Comprehensive Overview of Macrolides & Related Anti-Infective Drugs

1. Section 15. Infection disease andAnti-infective drugs (第十五篇 感染性疾病与抗感染药) 第二部分

2. content Part 3. Macrolides(大环内酯类), Lincomycin(林可霉素类), and Vancomycin(万古霉素) Part 4. Aminoglycosides(氨基糖苷类) and Polymyxins(多黏菌素类) Part 5. Tetracyclines(四环素类) and Chloramphenicol(氯霉素) Part 6. Synthetic antimicrobial agents(人工合成抗菌药)

3. 细菌蛋白质的合成的简介

4. aa1-tRNA A A aa3-tRNA aa2-tRNA 3 3 3 3 3 3 3 mRNA mRNA mRNA mRNA 1 1 1 2 2 2 1 1 1 1 2 2 2 2 T T T T T T T P P 2 1 2 1 1 1 2 2 R 3 1 3 3 2 1 1 2 3 1 30S 30S 50S 50S 细菌蛋白质的合成的简介

5. Part 3 Macrolides(大环内酯类), Lincomycin(林可霉素类), and Vancomycin(万古霉素)

6. Macrolides History 1952 Erythromycin(红霉素) 1970s Acetylspiramycin(乙酰螺旋霉素) Medecamycin(麦迪霉素) josamycin(交沙霉素) 1980s Clarithromycin (克拉霉素) Roxithromycin(罗红霉素) Azithromycin(阿奇霉素)

7. 14碳环大环内酯类： 红霉素(erythromycin) 克拉霉素(clarithromycin) 罗红霉素(roxithromycin) 15碳环大环内酯类： 阿奇霉素 (azithromycin) 16碳环大环内酯类： 吉他霉素(kitasamycin) 交沙霉素(josamycin) 乙酰螺旋霉素 (acetylspiramycin) 麦迪霉素(medecamycin) Macrolides

8. Macrolides STRUCTURE: (克拉霉素) (红霉素) (阿奇霉素)

9. First generation Erythromycin (红霉素) Antimicrobial activity Gram-positive organisms: pneumococci（肺炎双球菌）, streptococci（链球菌）, staphylococci（葡萄球菌） , diphtheriae （白喉）etc Gram-negative organisms:legionella（军团菌）,bacillus pertussis(百日咳), brucella(布氏) , meningococci（脑膜炎球菌）, diplococcus gonorrhoeae （淋病双球菌） etc Others: mycoplasma(支原体), chlamydia trachomatis(沙眼衣原体), rickettsia(立克次体), spirotchete (螺旋体), anaerobes(厌氧菌) etc. Macrolides

10. Mechanism of action Target 50s ribosomal RNA Mechanism inhibition of translocation of mRNA Macrolides

11. Macrolides ① Chloramphenicol ② ClindamycinMacrolides ③ Tertracyclines

12. Pharmokinetics Not stable at acid pH Metabolized in liver Excreted in bile Drugs: erythromycin stearate(硬脂酸红霉素） erythromycin ethylsuccinate（琥乙红霉素，利君沙） erythromycin estolate（无味红霉素） Macrolides

13. Macrolides Clinical uses • As penicillin substitute in penicillin-allergic or resistant patients with infections caused by staphylococci, streptococci and pneumococci • Pertussis，diphtheriae • Legionella and mycoplasma pneumonia • H.p infection

14. Macrolides Mechanism of resistance • Modification of the ribosomal binding site • Production of esterase that hydrolize macrolides • Active efflux system

15. Macrolides Adverse reactions • Gastrointestinal effects • Liver toxicity • Cardiotoxicity

16. Second generation Advantage : Broaderspectrum, higheractivity Orallyeffective High blood concentration Longer t 1/2 Less toxicity Mainly used in respitory tract infection Macrolides

17. Macrolides Azithromycin (阿齐霉素,丽珠奇乐） • Has the strongest activity against mycoplasma pneumoniae（肺炎支原体） • More effective on Gram-negative bacteria • Well tolerated • T1/2 :35~48h once daily • Mainly used in respitory tract infection

