Aminoglycosides ( 氨基糖苷类抗生素 )

1. Chapter 41 Aminoglycosides (氨基糖苷类抗生素) Yun-Bi Lu, PhD卢韵碧Dept. of Pharmacology, School of Medicine, Zhejiang Universityyunbi@zju.edu.cn 2013.12.23

2. 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

3. Aminoglycosides

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

5. 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)

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

7. General properties 3. Mechanism of action: • inhibit protein synthesis • act as Ionic-sorbent（离子吸附剂）, act directly on permeability of the cell membrane of bacterium.

8. Mechanism of action -inhibit protein synthesis

9. Mechanism of action -inhibit protein synthesis

10. Mechanism of action -inhibit protein synthesis

11. Mechanism of action -inhibit protein synthesis

12. Mechanism of action -inhibit protein synthesis

13. Mechanism of action -inhibit protein synthesis

14. Mechanism of action -inhibit protein synthesis

15. Mechanism of action -inhibit protein synthesis • 阻碍甲硫氨酰tRNA在A位结合，抑制30S始动复合物形成；使已结合在A位的甲硫氨酰tRNA解离，抑制70S始动复合物形成； • 与30S亚基P10蛋白结合，使A位歪曲，造成tRNA在翻译mRNA时出错； • 阻碍终止因子与核糖体A位结合，使合成的肽链不能释放； • 抑制核糖体70S亚基解离，造成核糖体耗竭。

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

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

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

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

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

21. 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. iii) causing breakup of polysomes into nonfunctional monosomes. iv) disrupt the normal cycle of ribosomal, make the ribosomal exhausted.

22. Mechanism of resistance Produces modifying enzyme Changes of Porins Active efflux system Altered ribosomal subunit

23. 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.

24. General properties ADME i) Absorption: not absorbed after p.o., 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.

25. 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

26. 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

27. General properties Adverse reactions i) Ototoxicity耳毒性 • involves progressive damage to and destruction of the sensory cells in the cochlea and vestibular organ in the ear (irreversible!! ). Ototoxicity (cochlea 耳蜗) • Kanamycin(1.6%)> Amikacin> Sisomicin> Gentamicin> Tobramycin(0.4%) Ototoxicity (vestibular organ 前庭) • Kanamycin(4.7%)> Streptomycin> Sisomicin> Gentamicin> Tobramycin(0.4%)

28. General properties Adverse reactions ii) Nephrotoxicity肾毒性 • consists of damage to the kidney tubules and be reversed if stop using. • Amikacin < Streptomycin or Tobramycin<Gentamicin < Kanamycin <Neomycin

29. Nephrotoxicity & Ototoxicity Blue, high frequency Red, low frequency

30. General properties Adverse reactions iii) Neuromuscular blockade (paralysis)神经肌肉麻痹 • generally occurred after intra-pleural or intra-peritoneal instillation of large doses of an aminoglycosides • Tobramycin < Gentamicin < Kanamycin or Amikacin <Streptomycin <Neomycin • Calcium salt or inhibitor of cholinesterase (neostigmine) is the preferred treatment for this toxicity.

32. General properties Adverse reactions iv) Allergic reaction • skin rashes fever, eosinophiliay (嗜酸粒细胞增多症）, anaphylactic shock, etc.

33. Aminoglycosides agents • Streptomycin （链霉素） • Gentamicin （庆大霉素） • Tobramycin（妥布霉素） • Amikacin（阿米卡星） • Netilmicin（奈替米星） • Neomycin（新霉素）

34. Aminoglycosides agents • Kanamycin(卡那霉素） • Arbekacin （阿贝卡星） • Dibekacin （地贝卡星） • Micronomicin（小诺米星） • Sisomicin（西索米星） • Etilmicin（依替米星） • Isepamicin（异帕米星） • Astromicin （阿司米星，福提霉素） • Spectinomycin （大观霉素），etc.

35. Streptomycin 1. ADME i) Absorption:IM ii) Distribution: mainly at extracellular fluid, crosses the BBB and achieves therapeutic concentrations with inflamed menings. iii) Excretion:90%, kidney age↑→ T1/2↑

36. Streptomycin 2.Clinical uses i) plague(鼠疫) and tularemia(兔热病): combination with an oral tetracycline. ii) tuberculosis: as first-line agent iii) bacterial endocarditis: (enterococcal肠球菌, viridans streptococcal草绿色链球菌, etc.), streptomycin and penicillin produce a synergistic bactericidal.

37. Streptomycin 3. Adverse reactions i) Allergic reaction skin rashes, fever, anaphylactic shock ii) Ototoxicity (cochlea > vestibular organ) iii) Neuromuscular blockade (paralysis) iv) Nephrotoxicity

38. Gentamicin 1. ADME Gentamicin can accumulate in cortex of the kidney . 2.Clinical use : ii) important agent (first choice) for serious G- bacillary infections (sepsis, pneumonia, etc.), because of its low cost and reliable activity.

39. Gentamicin 2.Clinical Uses : ii) infection induced by enterococcal肠球菌, viridans streptococcal 草绿色链球菌, staphylococcal 葡萄球菌etc. Gentamicin is used concurrently with other antibiotics (e.g. b-lactams) iii) prevent the infection induced by operation

40. Gentamicin 2.Clinical Uses : iv) local application: for treatment of infected burn, wounds, or skin lesions and the prevention of intravenous catheter infections, etc.

41. Gentamicin 3. Adverse reactions i) Ototoxicity (vestibular organ> cochlea) ii) Nephrotoxicity iii) Nausea and vomiting etc.

42. Tobramycin 1.antimicrobial activity & pharmacokinetics: very similar to those of getamicin. 2. Adverse reactions: Ototoxicity and Nephrotoxicity (may be less than dose gentamicin).

43. Amikacin 1.Antibacterial activity: The spectrum of antimicrobial activity of amikacin is the broadest in the group.

44. Amikacin 2.Clinical uses : • Treatment of G-bacillary infections which resistance to gentamicin and tobramycin. • Most strains resistance to amikacin found is also resistance to other aminoglycosides. • combination with b-lactams, produce a synergisticbactericidal（协同杀菌）.

45. Amikacin 3. Adverse reactions i) Ototoxicity (cochlea> vestibular organ) ii) Nephrotoxicity (may be less than gentamicin or Tobramycin). iii) Neuromuscular blockade (paralysis)，rarely iv) skin rashes, fever, nausea and vomiting etc.

46. Chapter 40 Macrolides, Lincomycins & Miscellaneous antibacterial agents

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

48. 14 member rings 14 member rings 15 member rings

49. General properties of Macrolides 1. Antimicrobial spectrum： • G+ organisms • G- cocci:Streptococcus pyogenes (化脓性链球菌) 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

50. 3. Mechanism of action: