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β-Lactam antibiotics

β-Lactam antibiotics. Classification. Penicillins Cephalosporins Other β-Lactam drugs Cephamycins （头霉素类） Carbapenems （碳青霉烯类） Oxacephalosporins （氧头孢烯类） β-Lactamase inhibitors （ β- 内酰胺酶抑制剂） Monolactums （单环 β- 内酰胺类）. Mechanism of action. Inhibiton of bacterial cell wall synthesis

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β-Lactam antibiotics

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  1. β-Lactam antibiotics

  2. Classification • Penicillins • Cephalosporins • Other β-Lactam drugs • Cephamycins（头霉素类） • Carbapenems（碳青霉烯类） • Oxacephalosporins （氧头孢烯类） • β-Lactamase inhibitors（ β-内酰胺酶抑制剂） • Monolactums（单环β-内酰胺类）

  3. Mechanism of action • Inhibiton of bacterial cell wall synthesis • Target: PBPs(penicillin-binding proteins) • Cell-wall autolytic enzyme

  4. Mechanism of resistance • Inactivation of drug by β-lactamase • Trapping mechanism • Modification of PBPs • Impared penetration of drug to target PBPs • Absence of autolysins

  5. Penicillins • History • Basic structure: 6-APA • Classification • Natural penicillins • Semisynthesized penicillins

  6. Penicillin G • Chemistry • Antimicrobial activity • Gram-positive cocci • Streptococci ,pneumococci , staphylcocci • Gram-positive rods • B.anthracis, diphtheriae, clostridium terani

  7. Penicillin G • Gram-negative cocci • Meningococci, diplococcus gonorrhoeae • Spirochete • treponema pallidum leptospirrosis

  8. Pharmacokinetics • Absorption • Distribution • metabolism • Excretion • 90% tubular secretion • 10% glomerular filtration

  9. Clinical uses First choice for the following infections • Infection caused by streptococci, pneumococci, meningococci etc • Infection caused by spirochetes • Infection caused by gram-positive rods

  10. Adverse reactions • Allergic reactions • Common: urticaria, fever,angioneurotic edema,eosinophlia, hemolytic anemia • Severe: anaphylactic shock • Herxheimer reaction

  11. Adverse reactions • Allergic reactions • Reason:degraded products of penicillin • Prevention: • History of allergic reactions • Skin test • Epinephrine

  12. Synthesized penicillins • Acid-resistant penicillins • Penicillinase-resistant penicillins • Extended-spectrum penicillins • Extended-spectrum penicillins against P.aeruginosa • Penicillins against gram-negative bacteria

  13. Acid-resistant penicillins • Drugs: penicillin V,phenethicillin • Character • Orally effective, not resist β-Lactamase • Lower potency than penicillin G • Clinical uses: moderate infections • Adverse reactions: allergic reaction

  14. Penicillinase-resistant penicillins • Drugs:oxacillin, cloxacillin, dicloxacillin • Clinical use • Infection caused by penicillin-resistant staphylococci

  15. Extended-spectrum penicillins • Ampicillin, amoxycillin, pivampicillin • Oral effective, susceptible to β-Lactamase • Broad spectrum: G+ G- • Clinical uses: infection caused by gram-negative rods

  16. Extended-spectrum Penicillins against P.aeruginosa • Carbenicillin,sulbencillin, ticarcillin, furbencillin, piperacillin, mezlocillin • Character: more activity on P.aeruginosa • Usually in combination with aminoglycosides

  17. Penicillins against gram-negative bacteria • Mecillinam, pivmecillinam, temocillin • Narrow-spectrum:mainly on G- rods • β-Lactamase resistant • Treatment of infections caused by G- rods

  18. Cephalosporins • Chemistry: 7-ACA • Classification: four generations • First-generation cephalosporins • Second- generation cephalosporins • Third-generation cephalosporins • Fourth- generation cephalosporins

  19. First-generation cephalosporins • Cephazolin, cephalothin,cefradine,cefalexin • Common characters: • Activity on gram-positive bacteria: first>second>third • Activity on gram-negative bacteria: first<second<third • Stability to β-Lactamase produced by gram-negative rods: first<second<third • Renal toxicity: first>second>third

  20. First-generation cephalosporins • Clinical uses • Penicillin-resistant staphylococcal infection • Minor to moderate infections caused by sensitive bacteria

  21. Second-generation cephalosporins • Cefamandole, cefuroxime,cefaclor • Common characters • More stable to β-Lactamase • More active on gram-negative bacteria • Less active on gram-positive bacteria • Less renal toxicity

  22. Second-generation cephalosporins • Effective on anaerobes • No effect on P.aeruginosa • Clinical uses • Gram-negative bacteria infections • Anaerobic infections

  23. Third-generation cephalosporins • Ceftriaxone, ceftazidime • Common characters • Much more active on gram-negative bacteria • Stable to extended β-Lactamase produced by gram-negative bacteria • Effective on anaerobes and P.aeruginosa • No renal toxicity • Penetrating body fluids and tissues well

  24. Third-generation cephalosporins • Clinical uses a wide variety of serious infections caused by organisms that are resistant to most other drugs

  25. Fourth- generation cephalosporins • Cefpirome,cefepime, cefclidin • Character: • Enhanced antimicrobial activity • Stable to ESBLs • More activity on gram-positive cocci • Clinical uses: • infections caused by organisms that are resistant to third-generation cephalosporins

  26. Other β-Lactam drugs

  27. Cephamycins • Cefoxitin • Similar to third-generation cephalosporins • More activity on anaerobes • Used to treat mixed anaerobic and aerobic infections

  28. Carbapenems • The most important antimicrobial agents in 1990’s • Wide spectrum and high activity • Resistant to mostβ-Lactamase(including ESBLs and cephalosporinase)

  29. Carbapenems • Thienamycin • Imipenem • Imipenem-cilastatin:tienam • Meropenem • Panipenem

  30. Oxacephalosporin • Latamoxef, flomoxef • Higher activity on anaerobes (especially Bacteroids fragilis)than third-generation cephalosporins • Well resitant to β-Lactamase

  31. β-Lactamase inhibitors • Clavulanic acid • Sulbactam • tazobactam

  32. β-Lactamase inhibitors • Weak antimicrobial action • Protect β-lactams from inactivation by β-lactamase • Synergism

  33. Monobactams • Aztreonam, carumonam • No effect on gram-positive bacteria and anaerobes • High activity on gram-negative bacteria • Penicillin-allergic patients tolerate well • Low toxcity

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