β-內(nèi)酰胺類抗生素(英文PPT)β-lactam-antibiotics課件

1、-內(nèi)酰胺類抗生素（英文PPT）-lactam antibioticsPenicillinsClassificationNarrow spectrum penicillinsAntistaphylococcal penicillinsBroad spectrum penicillinsExtended spectrum penicillins ( antipseudomonal penicillins).Mechanism of actionLike all -lactam antibiotics , inhibit the synthesis of bacterial cell wall .T

2、hrough inhibition transpeptidase enzymeThey are bactericidal on the actively growing bacteria.PharmacokineticsAbsorptionDepending on acid stability Absorption of most oral penicillins is impaired by food except amoxicillin .Metabolism & ExcretionNot metabolised Excreted unchanged in urineProbenecid

3、blocks their secretionNafcillin is mainly cleared by biliary routeOxacillin by both kidney & biliary route.DistributionRelatively insoluble in lipid Poor penetration into cells and BBBInflammation permits entrance into CSF.Proteins binding vary from 20%-90%Narrow spectrum penicillinsPenicillin G Sho

4、rt duration Acid unstablePenicillinase sensitiveUsed in enterococcal endocarditis usually with aminoglycosides To prevent gonorrheal opthalmia in new born .Procaine penicillinLong acting (every 12 h ) .Acid unstable Penicillinase sensitiveUsed to prevent subacute bacterial endocarditis due to dental

5、 extraction or tonsillectomy in patients with congenital or acquired valve disease .Benzathine penicillinLong acting (every 3-4 weeks )Acid unstable Penicillinase sensitive Treatment of -hemolytic streptococcal pharyngitis.Used as prophylaxis against reinfection with - hemolytic streptococci so prev

6、ent rheumatic fever .Once a week for 1-3 weeks for treatment of syphilis (2.4 milloion units I.M.)Phenoxymethyl penicillin (P. V)Less effective than penicillin GAcid stable Penicillinase sensitive Short acting Used in minor infections Penicillinase resistant to staphylococcal -lactamase producerMeth

7、icillin acid unstableNafcillin its absorption is erraticOxacillin, Cloxacillin,Dicloxacillin (acid stable ).Used in minor & severe Stap. infectionsBroad &Extended spectrum penicillinsAminopenicillinsCarboxypenicillinsUreidopenicillinsAminopenicillins(Ampicillin &Amoxicillin)Therapeutic uses1)H.influ

8、enza2)E.coli3)Salmonella&Shigella infections only ampicillin4)Prophylaxis of infective endocarditis5) Urinary tract infections6) Effective against penicillin resistant pneumococciCarboxypenicillins(Ticarcillin)&Ureidopenicillin(Piperacillin)Effective against pseudomonas aeruginosa & Enterobacter.Pen

9、icillinase sensitive Can be given in combination with -lactamase inhibitors as clavulanic acid ,sulbactam, tazobactam.Adverse effectsHypersensitivity reactions High dose in renal failure -seizureNaficillin (neutropenia)Oxacillin (hepatitis)Methicillin(nephritis)B.S.P.(pseudomembraneous colitis )Seco

10、ndary infectionsProblems relating to use & misuse of penicillins1- 90% of staphylococcal strains both in hospital or community are -lactamase producers2- New generations of microorganisms as H.influenzae , N.gonorrhoeae or pneumococci are resistant to penicillins3- Broad spectrum penicillins eradica

11、te normal flora causing superinfectionsCephalosporinsFirst-GenerationCefazolin, Cephalexin, cephradin.They are very effective against gram- positive cocciThey are given orally ,except cefazolin given I.V.I ,or I.M.ExcretionMainly through kidney Probenecid block tubular secretion and increase plasma

12、level .They can not cross B.B.B.Clinical usesUrinary tract infectionsMinor Staph.infections or minor polymicrobial infections as cellulitis or soft tissue abscess.Cefazolin is the drug of choice for surgical prophylaxis,also as alternative to antistaph.penicillin in allergic patients .Second -Genera

