1、-Lactam Antibiotics,1. PENICILLINS 2.Cephalosporins3.Carbapenems ( Imipenems ) 4. Monobactams ( Aztreonam),Penicillins,Classification Narrow spectrum penicillins Antistaphylococcal penicillins Broad spectrum penicillins Extended spectrum penicillins ( antipseudomonal penicillins).,Mechanism of actio
2、n,Like all -lactam antibiotics , inhibit the synthesis of bacterial cell wall . Through inhibition transpeptidase enzyme They are bactericidal on the actively growing bacteria.,Pharmacokinetics,Absorption Depending on acid stability Absorption of most oral penicillins is impaired by food except amox
3、icillin .,Metabolism & Excretion,Not metabolised Excreted unchanged in urine Probenecid blocks their secretion Nafcillin is mainly cleared by biliary route Oxacillin by both kidney & biliary route.,Distribution,Relatively insoluble in lipid Poor penetration into cells and BBB Inflammation permits en
4、trance into CSF. Proteins binding vary from 20%-90%,Narrow spectrum penicillins,Penicillin G Short duration Acid unstable Penicillinase sensitive Used in enterococcal endocarditis usually with aminoglycosides To prevent gonorrheal opthalmia in new born .,Procaine penicillin,Long acting (every 12 h )
5、 . Acid unstable Penicillinase sensitive Used to prevent subacute bacterial endocarditis due to dental extraction or tonsillectomy in patients with congenital or acquired valve disease .,Benzathine penicillin,Long acting (every 3-4 weeks ) Acid unstable Penicillinase sensitive Treatment of -hemolyti
6、c streptococcal pharyngitis. Used as prophylaxis against reinfection with - hemolytic streptococci so prevent 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 G Acid stable Penicillinase sen
7、sitive Short acting Used in minor infections,Penicillinase resistant to staphylococcal -lactamase producer,Methicillin acid unstable Nafcillin its absorption is erratic Oxacillin, Cloxacillin,Dicloxacillin (acid stable ). Used in minor & severe Stap. infections,Broad &Extended spectrum penicillins,A
8、minopenicillins Carboxypenicillins Ureidopenicillins,Aminopenicillins(Ampicillin &Amoxicillin),Therapeutic uses 1)H.influenza 2)E.coli 3)Salmonella&Shigella infections only ampicillin 4)Prophylaxis of infective endocarditis 5) Urinary tract infections 6) Effective against penicillin resistant pneumo
9、cocci,Carboxypenicillins(Ticarcillin)&Ureidopenicillin(Piperacillin),Effective against pseudomonas aeruginosa & Enterobacter. Penicillinase sensitive Can be given in combination with -lactamase inhibitors as clavulanic acid ,sulbactam, tazobactam.,Adverse effects,Hypersensitivity reactions High dose
10、 in renal failure -seizure Naficillin (neutropenia) Oxacillin (hepatitis) Methicillin(nephritis) B.S.P.(pseudomembraneous colitis ) Secondary infections,Problems relating to use & misuse of penicillins,1- 90% of staphylococcal strains both in hospital or community are -lactamase producers 2- New gen
11、erations of microorganisms as H.influenzae , N.gonorrhoeae or pneumococci are resistant to penicillins 3- Broad spectrum penicillins eradicate normal flora causing superinfections,Cephalosporins,First-Generation Cefazolin, Cephalexin, cephradin. They are very effective against gram- positive cocci T
12、hey are given orally ,except cefazolin given I.V.I ,or I.M.,Excretion,Mainly through kidney Probenecid block tubular secretion and increase plasma level . They can not cross B.B.B.,Clinical uses,Urinary tract infections Minor Staph.infections or minor polymicrobial infections as cellulitis or soft t
13、issue abscess. Cefazolin is the drug of choice for surgical prophylaxis,also as alternative to antistaph.penicillin in allergic patients .,Second -Generations,Cefaclor ,Cefamandole, Cefonicid Less active against gram-positive bacteria than first generation They have extended gram negative effect No
14、effect on P-aeruginosa or E-cocci.,Pharmacokinetics,Given orally or parenterally Can not cross B.B.B. Excreted through kidney Cefonicid is highly protein binding,Clinical uses,H-influenza infections Mixed anaerobic infections as peritonitis . Community acquired pneumonia,Third -Generations,Cefoperaz
15、one,Cefixime,Ceftriaxone They have extended gram- negative spectrum. Have an effect on P-aeruginosa . No effect on E-coli.,Pharmacokinetics,Main route I.V.I. Cefixime can be given orally Ceftriaxone has a long half- life (7-8h).can be given once every 24h. Cross B.B.B. Excreted through kidney .Ceftr
16、iaxone through bile.,Clinical uses,Serious infections Cefixime ,first line in treatment of gonorrhea. Meningitis P-aeruginosa infections.,Fourth -Generations,Cefepime More resistant to hydrolysis by -lactamase Active against P-aeruginosa & E-coli Clinical use as third generations.,Adverse Effects,Al
