Part 3 Macrolides, Lincomycins &Vancomycins

1. Chemotherapeutic drugs Part 3 Macrolides, Lincomycins &Vancomycins Wei-wei Hu, PhD huww@zju.edu.cn

2. Macrolides （大环内酯类）

3. Macrolides （大环内酯类） • First generation: • - Erythromycin(红霉素) • -Medecamycin(麦迪霉素) • - Spiramycin(螺旋霉素) • Second generation: • - Clarithromycin(克拉霉素) • - Azithromycin(阿奇霉素) • - Acetylmedecamycin(乙酰麦迪霉素) • Third generation: • - Telithromycin(替利霉素)

4. General properties of Macrolides 1.Chemistry: contain a macrocyclic lactone ring (usually containing 14 to 16 atoms) to which deoxy sugars are attached. 2.Antimicrobial activity: bactericidal or bacteriostatic, depending on the concentration, high activity in alkaline condition.

5. 3. Antimicrobial spectrum： G+ organisms: - cocci: streptococcus pyogenes, hemolytic streptococcus and streptococcus pneumoniae（化脓性、溶血性和肺炎链球菌）, staphylococcus (produce β-lactamase or MRSA耐甲氧西林的金葡菌) - bacilli: diphtheria（白喉）, bacillus anthraci（炭疽） ，破伤风杆菌 G- organisms: - cocci: meningococcus (脑膜炎奈瑟菌)， N. gonorrhoeae (淋病奈瑟菌) - bacilli:legionella pneumophila （军团菌）, bordertella pertussis（百日咳杆菌）, haemophilus influenzae （流感嗜血杆菌）（对大肠埃希菌、变形杆菌无效） Other： - mycoplasma pneumoniae （肺炎支原体） - chlamydia （衣原体） - rickettsia（立克次体） - spirochetes （螺旋体） General properties of Macrolides

6. General properties of Macrolides 4. Mechanism of action: 1. Preventing the peptidyl transfer 2. Blocking translocation of peptidyl tRNA from A site to P site 3. Inhibiting the formation of functional 70s ribosome

7. General properties of macrolides • 5. ADME of Macrolides: • Absorption: • Erythromycin is destroyed by stomach acid and must be administrated with enteric coating. • Stearates (硬脂酸) and ester (酯化) are fairly acid-resistant and somewhat better absorbed. • Clarithromycin and Azithromycin are stable to acid. • Food interferes with absorption (except Clarithromycin).

8. General properties of macrolides 5. ADME of macrolides: (2)Distribution: Erythromycin diffuses readily into most tissues, including prostatic fluid and placenta, BBB impenetrable. (3) Metabolism and Elimination: most metabolized in the liver, excreted in the bile； clarithromycin and its metabolite excreted in urine.

9. General properties of macrolides 6.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) Diphtheria（白喉） (5) Pertussis （百日咳） (6) Streptococcus （链球菌）, staphylococous （金葡菌） infections

10. General properties of macrolides 7.Adverse response: (1) GI effects: nausea, vomiting, abdominal cramps, etc. (2) Liver toxicity: Cholestatic hepatitis （胆汁淤积性肝炎）. (3) Auditory impairment. (4) Allergic reaction (5) Superinfections

11. General properties of macrolides 8. Resistance mechanism: (1) modification of the ribosomal binding site (2) production of esterase that hydrolyze macrolides (3) reduced permeability of cell membrane or active efflux (4) Ribosome mutation (base mutation of 23s rRNA or ribosome protein mutation) ***Cross-resistance is complete between erythromycin and the other macrolides.

12. General properties of macrolides • 9. Drug interaction • Erythromycin metabolites can inhibit cytochrome P450 enzyme.

13. Macrolides • Erythromycin (红霉素):chlamydia (支原体) and chlamydial (衣原体) infections, community-acquired pneumonia, penicillin substitute for staphylococcal, streptococcal or pneumococcal infection. Cause obvious GI reactions and liver toxicity. • Clarithromycin (克拉霉素) : highest activity, its metabolite has activity. • Azithromycin (阿奇霉素):penetrates into most tissues well and released slowly from tissues, permits once daily dosing. High activity against mycoplasma (支原体) andchlamydia(衣原体). Has PAE. • Telithromycin (泰利霉素): 酮内酯类抗生素， good absorption and penetration, high binding to ribosome, low efflux, effective to MLSB resistant bacteria.

14. Lincomycin & Clindamycin • resemble erythromycin in antibacterial spectrum, activity, mechanism and resistance. • bactericidal or bacteriostatic, depending on the concentration, • G+ coccus, G- coccus, anaerobe • but notmycobacteria pneumoniae (肺炎衣原体), virus, fungi, and resistant to aerobic G- bacilli, enterococcus, Clostridium difficile (难辨梭状芽孢杆菌)

15. Lincomycin & Clindamycin • Pharmacokinetics • p.o., ~ 90% protein-bound (Clindamycin) • penetrate well into most tissue, including bone, but not CSF (except toxoplasmic encephalitis). • Metabolized in liver and excreted via, bile, and urine

16. Lincomycin & Clindamycin • Clinical Uses • severe anaerobic infection • aerobic G+ cocci infection (金葡菌骨髓炎) • combination with pyrimethamine (乙氨嘧啶) for AIDS-related toxoplasmosis (弓形体病) & with primaquine (伯氨喹)forpneumocystis carinii pneumonia (卡氏肺囊虫肺炎).

