Macrolides

Macrolides

1. MACROLIDES DR. SUDAR CODI.R ASST. PROFESSOR PHARMACOLOGY MGMCRI

2. LEARNING OBJECTIVES General points on macrolides – spectrum, mechanism of action etc Eryhtromycin , azithro , roxithro & clarithromycin – uses & side effects Preparations of erythromycin

3. Antibiotics with Macrocyclic lactone ring with one or more sugars attached to it. Derived from Streptomyces erythreus Alternate to penicillin

4. Common Features Bacteriostatic & bactericidal at high concentrations Inhibits bacterial protein synthesis inactive on aerobic gram – ve bacilli alternate to penicillin used to eradicate carrier state in diphtheria, to treat legionellosis , treat atypical pneumonia, community acquired pneumonia, H.pylori infection, leprosy, chancroid , lymphogranuloma venereum Narrow spectrum derived from Streptomyces erythreus stimulates motilin receptors in gut Erythromycin acid labile- enteric coated tablets active on gram + rods & bacilli Activity is enhanced at alkaline pH.

5. ANTI MICROBIAL SPECTRUM

6. MECHANISM OF ACTION

7. RESISTANCE R esistance to erythromycin is usually plasmid-encoded. reduced permeability of the cell membrane or active efflux production (by Enterobacteriaceae ) of esterases that hydrolyze macrolides modification of the ribosomal binding site by chromosomal mutation or by producing methylase . Efflux and methylase production are the most important resistance mechanisms in gram-positive organisms. Cross-resistance is seen

8. ERYTHROMYCIN - PREPARATIONS Erythromycin base is destroyed by stomach acid and must be administered with enteric coating . Food interferes with absorption. Stearates, esters & are fairly acid-resistant and ethyl succinate better absorbed. The lauryl salt of the propionyl ester of erythromycin(erythromycin estolate ) is the best-absorbed oral preparation Erythromycin lactobionate & gluceptate used iv & produces high plasma concentration

9. ERYTHROMYCIN - PHARMACOKINETICS Wide distribution Concentrated in liver, excreted in bile Cross placenta & milk but not blood brain barrier Plasma half life of 1.6 hrs No dose adjustment in renal failure Dose – 250-500mg 6 th hourly 30% GERY OINTMENT to treat bolis , carbuncles etc

10. MACROLIDES – SIDE EFFECTS High doses causes reversible auditory impairment Stimulates motilin receptors in gut causing increased gastric contractions, hasten gastric emptying & promote intestinal motility Hepatitis with cholestatic jaundice occur with estolate & ethyl succinate after 1-2wks Hypersensitivity reactions to estolate form Others – thrombophlebitis on iv use, QT prolongation

11. MACROLIDES – DRUG INTERACTIONS

12. THERAPEUTIC USES AS AN ALTERNATE TO PENICILLIN Streptococcal pharyngitis, tonsillitis, mastoiditis, community acquired respiratory infections caused by pneumococci and H. Influenzae , alternative drug for prophylaxis of rheumatic fever and SABE Diphtheria: acute stage as well as for carriers-7 day treatment Tetanus: as an adjuvant to antitoxin, toxoid therapy Syphilis and gonorrhoea : only if tetracyclines cannot be used Leptospirosis: 250 mg 6 hourly for 7 days in patients allergic to penicillins . AS FIRST CHOICE Atypical mycoplasma pneumonia Diphtheria: eradicate carrier state Chancroid – erythromycin 2gm/day AS SECOND CHOICE Calymatobacter enteritis – FQ is DOC Legionairre’s pneumonia – azithromycin is DOC Chlamydia trachomatis - azithromycin is DOC Penicillinase resistant Staph.aureus effect on the symptoms depends on the stage of disease when treatment is started. (a) Prophylactic : during the 10 day incubation period- disease is prevented. (b) Catarrhal stage : which lasts for about a week-erythromycin may abort the next stage or reduce its duration and severity . (c) Paroxysmal stage: lasting 2-4 weeks-no effect on the duration and severity of 'croup ' despite eradication of the causative organism . (d) Convalescent stage: during which 'croup‘ gradually resolves (4-12 weeks)-is not modified