13、tionsCefaclor ,Cefamandole, CefonicidLess active against gram-positive bacteria than first generationThey have extended gram negative effect No effect on P-aeruginosa or E-cocci.PharmacokineticsGiven orally or parenterally Can not cross B.B.B.Excreted through kidney Cefonicid is highly protein bindi

14、ng Clinical uses H-influenza infectionsMixed anaerobic infections as peritonitis .Community acquired pneumoniaThird -GenerationsCefoperazone,Cefixime,CeftriaxoneThey have extended gram- negative spectrum.Have an effect on P-aeruginosa .No effect on E-coli.PharmacokineticsMain route I.V.I.Cefixime ca

15、n be given orally Ceftriaxone has a long half- life (7-8h).can be given once every 24h.Cross B.B.B.Excreted through kidney .Ceftriaxone through bile.Clinical usesSerious infectionsCefixime ,first line in treatment of gonorrhea.Meningitis P-aeruginosa infections.Fourth -GenerationsCefepimeMore resist

16、ant to hydrolysis by -lactamaseActive against P-aeruginosa & E-coliClinical use as third generations.Adverse EffectsAllergyThrombophilibitisInterstitial nephritis and tubular necrosis mainly with cephaloridine.Cephalosporins that contain a methylthiotetrazole group as cefamandole ,cefperazone cause

17、hypoprothrombinemiaAnd bleeding disorders .Vit.K twice weekly can prevent this .Methylthiotetrazole ring causes severe disulfiram-like reaction.Superinfections.Diarrhea.CarbapenemsImipenemBctericidal, inhibit bacterial cell wall synthesis.Has a wide spectrum of activity Sensetive to metallo- lactama

18、se .PharmacokineticsNot absorbed orally,taken by I.V.I.Inactivated by dehydropeptidases in renal tubules, so it is given with an inhibitor of renal dehydropeptidases,cilastatin for clinical use.Penetrates body tissues and fluids including c.s.f.Clinical uses Mixed aerobic and anaerobic infectionsCar

19、bapenem is the lactam of choice for treatment of enterobacter infections.Pseudomonal infections Intraabdominal infections Febrile neutropenic patientSepticaemia.MeropenemSimilar to imipenem but it is highly active against gram-negative aerobes .Not degraded by renal dehydropeptidaseAdverse effectsNa

20、usea,vomiting,diarrheaSkin rash and reaction at the site of infusionHigh dose with imipenem in renal failure cause seizurePatients allergic to penicillin may be allergic to carbapenems .MonobactamsAztronamActive only against gram-negative aerobic bacteria.Given I.V.Similar to -lactam in mechanism of

21、 action and adverse effects.Macrolides(MACROCYCLIC LACTONE RING 14-16 ATOMS)Erythromycin(14 atom lactone ring )Is effective against Legionella,cornybacteria,gram-positive cocci,chlamydia,helicobacterLess effective on gram-negative organisms.Mechanism of actionInhibit protein synthesis via binding to

22、 50 S ribosomal RNA subunit.Bactericidal at high conc.and bacteriostatic at low conc.PharmacokineticsDestroyed by stomach acid and must be administered with enteric coating .Food interferes with absorptionHalf-life 1.5hExcreted mainly through bile,5%only in urine.Cross placenta not B.B.B.Clinical us

23、esDrug of choice of corynebacterial infections Chlamydial infectionsCommunity acquired pneumoniaMycoplasmaLegionellaPenicillin allergic patients.Adverse effectsAnorexia,nausea,vomiting,diarrhea.Liver toxicity especially with the estolate coat produce acute cholestatic hepatitis Drug interactions as

