1、-内酰胺类抗生素（英文PPT）-lactam antibioticsPenicillinsnClassificationnNarrow spectrum penicillinsnAntistaphylococcal penicillinsnBroad spectrum penicillinsnExtended spectrum penicillins(antipseudomonal penicillins).Mechanism of actionnLike all-lactam antibiotics,inhibit the synthesis of bacterial cell wall.n
2、Through inhibition transpeptidase enzymenThey are bactericidal on the actively growing bacteria.PharmacokineticsnAbsorptionnDepending on acid stability nAbsorption of most oral penicillins is impaired by food except amoxicillin .Metabolism&ExcretionnNot metabolised nExcreted unchanged in urinenProbe
3、necid blocks their secretionnNafcillin is mainly cleared by biliary routenOxacillin by both kidney&biliary route.DistributionnRelatively insoluble in lipid nPoor penetration into cells and BBBInflammation permits entrance into CSF.nProteins binding vary from 20%-90%Narrow spectrum penicillinsnPenici
4、llin G nShort duration nAcid unstablenPenicillinase sensitivenUsed in enterococcal endocarditis usually with aminoglycosides nTo prevent gonorrheal opthalmia in new born.Procaine penicillinnLong acting(every 12 h).nAcid unstable nPenicillinase sensitivenUsed to prevent subacute bacterial endocarditi
5、s due to dental extraction or tonsillectomy in patients with congenital or acquired valve disease.Benzathine penicillinnLong acting(every 3-4 weeks)nAcid unstable nPenicillinase sensitive nTreatment of-hemolytic streptococcal pharyngitis.nUsed as prophylaxis against reinfection with-hemolytic strept
6、ococci so prevent rheumatic fever.nOnce a week for 1-3 weeks for treatment of syphilis(2.4 milloion units I.M.)Phenoxymethyl penicillin(P.V)nLess effective than penicillin GnAcid stable nPenicillinase sensitive nShort acting nUsed in minor infections Penicillinase resistant to staphylococcal-lactama
7、se producernMethicillin acid unstablenNafcillin its absorption is erraticnOxacillin,Cloxacillin,Dicloxacillin(acid stable).nUsed in minor&severe Stap.infectionsBroad&Extended spectrum penicillinsnAminopenicillinsnCarboxypenicillinsnUreidopenicillinsAminopenicillins(Ampicillin&Amoxicillin)nTherapeuti
8、c usesn1)H.influenzan2)E.colin3)Salmonella&Shigella infections only ampicillinn4)Prophylaxis of infective endocarditisn5)Urinary tract infectionsn6)Effective against penicillin resistant pneumococciCarboxypenicillins(Ticarcillin)&Ureidopenicillin(Piperacillin)nEffective against pseudomonas aeruginos
9、a&Enterobacter.nPenicillinase sensitive nCan be given in combination with-lactamase inhibitors as clavulanic acid,sulbactam,tazobactam.Adverse effectsnHypersensitivity reactions nHigh dose in renal failure-seizurenNaficillin(neutropenia)nOxacillin(hepatitis)nMethicillin(nephritis)nB.S.P.(pseudomembr
10、aneous colitis)nSecondary infectionsProblems relating to use&misuse of penicillinsn1-90%of staphylococcal strains both in hospital or community are-lactamase producersn2-New generations of microorganisms as H.influenzae,N.gonorrhoeae or pneumococci are resistant to penicillinsn3-Broad spectrum penic
11、illins eradicate normal flora causing superinfectionsCephalosporinsnFirst-GenerationnCefazolin,Cephalexin,cephradin.nThey are very effective against gram-positive coccinThey are given orally,except cefazolin given I.V.I,or I.M.ExcretionnMainly through kidney nProbenecid block tubular secretion and i
12、ncrease plasma level.nThey can not cross B.B.B.Clinical usesnUrinary tract infectionsnMinor Staph.infections or minor polymicrobial infections as cellulitis or soft tissue abscess.nCefazolin is the drug of choice for surgical prophylaxis,also as alternative to antistaph.penicillin in allergic patien
13、ts.Second-GenerationsnCefaclor,Cefamandole,CefonicidnLess active against gram-positive bacteria than first generationnThey have extended gram negative effect nNo effect on P-aeruginosa or E-cocci.PharmacokineticsnGiven orally or parenterally nCan not cross B.B.B.nExcreted through kidney nCefonicid i