13. ERYTHROMYCIN - LIMITATIONS narrow spectrum Gastric intolerance Gastric acid lability low oral bioavailability poor tissue penetration short half-life

14. NEWER MACROLIDES

15. ROXITHROMYCIN Semisynthetic Long-acting Acid-stable Macrolide; More Potent Against Branh . Catarrhalis , Card. Vaginalis And Legionella But Less Potent Against B. Pertussis. Good Enteral Absorption And Tissue Penetration, Plasma t 1/2 Of 12 Hr , Twice Daily Dosing Alternative To Erythromycin For Respiratory, ENT, Skin And Soft Tissue And Genital Tract Infections Dose: 150-300 Mg BD 30 Min Before Meals

16. CLARITHROMYCIN More active on MAC, My.leprae , My.pneumoniae , H.pylori Acid stable bioavailability of 50% metabolized by saturation kinetics- t1/2 is prolonged from 3-6 hours at lower doses to 6-9 hours at higher doses. SIDE EFECTS - High doses can cause reversible hearing loss , pseudomembranous enterocolitis, hepatic dysfunction or rhabdomyolysis. USES – URI, LRI, sinusitis , otitis media , whooping cough, atypical pneumonia, skin infections due to Strep. pyogenes and Staph . Aureus, MAC complex in AIDS, component of triple drug therapy in eradicating H.pylori , second choice in leprosy

17. AZITHROMYCIN Expanded Spectrum Improved Pharmacokinetics Better Tolerability Less Drug Interactions Good acid-stability Rapid oral absorption Marked tissue distribution and intracellular penetration – macrophages &fibroblasts higher efficacy better gastric tolerance convenient once a day dosing of 500 mg before meals USES: 1. DOC in Legionairre’s pneumonia – 500mg OD 1-2 wks 2. to treat chancroid – 1gm single dose 3. to treat LGV by C.trachomatis 1gm/day x 3 wks 4. DOC for Ch. Pneumonia 5. to treat donovanosis by Calymatobacter granulomatis 6. URI, LRI, sinusitis , otitis media , whooping cough, atypical pneumonia, skin infections due to Strep. pyogenes and Staph . Aureus, MAC complex in AIDS 7. to treat toxoplasmosis, typhoid, malaria

18. CLINDAMYCIN LINCOSAMIDE ANTIBIOTICS

19. CLINDAMYCIN MOA, Spectrum & resistance similar to erythrocin More active on anaerobes namely Bacterioides fragilis Pesudomembranous enterocolitis is important side effect treated by vancomycin, metronidazole USES: 1. Cl.perfringens infections of bones & joints 2. anaerobic B.fragilis infection causing abdominal, pelvic or lung abscess 3. prophylaxis of endocarditis in penicillin allergic patients undergoing dental surgery. 4 . combined with pyrimethamine for toxoplasmosis and with primaquine for Pneumocystis jiroveci pneumonia

20. SUMMARY Bacteriostatic & bactericidal at high concentrations Inhibits bacterial protein synthesis inactive on aerobic gram – ve bacilli alternate to penicillin used to eradicate carrier state in diphtheria,legionellosis,atypical pneumonia,com acqpneum , H.pylori infection, leprosy, chancroid , LGV, toxoplasmosis, malaria, typhoid Narrow spectrum derived from Streptomyces erythreus stimulates motilin receptors in gut Erythromycin acid labile- enteric coated tablets active on gram + rods & bacilli S/E – diahorrea , hepatitis with cholestatic jaundice, ototoxicity, hypersensitivity, QT prolongation, thrombophlebitis AZITHROMYCIN – expanded spectrum, acid stable, OD dosing, less drug interaction CLARITHROMYCIN – MAC, My.pneum , My.leprae , H.pylori (triple drug regimen) ROXITHROMYCIN – Long acting, acid stable, active on Branhella caterhalis CLINDAMYCIN – More action on B.fragilis , Cause pseudomembranous enterocolitis