MACROLIDES, KETOLIDES, LINCOSAMIDES, OXAZOLIDINONES & 0THER ANTIBACTERIAL DRUGS

1. MACROLIDES, KETOLIDES, LINCOSAMIDES, OXAZOLIDINONES & 0THER ANTIBACTERIAL DRUGS

2. 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

3. 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

4. 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

5. 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

7. 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

8. 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

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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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 )

16. 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

17. 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

18. 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

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

20. 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

21. 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

22. 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

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

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

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

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

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

28. 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

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

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

31. OXAZOLIDINONES • Linezolid, radezolid, torezolid • Inhibits bacterial protein synthesis by binding to the 50S near the interface with 30S. Thus formation of the ‘initiation complex’ required for bacterial protein translation • 100% oral BA

32. Vancomycin-resistant enterococcusfaecium, MRSA (endocarditis, bacteraemia), VRSA nosocomial & CAP • C diphtheriae, B anthracis, B fragilis, clostridia, L monocytogenes • Reversible thrombocytopenia, neutropenia, optic neuropathy

33. Linezolid is a reversible inhibitor of MAO  cheese reaction with food containing tyramine • Can also precipitate ‘serotonin syndrome’ (confusion, hypertension, seizures, tachycardia, muscle rigidity) if used with SSRI’s • Radezolid & torezolidare strutural analogues of linezolid, is in phase III trials for uncomplicated skin infections

34. STREPTOGRAMINS (PRISTINAMYCIN) • Streptogramin-B (quinupristin) & streptogramin-A (dalfopristin) in 30:70 ratio • Both bind to different sites of 50S subunit of 70S ribosome & prevent the extrusion of newly synthesised peptide chain from the ribosome l/t death

35. 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

36. POLYMYXIN-B & COLISTIN (POLYMYXIN-E) • Both peptide antibiotics function as cationic detergents & disrupt bacterial cell membrane osmotic integrity by displacing Ca2+ & Mg2+ from membrane lipid phosphates  intracellular constituents & death of bacteria

37. Bactericidal action on most gm –ve bacilli except Proteus, serratia, providencia & B fragilis • Used orally for oropharyngeal decontamination or suppression of intestinal flora in patients with high risk of endogenous infections • Colistimethate sodium has been used by inhalation in the management of respiratory infections, especially cystic fibrosis

38. Neurotoxicity (paraesthesia, ataxia, slurred speech) • nephrotoxicity (haematuria, proteinuria, electrolyte disturbances, tubular necrosis) • Potent NM blocking properties, may cause respiratory paralysis in patients of myasthenia gravis

39. MUPIROCIN • Obtained from pseudomonas fluorescens • Inhibits bacterial RNA & protein synthesis by binding to isoleucyl-t-RNA synthetase • Used topically in impetigo, folliculitis, burns, leg ulcers

40. FUSIDIC ACID • Inhibits bacterial protein synthesis by interfering with elongation of peptide chain • S aureus, corynebacterium, clostridium • Boils, impetigo, pyoderma • A/E rare except local irritation