药理学教学课件：Chapter 36 b-lactam Antibiotics Other Inhibitors of Celll Wall Sythesis

Chapter36．

-lactamAntibiotics&OtherInhibitorsofCellWallSythesis

I.BETA-LACTAMCOMPOUNDS

Penicillins（青霉素类）Cepharosporins（头孢菌素类）Cephamycins（头霉素类）非典型-内酰胺Carbapenems（碳青霉烯类）Monobectams（单环类）

Oxacephalosporins

(氧头孢烯类)

-lactamaseinhibitors(

内酰胺酶抑制剂)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厌氧菌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(调配)asthesodiumorpotassiumsaltofthefreeacid.Procainesaltsandbenzathine

(苄星)saltsofpenicillinGproviderepository(储藏处)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预防

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

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

(murein壁质,

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

(放线菌).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预防

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

Bacillusanthracis

(炭疽杆菌),clostridiumspecies(梭状芽胞杆菌属),andothergram-positiverodsandnon-beta-lactamase-producinggram-negativeanaerobicorganisms.(3)spirocheteinfections:

Treponema

pallidum

(苍白密螺旋体）,

Leptospira

(钩端螺旋体

),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外周胞质(或壁膜间隙，是革兰氏阴性菌的细胞膜与外膜之间的间隔区域)backacrosstheoutermembrane(eg,extrusion挤压ofnafcillin萘夫西林

bySalmonellatyphimurium伤寒杆菌).AdverseReactions

(1)Hypersensitivereactions:

Thepenicillinsareremarkablynontoxic,thesafestofantibiotics.Mostoftheseriousadverseeffectsareduetohypersensitivity.

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

andproductsofalkalinehydrolysis碱解boundtohostprotein.Thepreventionofandtreatmentofanaphylacticreactions:

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

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

endocarditisorneurosyphilis神经梅毒inahighlypenicillin-allergicpatient),desensitizationcanbeaccomplishedwithgraduallyincreasingdosesofpenicillin.(2)Otheradversereactions:phlebitis静脉炎

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

ofnervetissue;andcentralnervoussystemexcitability.Inpatientswithrenalfailure,penicillininhighdosescancauseseizures.

Herxheimerreaction(赫氏反应):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（双氯西林）,Nafcillin

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

Amipicillin

(氨苄西林)，Carbenicillin（羧苄西林），Piperacillin（哌拉西林）,etc.①havesimilarantibacterialactivityandabroaderspectrum;②alldestroyedbyβ-lactamase.(1)Ampicillin

(氨苄西林),Amoxicillin(阿莫西林):

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

Ticarcillin（替卡西林）:

belongtotheantipseudomonal

penicillins.WithactivityagainstPseudomonasaeruginosa

andsomeProteus(变形杆菌属).(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

(头孢羟氨苄),

cefazolin

(头孢唑林),

cephalexin

(头孢氨苄),

cephalothin

(头孢菌素),

cephapirin

(头孢吡硫),andcephradine

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

(1)Oral(cephalexin

头孢氨苄,

cephradine头孢拉啶,andcefadroxil头孢羟氨苄):Urineconcentrationisusuallyveryhigh.Excretionismainlybyglomerularfiltrationandtubularsecretionintotheurine.Tubularsecretoryblockingagents,eg,probenecid,mayincreaseserumlevelssubstantially.Inpatientswithimpairedrenalfunction,dosagemustbereduced(Table37-2).(2)Parenteral:Afteranintravenousinfusionof1g,thepeaklevelofcefazolin头孢唑林

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

(1)Oraldrugsmaybeusedforthetreatmentofurinarytractinfections,forminorstaphylococcallesions,orforminorpolymicrobialinfectionssuchascellulitis

(蜂窝织炎)orsofttissueabscess.However,oralcephalosporinsshouldnotberelieduponinserioussystemicinfections.(2)Cefazolinpenetrateswellintomosttissues.Itisthedrugofchoiceforsurgicalprophylaxis.Cefazolindoesnotpenetratethecentralnervoussystemandcannotbeusedtotreatmeningitis.Cefazolinisanalternativetoanantistaphylococcalpenicillinforpatientswhoareallergictopenicillin.2.SECOND-GENERATIONCEPHALOSPORINS

Membersofthisgroupincludecefaclor头孢克洛,cefamandole头孢孟多,cefonicid头孢尼西,cefuroxime头孢呋新,cefprozil头孢罗齐,loracarbef罗拉卡贝

andceforanide头孢雷特andthestructurallyrelatedcephamycins头霉素类

cefoxitin头孢西丁,cefmetazole头孢氰唑,cefotetan头霉双硫唑,whichhaveactivityagainstanaerobes.

