Macrolides, Lincomycins 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 Third generation：

Common properties of Macrolides

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

Mechanism of action Target 50s ribosomal RNA Mechanism inhibition of translocation of mRNA

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

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

Commomly used macrolides

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.

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

Erythromycin Adverse reactions Gastrointestinal effects Liver toxicity Cardiotoxicity

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）

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

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

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

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

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

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

Polypeptide antibiotics Vancomycin & Teicoplanin Polymyxins bactitracin

Vancomycin Mechanism of action Antimicrobial spectrum: 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%

Vancomycin Clinical uses Adverse reaction 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

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

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

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