MACROLIDES

1. MACROLIDES

2. Case scenario: A junior doctor prescribed tab. Erythromycin for respiratory infection of a known bronchial asthma patient who was taking theophylline for his asthma. After some days patient experienced nausea, vomiting, tremors and convulsions. What could be the reason for above condition?

3. MACROLIDES • Means a multimemberedlactone ring structure to which one or more deoxysugar molecules are attached • Prototype is erythromycin • Roxithromycin, clarithromycin & azithromycin are semisynthetic derivatives of erythromycin • Spiramycin is also related but obtained from streptomycesambafaciens Tacrolimus is also a macrolide

4. Erythromycin derived in 1952 from strain of Streptomyceserythreus from soil in Philippines • Structure • 14-membered macrocycliclactone ring • Related azalide class has 15-membered ring • FDA approved drugs • erythromycin • clarithromycin • azithromycin • dirithromycin • telithromycin

5. Protein synthesis inhibitors which act mainly by binding to 50S ribosomal subunits • Macrolides, ketolides, lincosamides, streptogramins, oxazolidinones • Micellaneous drugs include polymyxin-B, colistin (polymyxin-E), mupirocin & fusidic acid

6. MECHANISM OF ACTION • Binds to the Psite of the 50S bacterial ribosomal subunit. • Aminoacyl translocation and formation of initiation complex are blocked • Inhibitory or BACTERICIDAL

8. RESISTANCE • Reduced permeability of the cell membrane • Active efflux production (by Enterobacteriaceae) • Esterases that hydrolyze macrolides • Modification of the ribosomal binding site by chromosomal mutation

9. ANTIBACTERIAL SPECTRUM • Gm +vecocci: strep pneumoniae, strep pyogenes & staphylococci • Gm –vecocci: N gonorrhoeae, M catarrhalis • Gm +ve bacilli: C diphtheriae, B anthracis, L monocytogenes, C tetani • Gm –ve bacilli: L pneumophila, B pertusis, H influenza, H ducreyi

10. Acid fast bacilli: M kansasii, MA intracellulare, MAC & M leprae • Spirochaetes • M pneumoniae, U urealyticum, C trachomatis

11. ERYTHROMYCIN • Prototype • Distributed into total body water • Poor CSF penetration • Food interferes with absorption • Serum half life is app. 1.5 h normally and 5 hours in patients with anuria • Not removed by dialysis • Not metabolized and actively secreted in bile ( major route of excretion) • Traverses the placenta and reaches the fetus

12. Oral- stearate, ethyl succinate, estolate salts • 250-500 mg q 6 h adults, 40 mg/kg/d – children • Parenteral- lactobionate, gluceptate • 0.5-1 g q 6 hours for adults, 20-40 mg/kg/d for children

13. GIT dysfunction, intrahepaticcholestatic jaundice • Erythromycin metabolites can inhibit cyp p450 enzymes and thus increase the serum concs of theophylline, oral anticoagulants, cyclosporine and methylprednisolone; also oral digoxin by increasing its B/A

14. Indications for erythromycin 1. Alternative to penicillin in allergic pts ( Staph.Aureus, S. pyogens, S.pneumoniae or T.pallidum ) 2. Diphtheria & whooping cough – drug of choice 3. Legionnaires disease- drug of choice 4. Pneumoniae ( M. pneumoniae ) – children 5. Chlamydia trachomatis

15. CLARITHROMYCIN • Hydroxylated derivative of erythromycin • more active against Gm (+) pathogens, Legionella and Chlamydia than Erythromycin • lower frequency of GIT effects, less frequent dosing • Longer Half life of 6-7 hours • given at 250-500 mg twice daily

16. Metabolised in liver to 14-hydroxyclarithromycin • Dose adjustment needed in patients with compromised renal functions • Very effective against • MAC, H influenzae, T gondii, M leprae, H pylori Indications Pharyngitis / tonsilitis Otitis, sinusitis Adjunct in treatment of duodenal ulcer ( H. pylori )

