Macrolides

macrolides

1. MACROLIDES By Dr. Mohammed Yaqub Pasha

2. Introduction The term Macrolide was originally given to antibiotics produced by species of Streptomyces . Erythromycin was discovered in 1952 by McGuire and coworkers from a strain of Streptomyces erythreus .

3. General Structure They all contain three characteristics parts in the molecule: A highly substituted macrocyclic lactone : aglycone . A ketone group. An amino desoxysugar : glycon , and in some of the macrolides , a neutral desoxysugar which are glycosisically attached to the aglycone ring.

4. Mechanism of Action Macrolides - bacteriostatic agents A ttach to the P site of 50s portion of bacterial ribosomes and inhibit the protein synthesis Prevent translocation during elongation of protein synthesis Do not inhibit the 60s/40s subunits of mammalian cells – selective toxicity

5. Mechanism of action

6. Resistance From one of four mechanisms Drug efflux by an active pump mechanism Modification of receptor sites on 50s ribosome – decreased binding of the drug Macrolide hydrolysis by esterases produced by Enterobacteriaceae Failure to permeate through bacterial cell membrane

7. Spectrum of Antibacterial Activity Macrolides are similar to penicillins regarding their spectrum of activity They are effective against penicillin-resistant strains Macrolides are effective against most of the G(+) bacteria, cocci or bacillus, they have antibiotic activity against G(-) cocci ,especially Neisseria Species

8. Typical therapeutic applications of macrolides .

9. ERYTHROMYCIN Antimicrobial spectrum: Mostly gram-positive Highly sensitive: Str. pyogenus , Str. pneumoniae , N. gonorrhoeae , C. diphtheriae , Listeria , Campylobacter, Legionella , Branhamella catarrhalis , Gardnerella vaginalis , Mycoplasma Moderately sensitive: H. ducreyi , H. influenzae , B. pertussis , Chlamydia trachomatis , Str. Viridans , N.meningitidis , Rickettsiae Not sensitive: Enterobacteriaceae , B. fragilis

10. Pharmacokinetics: Acid labile Incomplete absorption Food delays absorption Inactivated by gastric acid – Enteric coated tablets/ester salts Widely distributed, 70-80% plasma protein bound Does not cross blood brain barrier t-1.5 hr, persists longer in tissues No need of dose alteration in renal failure

11. USES As an alternative to penicillin: Streptococcal pharyngitis , tonsillitis, mastoiditis , community acquired pneumonia Prophylaxis of rheumatic fever and SABE Diphtheria Tetanus Syphilis and gonorrhoea Leptospirosis

12. 1st choice in Atypical pneumonia ( mycoplasma pneumonia) Whooping cough Chancroid 2 nd choice in Campylobacter gastroenteritis Legionnaires pneumonia Chlamydia trachomatis

13. ROXITHROMYCIN Semisynthetic longer-acting acid stable macrolide More potent against Branhamella catarrhalis , Gardnerella vaginalis , Legionella Less potent against B. pertussis Similar efficacy, better gastric tolerability

14. Spectrum includes MAC, Mycobacterium leprae More active against H. pylori, Moraxella , Legionella , Mycoplasma pneumonia More acid stable, rapidly absorbed

15. CLARITHROMYCIN Absorbed rapidly from the GI tract Can be given with or without food saturation kinetics active metabolite Bioavailability - 50-55% T1/2 6-7 hrs, excreted through kidney

16. Spectrum includes MAC, Mycobacterium leprae More active against H. pylori, Moraxella , Legionella , Mycoplasma pneumonia

17. USES 200-500 mg BD Clarithromycin or azithromycin - first-line therapy for prophylaxis and treatment of disseminated infection caused by M. avium-intracellulare in AIDS patients Clarithromycin + minocycline used in lepromatous leprosy Clarithromycin 500mg + omeprazole 20mg + amoxycillin 1gm BD (14 days) – PUD

18. AZITHROMYCIN Expanded spectrum – H. influenza, Mycoplasma , Chlamydia pneumoniae , Legionella , Moraxella , MAC, Campylobacter, Ch. Trachomatis , H. ducreyi , N.gonorrhoeae , penicillinase producing Staph. Aureus Higher efficacy

19. Improved pharmacokinetics – acid-stability, rapid oral absorption, intracellular penetration, high concentrations inside macrophages and fibroblasts Better gastric tolerability Fewer drug interactions Convenient once daily dosing

20. Administration and fate of the macrolide antibiotics

21. 1 st choice in Legionnaire pneumonia Clamydia trachomatis Donovanosis Chancroid PPNG Single 1gm dose – chlamydia cervicitis & urethritis 500mg OD – disseminated infection by MAC in AIDS Excellent action against Toxoplasma gondii

22. Other uses – Pharyngitis , otitis media, skin and soft tissue infections, prophylaxis and treatment of MAC in AIDS patients

23. Adverse effects 1. Hepatotoxicity Cholestatic hepatitis - erythromycin estolate Nausea, vomiting, intestinal cramps Hypersensitivity reaction 2. GI toxicity Erythromycin- epigastric distress Dose related Reduced by prolonging the infusion time to 1 hr/ pretreatment with glycopyrrolate

24. 3. Cardiac toxicity Cardiac arrythmias , QT prolongation, ventricular tachycardia 4. Toxic and irritative effects Fever, eosinophilia , skin eruptions Transient auditory impairment- erythromycin i.v erythromycin – thrombophlebitis

25. DRUG INTERACTIONS Erythromycin, clarithromycin - inhibit CYP3A4. may increase concentrations of: Theophylline Digoxin , Disopyramide Carbamazepine Valproic acid Cyclosporine Terfenadine , Astemizole Phenytoin Cisapride Warfarin Ergot alkaloids Azithromycin - no drug interactions

26. THANK YOU