18. Macrolides Roxithromycin （罗红霉素，严迪） • 1987 France • The highest blood concentration • F 72%~85% • Respiratory tract infection and soft tissue infection • Low adverse effects

19. Macrolides Clarithromycin（甲红霉素,克拉霉素） • Has the strongest activity on Gram-positive bacteria, legionella pneumophila, chlamydia pneumoniae and H.p • Good pharmacokinetic property • Low toxicity

20. Third generation Ketolides(酮基大环内酯类) Ketolides are semisynthetic 14-membered-ring macrolides, differing from erythromycin by substitution of a 3-keto group for the neutral sugar L-cladinose. Telithromycin (泰利霉素) It is active in vitro against Streptococcus pyogenes, S pneumoniae, S aureus, H influenzae, Moraxella catarrhalis, mycoplasmas, Legionella, Chlamydia, H pylori, N gonorrhoeae, B fragilis, T gondii, and nontuberculosis mycobacteria. Many macrolide-resistant strains (macrolides-lincomycins-streptogramins, MLS)are susceptible to ketolides because the structural modification of these compounds renders them poor substrates for efflux pump-mediated resistance and they bind to ribosomes of some bacterial species with higher affinity than macrolides. Macrolides

21. Part 3-2 Lincomycin (林可霉素)and Clindamycin（克林霉素） Lincomycin & Clindamycin ① Chloramphenicol ② ClindamycinMacrolides ③ Tertracyclines Mechanism : Binding to 50s ribosome subunit and inhibiting protein synthesis

22. Antimicrobial activity Gram-positive organisms Bacteroide fragilis and other anaerobes Pharmacokinetics Absorbed well Penetrate well into most tissues including bone Lincomycin & Clindamycin

23. Clinical uses Severe anaerobic infection Acute or chronical suppurative osteomylitis（化脓性骨髓炎）, arthritis caused by susceptive organisms especially Staphylococci aureus（金黄色葡萄球菌） Adverse reactions Gastrointestinal effects: severe diarrhea and pseudomembranous enterocolitis caused by Clostridium difficile（难辨梭状芽孢杆菌）: vancomycin & metronidazole(甲硝唑) Impaired liver function , neutropenia(中性粒细胞减少) Lincomycin & Clindamycin

24. Part 3-3 ----------last choice Vancomycin (万古霉素) & Teicoplanin（替考拉宁） Vancomycin

25. Vancomycin (万古霉素) Mechanism of action--Inhibit cell wall synthesis Vancomycin -Lactam antibiotics vancomycin transpeptidase

26. Vancomycin(万古霉素) Vancomycin • Antimicrobial spectrum: • Narrow spectrum, active only against gram-positive bacteria paticularly staphylococci • Pharmacokinetics • Poorly absorbed from intestinal tract, iv • Excreted from glomerular filtration 90%

27. Vancomycin(万古霉素) Clinical uses Infection caused by MRSA, MRSE and penicillin-resistant pneumococcus Treatment of antibiotic-associated enterocolitis caused by clostridium difficile po Adverse reaction Ototoxicity & nephrotoxicity Red-man syndrome Vancomycin

28. Teicoplanin(替考拉宁) Similar to vancomycin in mechanism and antimicrobial spectrum Can be given im as well as iv Less adverse reactions Vancomycin

29. Part 3-4Oxazolidinones(恶唑烷酮类)Linezolid (利奈唑胺) Linezolid is a member of the oxazolidinones, a new class of synthetic antimicrobials. Antimicrobial spectrum: It is active against gram-positive organisms including staphylococci, streptococci, enterococci, gram-positive anaerobic cocci, and gram-positive rods such as corynebacteria and Listeria monocytogenes. It is primarily a bacteriostatic agent except for streptococci for which it is bactericidal. There is modest in vitro activity against Mycobacterium tuberculosis. Mechanism of action Linezolid inhibits protein synthesis by preventing formation of the ribosome complex that initiates protein synthesis. Its unique binding site, located on 23S ribosomal RNA of the 50S subunit, results in no cross-resistance with other drug classes. Mechanism of Resistance Resistance is caused by mutation of the linezolid binding site on 23S ribosomal RNA. Linezolid

