Macrolide (l)
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This document discusses macrolide antibiotics, including their history, mechanisms of action, antimicrobial spectra, pharmacokinetic properties, clinical uses, and dosing. It describes the development of erythromycin in 1952 and subsequent generations including clarithromycin, azithromycin, and others. These antibiotics inhibit protein synthesis by binding the bacterial ribosome. Newer macrolides like azithromycin and clarithromycin have broader spectra, better tolerability, and longer half-lives compared to erythromycin. Common uses include respiratory, genitourinary, and skin infections.
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Macrolide (l)
- 2. • 1952 Erythromycin • 1970s Acetylspiramycin Medecamycin, Josamycin • 1980s Clarithromycin Roxithromycin Azithromycin 10/5/2013
- 3. • 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
- 4. • Naturally-occurring macrolide derived from Streptomyces erythreus • Problems with erythromycin • Acid labile • Narrow spectrum • Poor GI tolerance • Short elimination half-life 10/5/2013
- 5. Clarithromycin and Azithromycin • Broader spectrum of activity • Improved PK properties – • Better bioavailability • Better tissue penetration • Prolonged half-lives • Improved tolerability 10/5/2013
- 6. • 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
- 8. 10/5/2013
- 9. 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
- 10. 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
- 11. Anaerobes – Upper airway anaerobes Atypical Bacteria – All have excellent activity • Legionella pneumophila - DOC • Chlamydia sp. • Mycoplasma sp. • Ureaplasma 10/5/2013
- 12. Other Bacteria – • Mycobacterium avium complex (MAC – only A and C), • Treponema pallidum, • Campylobacter • Borrelia, Bordetella • Brucella • Pasteurella 10/5/2013
- 13. Activity Erythro Azithro Clarithro H. infuenzae ++ +++ ++ Moraxella catarahalis ++ +++ ++ Mycoplasma ++ +++ ++ Legionella ++ +++ ++ Strepto/staph +++ ++ +++ 10/5/2013
- 14. 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
- 15. Distribution Extensive tissue and cellular distribution clarithromycin and azithromycin with extensive penetration Minimal CSF penetration 10/5/2013
- 16. 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
- 17. • 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
- 18. 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
- 19. • ENT infections , Tonsillitis, URTI • Mycoplasma pneumonie infections • Legionnaires Disease • Chlamydial infections (any macrolides) • Diphtheria (erythromycin) • Pertussis (erythromycin) 10/5/2013
- 20. • 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
- 21. “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
- 22. • 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
- 23. • 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
- 24. • 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
- 25. • 1987 France • Reaches highest blood concentration • Bioavailability upto 72%~85% • Respiratory tract infection and soft tissue infection • Low adverse effects 10/5/2013
- 26. • 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
- 27. • Erythromycin: 1-2 g/ day divided into 4 doses • Clarithromycin: 250-500 mg twice a day. • Azithromycin: 250 mg/ day 10/5/2013