藥理學(xué)教學(xué)課件：Chapter 36 b-lactam Antibiotics Other Inhibitors of Celll Wall Sythesis

Chapter36．

-lactamAntibiotics&OtherInhibitorsofCellWallSythesis

I.BETA-LACTAMCOMPOUNDS

Penicillins（青霉素類）Cepharosporins（頭孢菌素類）Cephamycins（頭霉素類）非典型-內(nèi)酰胺Carbapenems（碳青霉烯類）Monobectams（單環(huán)類）

Oxacephalosporins

(氧頭孢烯類)

-lactamaseinhibitors(

內(nèi)酰胺酶抑制劑)Theysharefeaturesofchemistry,mechanismofaction,pharmacologicandclinicaleffects,andimmunologiccharacteristicswithcephalosporins,monobactams,carbapenems,andbeta-lactamaseinhibitors,whichalsoarebeta-lactamcompounds.A.PENICILLINSTheattachmentofdifferentsubstitutents代替物to6-aminopenicillanicaciddeterminestheessentialpharmacologicandantibacterialpropertiesoftheresultingmolecules.Penicillinscanbeassignedtothebelowgroups.Naturalpenicilln-penicillinG.Thesehavethegreatestactivityagainstgram-positiveorganisms,gram-negativecocci,andnon-beta-lactamase-producinganaerobes厭氧菌andlittleactivityagainstgram-negativerods.Theyaresusceptibletohydrolysisbybeta-lactamases.ChemistryStructuralintegrityofthe6-aminopenicillanicacidnucleusisessentialforthebiologicactivityofthesecompounds.Ifthebeta-lactamringisenzymaticallycleavedbybacterialbeta-lactamases,theresultingproduct,penicilloicacid(青霉噻唑酸),lacksantibacterialactivity.However,itisanantigenic抗原的

determinantofthepenicillins,actingasasensitizingstructurewhenattachedtohostproteins.Productsofalkalinehydrolysisofthepenicillinsalsocontributetosensitization.TheprincipalclinicallimitationsofpenicillinGwereitsinstabilityatacidicpH,susceptibilitytodestructionbybeta-lactamase(penicillinase),anditsrelativeinactivityagainstgram-negativebacilli.Isolationofthenucleus,6-aminopenicillanicacid,allowedforthedevelopmentofnumeroussemisynthetic

penicillinsthatarestabletoacidpH,resistanttobeta-lactamase,andactiveagainstbothgram-positiveandgram-negativebacteria.PenicillinUnitsandFormulations

TheactivityofpenicillinGwasoriginallydefinedinunits.Crystallinesodiumpenicillincontainsapproximately1600units/mg(1unit=0.6μg;1millionunitofpenicillin=0.6g).Semisynthetic

penicillinsareprescribedbyweightratherthanunits.Mostpenicillinsaredispensed(調(diào)配)asthesodiumorpotassiumsaltofthefreeacid.Procainesaltsandbenzathine

(芐星)saltsofpenicillinGproviderepository(儲藏處)formsforintramuscularinjection.Indrycrystallineform,penicillinsaltsarestableforlongperiods(eg,foryearsat4℃).Solutionslosetheiractivityrapidly(eg,24hoursat20℃)andmustbepreparedfreshforadministration.Pharmacokinetics

PenicillinGisacid-instableandcannotbeenabsorbed.Administrationbytheintravenousrouteispreferredbecauseofirritationandlocalpainproducedbytheintramuscularinjectionoflargedoses.Lessprotein-boundproducehigherlevelsoffreedruginserum.PenicillinGiswidelydistributedinbodyfluidsandtissues.Theconcentrationsinmosttissuesareequaltothoseinserum.Theyarepolarmolecules,andtheconcentrationwithincellsislessthanthatinextracellularfluids.Penetrationintotheeye,theprostate,andthecentralnervoussystemispoor.However,withactiveinflammationofthemeninges,asinbacterialmeningitis,penicillinconcentrationsaresufficienttokillsusceptiblestrainsofpneumococciandmeningococci.Penicillinisrapidlyexcretedbythekidneyintotheurine;smallamountsarealsoexcretedintosputurn