14、s highly protein binding Clinical uses nH-influenza infectionsnMixed anaerobic infections as peritonitis.nCommunity acquired pneumoniaThird-GenerationsnCefoperazone,Cefixime,CeftriaxonenThey have extended gram-negative spectrum.nHave an effect on P-aeruginosa.nNo effect on E-coli.PharmacokineticsnMa
15、in route I.V.I.nCefixime can be given orally nCeftriaxone has a long half-life(7-8h).can be given once every 24h.nCross B.B.B.nExcreted through kidney.Ceftriaxone through bile.Clinical usesnSerious infectionsnCefixime,first line in treatment of gonorrhea.nMeningitis nP-aeruginosa infections.Fourth-G
16、enerationsnCefepimenMore resistant to hydrolysis by-lactamasenActive against P-aeruginosa&E-colinClinical use as third generations.Adverse EffectsnAllergynThrombophilibitisnInterstitial nephritis and tubular necrosis mainly with cephaloridine.nCephalosporins that contain a methylthiotetrazole group
17、as cefamandole,cefperazone cause hypoprothrombinemianAnd bleeding disorders.nVit.K twice weekly can prevent this.nMethylthiotetrazole ring causes severe disulfiram-like reaction.nSuperinfections.nDiarrhea.CarbapenemsnImipenemnBctericidal,inhibit bacterial cell wall synthesis.nHas a wide spectrum of
18、activity nSensetive to metallo-lactamase.PharmacokineticsnNot absorbed orally,taken by I.V.I.nInactivated by dehydropeptidases in renal tubules,so it is given with an inhibitor of renal dehydropeptidases,cilastatin for clinical use.nPenetrates body tissues and fluids including c.s.f.Clinical uses nM
19、ixed aerobic and anaerobic infectionsnCarbapenem is the lactam of choice for treatment of enterobacter infections.nPseudomonal infections nIntraabdominal infections nFebrile neutropenic patientnSepticaemia.MeropenemnSimilar to imipenem but it is highly active against gram-negative aerobes.nNot degra
20、ded by renal dehydropeptidaseAdverse effectsnNausea,vomiting,diarrheanSkin rash and reaction at the site of infusionnHigh dose with imipenem in renal failure cause seizurenPatients allergic to penicillin may be allergic to carbapenems.MonobactamsnAztronamnActive only against gram-negative aerobic ba
21、cteria.nGiven I.V.nSimilar to-lactam in mechanism of action and adverse effects.Macrolides(MACROCYCLIC LACTONE RING 14-16 ATOMS)nErythromycin(14 atom lactone ring)nIs effective against nLegionella,cornybacteria,gram-positive cocci,chlamydia,helicobacternLess effective on gram-negative organisms.Mech
22、anism of actionnInhibit protein synthesis via binding to 50 S ribosomal RNA subunit.nBactericidal at high conc.and bacteriostatic at low conc.PharmacokineticsnDestroyed by stomach acid and must be administered with enteric coating.nFood interferes with absorptionnHalf-life 1.5hnExcreted mainly throu
23、gh bile,5%only in urine.nCross placenta not B.B.B.Clinical usesnDrug of choice of corynebacterial infections nChlamydial infectionsnCommunity acquired pneumonianMycoplasmanLegionellanPenicillin allergic patients.Adverse effectsnAnorexia,nausea,vomiting,diarrhea.nLiver toxicity especially with the es
24、tolate coat produce acute cholestatic hepatitis nDrug interactions as it is cytochrome p450 inhibitor.nHypersensitivity reactions.Clarithromycin(14 atom lactone ring)nAcid stablenMechanism of action as erythromycinnSpectrum as erythromycin but more active against Mycobacterium avium complex.m.leprae
25、.Toxoplasma gondii.nHalf life 6h.nMetabolised in liver(active metabolites).Partially excreted in urine nDrug interactions similar to erythromycinnHas a lower frequency of gastric upset nAnd less frequent dosing nMore tolerablenMore expensiveAzithromycin(15 lactone ring)nSame mechanism of action nSim