17、lergy Thrombophilibitis Interstitial nephritis and tubular necrosis mainly with cephaloridine. Cephalosporins that contain a methylthiotetrazole group as cefamandole ,cefperazone cause hypoprothrombinemia,And bleeding disorders . Vit.K twice weekly can prevent this . Methylthiotetrazole ring causes
18、severe disulfiram-like reaction. Superinfections. Diarrhea.,Carbapenems,Imipenem Bctericidal, inhibit bacterial cell wall synthesis. Has a wide spectrum of activity Sensetive to metallo- lactamase .,Pharmacokinetics,Not absorbed orally,taken by I.V.I. Inactivated by dehydropeptidases in renal tubule
19、s, 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 infections Carbapenem is the lactam of choice for treatment of enterobacter infections. Pseudomonal infections Int
20、raabdominal infections Febrile neutropenic patient Septicaemia.,Meropenem,Similar to imipenem but it is highly active against gram-negative aerobes . Not degraded by renal dehydropeptidase,Adverse effects,Nausea,vomiting,diarrhea Skin rash and reaction at the site of infusion High dose with imipenem
21、 in renal failure cause seizure Patients allergic to penicillin may be allergic to carbapenems .,Monobactams,Aztronam Active only against gram-negative aerobic bacteria. Given I.V. Similar to -lactam in mechanism of action and adverse effects.,Macrolides(MACROCYCLIC LACTONE RING 14-16 ATOMS),Erythro
22、mycin(14 atom lactone ring ) Is effective against Legionella,cornybacteria,gram-positive cocci,chlamydia,helicobacter Less effective on gram-negative organisms.,Mechanism of action,Inhibit protein synthesis via binding to 50 S ribosomal RNA subunit. Bactericidal at high conc.and bacteriostatic at lo
23、w conc.,Pharmacokinetics,Destroyed by stomach acid and must be administered with enteric coating . Food interferes with absorption Half-life 1.5h Excreted mainly through bile,5%only in urine. Cross placenta not B.B.B.,Clinical uses,Drug of choice of corynebacterial infections Chlamydial infections C
24、ommunity acquired pneumonia Mycoplasma Legionella Penicillin allergic patients.,Adverse effects,Anorexia,nausea,vomiting,diarrhea. Liver toxicity especially with the estolate coat produce acute cholestatic hepatitis Drug interactions as it is cytochrome p450 inhibitor. Hypersensitivity reactions .,C
25、larithromycin(14 atom lactone ring),Acid stable Mechanism of action as erythromycin Spectrum as erythromycin but more active against Mycobacterium avium complex.m.leprae.Toxoplasma gondii. Half life 6h. Metabolised in liver (active metabolites ).,Partially excreted in urine,Drug interactions similar
26、 to erythromycin Has a lower frequency of gastric upset And less frequent dosing More tolerable More expensive,Azithromycin(15 lactone ring ),Same mechanism of action Similar spectrum as clarithromycin,but more active on H-influenza &chlamydia. Half-life 3 days . Rapidaly absorbed and well tolerated
27、 . Free of drug interactions Excreated in bile and urine,Clinical uses,Upper and lower respiratory tract infections Skin infections Alternative to penicillin in allergic patients Urethritis or cervicitis mainly by chlamydial infections .,Adverse effects,Gstric upset (less than erythromycin ) Allergi
28、c Superinfections Liver affection,Tetracyclines,Broad spectrum antibiotics Bacteriostatic,inhibits protein synthesis reversibly by binding to 30 S ribosomal subunits .,Pharmacokinetics,Absorption: Poorly absorbed 30% as chlortetracycline Medialy absorbed 60-70% as tetracycline ,oxytetracycline and d
29、emeclocycline Highly absorbed 95-100% as doxycycline and minocycline. Absorption is impaired by food except,Doxycycline and minocycline,Absorption of all preparations is impaired by divalent cations,milk and its products ,antacids and alkaline pH. Plasma protein binding 40-80%. Minocycline reaches v
30、ery 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 once daily ). Intermediate
31、(12h) demeclocycline,Short acting (6-8h)oxy,tetracyclines.,Clinical uses: Mycoplasma pneumonia Chlamydial infections Rickettsial infections Spirocates Brucellosis Anthrax,Clinical uses,Cholera Traveller,s diarrhea Helicobacter pylori Acne(minocycline&doxycycline) Bronchitis Protozoal infections Mino
32、cycline to eradicate meningococci carrier,Not used in:,Streptococcal & staphylococcal infections . Gonococcal infections Meningococcal infections Typhoid fever,Adverse effects,I.M.(pain & inflammation) I.V.(thrombophilbitis) Gastric upset (N.,V.,D.) Enterocolitis Super infections Damage growing bone
33、 &teeth.,Adverse effects,Yellowish brown discolorationof teeth &dental caries. Liver toxicity Kidney toxicity (tubular necrosis). Photosensitization(demeclocycine) Vestibular reaction(vertigo,dizziness,) (Doxycycline &minocycline).,Contraindications,With milk or its products,or antacids. Pregnancy C