(痰)andmilk.About10%ofrenalexcretionisbyglomerularfiltrationand90%bytubularsecretion.ThenormalhalflifeofpenicillinGisapproximately30minutes;renalfailure,itmaybeaslongas10hours.Benzathineandprocainepenicillinsareformulatedtodelayabsorption,resultinginprolongedbloodandtissueconcentrations.Thelatterissufficienttoprotectagainst預(yù)防

beta-hemolyticstreptococcalinfectionandtheformertotreatanestablishedinfectionwiththeseorganisms.Forpenicillinsthatareclearedbythekidney,thedosemustbeadjustedaccordingtorenalfunction.Becauseclearanceofpenicillinsislessefficientinthenewborn,dosesadjustedforweightalonewillresultinhighersystemicconcentrationsforlongerperiodsthanintheadult.MechanismofAction

Allbeta-lactamantibioticsinhibitbacterialgrowthbyinterferingwithaspecificstepinbacterialcellwallsynthesis.Thecellwallisarigidouterlayerthatcompletelysurroundsthecytoplasmicmembrane(Figure37-3).Itmaintainstheshapeofthecellandpreventscelllysisthatwouldoccurasaresultofthehighosmoticpressurewithinthecellcomparedtoitsexternalenvironment.Cellwalliscomposedofacomplexcross-linkedpolymer,peptidoglycan肽聚糖

(murein壁質(zhì),

mucopeptide粘肽),consistingofpolysaccharides多糖andpolypeptides.Thepolysaccharidecontainsalternatingaminosugars,N-acetylglucosamine（乙酰葡糖胺）

andN-acetylmuramicacid（乙酰胞壁酸）(Figure37-4).Afive-amino-acidpeptideislinkedtotheN-acetylmuramicacidsugar.ThispeptideterminatesinD-alanyl-D-alanine.Penicillin-bindingproteins(PBPs)catalyzethetranspeptidasereactionthatremovestheterminalalaninetoformacrosslinkwithanearbypeptide,whichgivescellwallitsstructuralrigidity.Beta-lactamantibioticsarestructuralanalogsofthenaturalD-Ala-D-AlasubstrateandtheyarecovalentlyboundbyPBPsattheactivesite.Afterabeta-lactamantibiotichasattachedtothePBP,thetranspeptidationreactionisinhibited(Figure37-5),peptidoglycansynthesisisblocked,andthecelldies.Theexactmechanismresponsibleforcelldeathisnotcompletelyunderstood,butautolysins（自溶素）,bacterialenzymesthatremodelandbreakdowncellwall,areinvolved.Penicillinsandcephalosporinsarebactericidalonlyifcellsareactivelygrowingandsynthesizingcellwall.AntimicrobialactivityThepenicillin-susceptibleorganismsarenon-penicillinase-producingstrainsofmostcocci,gram-positivebacilli,spirochetesandactinomyces

(放線菌).ClinicalUses

Penicillinsarebyfarthemostwidelyeffectiveandthemostextensivelyusedantibiotics.Bloodlevelsofallpenicillinscanberaisedbysimultaneousadministrationofprobenecid,0.5g(10mg/kginchildren)every6hoursorally,whichimpairstubularsecretionofweakacidssuchasbeta-lactamcompounds.(1)PenicillinGisthedrugofchoiceforcocciinfectionscausedbystreptococci(pharyngitis咽炎,scarletfever,pneumonia,arthritis,endocarditis,etc.),meningococci,enterococci,Gonococci(淋球菌),

penicillin-susceptiblepneumococci,non-beta-lactamase-producingstaphylococci.PenicillinGwhenadministeredatdosesof18-24millionunitsisinhibitoryforenterococci,butthesimultaneousadministrationofanaminoglycosideisnecessarytoachieveabactericidaleffect,whichisrequiredwhentreatingenterococcal

endocarditis.BenzathinepenicillinandprocainepenicillinGforintramuscularinjectionyieldlowbutprolongeddruglevels.Asingleinjectionofbenzathinepenicillin,givenintramuscularly,issatisfactoryfortreatmentofbeta-hemolyticstreptococcalpharyngitis,syphilis(梅毒),andprophylaxisagainst預(yù)防

reinfectionwithbeta-hemolyticstreptococci.ProcainepenicillinG,whichinthepastwasusedfortreatinguncomplicatedpneumococcalpneumoniaorgonorrhea(淋病),israrelyusednowadaysbecausemanystrainsarepenicillin-resistant.(2)Gram-positivebacilliinfection:

Bacillusanthracis

(炭疽桿菌),clostridiumspecies(梭狀芽胞桿菌屬),andothergram-positiverodsandnon-beta-lactamase-producinggram-negativeanaerobicorganisms.(3)spirocheteinfections:

Treponema

pallidum

(蒼白密螺旋體）,

Leptospira

(鉤端螺旋體

),Syphilis(梅毒),andtheinfectionsofmanyotherspirochetes.(4)actinomycesinfections:highdose,longperiod.ResistanceResistancetopenicillinsandotherbeta-lactamsisduetooneoffourgeneralmechanisms:(1)inactivationofantibioticbybeta-lactamase:Beta-lactamaseproductionisthemostcommonmechanismofresistance.Morethan100differentbeta-lactamaseshavebeenidentified.(2)modificationoftargetPBPs:Itisresponsibleformethicillin

(甲氧西林)resistanceinstaphylococciandpenicillinresistanceinpneumococci.TheseresistantorganismsproducePBPsthathavelowaffinityforbindingbeta-lactamantibiotics,andasaresulttheyarenotinhibitedexceptatrelativelyhighdrugconcentrations,whichmayexceedwhatisclinicallyachievable.(3)impairedpenetrationofdrugtotargetPBPs:Beta-lactamantibioticscrosstheoutermembraneandentergram-negativeorganismsviaoutermembraneproteinchannels(porins).Absenceoftheproperchannelordown-regulationofitsproductioncanpreventorgreatlyreducedrugentryintothecell.(4)thepresenceofaneffluxpump:Impairedpenetrationaloneisusuallynotsufficienttoconferresistance,becauseenoughantibioticeventuallyentersthecelltoinhibitgrowth.However,thisbarriercanbecomeimportantinthepresenceofabeta-lactamase,whichhydrolyzesantibioticasitslowlyentersthecell.Gram-negativeorganismsalsomayproduceaneffluxpump,whichconsistsofcytoplasmicandperiplasmicproteincomponents,thatefficientlytransportsomebeta-lactamantibioticsfromtheperiplasm外周胞質(zhì)(或壁膜間隙，是革蘭氏陰性菌的細(xì)胞膜與外膜之間的間隔區(qū)域)backacrosstheoutermembrane(eg,extrusion擠壓ofnafcillin萘夫西林

bySalmonellatyphimurium傷寒桿菌).AdverseReactions

(1)Hypersensitivereactions:

Thepenicillinsareremarkablynontoxic,thesafestofantibiotics.Mostoftheseriousadverseeffectsareduetohypersensitivity.

Allpenicillinsarecross-sensitizingandcross-reacting.Anypreparationcontainingpenicillin,includingfoodsorcosmetics(整容劑),mayinducesensitization.Symptomsofhypersensitivereactions(10%):itching(瘙癢),rashes,fever,serumsickness,angioneuroticedema.anaphylacticshock(5/10000).Ingeneral,sensitizationoccursindirectproportiontothedurationandtotaldoseofpenicillinreceivedinthepast.Theresponsibleantigenicdeterminantsaredegradationproductsofpenicillins,particularlypenicilloicacid青霉噻唑酸

andproductsofalkalinehydrolysis堿解boundtohostprotein.Thepreventionofandtreatmentofanaphylacticreactions:

Becauseofthepotentialforanaphylaxis,however,penicillinshouldbeadministeredwithcautionorasubstitutedruggivenifthereisahistoryofpenicillinallergy.Theincidenceofallergicreactionsinsmallchildrenisnegligible.①Inquirethehistoryofpenicillinallergicreaction:②

Cutaneoustest:③Theemergencymeasuresofanaphylacticshock:adrenaline0.5-1mg,subcutaneousorintramuscularinjection.Mostpatientsallergictopenicillinscanbetreatedwithalternativedrugs.However,ifnecessary(eg,treatmentofenterococcal

endocarditisorneurosyphilis神經(jīng)梅毒inahighlypenicillin-allergicpatient),desensitizationcanbeaccomplishedwithgraduallyincreasingdosesofpenicillin.(2)Otheradversereactions:phlebitis靜脈炎

(i.v.);injectionsiteinflammatoryreactions(i.m);degeneration變性

ofnervetissue;andcentralnervoussystemexcitability.Inpatientswithrenalfailure,penicillininhighdosescancauseseizures.

Herxheimerreaction(赫氏反應(yīng)):Thetreatmentofsyphilis,spirochete,etc.Thesymptomsisexacerbed.Semisynthetic

penicillins1.Pencillinsfororaladministrition(Thegastricacid-resistantPenicillins):

Phenoxymethylpenicillin

(苯氧甲基青霉素,PenicillinV).

