² Lactam antibiotics

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  • 1. -Lactam Antibiotics 1. PENICILLINS 2.Cephalosporins 3.Carbapenems ( Imipenems ) 4. Monobactams ( Aztreonam)

2. Penicillins Classification Narrow spectrum penicillins Antistaphylococcal penicillins Broad spectrum penicillins Extended spectrum penicillins ( antipseudomonal penicillins). 3. Mechanism of action Like all -lactam antibiotics , inhibit the synthesis of bacterial cell wall . Through inhibition transpeptidase enzyme They are bactericidal on the actively growing bacteria. 4. Pharmacokinetics Absorption Depending on acid stability Absorption of most oral penicillins is impaired by food except amoxicillin . 5. 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. 6. Distribution Relatively insoluble in lipid Poor penetration into cells and BBB Inflammation permits entrance into CSF. Proteins binding vary from 20%-90% 7. 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 . 8. Procaine penicillin Long acting (every 12 h ) . Acid unstable Penicillinase sensitive Used to prevent subacute bacterial endocarditis due to dental extraction or tonsillectomy in patients with congenital or acquired valve disease . 9. Benzathine penicillin Long acting (every 3-4 weeks ) Acid unstable Penicillinase sensitive Treatment of -hemolytic 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.) 10. Phenoxymethyl penicillin (P. V) Less effective than penicillin G Acid stable Penicillinase sensitive Short acting Used in minor infections 11. 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 12. Broad &Extended spectrum penicillins Aminopenicillins Carboxypenicillins Ureidopenicillins 13. 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 pneumococci 14. Carboxypenicillins(Ticarcillin)&Ur eidopenicillin(Piperacillin) Effective against pseudomonas aeruginosa & Enterobacter. Penicillinase sensitive Can be given in combination with - lactamase inhibitors as clavulanic acid ,sulbactam, tazobactam. 15. Adverse effects Hypersensitivity reactions High dose in renal failure ---seizure Naficillin (neutropenia) Oxacillin (hepatitis) Methicillin(nephritis) B.S.P.(pseudomembraneous colitis ) Secondary infections 16. Problems relating to use & misuse of penicillins 1- 90% of staphylococcal strains both in hospital or community are -lactamase producers 2- New generations of microorganisms as H.influenzae , N.gonorrhoeae or pneumococci are resistant to penicillins 3- Broad spectrum penicillins eradicate normal flora causing superinfections 17. Cephalosporins First-Generation Cefazolin, Cephalexin, cephradin. They are very effective against gram- positive cocci They are given orally ,except cefazolin given I.V.I ,or I.M. 18. Excretion Mainly through kidney Probenecid block tubular secretion and increase plasma level . They can not cross B.B.B. 19. Clinical uses Urinary tract infections Minor 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 . 20. Second -Generations Cefaclor ,Cefamandole, Cefonicid Less active against gram-positive bacteria than first generation They have extended gram negative effect No effect on P-aeruginosa or E-cocci. 21. Pharmacokinetics Given orally or parenterally Can not cross B.B.B. Excreted through kidney Cefonicid is highly protein binding 22. Clinical uses H-influenza infections Mixed anaerobic infections as peritonitis . Community acquired pneumonia 23. Third -Generations Cefoperazone,Cefixime,Ceftriaxone They have extended gram- negative spectrum. Have an effect on P-aeruginosa . No effect on E-coli. 24. 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 .Ceftriaxone through bile. 25. Clinical uses Serious infections Cefixime ,first line in treatment of gonorrhea. Meningitis P-aeruginosa infections. 26. Fourth -Generations Cefepime More resistant to hydrolysis by - lactamase Active against P-aeruginosa & E-coli Clinical use as third generations. 27. Adverse Effects Allergy Thrombophilibitis Interstitial nephritis and tubular necrosis mainly with cephaloridine. Cephalosporins that contain a methylthiotetrazole group as cefamandole ,cefperazone cause hypoprothrombinemia 28. And bleeding disorders . Vit.K twice weekly can prevent this . Methylthiotetrazole ring causes severe disulfiram-like reaction. Superinfections. Diarrhea. 29. Carbapenems Imipenem Bctericidal, inhibit bacterial cell wall synthesis. Has a wide spectrum of activity Sensetive to metallo- lactamase . 30. Pharmacokinetics Not 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. 31. Clinical uses Mixed aerobic and anaerobic infections Carbapenem is the lactam of choice for treatment of enterobacter infections. Pseudomonal infections Intraabdominal infections Febrile neutropenic patient Septicaemia. 32. Meropenem Similar to imipenem but it is highly active against gram-negative aerobes . Not degraded by renal dehydropeptidase 33. Adverse effects Nausea,vomiting,diarrhea Skin rash and reaction at the site of infusion High dose with imipenem in renal failure cause seizure Patients allergic to penicillin may be allergic to carbapenems . 34. Monobactams Aztronam Active only against gram-negative aerobic bacteria. Given I.V. Similar to -lactam in mechanism of action and adverse effects. 35. Macrolides(MACROCYCLIC LACTONE RING 14-16 ATOMS) Erythromycin(14 atom lactone ring ) Is effective against Legionella,cornybacteria,gram-positive cocci,chlamydia,helicobacter Less effective on gram-negative organisms. 36. Mechanism of action Inhibit protein synthesis via binding to 50 S ribosomal RNA subunit. Bactericidal at high conc.and bacteriostatic at low conc. 37. 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. 38. Clinical uses Drug of choice of corynebacterial infections Chlamydial infections Community acquired pneumonia Mycoplasma Legionella Penicillin allergic patients. 39. 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 . 40. Clarithromycin(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 ). 41. Partially excreted in urine Drug interactions similar to erythromycin Has a lower frequency of gastric upset And less frequent dosing More tolerable More expensive 42. 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 . Free of drug interactions Excreated in bile and urine 43. Clinical uses Upper and lower respiratory tract infections Skin infections Alternative to penicillin in allergic patients Urethritis or cervicitis mainly by chlamydial infections . 44. Adverse effects Gstric upset (less than erythromycin ) Allergic Superinfections Liver affection 45. Tetracyclines Broad spectrum antibiotics Bacteriostatic,inhibits protein synthesis reversibly by binding to 30 S ribosomal subunits . 46. Pharmacokinetics Absorption: Poorly absorbed 30% as chlortetracycline Medialy absorbed 60-70% as tetracycline ,oxytetracycline and demeclocycline Highly absorbed 95-100% as doxycycline and minocycline. Absorption is impaired by food except 47. 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 very high conc. In tears and saliva, makes it useful in eradication of meningococcal carrier. 48. 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 (12h) demeclocycline 49. Short acting (6- 8h)oxy,tetracyclines. Clinical uses: Mycoplasma pneumonia Chlamydial infections Rickettsial infections Spirocates Brucellosis Anthrax 50. Clinical uses Cholera Traveller,s diarrhea Helicobacter pylori Acne(minocycline&doxycycline) Bronchitis Protozoal infections Minocycline to erad