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

(1)Oral:

Cefaclor头孢克洛,cefuroxime头孢呋新,cefprozil头孢罗齐,andloracarbef罗拉卡贝canbegivenorally.(2)Parenteral:

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

ClinicalUses

Theoralsecond-generationcephalosporinsareactiveagainstbeta-lactamase-producingHinfluenzae

(流感嗜血杆菌)orBranhamella

catarrhalis

(卡他菌属)andhavebeenprimarilyusedtotreatsinusitis鼻窦炎,otitis耳炎,orlowerrespiratorytractinfections,inwhichtheseorganismshaveanimportantrole.

Becauseoftheiractivityagainstanaerobes(includingBfragilis脆弱类杆菌),cefoxitin头孢西丁,cefotetan头霉双硫唑,orcefmetazole头孢氰唑canbeusefulinsuchmixedanaerobicinfectionsasperitonitis(腹膜炎)ordiverticulitis(憩室炎).

3.THIRD-GENERATIONCEPHALOSPORINS

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

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

Third-generationcephalosporinsareusedtotreatawidevarietyofseriousinfectionscausedbyorganismsthatareresistanttomostotherdrugs.Becauseoftheirpenetrationofthecentralnervoussystem,third-generationcephalosporinscanbeusedtotreatmeningitis.Otherpotentialindicationsincludeempiricaltherapyofsepsisofunknowncauseinboththeimmunocompetent

(免疫活性)andtheimmunocompromised

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

Cefepime

(头孢吡肟),isinmanywayssimilartothird-generationagents,butitismoreresistanttohydrolysisbychromosomalbeta-lactamasesandsomeextended-spectrumbeta-lactamasesthatinactivatemanyofthethird-generationcephalosporins.IthasgoodactivityagainstPaeruginosa铜绿假单胞菌,

Enterobacteriaceae(肠杆菌科),

Saureus(金葡菌),andSpneumoniae(肺炎球菌).Itishighlyactiveagainsthaemophilus嗜血杆菌属andneisseria奈瑟氏菌属.Unlikeceftazidime

头孢他啶,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血栓性静脉炎

afterintravenousinjection.Renaltoxicity,includinginterstitialnephritisandeventubularnecrosis,andhascausedthewithdrawalofcephaloridine

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

头孢孟多,moxalactam

羟羧氧酰胺菌素,cefmetazole

头孢氰唑,cefotetan

头霉双硫唑,cefoperazone

头孢哌酮)frequentlycausehypoprothrombinemia

(低凝血酶原血症)andbleedingdisorders.AdministrationofvitaminKcanpreventthis.Drugswiththemethylthiotetrazoleringcanalsocauseseveredisulfiram-like戒酒硫(双硫仑)样反应reactions;consequently,alcoholandalcohol-containingmedicationsmustbeavoided.

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

1.Cephamycins

(头霉素类)Itisfermentation发酵productsofstreptomyces

(链霉菌属)andsometotallysyntheticdrugssuchasmoxalactam

(头孢西丁)

resemblecephalosporins.Ithasthesimilarantibacterialactivityandspectrumtothe2ndgeneration

Cepharosporins.Forthetreatmentofanaerobicinfections.2.MONOBACTAMS(单环类)Aztreonam

(氨曲南),

Carumonam

(卡芦莫南):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(克拉维酸),

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

(免疫受损)andimmunocompetent

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

Thecarbapenems

(碳青霉烯类)arestructurallyrelatedtobeta-lactamantibiotics(Imipenem亚胺培南

andmeropenem(美洛培南).Imipenemhasawidespectrumwithgoodactivityagainstmanygram-negativerods,gram-positiveorganisms,andanaerobes.Itisresistanttomostbeta-lactamasesbutnotmetallo-beta-lactamases.Imipenemisinactivatedbydehydropeptidases氢肽酶(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(发热性)

neutropenic中性白细胞减少症patients.Themostcommonadverseeffectsofimipenemarenausea,vomiting,diarrhea,skinrashes,andreactionsattheinfusionsites.Excessivelevelsinpatientswithrenalfailuremayleadtoseizures.Meropenemislesslikelytocauseseizuresthanimipenem.Patientsallergictopenicillinsmaybeallergictocarbapenemsaswell.5.