（1）Theoralformofpenicillin.（2）resistanttogastricacid,wellabsorbed(60%)whenitisgivenonanemptystomach.Thehalf-lifeislongerthanpenicillinG.AsatisfactorysubstituteforPenicillinGagainstgonorrhoea淋病andmeningococcalmeningitis.（3）PenicillinVisindicatedonlyinminorinfectionsbecauseofitsrelativelypoorbioavailability.2.ThePenicillinase-resistantPenicillins:

Methicillin（甲氧西林）,Oxacillin（苯唑西林）,Cloxacillin（氯唑西林）,Dicloxacillin（雙氯西林）,Nafcillin

(萘夫西林），etc.①stableinanacidicmedium；②resistanttocleavagebypenicillinase；③Thesepenicillinsareresistanttostaphylococcalbeta-lactamases.Theyareactiveagainststaphylococciandstreptococcibutinactiveagainstenterococci,anaerobicbacteria,andgram-negativecocciandrods.usefortreatmentofPenicillinG-resistantstaphylococciinfection.④Nafcillinisprimarilyclearedbybiliaryexcretion,andoxacillin苯唑西林,dicloxacillin雙氯西林,andcloxacillin氯唑西林areeliminatedbyboththekidneyandbiliaryexcretion,thus,nodosageadjustmentisrequiredforthesedrugsinrenalfailure.3.BroadspectrumPenicillins(Extended-spectrumpenicillins):

Amipicillin

(氨芐西林)，Carbenicillin（羧芐西林），Piperacillin（哌拉西林）,etc.①havesimilarantibacterialactivityandabroaderspectrum;②alldestroyedbyβ-lactamase.(1)Ampicillin

(氨芐西林),Amoxicillin(阿莫西林):

Thesedrugsretaintheantibacterialspectrumofpenicillinandhaveimprovedactivityagainstgram-negativeorganisms,buttheyaredestroyedbybeta-lactamases.Pseudomonasaeruginosa-resistanceTherapeuticApplications:Upperrespiratoryinfections;Urinarytractinfections;Meningitis;Salmonellainfections.(2)Carbenicillin（羧芐西林）,

Ticarcillin（替卡西林）:

belongtotheantipseudomonal

penicillins.WithactivityagainstPseudomonasaeruginosa

andsomeProteus(變形桿菌屬).(3)Piperacillin（哌拉西林）Mezlocillin

(美洛西林）:Hasthebroadestantibacterialspectrumandthemostactivityofthepenicillins,withactivityagainstPseudomonasaeruginosaetc.TherapeuticApplications:Forthetreatmentofthepatientswithsevereinfectioncausedbygram-negativebacteria,usuallyincombinationwithaminoglycosides.(4)Mecillinam（美西林）,

ivmecillinam（匹美西林）,

emocillin（替莫西林）,

ormidacillin（福米西林）,etc.Anti-gram-negativebacillipenicillins.B.CEPHALOSPORINS

Cephalosporinsaresimilartopenicillinschemically,inmechanismofaction,andtoxicity.Cephalosporinsaremorestablethanpenicillinstomanybacterialbeta-lactamasesandthereforeusuallyhaveabroaderspectrumofactivity.ChemistryThenucleusofthecephalosporins,7-aminocephalosporanicacid.bearsacloseresemblanceto6-aminopenicillanicacid.TheyaresolubleinwaterandrelativelystabletopHandtemperaturechanges.ClassificationThewell-acceptedsystemofclassificationby“generations”isbasedongeneralfeaturesofantimicrobialactivity.Cephalosporinscanbeclassifiedintofourmajorgroupsorgenerations,dependingmainlyonthespectrumofantimicrobialactivity.Asageneralrule,first-generationcompoundshavebetteractivityagainstgram-positiveorganismsandthelatercompoundsexhibitimprovedactivityagainstgram-negativeaerobicorganisms.1.FIRSTGENERATIONCEPHALOSPORINS

Thisgroupincludescefadroxil

(頭孢羥氨芐),

cefazolin

(頭孢唑林),

cephalexin

(頭孢氨芐),

cephalothin

(頭孢菌素),

cephapirin

(頭孢吡硫),andcephradine

(頭孢拉啶).Thesedrugsareveryactiveagainstgram-positivecocci,includingpneumococci,streptococci,andstaphylococci.Cephalosporinsarenotactiveagainstmethicillin-resistantstrainsofstaphylococci.Pharmacokinetics