24、it is cytochrome p450 inhibitor.Hypersensitivity reactions .Clarithromycin(14 atom lactone ring)Acid stableMechanism of action as erythromycinSpectrum as erythromycin but more active against Mycobacterium avium complex.m.leprae.Toxoplasma gondii.Half life 6h.Metabolised in liver (active metabolites

25、).Partially excreted in urine Drug interactions similar to erythromycinHas a lower frequency of gastric upset And less frequent dosing More tolerableMore expensiveAzithromycin(15 lactone ring )Same mechanism of action Similar spectrum as clarithromycin,but more active on H-influenza &chlamydia.Half-

26、life 3 days .Rapidaly absorbed and well tolerated .Free of drug interactionsExcreated in bile and urine Clinical usesUpper and lower respiratory tract infections Skin infections Alternative to penicillin in allergic patients Urethritis or cervicitis mainly by chlamydial infections .Adverse effects G

27、stric upset (less than erythromycin )Allergic Superinfections Liver affectionTetracyclinesBroad spectrum antibiotics Bacteriostatic,inhibits protein synthesis reversibly by binding to 30 S ribosomal subunits .PharmacokineticsAbsorption:Poorly absorbed 30% as chlortetracyclineMedialy absorbed 60-70%

28、as tetracycline ,oxytetracycline and demeclocyclineHighly absorbed 95-100% as doxycycline and minocycline.Absorption is impaired by food exceptDoxycycline and minocyclineAbsorption of all preparations is impaired by divalent cations,milk and its products ,antacids and alkaline pH.Plasma protein bind

29、ing 40-80%.Minocycline reaches very high conc. In tears and saliva, makes it useful in eradication of meningococcal carrier.They cross placenta barrier .Excreated through bile and urine Doxycycline is eliminated by nonrenal route .According to half-life :Long acting; doxycycline &minocycline(16-18h

30、once daily ).Intermediate (12h) demeclocyclineShort acting (6-8h)oxy,tetracyclines.Clinical uses:Mycoplasma pneumoniaChlamydial infectionsRickettsial infectionsSpirocatesBrucellosisAnthraxClinical usesCholeraTraveller,s diarrheaHelicobacter pyloriAcne(minocycline&doxycycline)BronchitisProtozoal infe

31、ctionsMinocycline to eradicate meningococci carrierNot used in:Streptococcal & staphylococcal infections .Gonococcal infectionsMeningococcal infectionsTyphoid feverAdverse effectsI.M.(pain & inflammation)I.V.(thrombophilbitis)Gastric upset (N.,V.,D.)EnterocolitisSuper infectionsDamage growing bone &

32、teeth.Adverse effectsYellowish brown discolorationof teeth &dental caries.Liver toxicity Kidney toxicity (tubular necrosis).Photosensitization(demeclocycine)Vestibular reaction(vertigo,dizziness,)(Doxycycline &minocycline).ContraindicationsWith milk or its products,or antacids.PregnancyChildren unde

33、r 8 years.ChloramphenicolBroad spectrum antibioticsBacteriostatic,inhibits protein synthesis by binding to 50S ribosomal subunits.Rapidly &completely absorbedRapidly distributed Cross placental barrier &B.B.B.Metabolised in liver Excreted mainly through urineEnzyme inhibitor(p450)Clinical usesSeriou

34、s rickettsial infectionsIn children whom tetracyclines are contraindicatedMeningitisIn allergic patients to penicillinTopically in bacterial eye infections except in chlamydial infections.Adverse effectsGastric upset (N.,V.,D.)Super infectionsBone marrow depressionGray baby syndromeHypersensitivity

35、reactionsDrug interactionsAminoglycosidesBactericidal antibioticsInhibits protein synthesis by binding to 30S ribosomal subunits.Active against gram negative aerobic organisms.Poorly absorbed orallyGiven parenterally (I.M,I.V.)Not freely cross BBBAminoglycosidesExcreted mainly unchanged in urineMore