17. ROXITHROMYCIN • Semisynthetic derivative of erythromycin • Long acting (t1/2 12hrs) • Acid stable, food does not interfere with its oral absorption • More preferred in otitis media, sinusitis, pneumonia c/b M catarrhalis, legionella

18. AZITHROMYCIN • More active than erythromycin against several gram (-) pathogens • Maintains high concentrations for prolonged periods into a number of tissues (lungs, tonsil, cervix) • Tissue half life – 2-4 days(longest t1/2) • More acid stable with wider tissue distribution

19. long half-life allows once daily oral administration and shortening of treatment in many cases • a single 1 g dose of azithromycin is as effective as a 7 day course of doxycyclinefor chlamydialcervicitis and urethritis • Community acquired pneumonia – 500 mg loading dose, f/b 250 mg • Does not inactivate cytochrome p450 enzymes and free of the drug interactions that occur with erythromycin and clarithromycin

20. Indications • Pharyngitis/ tonsilitis ( s. pyogens ), • otitis • sinusitis ( Staph. Aureus & H. influenzae ) • Uncomplicated genital chlamydial infections

21. SPIRAMYCIN • Oral + I/V • High tissue distribution except CSF • Metabolised in liver & excreted (90%) in the bile • T1/2 is 8hrs • DOC in toxoplasmosis of pregnancy

22. ADVERSE EFFECTS • Allergic reactions, rashes, fever, eosinophilia, skin eruptions • Cholestatic hepatitis – jaundice, fever, leukopenia • Erythro is associated with reversible ototoxicity • I/V erthromycin is associated with thromboplebitis • Causes diarrhea by stimulating motilin receptors

23. INTERACTIONS • Erythro & clarithro inhibit CYP3A4  inhibit metabolism & increases the serum levels of theophylline, carbamazepine, statins, warfarin, pimozide, terfenadine & cisapride • Terfenadine, astemizole or cisapride-torsades de pointes(PVT) • Decrease digoxin metabolism by inhibiting microbial flora responsible for degrading digoxin

24. Macrolides are DOC in (CLAW) • Chancroid • Legionella infections • Atypical pneumonia • Whooping cough

25. LINCOSAMIDES • Lincomycin (obsolete, not used) & clindamycin • Bind to 50S resulting in bacteriostatic inhibition of bacterial protein synthesis

26. Streptococci, pneumococci, staphylococci (except MRSA), B fragilis, Clostridium (except difficile) • Excellent against corynebacterium acnes • In combination effective against T gondii & Pneumocystiscarinii

27. Resistance • Alteration of 50S by adenine methylation • Chromosomal mutation of 50S (receptor alteration) • Drug inactivation by a plasmid mediated adenyltransferase

28. ADVERSE EFFECTS • Clindamycin associated diarrhoea & PMC • Nausea, vomiting, abdominal cramps & metallic taste • Nm blockade similar to AG • HS reactions

29. KETOLIDES • Telithromycin & celithromycin • 14 membered ring macrolidesspecificallydesigned for activity against Community acquired RTI • Achieves high tissue concn. in respiratory fluid, saliva, alveolar macrophages & bronchial mucosa • T1/2 - 13.5hrs

30. Gm +vecocci strep pyogenes, strep pneumoniae, s aureus • Gm –vecocci M catarrhalis, N gonorrhoeae, N menigitidis • Gm –ve bacilli  H influenzae, L pneumophila

31. Telithromycin mainly indicated for macrolide-resistant CAPs, acute exacerbations of chronic bronchitis, sinusitis & streptpharyngitis • Celithromycin more potent than telithromycin

32. Bacteraemia c/b vancomycin resistant E faecium, skin infections • Nosocomial pneumonia • Combination has a prolonged post-antibiotic effect & hence can be administered at 12hrly, I/V • Pain at the site of infusion & moderate infusion-related arthralgia-myalgia syndrome

34. REFERENCES • 1. Tripathi K.D., Essentials of Medical Pharmacology 8th ed. Jaypee Brothers 2013 • 2. Satoskar R.S. & Bhandarkar S.D., Pharmacology and Pharmacotherapeutics, 25th ed. Elsevier 2017.