Macrolide (l)

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Macrolide (l)

  1. 1. • 1952 Erythromycin • 1970s Acetylspiramycin Medecamycin, Josamycin • 1980s Clarithromycin Roxithromycin Azithromycin 10/5/2013
  2. 2. • Belong to the Polyketide class of natural products. • A group of antibiotics consisting of a macrolide ring • A large lactone ring to which one or more deoxy sugars, are attached. • The lactone ring can be either 14, 15 or 16 membered. 10/5/2013
  3. 3. • Naturally-occurring macrolide derived from Streptomyces erythreus • Problems with erythromycin • Acid labile • Narrow spectrum • Poor GI tolerance • Short elimination half-life 10/5/2013
  4. 4. Clarithromycin and Azithromycin • Broader spectrum of activity • Improved PK properties – • Better bioavailability • Better tissue penetration • Prolonged half-lives • Improved tolerability 10/5/2013
  5. 5. • Inhibits protein synthesis by reversibly binding to the 50S ribosomal subunit • Suppression of RNA-dependent protein synthesis by inhibition of translocation of mRNA • Typically bacteriostatic activity • Bactericidal at high concentrations against very susceptible organisms 10/5/2013
  6. 6. 10/5/2013 RAHUL
  7. 7. 10/5/2013
  8. 8. Gram-Positive Aerobes : Erythromycin & clarithromycin display the best activity (Clarithro>Erythro>Azithro) • Methicillin-susceptible Staphylococcus aureus • Streptococcus pneumoniae (only PSSP) – resistance is developing • Group and viridans streptococci • Bacillus sp. • Corynebacterium sp. 10/5/2013
  9. 9. Gram-Negative Aerobes – Newer macrolides with enhanced activity (Azithro>Clarithro>Erythro) •H. influenzae (not erythro), •M. catarrhalis, •Neisseria sp. • Do NOT have activity against any Enterobacteriaceae 10/5/2013
  10. 10. Anaerobes – Upper airway anaerobes Atypical Bacteria – All have excellent activity • Legionella pneumophila - DOC • Chlamydia sp. • Mycoplasma sp. • Ureaplasma 10/5/2013
  11. 11. Other Bacteria – • Mycobacterium avium complex (MAC – only A and C), • Treponema pallidum, • Campylobacter • Borrelia, Bordetella • Brucella • Pasteurella 10/5/2013
  12. 12. Activity Erythro Azithro Clarithro H. infuenzae ++ +++ ++ Moraxella catarahalis ++ +++ ++ Mycoplasma ++ +++ ++ Legionella ++ +++ ++ Strepto/staph +++ ++ +++ 10/5/2013
  13. 13. Absorption Erythromycin – variable absorption, food may decrease the absorption • Base: destroyed by gastric acid; enteric coated • Esters and ester salts: more acid stable Clarithromycin – acid stable and well- absorbed regardless of presence of food Azithromycin –acid stable; food decreases absorption of capsules 10/5/2013
  14. 14. Distribution  Extensive tissue and cellular distribution  clarithromycin and azithromycin with extensive penetration  Minimal CSF penetration 10/5/2013
  15. 15. Elimination  Clarithromycin is the only macrolide partially eliminated by the kidney (18% of parent and all metabolites)  Hepatically eliminated: ALL  NONE of the macrolides are removed during hemodialysis !....  Variable elimination half-lives  1.4 hours for erythr 3 to 7 hours for clarithro;  68 hours for azithro 10/5/2013
  16. 16. • Gastrointestinal – up to 33 % Nausea, vomiting, diarrhea, dyspepsia Gastic pain, cramps Most common with erythro; less with new agents • Cholestatic hepatitis - rare  > 1 to 2 weeks of erythromycin estolate • Thrombophlebitis – IV Erythro and Azithro Dilution of dose; slow administration • Other: Ototoxicity (high dose erythro ); QTc prolongation; Allergy 10/5/2013
  17. 17. Erythromycin and Clarithromycin ONLY– are inhibitors of cytochrome p450 system in the liver; may increase concentrations of: Theophylline Digoxin, Disopyramide Carbamazepine Valproic acid Cyclosporine Terfenadine, Astemizole Phenytoin Cisapride Warfarin Ergot alkaloids 10/5/2013
  18. 18. • ENT infections , Tonsillitis, URTI • Mycoplasma pneumonie infections • Legionnaires Disease • Chlamydial infections (any macrolides) • Diphtheria (erythromycin) • Pertussis (erythromycin) 10/5/2013
  19. 19. • Strep/Staph Infections; alternatives in patients allergic to Penicillin • Prophylaxis against endocarditis in dental procedures • Campylobacter/ Helicobacter Infections :clarithro • Tetanus: in patients allergic to Penicillin • Mycobacterial Infections: Clathri / Azithro Ist choice 10/5/2013
  20. 20. “Drug of Choice” for  Mycoplasma pneumoniae Legionella pneumophila  Chlamydia pneumoniae, C. trachomatis Bordetella pertussis (whooping cough) C. diphtheriae Esters of erythromycin -sterate/estolate/ethylsuccinate are resistant to inactivation. 10/5/2013
  21. 21. • Advantages : • Broader spectrum, higher activity • Orally effective • High blood concentration • Longer t 1/2 • Less toxicity • Mainly used in respiratory tract infection 10/5/2013
  22. 22. • Strongest activity against mycoplasma pneumoniae. • Less effective against gram (+) bacteria than erythro /clarithro. • More effective on Gram-negative bacteria, H.influenzae, Legionella. • Excellent action against Toxoplasma gondii • Well tolerated • T1/2 :35~48h once daily • Mainly used in respitory tract infection 10/5/2013
  23. 23. • Excellent tissue concentration : 10- to 100- fold higher conc. than serum • prolonged persistence of good conc. in cells • 3- or 5-days therapy is possible (except for severe Legionella pneumonia) • Pregnant women infected with Scrub typhus : Azithromycin can substitute for doxycycline 10/5/2013
  24. 24. • 1987 France • Reaches highest blood concentration • Bioavailability upto 72%~85% • Respiratory tract infection and soft tissue infection • Low adverse effects 10/5/2013
  25. 25. • Has the strongest activity on Gram-positive bacteria, Legionella pneumophila, Chlamydia pneumoniae and H.pylori • Good pharmacokinetic property • Low toxicity USES : • Atypical mycobacterial infections (MAC) • Resistant leprosy • Toxoplasmosis • H.Pylori induced peptic ulcers. 10/5/2013
  26. 26. • Erythromycin: 1-2 g/ day divided into 4 doses • Clarithromycin: 250-500 mg twice a day. • Azithromycin: 250 mg/ day 10/5/2013

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