26、ilar spectrum as clarithromycin,but more active on H-influenza&chlamydia.nHalf-life 3 days.nRapidaly absorbed and well tolerated.nFree of drug interactionsnExcreated in bile and urine Clinical usesnUpper and lower respiratory tract infections nSkin infections nAlternative to penicillin in allergic p
27、atients nUrethritis or cervicitis mainly by chlamydial infections.Adverse effects nGstric upset(less than erythromycin)nAllergic nSuperinfections nLiver affectionTetracyclinesnBroad spectrum antibiotics nBacteriostatic,inhibits protein synthesis reversibly by binding to 30 S ribosomal subunits.Pharm
28、acokineticsnAbsorption:nPoorly absorbed 30%as chlortetracyclinenMedialy absorbed 60-70%as tetracycline,oxytetracycline and demeclocyclinenHighly absorbed 95-100%as doxycycline and minocycline.nAbsorption is impaired by food exceptDoxycycline and minocyclinenAbsorption of all preparations is impaired
29、 by divalent cations,milk and its products,antacids and alkaline pH.nPlasma protein binding 40-80%.nMinocycline reaches very high conc.In tears and saliva,makes it useful in eradication of meningococcal carrier.They cross placenta barrier.nExcreated through bile and urine nDoxycycline is eliminated
30、by nonrenal route.nAccording to half-life:nLong acting;doxycycline&minocyclinen(16-18h once daily).nIntermediate(12h)demeclocyclineShort acting(6-8h)oxy,tetracyclines.nClinical uses:nMycoplasma pneumonianChlamydial infectionsnRickettsial infectionsnSpirocatesnBrucellosisnAnthraxClinical usesnCholera
31、nTraveller,s diarrheanHelicobacter pylorinAcne(minocycline&doxycycline)nBronchitisnProtozoal infectionsnMinocycline to eradicate meningococci carrierNot used in:nStreptococcal&staphylococcal infections.nGonococcal infectionsnMeningococcal infectionsnTyphoid feverAdverse effectsnI.M.(pain&inflammatio
32、n)nI.V.(thrombophilbitis)nGastric upset(N.,V.,D.)nEnterocolitisnSuper infectionsnDamage growing bone&teeth.Adverse effectsnYellowish brown discolorationof teeth&dental caries.nLiver toxicity nKidney toxicity(tubular necrosis).nPhotosensitization(demeclocycine)nVestibular reaction(vertigo,dizziness,)
33、n(Doxycycline&minocycline).ContraindicationsnWith milk or its products,or antacids.nPregnancynChildren under 8 years.ChloramphenicolnBroad spectrum antibioticsnBacteriostatic,inhibits protein synthesis by binding to 50S ribosomal subunits.nRapidly&completely absorbednRapidly distributed nCross place
34、ntal barrier&B.B.B.nMetabolised in liver nExcreted mainly through urinenEnzyme inhibitor(p450)Clinical usesnSerious rickettsial infectionsnIn children whom tetracyclines are contraindicatednMeningitisnIn allergic patients to penicillinnTopically in bacterial eye infections except in chlamydial infec
35、tions.Adverse effectsnGastric upset(N.,V.,D.)nSuper infectionsnBone marrow depressionnGray baby syndromenHypersensitivity reactionsnDrug interactionsAminoglycosidesnBactericidal antibioticsnInhibits protein synthesis by binding to 30S ribosomal subunits.nActive against gram negative aerobic organism
36、s.nPoorly absorbed orallynGiven parenterally(I.M,I.V.)nNot freely cross BBBAminoglycosidesnExcreted mainly unchanged in urinenMore active in alkaline mediumnHave common adverse effects:nOtotoxicitynNephrotoxicitynNeuromuscular blocking effectnCNS(not common).Clinical usesnStreptomycinnT.B.in combina
37、tion with other antituberculous drugs.nEnterococcal endocarditis with penicillin.nSevere brucellosis with tetracyclineGentamicinnSevere infections caused by gram negative organisms as sepsis,urinary tract infections&pneumonia caused by pseudomonas.nTopically for the treatment of infected burns,wound
38、s,skin lesions,ocular,ear infections.TobramycinnMore active against pseudomonas than gentamicin.nIneffective against mycobacterianLess nephrotoxic and ototoxic than gentamicin.nUsed in treatment of bacteremia,osteomyelitis and pneumonia.AmikacinnHas the broadest spectrum nUsed for serious nosocomial