17. Lincomycin & Clindamycin • Adverse response: • (1)Gastrointestinal effects: • nausea, vomiting, abdominal pain, diarrhea • antibiotic-associated colitis is caused by toxigenic C difficile (pseudomembranous colitis, 难辨梭状芽孢杆菌引起的伪膜性结肠炎). • --Superinfection(二重感染)：an infection following a previous infection, especially when caused by microorganisms that are resistant or have become resistant to the antibiotics used earlier • (2)allergic reaction • (3)impaired liver function (occasionally)

18. Vancomycins - Vancomycin - Norvancomycin - Teicoplanin Antibacterial activity (Narrow spectrum) bactericidal for G+ bacteria (especially G+ ococci, including MRSA & MRSE耐甲氧西林表皮葡萄球菌),Clostridium difficile (难辨羧杆菌), Bacterooides fragilis (脆弱拟杆菌, 去甲万古)

19. Vancomycins • Antibacterial Mechanism • Inhibiting cell wall synthesis by binding to the D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide.

20. Fig. Antibacterial Mechanism of Vancomycins

21. Vancomycins • Resistance • - vancomycin-resistant enterococci mechanism: occurred because of the alteration of D-Ala-D-Ala. • - vancomycin-resistant staphylococous auteus mechanism: • * cell wall thickening • * change of the component of cell wall • * change of PBP

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

23. Vancomycins Clinical Uses 1) severe infection caused by MRSA etc. 2) alternative for β-lactams 3) enterococcal (肠球菌) or staphyococcal (链球菌) endocarditis(心内膜炎)(combination with gentamicin). 4) pseudomembranous colitis ***Overuse should be avoided, in view of limited options for treatment of resistant gram positive infections.

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

25. Chemotherapeutic drugs Part 4 Aminoglycosides & Polymyxins

26. Aminoglycosides 氨基糖苷类抗生素

27. History Aminoglycosides • 1944 Streptomycin (链霉素based on the research made by Waksman and coworkers within 1939-1943) • 1957 kanamycin卡那霉素 • 1964 gentamicin庆大霉素 • 1967 tobramycin妥布霉素 • Amikacin & netilmicin阿米卡星和奈替米星(semisynthetic)

28. Nobel Prize

29. Aminoglycosides • Amikacin阿米卡星，丁胺卡那霉素 • Netilmicin奈替米星 • B kanamycin卡那霉素B • Arbekacin阿贝卡星 • Dibekacin地贝卡星 • Etilmicin依替米星 • Isepamicin异帕米星 • Streptomycin链霉素 • Neomycin新霉素 • Kanamycin卡那霉素 • Tobramycin妥布霉素 • Gentamicin 庆大霉素 • Micronomicin 小诺米星 • Sisomicin 西索米星 • Astromicin 阿司米星

30. Aminoglycosides 1. Antimicrobial activity: i) rapidly bactericidal to resting bacterium ii)broad-spectrum：G- bacilli ，G+ organisms (including MRSA - netilmicin) , TB , less acitive to G- cocci, and ineffective for anaerobic strains. iii) clinical applications: for the treatment of aerobic G- bacilli infections and tuberculosis iv) unabsorbable in GI tract v) more active in alkaline environment

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

32. Aminoglycosides General properties 2. Mechanisms of action: (1) act as ionic- sorbent, act directly on permeability of the cell membrane of bacterium.

33. Aminoglycosides 2.Mechanism of action (2) inhibit the whole process of protein synthesis i) Interfering with the initiation complex of peptide formation (30S or 70S). 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.

35. Aminoglycosides 3. Mechanism of Resistance i) The microorganism produces a transferase enzyme that inactivate the aminoglycoside by adenylation, acetylation, or phosphorylation. ii) The receptor protein on the 30S ribosomal subunit may be deleted or altered as a result of mutation. iii) Impaired entry of aminoglycoside into the cell. iv) Increased efflux

36. Diagrammatic representation of transfer and transfer reduction of aminoglycoside across the bacterial cell wall. • If it is modified by acetylation, adenylation, or phosphorylation, the drug will not bind to ribosomes and will leave the bacterial cell.

37. Aminoglycosides 4. ADME i) Absorption: not absorbed by oral, but rapidly absorbed after i.m. ii) Distribution: minimal binding to plasma protein; high concentrations in secretions and body fluids; unable to cross cell membrane and BBB, able to cross the placenta. Tissue level is low except in the cortex of kidney and endolymph and perilymph of inner ear. iii) Metabolism and Elimination: excreted mainly by glomerular filtration. Accumulation occurs in renal failure with dose-related toxic effects.

