Macrolides, Lincomycins &Vancomycins

1. Section 3 Macrolides, Lincomycins &Vancomycins Yun-Bi Lu, PhD卢韵碧Dept. of Pharmacology, School of Medicine, Zhejiang Universityyunbi@zju.edu.cn

2. Part A Macrolides • Erythromycin (红霉素) • Clarithromycin (克拉霉素) • Azithromycin (阿奇霉素) • Telithromycin(泰利霉素)

3. 14 member rings 14 member rings 15 member rings

4. General properties of Macrolides 1. Antimicrobial spectrum： • G+ organisms • G- cocci:Streptococcus pyogenes and pneumoniae • Mycoplasma pneumoniae(肺支原体) and Legionnella (军团菌)etc. 2. Antimicrobial activity: • bactericidal and bacteriostatic, depending on the concentration. • more active at alkaline

5. subunit macrolide 3. Mechanism of action:

6. 4. Mechanism of resistance: • modification of the ribosomal binding site • production of esterase that hydrolyze macrolides. • reduced permeability of cell membrane or • active effluxsystem is involved. • Cross-resistance is complete between • erythromycin and the other macrolides.

7. General properties of Macrolides 4. ADME 1) Absorption: Stearate and ester of erythromycin are fairly acid-resistant and somewhat batter absorbed. Food interferes with absorption.

8. General properties of Macrolides 4. ADME 2) Distribution: does not cross BBB. 3) Elimination: it is concentrated in the liver, where some is unactived, while some is excreted in active form in the bile.

9. General properties of Macrolides 5.Clinical Uses: 1) Mycoplasma (支原体) infections. 2) Legionnaire’s disease (军团菌病). 3) Chlamydia infections (衣原体感染). 4) Streptococcus (链球菌) infections. 5) Diphtheria (白喉), chincough(百日咳). 6) toxoplasmosis(弓形虫病).

10. General properties of Macrolides 6.Adverse response: 1) GI Effects: nausea, vomiting, abdominal cramps(痉挛)… 2) Liver Toxicity: Cholestatic hepatitis (胆汁淤积性肝炎). 3) Cardiotoxic effects 4) Auditory impairment (Ototoxicity) Hypersensitivity reactions Superinfections

11. General properties of Macrolides • 7. Drug interactions • Erythromycin metabolites can inhibit cytochrome P450 enzyme.

12. Macrolides • Erythromycin (红霉素) • Clarithromycin (克拉霉素) • Azithromycin (阿奇霉素) • Telithromycin(泰利霉素)

13. Part B Lincomycin & Clindamycin • Lincomycin (林可霉素) • Clindamycin (克林霉素)

15. Lincomycin & Clindamycin • Antimicrobial properties • resemble erythromycin in antibacterial spectrum, activity, mechanism and resistance.

16. Mechanism of action: ①Chloramphenicol ②Macrolides, Clindamycin ③Tetracyclines

17. Lincomycin & Clindamycin • Pharmacokinetics • about 90% protein-bound • excretion via the liver,bile, and urine • penetrate well into most tissue, including bone, but not CSF.

18. Lincomycin & Clindamycin • Clinical Uses • severe anaerobic infection • aerobic G+ cocci infection • combination with pyrimethamine (乙胺嘧啶) for AIDS-related toxoplasmosis（弓形体病） • combination with primaquine (伯氨喹) for AIDS-related pneumocystis carinii pneumonia（肺囊虫性肺炎）.

19. Lincomycin & Clindamycin Adverse response: 1) GI effects: Antibiotic-associated colitis (pseudomembranous colitis伪膜性结肠炎). 2) allergic reaction 3) impaired liver function

20. Vancomycins Vancomycin (万古霉素) Norvancomycin (去甲万古霉素) Teicoplanin (替考拉宁，太古霉素)

22. Vancomycins Antibacterial activity bactericidal for G+ bacteria ( especially G+ ococci, including MRSA & MRSE)

23. Vancomycins • Antibacterial Mechanism • Inhibiting cell wall synthesis by binding to the D-Ala-D-Ala terminus of nascent peptidoglycan penta-peptide. • Resistance • occurred because of the alteration of D-Ala-D-Ala to the D-Ala-D-Ser.

24. Fig. Antibacterial Mechanism of Vancomycins

25. Vancomycins • ADME • Oral administration (poorly absorbed). • Intravenous administration, is excreted by glomerular filtration (accumulates when renal function is impaired). • Widely distributed in the body, including CSF when the meninges is inflamed.

