MACROLIDES 10SEPT 13

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MACROLIDES:

MACROLIDES Dr. RAGHU PRASADA M S MBBS,MD ASSISTANT PROFESSOR DEPT. OF PHARMACOLOGY SSIMS & RC.

Mechanism of Action :

Mechanism of Action Inhibits protein synthesis by reversibly binding to the 50S ribosomal subunit . Suppression of RNA-dependent protein synthesis Macrolides typically display bacteriostatic activity, but may be bactericidal when present at high concentrations against very susceptible organisms Time-dependent activity

PowerPoint Presentation:

Advantage of newer macrolides : Broader spectrum, higher activity, Orally effective High blood concentration, Longer t ½, Less toxicity Mainly used in respiratory tract infection

Mechanisms of Resistance :

Mechanisms of Resistance Active efflux (accounts for 80% ) – mef gene encodes for an efflux pump which pumps the macrolide out of the cell away from the ribosome; confers low level resistance to macrolides Altered target sites – encoded by the erm gene which alters the macrolide binding site on the ribosome; confers high level resistance to all macrolides , clindamycin . Cross-resistance occurs between all macrolides

Macrolide Spectrum of Activity:

Macrolide Spectrum of Activity G+ve - S. pneumoniae , C.diptheriae G- ve - L.pneumophila , B.pertusis Anaerobes – activity against upper airway anaerobes Atypical Bacteria – all macrolides have excellent Activity against atypical bacteria including: Legionella pneumophila Chlamydia sp. Mycoplasma sp. Ureaplasma urealyticum Other Bacteria – Mycobacterium avium complex (MAC – only A and C), Treponema pallidum , Campylobacter, Borrelia , Brucella , Pasteurella

PowerPoint Presentation:

Erythromycin As penicillin substitute in penicillin-allergic or resistant patients with infections caused by staphylococci, streptococci and pneumococci Pertussis , diphtheriae Legionella and mycoplasma pneumonia Clarithromycin Has the strongest activity on Gram-positive bacteria, legionella pneumophila , chlamydia pneumoniae and H.p Good pharmacokinetic property Low toxicity Has the strongest activity against mycoplasma pneumoniae

PowerPoint Presentation:

Azithromycin More effective on Gram-negative bacteria Well tolerated, once daily Mainly used in respiratory tract infection Roxythromycin The highest blood concentration,F 72%~85% Respiratory tract infection and soft tissue infection Low adverse effects

Absorption :

Absorption Erythromycin – variable absorption (F = 15-45%); 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 (F = 55%) regardless of presence of food Azithromycin –acid stable; F = 38%; food decreases absorption of capsules

Distribution & Elimination :

Distribution & Elimination Extensive tissue and cellular distribution – clarithromycin and azithromycin with extensive penetration Minimal CSF penetration Clarithromycin is the only macrolide partially eliminated by the kidney (18% of parent and all metabolites); requires dose adjustment when CrCl < 30 ml/min Hepatically eliminated: ALL NONE of the macrolides are removed during hemodialysis! Variable elimination half-lives (1.4 hours for erythro ; 3 to 7 hours for clarithro ; 68 hours for azithro )

Therapeutic uses:

Therapeutic uses Atypical pneumonia Legionnaire’s pneumonia Whooping cough Eradication of corynebacterium diptheriae Camphylobacter gastroenteritis Chancroid due to H.ducreyi Chlamydial conjunctivitis and urethritis

Adverse effects:

Adverse effects Gastrointestinal – up to 33 % Nausea, vomiting, diarrhea, dyspepsia 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 in patients with RI); QTc prolongation; allergy

Drug interaction:

Drug interaction Erythromycin and Clarithromycin – 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

Nonantibiotic applications of Macrolides:

Nonantibiotic applications of Macrolides Diffuse panbronchiolitis (DPB) Cystic fibrosis (CF) Acute bacterial sinusitis (ABS) Asthma Chronic obstructive pulmonary disease (COPD) Bronchiectasis Chronic bronchitis

Lincosamides :

Lincosamides Lincomycin Clindamycin Antibacterial spectrum : lincosamides are active against staphylococci, gram-positive and gram-negative anaerobes, including Bacteroides fragilis . Mechanism Binding to 50s ribosome subunit and inhibiting protein synthesis Pharmacokinetics Absorbed well, Penetrate well into most tissues including bone about 90% protein-bound excretion via the liver, bile, and urine penetrate well into most tissue, including bone, but not CSF.

Resistance :

Resistance Alteration of 50s ribosomal subunit by adenine methylation Chromosomal mutation of 50s ribosomal protein Drug inactivation Dose -150-300mg every 6 th hourly

Lincosamides-Therapeutic uses :

Lincosamides -Therapeutic uses Severe anaerobic infection Acute or chronical suppurative osteomylitis , arthritis caused by susceptive organisms especially Staphylococci aureus aerobic G+ cocci infection combination with pyrimethamine for AIDS-related toxoplasmosis combination with primaquine for AIDS-related pneumocystis carinii pneumonia

Adverse reactions :

Adverse reactions Adverse reactions Gastrointestinal effects: severe diarrhea and pseudomembranous enterocolitis caused by Clostridium difficile Higher IV dose –neuromuscular blockade Other :Impaired liver function , neutropenia, hypersensitivity

ketolides:

ketolides Telithromycin and cethromycin Telithromycin is semisynthetic derivative of erythomycin Tighter binding to ribosomes Decreased incidence of resistance Longer post antibiotic effect T1/2- 13hrs Has activity against erythromycin resistant G+ve cocci Mainly for macrolide resistant CAP, chronic bronchitis Dose -800mg OD for 10 days

Ketolides – Cethromycin :

Ketolides – Cethromycin More potent than telithromycin Used against macrolide resistant streptococci and enterococci Resistance - Ribosomal modification via inducible or constitutive methylation . Ribosomal modification via point mutation- h.pylori Drug efflux- S.pyogenes Adverse reactions Diarrhoea , nausea Drug interaction Prolonged QT interval (cisapride, terfenadine ) Increased blood levels of theophylline, midazolam

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