(1)Oral(cephalexin

頭孢氨芐,

cephradine頭孢拉啶,andcefadroxil頭孢羥氨芐):Urineconcentrationisusuallyveryhigh.Excretionismainlybyglomerularfiltrationandtubularsecretionintotheurine.Tubularsecretoryblockingagents,eg,probenecid,mayincreaseserumlevelssubstantially.Inpatientswithimpairedrenalfunction,dosagemustbereduced(Table37-2).(2)Parenteral:Afteranintravenousinfusionof1g,thepeaklevelofcefazolin頭孢唑林

is90-120pg/mL.Cefazolincanalsobeadministeredintramuscularly.Excretionisviathekidney,anddoseadjustmentsmustbemadeforimpairedrenalfunction.ClinicalUses

(1)Oraldrugsmaybeusedforthetreatmentofurinarytractinfections,forminorstaphylococcallesions,orforminorpolymicrobialinfectionssuchascellulitis

(蜂窩織炎)orsofttissueabscess.However,oralcephalosporinsshouldnotberelieduponinserioussystemicinfections.(2)Cefazolinpenetrateswellintomosttissues.Itisthedrugofchoiceforsurgicalprophylaxis.Cefazolindoesnotpenetratethecentralnervoussystemandcannotbeusedtotreatmeningitis.Cefazolinisanalternativetoanantistaphylococcalpenicillinforpatientswhoareallergictopenicillin.2.SECOND-GENERATIONCEPHALOSPORINS

Membersofthisgroupincludecefaclor頭孢克洛,cefamandole頭孢孟多,cefonicid頭孢尼西,cefuroxime頭孢呋新,cefprozil頭孢羅齊,loracarbef羅拉卡貝

andceforanide頭孢雷特andthestructurallyrelatedcephamycins頭霉素類

cefoxitin頭孢西丁,cefmetazole頭孢氰唑,cefotetan頭霉雙硫唑,whichhaveactivityagainstanaerobes.

Ingeneral,theyareactiveagainstorganismsaffectedbyfirst-generationdrugs,buttheyhaveanextendedgram-negativecoverage范圍.Allsecond-generationcephalosporinsarelessactiveagainstgram-positivebacteriathanthefirst-generationdrugs.Pharmacokinetics

(1)Oral:

Cefaclor頭孢克洛,cefuroxime頭孢呋新,cefprozil頭孢羅齊,andloracarbef羅拉卡貝canbegivenorally.(2)Parenteral:

Therearemarkeddifferencesamongdrugsinhalf-life,proteinbinding,andintervalbetweendoses.Ingeneral,intramuscularinjectionistoopainfultobeused.Inrenalfailure,dosageadjustmentsarerequired(Table37-2).

ClinicalUses

Theoralsecond-generationcephalosporinsareactiveagainstbeta-lactamase-producingHinfluenzae

(流感嗜血桿菌)orBranhamella

catarrhalis

(卡他菌屬)andhavebeenprimarilyusedtotreatsinusitis鼻竇炎,otitis耳炎,orlowerrespiratorytractinfections,inwhichtheseorganismshaveanimportantrole.

Becauseoftheiractivityagainstanaerobes(includingBfragilis脆弱類桿菌),cefoxitin頭孢西丁,cefotetan頭霉雙硫唑,orcefmetazole頭孢氰唑canbeusefulinsuchmixedanaerobicinfectionsasperitonitis(腹膜炎)ordiverticulitis(憩室炎).

3.THIRD-GENERATIONCEPHALOSPORINS

Includingcefoperazone頭孢哌酮,cefotaxime頭孢噻肟,ceftazidime頭孢他啶,ceftizoxime頭孢唑肟,ceftriaxone頭孢曲松,cefrxime,cefpodoxime(proxetil頭孢泊肟酯),ceftibuten頭孢布坦,andmoxalactam羥羧氧酰胺菌素.Themajorfeaturesofthesedrugs(exceptcefoperazone)aretheirexpandedgram-negativecoverageandtheabilityofsometocrosstheblood-brainbarrier.Pharmacokinetics

