Inhibitors of protein synthesis

1. Inhibitors of protein synthesis • Macrolides • Tertracyclines • Aminoglycosides • Chloramphenicol

2. MACROLIDES Mechanism of action : Inhibits protein synthesis by binding to 50S ribosomal subunits • Bactericidal at high concentration & bacteriostatic at low concentration.

3. Erythromycin • Is effective against : Legionella, cornybacteria, gram-positivecocci, chlamydia, helicobacter • Less effectiveon : gram-negativeorganisms.

4. Pharmacokinetics • Destroyed by gastric acidity and must be administered with enteric coating . • Food interferes with absorption • Half-life 1.5h • Excreted mainly through bile,5%only in urine. • Cross placentanot B.B.B.

5. Continue • Distribute well to all body fluids except CSF. • It is one of the few antibiotics that diffuses into prostatic fluids

6. Clinical uses • Drug of choice of corynebacterial infections • Chlamydial infections • Community acquired pneumonia • Mycoplasma • Legionella • Penicillin allergic patients.

7. Adverse effects • GIT .upset • Liver toxicity especially with the estolate coat produce acute cholestatic hepatitis • Drug interactions as it is cytochrome p-450 inhibitor. • Hypersensitivity reactions .

8. Clarithromycin • Acid stable • Spectrum as erythromycin but more active against Mycobacterium avium complex. & leprae.Toxoplasma gondii. • Half –life 6h. • Metabolized in liver (active metabolites ).

9. Enzyme inhibitor for P450 • Has a lower frequency of gastric intolerance • less frequent dosing • More tolerable • More expensive

10. Azithromycin • Similar spectrum as clarithromycin. More active on H-influenza &chlamydia. • Half-life 3 days . • Rapidly absorbed and well tolerated . • Should be given one hour before or 2 hours after meals • Does not affect P450 enzymes • Excreted in bile and urine

11. Clinical uses • Upper and lower respiratory tract infections • Skin infections • Alternative to penicillin in allergic patients • Urethritis or cervicitis mainly by chlamydial infections .

12. Adverse effects • Gstric upset (less than erythromycin ) • Allergic • Superinfections

13. Tetracyclines • Broad -spectrum antibiotics • Bacteriostatic • Inhibits protein synthesisby bindingto30 Sribosomal subunit

14. Pharmacokinetics Absorption: • Poorly absorbed(30%) chlortetracycline • Medialy absorbed(60-70%) demeclocycline • Highly absorbed(95-100% ) doxycycline and minocycline.

15. Continue • Absorption is impaired by1- food except with doxycycline & minocycline. 2- by divalent cations, milk and its products ,antacids and alkaline pH • Minocycline reaches very high conc. In tears and saliva.

16. Tetracycline group crossplacental barrier & concentrate in fetal bone & teeth. • Excreted through bile and urine • Doxycycline is eliminatedvia bile .

17. Doxycycline can be used for treating infections in renally compromised patients • Tetracyclines are also excreted in breast milk

18. Half-life : • Long acting:doxycycline &minocycline (16-18h once daily ). • Intermediate:(12h) demeclocycline • Short acting : ( 6-8 h ) tetracycline

19. Clinical uses • Drug of choice in : Mycoplasma pneumonia Chlamydial infections Rickettsial infections Spirochetal infections Brucellosis

20. Effective in : • Cholera • Traveller,s diarrhea • Helicobacter pylori • Acne • Bronchitis • Protozoal infections • Minocycline to eradicate meningococcal carrier

21. Not used in: • Streptococcal & staphylococcal infections . • Gonococcal infections • Meningococcal infections • Typhoid fever

22. Adverse effects • I.M. (pain & inflammation) • I.V. (thrombophilbitis) • Gastric upset • Super infections • Damage growing bone

23. Continue • Yellowish brown discoloration & dental caries • Hypoplasia in primary teeth • Hepatotoxicity • Phototoxicity • Vestibular problems : Doxycycline &minocycline.

