Macrolide (l)

1. Macrolides Dr . Rahul Kunkulol Asso. Prof . Pharmacology

2. History 1952 Erythromycin 1970s Acetylspiramycin Medecamycin , J osamycin 1980s Clarithromycin Roxithromycin Azithromycin 6/18/2013 RAHUL

3. Macrolides Belong to the P olyketide 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 . 6/18/2013 RAHUL

4. Erythromycin N aturally-occurring macrolide derived from Streptomyces erythreus P roblems with erythromycin Acid labile Narrow spectrum Poor GI tolerance Short elimination half-life 6/18/2013 RAHUL

5. Structural derivatives Clarithromycin and Azithromycin Broader spectrum of activity Improved PK properties – Better bioavailability Better tissue penetration Prolonged half-lives Improved tolerability 6/18/2013 RAHUL

6. Mechanism of Action 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 B actericidal at high concentrations against very susceptible organisms 6/18/2013 RAHUL

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9. Macrolide Spectrum of Activity 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. 6/18/2013 RAHUL

10. Macrolide Spectrum of Activity 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 6/18/2013 RAHUL

11. Macrolide Spectrum of Activity Anaerobes – Upper airway anaerobes Atypical Bacteria – All have excellent activity Legionella pneumophila - DOC Chlamydia sp. Mycoplasma sp. Ureaplasma 6/18/2013 RAHUL

12. Macrolide Spectrum of Activity Other Bacteria – Mycobacterium avium complex (MAC – only A and C), Treponema pallidum , Campylobacter Borrelia , Bordetella Brucella Pasteurella 6/18/2013 RAHUL

13. Macrolide Spectrum of Activity Activity Erythro Azithro Clarithro H. infuenzae ++ +++ ++ Moraxella catarahalis ++ +++ ++ Mycoplasma ++ +++ ++ Legionella ++ +++ ++ Strepto /staph +++ ++ +++ 6/18/2013 RAHUL

14. Mechanisms of Resistance Active efflux: Efflux pump which pumps the macrolide away from the ribosome; confers low level resistance to macrolides. Altered target sites: Ribosome protection which alters the macrolide binding site on the ribosome; confers high level resistance to all macrolides. Cross-resistance occurs between all macrolides 6/18/2013 RAHUL

15. Pharmacokinetics 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 6/18/2013 RAHUL

16. Pharmacokinetics Distribution Extensive tissue and cellular distribution clarithromycin and azithromycin with extensive penetration Minimal CSF penetration 6/18/2013 RAHUL

17. Pharmacokinetics 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 6/18/2013 RAHUL

18. Adverse Effects 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 6/18/2013 RAHUL

19. Drug Interactions 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 6/18/2013 RAHUL

20. Therapeutic Use ENT infections , Tonsillitis, URTI Mycoplasma pneumonie infections Legionnaires Disease Chlamydial infections (any macrolides) Diphtheria (erythromycin) Pertussis (erythromycin) 6/18/2013 RAHUL

21. Therapeutic Use 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 6/18/2013 RAHUL

22. Clinical Uses of Erythromycin “ 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 . 6/18/2013 RAHUL

23. New macrolides antibiotics Advantages : Broader spectrum, higher activity Orally effective High blood concentration Longer t 1/2 Less toxicity Mainly used in respiratory tract infection 6/18/2013 RAHUL

24. Azithromycin S trongest 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 6/18/2013 RAHUL

25. Clinical Uses of Azithromycin 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 6/18/2013 RAHUL

26. Roxithromycin 1987 France Reaches highest blood concentration Bioavailability upto 72%~85% Respiratory tract infection and soft tissue infection Low adverse effects 6/18/2013 RAHUL

27. Clarithromycin Has the strongest activity on Gram-positive bacteria, L egionella pneumophila , Chlamydia pneumoniae and H.pylori Good pharmacokinetic property Low toxicity USES : Atypical mycobacterial infections (MAC) Resistant leprosy Toxoplasmosis H.Pylori induced peptic ulcers. 6/18/2013 RAHUL