Theypenetratebodyfluidsandtissueswellandachievelevelsinthecerebrospinalfluidsufficienttoinhibitmostpathogens,includinggram-negativerods.Thehalt-livesandthenecessarydosingintervalsvarygreatly.Theexcretionofcefoperazone頭孢哌酮andceftriaxone頭孢曲松ismainlythroughthebiliarytract,andnodosageadjustmentisrequiredinrenalinsufficiency.Theothersareexcretedbythekidneyandthereforerequiredosageadjustmentinrenalinsufficiency.ClinicalUses

Third-generationcephalosporinsareusedtotreatawidevarietyofseriousinfectionscausedbyorganismsthatareresistanttomostotherdrugs.Becauseoftheirpenetrationofthecentralnervoussystem,third-generationcephalosporinscanbeusedtotreatmeningitis.Otherpotentialindicationsincludeempiricaltherapyofsepsisofunknowncauseinboththeimmunocompetent

(免疫活性)andtheimmunocompromised

(免疫受損)patientandtreatmentofinfectionsforwhichacephalosporinistheleasttoxicdrugavailable.4.FOURTH-GENERATIONCEPHALOSPORINS

Cefepime

(頭孢吡肟),isinmanywayssimilartothird-generationagents,butitismoreresistanttohydrolysisbychromosomalbeta-lactamasesandsomeextended-spectrumbeta-lactamasesthatinactivatemanyofthethird-generationcephalosporins.IthasgoodactivityagainstPaeruginosa銅綠假單胞菌,

Enterobacteriaceae(腸桿菌科),

Saureus(金葡菌),andSpneumoniae(肺炎球菌).Itishighlyactiveagainsthaemophilus嗜血桿菌屬andneisseria奈瑟氏菌屬.Unlikeceftazidime

頭孢他啶,however,cefepimehasgoodactivityagainstmostpenicillin-resistantstrainsofstreptococci,anditmaybeusefulintreatmentofenterobacterinfections.Otherwise,itsclinicalroleissimilartothatofthird-generationcephalosporins.5.ADVERSEEFFECTSOFCEPHALOSPORINS

(1)Allergy:Cephalosporinsaresensitizingandmayelicitavarietyofhypersensitivityreactionsthatareidenticaltothoseofpenicillins,includinganaphylaxis,fever,skinrashes,nephritis,granulocytopenia,andhemolyticanemia.However,thechemicalnucleusofcephalosporinsissufficientlydifferentfromthatofpenicillinssothatsomeindividualswithahistoryofpenicillinallergymaytoleratecephalosporins.Thefrequencyofcross-allergenicitybetweenthetwogroupsofdrugsprobablyisaround5-10%.However,patientswithahistoryofanaphylaxistopenicillinsshouldnotreceivecephalosporins.(2)Toxicity:Localirritationcanproduceseverepainafterintramuscularinjectionandthrombophlebitis血栓性靜脈炎

afterintravenousinjection.Renaltoxicity,includinginterstitialnephritisandeventubularnecrosis,andhascausedthewithdrawalofcephaloridine

(頭孢噻啶).Cephalosporinsthatcontainamethylthiotetrazole甲硫基四氮唑group(eg,cefamandole

頭孢孟多,moxalactam

羥羧氧酰胺菌素,cefmetazole

頭孢氰唑,cefotetan

頭霉雙硫唑,cefoperazone

頭孢哌酮)frequentlycausehypoprothrombinemia

(低凝血酶原血癥)andbleedingdisorders.AdministrationofvitaminKcanpreventthis.Drugswiththemethylthiotetrazoleringcanalsocauseseveredisulfiram-like戒酒硫(雙硫侖)樣反應(yīng)reactions;consequently,alcoholandalcohol-containingmedicationsmustbeavoided.

(3)Superinfection:Manysecond-andparticularlythird-generationcephalosporinsareineffectiveagainstgram-positiveorganisms,especiallymethicillin-resistantstaphylococciandenterococci.Duringtreatmentwithsuchdrugs,theseresistantorganisms,aswellasfungi,oftenproliferateandmayinducesuperinfection.II.OTHERBETA-LACTAMDRUGS

1.Cephamycins

(頭霉素類)Itisfermentation發(fā)酵productsofstreptomyces

(鏈霉菌屬)andsometotallysyntheticdrugssuchasmoxalactam

(頭孢西丁)

resemblecephalosporins.Ithasthesimilarantibacterialactivityandspectrumtothe2ndgeneration

Cepharosporins.Forthetreatmentofanaerobicinfections.2.MONOBACTAMS(單環(huán)類)Aztreonam