26. Vancomycins • Clinical Uses • 1) severe infection caused by MRSA etc. • 2) alternative for b-lactam • 3) enterococcal or staphyococcal endocarditis (combination with gentamicin). • 4) pseudomembranous colitis

27. Pseudomembranous enterocolitis Pseudomembranous colitis. Endoscopic en face view of colon wall demonstrating several pseudomembranes (arrows). Hurley and Ngueyn Arch Intern Med. 2002;162:2177-2184.

28. Pseudomembranous enterocolitis Focal ulceration can be seen at the tips of the mucosa. The exudate of fibrin and inflammatory tissue. Normal

29. Vancomycins • Adverse Reactions • 1) Hypersensitive reaction • (e.g. red man syndrome) • 2) Ototoxicity • 3) Nephrotoxicity • 4) Gl effects, etc.

30. Section 4 Aminoglycosides & polymyxins

31. Part A Aminoglycosides Overview • History and Source : the research made by Waksman and coworks within 1939-1943 • Clinical Applications: for the treatment of aerobic G- bacterial infections and tuberculosis • Two classes: crude product and semisynthetic derivative

32. Aminoglycosides

33. General properties 1. Antimicrobial activity: i) rapidly bactericidal to resting bacterium ii) broad-spectrum iii) more active at alkaline

34. Peak Concentration Blood Concentration Bacterial growth is inhibited long after concentration below the MIC MIC Time (h) General properties 1. Antimicrobial activity: iv) concentration-dependent activity v) the duration of post antibiotic effect (PAE) is concentration- dependent (10 hours). vi) first exposure effect (FEE)

35. General properties 2. Antimicrobial spectrum： • aerobicG-bacilli and cocci • aerobicG+ organisms • Streptomycin and kanamycin are also active against Mycobacterium tuberculosis

36. General properties 3. Mechanism of action: • inhibit protein synthesis • act as Ionic- sorbent, act directly on permeability of the cell membrane of bacterium.

37. Mechanism of action -inhibit protein synthesis • Blocks the initiation of protein synthesis

38. Mechanism of action -inhibit protein synthesis • Blocks the initiation of protein synthesis

39. Mechanism of action -inhibit protein synthesis

40. Mechanism of action -inhibit protein synthesis

41. Mechanism of action -inhibit protein synthesis • Incorporation of incorrect amino acid

42. Mechanism of action -inhibit protein synthesis • Blocks further translocation and • elicits premature terminations

43. Mechanism of action -inhibit protein synthesis • disrupt the normal cycle of ribosomal, • make the ribosomal exhausted

44. Mechanism of action -inhibit protein synthesis i) Interfering with the initiation complex of peptide formation. ii) Inducing misreading of mRNA, which causes the incorporation of incorrect amino acid into peptide, resulting nonfunctional or toxic protein.

45. Mechanism of action -inhibit protein synthesis iii) causing breakup of polysomes into nonfunctional monosomes. iv) disrupt the normal cycle of ribosomal, make the ribosomal exhausted.

46. Mechanism of resistance produces enzymes Changes of Porins Altered ribosomal subunit Active efflux system

47. Mechanism of Resistance i) The microorganism produces a transferase enzyme or enzymes that inactivate the aminoglycoside by adenylyation, acetylation, or phosphorylation. ii) Impaired entry of aminoglycoside into the cell. iii) The receptor protein on the 30S ribosomal subunit may be deleted or altered as a result of mutation.

48. General properties ADME i) Absorption: not absorbed after po, but rapidly absorbed after IM, peak time 0.5-2h. ii) Distribution: Binding to plasma protein is minimal, do not enter cell, nor do they cross BBB,but they cross the placenta, reach high concentrations in secretions and body fluids. Tissue level is low expect in the cortex of kidney.

49. General properties ADME iii) Elimination: excreted mainly by glomerular filtration. If renal function is impaired, accumulation occurs with a increase in those toxic effects which are dose related. T1/2=2-3h

50. General properties Clinical Uses • be mostly used against aerobicG-bacteria (bacilli, enteric) and in sepsis, be almost always used in combination with b-lactam antibiotic or fluoroqunolones (氟喹诺酮类) • against aerobicG+bacteria and in sepsis, be almost always used in combination with penicillins or vancomycin • against Mycobacterium tuberculosis