34、hildren under 8 years.,Chloramphenicol,Broad spectrum antibiotics Bacteriostatic,inhibits protein synthesis by binding to 50S ribosomal subunits. Rapidly &completely absorbed Rapidly distributed Cross placental barrier &B.B.B. Metabolised in liver Excreted mainly through urine Enzyme inhibitor(p450)
35、,Clinical uses,Serious rickettsial infections In children whom tetracyclines are contraindicated Meningitis In allergic patients to penicillin Topically in bacterial eye infections except in chlamydial infections.,Adverse effects,Gastric upset (N.,V.,D.) Super infections Bone marrow depression Gray
36、baby syndrome Hypersensitivity reactions Drug interactions,Aminoglycosides,Bactericidal antibiotics Inhibits protein synthesis by binding to 30S ribosomal subunits. Active against gram negative aerobic organisms. Poorly absorbed orally Given parenterally (I.M,I.V.) Not freely cross BBB,Aminoglycosid
37、es,Excreted mainly unchanged in urine More active in alkaline medium Have common adverse effects : Ototoxicity Nephrotoxicity Neuromuscular blocking effect CNS (not common ).,Clinical uses,Streptomycin T.B. in combination with other antituberculous drugs. Enterococcal endocarditis with penicillin. S
38、evere brucellosis with tetracycline,Gentamicin,Severe 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.,Tobramycin,More active against pseudomon
39、as than gentamicin. Ineffective against mycobacteria Less nephrotoxic and ototoxic than gentamicin. Used in treatment of bacteremia, osteomyelitis and pneumonia.,Amikacin,Has the broadest spectrum Used for serious nosocomial infections by gram negative organisms. In T.B. as alternative to streptomyc
40、in Atypical mycobacterial infections,Neomycin,Highly nephrotoxic ,used only orally for gut sterilization before surgery or topically in skin infections,burn or eye infections.,Contraindications of aminoglycosides,Renal dysfunction Pregnancy Diminished hearing Myasthenia gravis Respiratory problems,P
41、recautions with:,Loop diuretics Cephalosporins Monitor plasma level is useful. Neostigmine reverses respiratory depression.,FLUOROQUINOLONES (Ciprofloxacin,ofloxacin,norfloxaci,Mechanism of action: Block bacterial DNA synthesis by inhibiting bacterial topoisomerase11(DNA gyrase ) and topoisomerase 1
42、V. Antibacterial activity : Highly active against gram-negative aerobic bacteria. Active against gram-positive bacteria. Mycoplasma,chlamydia,legionella,mycobacteria.,Pharmacokinetics,Well absorbed orally. Widely distributed in body fluids & tissues. Half-life(3-10h). Absorption is impaired by antac
43、ids. Concentrated mainly in prostate,kidney,neutrophils ,macrophages. Excreted through kidney.,Clinical uses,U.T.I.caused by multidrug resistance organisms as pseudomonas. Bacterial diarrhea. Soft tissues,bones,joints,intra-abdominal, respiratory infections caused by multidrug resistance organisms.
44、Gonococcal infections. Legionellosis. Chlamydial urethritis or cervicitis T.B & atypical T.B.,Adverse effects,N.V.D. Headache,dizziness,insomnia Skin rash ,abnormal liver enzymes. QT prolongation Damage growing cartilage causing arthropathy. Tendinitis in adults,Drug interactions & contraindications
45、,With antacids Elevate serum levels of theophyline increase the risk of seizure. Contraindicated in children ,adolescents ,pregnancy ,lactation ,epileptic patients.,Miscellaneous Antibiotics,Polymyxins Active against gram-negative including pseudomonas. Polymyxin B is only available. Bactericidal in
46、hibits cell wall synthesis. Used only topically . Highly nephrotoxic.,Spectinomycin,Bactericidal,inhibits protein 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.,C
47、lindamycin,Active against gram-positive and anaerobic bacteria. Inhibits protein synthesis by binding to 50S ribosomal subunits. Given orally or parenterally Widely distributed Cross placenta not BBB. Metabolised in liver giving active metabolites.,Excreted in bile & 10% in urine.,Clinical uses: Ana
48、erobic infections minly in bones and joints . Conjunctivitis. In combination with aminoglycosides or cephalosporin is used to treat penetrating wounds of the abdomen & the gut. Female genital tract e.g. septic abortion ,pelvis abscess. Instead of erythromycin for prophylaxis of endocarditis. Adverse
49、 effects : Diarrhea,Pseudomembranous colitis,hepatotoxicity,bone marrow suppression.,Other inhibitors to cell wall synthesis,Vancomycin Bactericidal Active only on gram +ve bacteria. Poorly absorbed orally Given by I.v.I Not freely cross BBB Excreted mainly through kidney,Clinical uses,Endocarditis mainly caused by methicillin resistant staphylococci. Alternative to penicillin in enterococcal endocarditis( in combination with gentamicin). Meningitis( in combination with ceftriaxone or rifampin in highly resistant pneumococcus strains). Orally in antibiotic associated enterocolitis,