(氨曲南),

Carumonam

(卡蘆莫南):Thesearedrugswithamonocyclicbeta-lactamring.Theyarerelativelyresistanttobeta-lactamasesandactiveagainstgram-negativerods.Theyhavenoactivityagainstgram-positivebacteriaoranaerobes.Aztreonam

(氨曲南)isamonobactam,resemblesaminoglycosidesinitsspectrumofactivity.Belongstonarrow-spectrumantibiotic.Thehalf-lifeis1-2hoursandisgreatlyprolongedinrenalfailure.Forthetreatmentofaerobicgram-negativebacilliinfections.Penicillin-allergicpatientstolerateaztreonamwithoutreaction.Occasionalskinrashesandelevationsofserumaminotransferasesoccurduringadministrationofaztreonam,butmajortoxicityhasnotyetbeenreported.3.BETA-LACTAMASEINHIBITORS

Clavulanicacid(克拉維酸),

Sulbactam

(舒巴坦)&Tazobactam

(三唑巴坦):Bindingtoβ-lactamasesandinactivatethem,thuspreventingthedestructionofβ-lactamantibioticsthataresubstratesfortheseenzyme.Thesesubstancesresemblebeta-lactammoleculesbutthemselveshaveveryweakantibacterialaction.Theyarepotentinhibitorsofmanybutnotallbacterialbeta-lactamasesandcanprotecthydrolyzable

penicillinsfrominactivationbytheseenzymes.Beta-lactamaseinhibitorsaremostactiveagainstAmblerclassAbeta-lactamases.TheyarenotgoodinhibitorsofclassCbeta-lactamases.Beta-lactamaseinhibitorsareavailableonlyinfixedcombinationswithspecificpenicillins.Theantibacterialspectrumofthecombinationisdeterminedbythecompanionpenicillin,notthebeta-lactamaseinhibitor.Theindicationsforpenicillin-beta-lactamaseinhibitorcombinationsareempiricaltherapyforinfectionscausedbyawiderangeofpotentialpathogensinbothimmunocompromised

(免疫受損)andimmunocompetent

(免疫活性)patientsandtreatmentofmixedaerobicandanaerobicinfections,suchasintra-abdominalinfections.Adjustmentsforrenalinsufficiencyaremadebasedonthepenicillincomponent.4.CARBAPENEMS

Thecarbapenems

(碳青霉烯類)arestructurallyrelatedtobeta-lactamantibiotics(Imipenem亞胺培南

andmeropenem(美洛培南).Imipenemhasawidespectrumwithgoodactivityagainstmanygram-negativerods,gram-positiveorganisms,andanaerobes.Itisresistanttomostbeta-lactamasesbutnotmetallo-beta-lactamases.Imipenemisinactivatedbydehydropeptidases氫肽酶(dipeptidase二肽酶)inrenaltubules,resultinginlowurinaryconcentrations.Consequently,itisadministeredtogetherwithcilastatin西司他丁

whichinhibitsthedegradationofimipenembyarenaltubulardipeptidase,forclinicaluse.Meropenem美洛培南issimilartoimipenembuthasslightlygreateractivityagainstgram-negativeaerobesandslightlylessactivityagainstgram-positives.Itisnotsignificantlydegradedbyrenaldehydropeptidaseanddoesnotrequireaninhibitor.Imipenempenetratesbodytissuesandfluidswell,includingthecerebrospinalfluid.Thedosemustbereducedinrenalinsufficiency.Meropenemalsopenetrateswellintotissuesandcerebrospinalfluid.Imipenemormeropenemisindicatedforinfectionscausedbysusceptibleorganismsthatareresistanttootheravailabledrugs.Pseudomonasmayrapidlydevelopresistancetoimipenem,sosimultaneoususeofanaminoglycosideisrecommendedforinfectionscausedbytheseorganisms.Imipenemormeropenemwithorwithoutanaminoglycosidemaybeeffectivetreatmentforfebrile(發(fā)熱性)

neutropenic中性白細(xì)胞減少癥patients.Themostcommonadverseeffectsofimipenemarenausea,vomiting,diarrhea,skinrashes,andreactionsattheinfusionsites.Excessivelevelsinpatientswithrenalfailuremayleadtoseizures.Meropenemislesslikelytocauseseizuresthanimipenem.Patientsallergictopenicillinsmaybeallergictocarbapenemsaswell.5.