39、 infections by gram negative organisms.nIn T.B.as alternative to streptomycinnAtypical mycobacterial infections NeomycinnHighly nephrotoxic,used only orally for gut sterilization before surgery or topically in skin infections,burn or eye infections.Contraindications of aminoglycosidesnRenal dysfunct
40、ionnPregnancynDiminished hearing nMyasthenia gravisnRespiratory problemsPrecautions with:nLoop diureticsnCephalosporinsnMonitor plasma level is useful.nNeostigmine reverses respiratory depression.FLUOROQUINOLONES(Ciprofloxacin,ofloxacin,norfloxacinMechanism of action:nBlock bacterial DNA synthesis b
41、y inhibiting bacterial topoisomerase11(DNA gyrase)and topoisomerase 1V.nAntibacterial activity:nHighly active against gram-negative aerobic bacteria.nActive against gram-positive bacteria.nMycoplasma,chlamydia,legionella,mycobacteria.PharmacokineticsnWell absorbed orally.nWidely distributed in body
42、fluids&tissues.nHalf-life(3-10h).nAbsorption is impaired by antacids.nConcentrated mainly in prostate,kidney,neutrophils,macrophages.nExcreted through kidney.Clinical usesnU.T.I.caused by multidrug resistance organisms as pseudomonas.nBacterial diarrhea.nSoft tissues,bones,joints,intra-abdominal,res
43、piratory infections caused by multidrug resistance organisms.nGonococcal infections.nLegionellosis.nChlamydial urethritis or cervicitisnT.B&atypical T.B.Adverse effectsnN.V.D.nHeadache,dizziness,insomnianSkin rash,abnormal liver enzymes.nQT prolongationnDamage growing cartilage causing arthropathy.n
44、Tendinitis in adults Drug interactions&contraindicationsnWith antacidsnElevate serum levels of theophyline increase the risk of seizure.nContraindicated in children,adolescents,pregnancy,lactation,epileptic patients.Miscellaneous AntibioticsnPolymyxinsnActive against gram-negative including pseudomo
45、nas.nPolymyxin B is only available.nBactericidal inhibits cell wall synthesis.nUsed only topically.nHighly nephrotoxic.n SpectinomycinnBactericidal,inhibits protein synthesis by binding to 30S ribosomal subunits.nGiven I.M.I.as a single dose in treatment of gonorrhea.nPain at the site of injection.n
46、Excreted through kidney.nNephrotoxicity is rare.ClindamycinnActive against gram-positive and anaerobic bacteria.nInhibits protein synthesis by binding to 50S ribosomal subunits.nGiven orally or parenterallynWidely distributednCross placenta not BBB.nMetabolised in liver giving active metabolites.Exc
47、reted in bile&10%in urine.nClinical uses:nAnaerobic infections minly in bones and joints.nConjunctivitis.nIn combination with aminoglycosides or cephalosporin is used to treat penetrating wounds of the abdomen&the gut.nFemale genital tract e.g.septic abortion,pelvis abscess.nInstead of erythromycin
48、for prophylaxis of endocarditis.nAdverse effects:nDiarrhea,Pseudomembranous colitis,hepatotoxicity,bone marrow suppression.Other inhibitors to cell wall synthesisnVancomycinnBactericidalnActive only on gram+ve bacteria.nPoorly absorbed orally nGiven by I.v.InNot freely cross BBBnExcreted mainly thro
49、ugh kidneyClinical uses nEndocarditis mainly caused by methicillin resistant staphylococci.nAlternative to penicillin in enterococcal endocarditis(in combination with gentamicin).nMeningitis(in combination with ceftriaxone or rifampin in highly resistant pneumococcus strains).nOrally in antibiotic a
50、ssociated enterocolitisAdverse effects nIrritation at the site of injectionnOtotoxicity&nephrotoxicity.nRed man or red neck syndrome.nGastric upset.BacitracinnBactericidalnNo cross resistance between it and other antimicrobial drugs.nActive against gram+ve organismsnUsed only topically in skin,eye,n