24. Contraindications • With : milk or its products, or antacids. • Pregnancy may cause fatal hepatotoxicity • Children under 8 years.

25. Chloramphenicol • Broad spectrum antibiotics • Bactericidal or bacteriostatic • Inhibits protein synthesis by binding to 50S ribosomal subunits. • Cross placental barrier &B.B.B. • Enzyme inhibitor (p450)

26. Clinical uses • Serious rickettsial infections • In children whom tetracyclines are contraindicated • Meningococcal meningitis • Topically in bacterial eye infections except in chlamydial infections.

27. Adverse effects • Gastric upset • Super infections • Bone marrow depression • Gray baby syndrome • Hypersensitivity reactions • Drug interactions

28. Aminoglycosides • Bactericidal antibiotics • Inhibits protein synthesis by binding to 30S ribosomal subunits. • Active against gram negative aerobic organisms. • Poorly absorbed orally • Given I.M,I.V., intrathecal • Not freely cross BBB, cross placenta

29. Aminoglycosides • Excreted unchanged in urine • More active in alkaline medium • Adverse effects : • Ototoxicity • Nephrotoxicity • Neuromuscular blocking effect • Contact dermatitis

30. Streptomycin Clinical uses • T.B. in combination with other drugs. • Enterococcal endocarditis with penicillin. • Severe brucellosis with tetracycline

31. Gentamicin • Severe infections caused by gram negative organisms as sepsis ,urinary tract infections & pneumonia caused by pseudomonas or enterobacter. • Topically for the treatment of infected burns, wounds, skin , ocular & ear infections.

32. Tobramycin • More active against pseudomonas than gentamicin. • Less nephrotoxic and ototoxic than gentamicin. • Used in treatment of bacteremia, osteomyelitis and pneumonia.

33. Amikacin • Has the broadest spectrum • Used for serious nosocomial infections by gram negative organisms. • In T.B. as alternative to streptomycin • Atypical mycobacterial infections

34. Neomycin • Highly nephrotoxic ,used only orally for gut sterilization before surgery or topically in skin ,burn or eye infections.

35. Neomycin • Highly nephrotoxic ,used only orally for gut sterilization before surgery or topically in skin ,burn or eye infections.

36. Contraindications • Renal dysfunction • Pregnancy • Diminished hearing • Myasthenia gravis • Respiratory problems

37. Inhibitors of DNA Gyrase • FLUOROQUINOLONES

38. Ciprofloxacin Mechanism of action: • Block bacterial DNA synthesis by inhibiting bacterial topoisomerase11(DNA gyrase ) and topoisomerase 1V. • All are bactericidal

39. Antibacterial activity • Gram-negative aerobic bacteria. • Gram-positive bacteria. • Mycoplasma, chlamydial, legionella infections • Some mycobacteria. • Anaerobic bacteria ( moxifloxacin)

40. Pharmacokinetics • Well absorbed orally or intravenously • Widely distributed in body fluids & tissues. • Half-life(3-10h). • Absorption is impaired by antacids. • Concentrated mainly in prostate, kidney, bone ,lung.

41. Pharmacokinetics • Excreted by the renal route , except moxifloxacin.

42. Clinical uses • U.T.I.caused by multidrug resistance organisms as pseudomonas. • Bacterial diarrhea. • Soft tissues, bones,joints,intra-abdominal, respiratory infections caused by multidrug resistance organisms

43. Clinical uses • Gonococcal infections • Legionellosis • Chlamydial urethritis or cervicitis • T.B & atypical T.B. • Meningococcal carriers

44. Adverse effects • Gastric upset • Headache ,dizziness, insomnia • Phototoxicity • Damage growing cartilage causing arthropathy.

45. Drug interactions & contraindications • With antacid or divalent cations • Ciprofloxacin increase serum levels of theophylline , warfarin or cyclosporine. • Contraindicated : children ,adolescents ,epileptic patients or in patients taking antiarrhythmic drugs .