromycinismoreactiveagainstM aviumcomplex ClarithromycinalsohasactivityagainstM leprae T gondii andH pylori Erythromycin resistantstreptococciandstaphylococciarealsoresistanttoclarithromycin Theadvantagesofclarithromycincomparedwitherythromycinarelowerincidenceofgastrointestinalintoleranceandlessfrequentdosing Azithromycinhasspectrumofactivityandclinicalusesvirtuallyidenticaltothoseofclarithromycin AzithromycinisactiveagainstM aviumcomplexandT gondii Azithromycinisslightlylessactivethanerythromycinandclarithromycinagainststaphylo cocciandstreptococciandslightlymoreactiveagainstH influenzae Azithromycinishighlyactiveagainstchlamydia Itplasmat1 2islong TelithromycinisactiveinvitroagainstS pyogenes S pneumoniae S aureus H influenzae Moraxellacatarrhalis mycoplasmas Legionella Chlamydia H pylori N gonorrhoeae B fragilis andT gondii Manymacrolide resistantstrainsaresusceptibletoketolides V LINCOSAMIDES Clindamycinisachlorine substitutedderivativeoflincomycin anantibioticthatiselaboratedbyStreptomyceslincolnensis Clindamycinisindicatedfortreatmentofanaerobicinfectioncausedbybacteroidesandotheranaerobesthatoftenparticipateinmixedinfections Clindamycin sometimesincombinationwithanaminoglycosideorcephalosporin isusedtotreatpenetratingwoundsoftheabdomenandthegut infectionsoriginatinginthefemalegen