36、 active in alkaline mediumHave common adverse effects :OtotoxicityNephrotoxicityNeuromuscular blocking effectCNS (not common ).Clinical usesStreptomycinT.B. in combination with other antituberculous drugs.Enterococcal endocarditis with penicillin.Severe brucellosis with tetracyclineGentamicinSevere

37、infections caused by gram negative organisms as sepsis ,urinary tract infections & pneumonia caused by pseudomonas.Topically for the treatment of infected burns,wounds,skin lesions,ocular, ear infections.TobramycinMore active against pseudomonas than gentamicin.Ineffective against mycobacteriaLess n

38、ephrotoxic and ototoxic than gentamicin.Used in treatment of bacteremia, osteomyelitis and pneumonia.AmikacinHas the broadest spectrum Used for serious nosocomial infections by gram negative organisms.In T.B. as alternative to streptomycinAtypical mycobacterial infections NeomycinHighly nephrotoxic

39、,used only orally for gut sterilization before surgery or topically in skin infections,burn or eye infections.Contraindications of aminoglycosidesRenal dysfunctionPregnancyDiminished hearing Myasthenia gravisRespiratory problemsPrecautions with:Loop diureticsCephalosporinsMonitor plasma level is use

40、ful.Neostigmine reverses respiratory depression.FLUOROQUINOLONES(Ciprofloxacin,ofloxacin,norfloxaciMechanism of action: Block bacterial DNA synthesis by inhibiting bacterial topoisomerase11(DNA gyrase ) and topoisomerase 1V.Antibacterial activity :Highly active against gram-negative aerobic bacteria

41、.Active against gram-positive bacteria.Mycoplasma,chlamydia,legionella,mycobacteria.PharmacokineticsWell absorbed orally.Widely distributed in body fluids & tissues.Half-life(3-10h).Absorption is impaired by antacids.Concentrated mainly in prostate,kidney,neutrophils ,macrophages.Excreted through ki

42、dney. Clinical usesU.T.I.caused by multidrug resistance organisms as pseudomonas.Bacterial diarrhea.Soft tissues,bones,joints,intra-abdominal, respiratory infections caused by multidrug resistance organisms.Gonococcal infections.Legionellosis.Chlamydial urethritis or cervicitisT.B & atypical T.B.Adv

43、erse effectsN.V.D.Headache,dizziness,insomniaSkin rash ,abnormal liver enzymes.QT prolongationDamage growing cartilage causing arthropathy.Tendinitis in adults Drug interactions & contraindicationsWith antacidsElevate serum levels of theophyline increase the risk of seizure.Contraindicated in childr

44、en ,adolescents ,pregnancy ,lactation ,epileptic patients.Miscellaneous AntibioticsPolymyxinsActive against gram-negative including pseudomonas.Polymyxin B is only available.Bactericidal inhibits cell wall synthesis.Used only topically .Highly nephrotoxic. SpectinomycinBactericidal,inhibits protein

45、synthesis by binding to 30S ribosomal subunits.Given I.M.I.as a single dose in treatment of gonorrhea.Pain at the site of injection.Excreted through kidney .Nephrotoxicity is rare.ClindamycinActive against gram-positive and anaerobic bacteria.Inhibits protein synthesis by binding to 50S ribosomal su

46、bunits.Given orally or parenterallyWidely distributedCross placenta not BBB.Metabolised in liver giving active metabolites.Excreted in bile & 10% in urine.Clinical uses:Anaerobic infections minly in bones and joints .Conjunctivitis.In combination with aminoglycosides or cephalosporin is used to trea

47、t penetrating wounds of the abdomen & the gut.Female genital tract e.g. septic abortion ,pelvis abscess.Instead of erythromycin for prophylaxis of endocarditis.Adverse effects :Diarrhea,Pseudomembranous colitis,hepatotoxicity,bone marrow suppression.Other inhibitors to cell wall synthesisVancomycinBactericidalActive only on gram +ve bacteria.Poorly absorbed orally Given by I.v.INot freely cross