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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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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 • Target: PBPs(penicillin-binding proteins) • Cell-wall autolytic enzyme
Mechanism of resistance • Inactivation of drug by β-lactamase • Trapping mechanism • Modification of PBPs • Impared penetration of drug to target PBPs • Absence of autolysins
Penicillins • History • Basic structure: 6-APA • Classification • Natural penicillins • Semisynthesized penicillins
Penicillin G • Chemistry • Antimicrobial activity • Gram-positive cocci • Streptococci ,pneumococci , staphylcocci • Gram-positive rods • B.anthracis, diphtheriae, clostridium terani
Penicillin G • Gram-negative cocci • Meningococci, diplococcus gonorrhoeae • Spirochete • treponema pallidum leptospirrosis
Pharmacokinetics • Absorption • Distribution • metabolism • Excretion • 90% tubular secretion • 10% glomerular filtration
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
Adverse reactions • Allergic reactions • Common: urticaria, fever,angioneurotic edema,eosinophlia, hemolytic anemia • Severe: anaphylactic shock • Herxheimer reaction
Adverse reactions • Allergic reactions • Reason:degraded products of penicillin • Prevention: • History of allergic reactions • Skin test • Epinephrine
Synthesized penicillins • Acid-resistant penicillins • Penicillinase-resistant penicillins • Extended-spectrum penicillins • Extended-spectrum penicillins against P.aeruginosa • Penicillins against gram-negative bacteria
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
Penicillinase-resistant penicillins • Drugs:oxacillin, cloxacillin, dicloxacillin • Clinical use • Infection caused by penicillin-resistant staphylococci
Extended-spectrum penicillins • Ampicillin, amoxycillin, pivampicillin • Oral effective, susceptible to β-Lactamase • Broad spectrum: G+ G- • Clinical uses: infection caused by gram-negative rods
Extended-spectrum Penicillins against P.aeruginosa • Carbenicillin,sulbencillin, ticarcillin, furbencillin, piperacillin, mezlocillin • Character: more activity on P.aeruginosa • Usually in combination with aminoglycosides
Penicillins against gram-negative bacteria • Mecillinam, pivmecillinam, temocillin • Narrow-spectrum:mainly on G- rods • β-Lactamase resistant • Treatment of infections caused by G- rods
Cephalosporins • Chemistry: 7-ACA • Classification: four generations • First-generation cephalosporins • Second- generation cephalosporins • Third-generation cephalosporins • Fourth- generation cephalosporins
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
First-generation cephalosporins • Clinical uses • Penicillin-resistant staphylococcal infection • Minor to moderate infections caused by sensitive bacteria
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
Second-generation cephalosporins • Effective on anaerobes • No effect on P.aeruginosa • Clinical uses • Gram-negative bacteria infections • Anaerobic infections
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
Third-generation cephalosporins • Clinical uses a wide variety of serious infections caused by organisms that are resistant to most other drugs
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
Cephamycins • Cefoxitin • Similar to third-generation cephalosporins • More activity on anaerobes • Used to treat mixed anaerobic and aerobic infections
Carbapenems • The most important antimicrobial agents in 1990’s • Wide spectrum and high activity • Resistant to mostβ-Lactamase(including ESBLs and cephalosporinase)
Carbapenems • Thienamycin • Imipenem • Imipenem-cilastatin:tienam • Meropenem • Panipenem
Oxacephalosporin • Latamoxef, flomoxef • Higher activity on anaerobes (especially Bacteroids fragilis)than third-generation cephalosporins • Well resitant to β-Lactamase
β-Lactamase inhibitors • Clavulanic acid • Sulbactam • tazobactam
β-Lactamase inhibitors • Weak antimicrobial action • Protect β-lactams from inactivation by β-lactamase • Synergism
Monobactams • Aztreonam, carumonam • No effect on gram-positive bacteria and anaerobes • High activity on gram-negative bacteria • Penicillin-allergic patients tolerate well • Low toxcity