38. Aminoglycosides 5. Clinical Uses • mostly used against infection induced by aerobicG-bacilli . • G- bacilli induced severe infection, such as sepsis(败血症), pneumonia and meningitis, almost always used in combination with b-lactam antibiotics and fluoroquinolones. • G+ cocci severe infection:combined with vancomycin, β-lactamase- resistant penicillins • TB (streptomycin and Kanamycin) and atypical mycobacteria分枝杆菌 (Amikacin)

39. Aminoglycosides 7. Adverse reactions i) Ototoxicity （耳毒性） Caused by progressive destruction of vestibular and cochlear sensory cells (hearing loss irreversible!!). Cochlear toxicity: tinnitus （耳鸣） and high frequency hearing loss Kanamycin>Amikacin>Sisomicin>Gentamicin>Tobramycin Vestibular toxicity: vertigo, ataxia and loss of balance Kanamycin>Streptomycin>Sisomicin>Gentamicin>Tobramycin

40. Aminoglycosides 7. Adverse reactions ii) Nephrotoxicity consists of damage to the kidney tubules but reversible Neomycin> Kanamycin>Gentamicin>Streptomycin or Tobramycin>Amikacin

41. Aminoglycosides 7. Adverse reactions iii) Neuromuscular blockade (paralysis) • generally occurred after intra-pleural or intra-peritoneal instillation of large doses of aminoglycosides • Treatment: Calcium salt or inhibitor of cholinesterase (neostigmine) . Neomycin>Streptomycin>Amikacin or Kanamycin> Gentamicin>Tobramycin

42. Aminoglycosides 7. Adverse reactions iv) Allergic reaction skin rashes, fever, angioneurotic edema,anaphylactic shock, etc.

43. Streptomycin 1. ADME i) Absorption: im ii) Distribution: mainly at extracellular fluid, can cross the BBB when meninges is inflamed. iii) Excretion:90% from kidney 2.Clinical uses i) plague鼠疫and tularemia土拉菌病(兔热病): combination with an oral tetracycline. ii) tuberculosis: as a first-line agent iii) bacterial endocarditis: (enterococcal, viridans streptococcal, etc.), streptomycin and penicillin produce a synergistic bactericidal effect.

44. Streptomycin 3. Adverse reactions i) Allergic reaction skin rashes, fever, anaphylactic shock ii) Ototoxicity: disturbance of vestibular function, deafness of newborn iii) Neuromuscular blockade (paralysis)：avoided in Myasthenia Gravis, avoided combining with anesthetics, scoline iv) Nephrotoxicity

45. Gentamicin 1. ADME Gentamicin can accumulate in cortex of the kidney . 2.Clinical use : i) serious G- bacillary infections (sepsis, pneumonia, etc.). ii) infection induced by enterococcus, viridans streptococcus, staphylococcus etc. (in combinationwith other antibiotics, e.g. b-lactams) iii) prevent the infection induced by operation (e.g., gastrointestinal operation ) iv) local application or intrathecal administration (rarely use)

46. Tobramycin 1. Features • The antimicrobial activity and pharmacokinetic properties of tobramycin are very similar to those of getamicin. 2. Adverse reactions • Ototoxicity less toxic to cochlear and vestibular • Nephrotoxicity less renal tubular damage

47. Amikacin 1.Antibacterial activity: the broadest in the group. - effective against G- bacilli and staphylococcus aureus - ineffective to other G+ cocci - tolerance to modifying enzyme of enteric G- bacilli and pseudomonas 2.Clinical uses : - treatment of G- bacillary infections which are resistant to gentamicin and tobramycin. - most strains resistant to amikacin found also resistant to other aminoglycosides. - combination with b-lactams, produce a synergistic bactericidal effect.

48. Netilmicin 1. Broad spectrum, especially strong effect against aerobic G- bacilli.Effective against MRSA and strains resistant to other aminoglycosides. 2. Tolerant to many aminoglycosides- inactivating enzymes. 3. Less toxic

49. Polymyxins 多粘菌素 1.Notice: because of the extreme toxicity, they are now rarely used. 2.Antibacterial activity:narrow spectrum (G- bacilli), slow active, bactericidal. Not active to G+ organisms, G- coccus, Bacterooides fragilis(脆弱杆菌）, proteusbacillus vulgaris（变形杆菌）, serratia plymuthica（沙雷菌属） 卫生部在10月9印发了《产NDM－1泛耐药肠杆菌科细菌感染诊疗指南（试行版）》: 轻、中度感染：敏感药物单用即可，如氨基糖苷类、喹诺酮类、磷霉素等，也可以联合用药，如氨基糖苷类联合环丙沙星、环丙沙星联合磷霉素等。无效患者可以选用替加环素、多粘菌素。

50. Polymyxins 3. Mechanism of action: they interact with phospholipids (are surface-active) and penetrate into and disrupt the structure of cell membranes. 4. Clinical uses: substitute of β-lactams and aminoglycosides, to treatinfection of pseudomonas aeruginosa (铜绿假单胞菌属） and other G- bacilli, local application.