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Chapter 38 Macrolides, Lincomycins and Polymycins

Chapter 38 Macrolides, Lincomycins and Polymycins. 大环内酯类药物. 14 元大环内酯类 ：红霉素、 罗红霉素、克拉霉素 、地红霉素 15 元大环内酯类 ： 阿奇霉素 16 元大环内酯类 ：螺旋霉素、乙酰螺旋霉素、麦迪霉素、麦白霉素、罗他霉素、柱晶白霉素、交沙霉素、米欧卡霉素. Macrolides. First generation ： 1950’s—erythromycin Second generation ： 1970’s—claithromycin azithromycin

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Chapter 38 Macrolides, Lincomycins and Polymycins

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  1. Chapter 38 Macrolides, Lincomycins and Polymycins

  2. 大环内酯类药物 • 14元大环内酯类：红霉素、罗红霉素、克拉霉素、地红霉素 • 15元大环内酯类：阿奇霉素 • 16元大环内酯类：螺旋霉素、乙酰螺旋霉素、麦迪霉素、麦白霉素、罗他霉素、柱晶白霉素、交沙霉素、米欧卡霉素

  3. Macrolides • First generation ： 1950’s—erythromycin • Second generation：1970’s—claithromycin azithromycin • Third generation：

  4. Common properties of Macrolides

  5. Antibacterial activity • First generation • Most G+ organisms: pneumococci, streptococci, staphylococci , diphtheriae etc • Part G- organisms:legionella（军团菌）,bacillus pertussis(百日咳), brucella(布氏) etc • Others: mycoplasma(支原体), chlamydia trachomatis(沙眼衣原体), rickettsia(立克次体), spirochete ,anaerobes etc. • Second generation • More active on G- organisms

  6. Mechanism of action • Target 50s ribosomal RNA • Mechanism inhibition of translocation of mRNA

  7. Mechanism of resistance • Production of inactivating enzymes • Modification of the ribosomal binding site • Active efflux system • MLSR

  8. Pharmokinetics • Absorption • Erythromycin: not stable at acid pH • New macrolides: stable po • Distribution • Metabolism: • Erythromycin&clarithromycin: in liver • Excretion • Erythromycin&azithromycin: bile • Clarithromycin: kidney

  9. Commomly used macrolides

  10. Erythromycin • Antimicrobial activity • Gram-positive organisms: pneumococci, streptococci, staphylococci , diphtheriae etc • Gram-negative organisms:legionella（军团菌）,bacillus pertussis(百日咳), brucella(布氏) , meningococci, diplococcus gonorrhoeae etc • Others:mycoplasma(支原体), chlamydia trachomatis(沙眼衣原体), rickettsia(立克次体), spirochete ,anaerobes etc.

  11. Erythromycin • Clinical uses • As penicillin substitute in penicillin-allergic or resistant patients with infections caused by staphylococci, streptococci and pneumococci • Pertussis，diphtheriae • Legionella and mycoplasma pneumonia • H.p infection

  12. Erythromycin • Adverse reactions • Gastrointestinal effects • Liver toxicity • Cardiotoxicity

  13. Erythromycin • Erythromycin lactobionate(乳糖酸红霉素） • erythromycin estolate（无味红霉素) • erythromycin stearate(硬脂酸红霉素） • erythromycin ethylsuccinate（琥乙红霉素， 利君沙）

  14. New macrolides antibiotics • Advantage : • Broader spectrum, higher activity • Orally effective • High blood concentration • Longer t 1/2 • Less toxicity • Mainly used in respiratory tract infection

  15. Clarithromycin（甲红霉素,克拉霉素） • Has the strongest activity on Gram-positive bacteria, legionella pneumophila, chlamydia pneumoniae and H.p • Good pharmacokinetic property • Low toxicity

  16. Azithromycin (阿齐霉素,丽珠奇乐） • Has the strongest activity against mycoplasma pneumoniae（肺炎支原体） • More effective on Gram-negative bacteria • Well tolerated • T1/2 :35~48h once daily • Mainly used in respitory tract infection

  17. Roxithromycin（罗红霉素，严迪） • 1987 France • The highest blood concentration • F 72%~85% • Respiratory tract infection and soft tissue infection • Low adverse effects

  18. Lincomycin and Clindamycin • Antimicrobial activity • Gram-positive organisms • Bacteroide fragilis and other anaerobes • Mechanism • Binding to 50s ribosome subunit and inhibiting protein synthesis • Pharmacokinetics • Absorbed well • Penetrate well into most tissues including bone

  19. Clindaycin • Clinical uses • Severe anaerobic infection • Acute or chronical suppurative osteomylitis , arthritis caused by susceptive organisms especially Staphylococci aureus • Adverse reactions • Gastrointestinal effects: severe diarrhea and pseudomembranous enterocolitis caused by Clostridium difficile :vancomycin & metronidazole • Other :Impaired liver function , neutropenia

  20. Polypeptide antibiotics • Vancomycin & Teicoplanin • Polymyxins • bactitracin

  21. Vancomycin • Mechanism of action • Inhibit cell wall synthesis • Antimicrobial spectrum: • Narrow spectrum, active only against gram-positive bacteria paticularly staphylococci • Pharmacokinetics • Poorly absorbed from intestinal tract, iv • Excreted from glomerular filtration 90%

  22. Vancomycin • Clinical uses • Infection caused by MRSA, MRSE and penicillin-resistant pneumococcus • Treatment of antibiotic-associated enterocolitis caused by clostridium difficile po • Adverse reaction • Ototoxicity & nephrotoxicity • Red-man syndrome

  23. Teicoplanin • Similar to vancomycin in mechanism and antimicrobial spectrum • Can be given im as well as iv • Less adverse reactions

  24. Polymyxins • Active only against gram-negative rods, particularly P.aeruginosa • Mechanism:increase permeability of cell membrane • Mainly used in P.aeruginosa infection when other drugs are resistant • Toxicity: nephrotoxicity & neurotoxicity

  25. Baciteracin • Active against gram-positive bacteria • Inhibit cell wall formation • No cross-resistance with other agents • Topical use only because of nephrotoxicity

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