30. Adverse reaction The principal toxicity of linezolid is hematologic—reversible and generally mild. Thrombocytopenia(血小板减少症) is the most common manifestation (seen in approximately 3% of treatment courses), particularly when the drug is administered for longer than 2 weeks. Neutropenia may also occur, most commonly in patients with a predisposition to or underlying bone marrow suppression. Pharmacokinetics Linezolid is 100% bioavailable after oral administration and has a half-life of 4–6 hours. It is metabolized by oxidative metabolism, yielding two inactive metabolites. It is neither an inducer nor an inhibitor of cytochrome P450 enzymes. Peak serum concentrations average 18 g/mL following a 600 mg oral dose. The recommended dose for most indications is 600 mg twice daily, either orally or intraveneously. Clinical uses vancomycin-resistant E faecium infections; nosocomial pneumonia(医院获得性肺炎); community-acquired pneumonia(社区获得性肺炎); skin infections Linezolid

31. Part3-5 Streptogramins(链阳性菌素) Streptogramins are effective in the treatment of Vancomycin-resistant Staphylococcus aureus (VRSA) and Vancomycin-resistant enterococcus (VRE), two of the most rapidly-growing strains of multidrug-resistant bacteria. Members include: Quinupristin/dalfopristin (喹奴普丁－达福普丁) Pristinamycin Virginiamycin NXL 103, a new oral streptogramin currently in phase II trials (As of). It will be used to treat respiratory tract infections. Streptogramins

32. Part3-6 lipopeptide antibiotic Daptomycin(达托霉素) Mechanism of action Disruption of the bacterial membrane through the formation of transmembrane channels, resulting in a loss of membrane potential leading to inhibition of protein, DNA and RNA synthesis, which results in bacterial cell death. Daptomycin

33. Antimicrobial spectrum: Daptomycin is unable to permeate the outer membrane of Gram-negative bacteria, thus its spectrum is limited to Gram-positive organisms only. Daptomycin has activity against Staphylococci (including MRSA, VISA, and VRSA), Enterococci (both E. faecalis and E.faecium, including VRE), and Streptococci (including DRSP), as well as most other aerobic and anaerobic Gram-positive bacteria. Daptomycin

34. Polypeptide antibiotics • Vancomycin & Teicoplanin • Polymyxins • bactitracin

35. Polymycins • Active only against gram-negative rods, particularly P.aeruginosa • Mechanism:increase permeability of cell membrane • Mainly used in P.aeruginosa infection when other drugs are resistant • Toxicity: nephrotoxicity & neurotoxicity

36. Baciteracin • Active against gram-positive bacteria • Inhibit cell wall formation • No cross-resistance with other agents • Topical use only because of nephrotoxicity

37. Part 4 Aminoglycosides(氨基糖苷类) & Polymyxins(多黏菌素类)

38. Aminoglycosides （氨基苷类） Summarization of aminoglycosides The aminoglycosides are compounds contanining characteristic amino sugars joined to a hexose nucleus in glycosidic(糖苷） linkage. Most amino- glycosides, which are prepared by natural fermentation from various species of streptomyces, are a group of bactericidal drugs sharing chemical, antimicrobial, pharmacological, and toxic characteristics.

39. Aminoglycosides （氨基苷类） • Natural Aminoglycosides • 链霉素(streptomycin) 庆大霉素(gentamicin) • 新霉素(neomycin) 西索米星(sisomicin) • 妥布霉素(tobramycin) 小诺米星(micronomicin) • 卡那霉素(kanamycin) • 大观霉素(spectinomycin) • Semisynthetic Aminoglycosides • 阿米卡星 (amikacin) 奈替米星(netilmicin)

40. Structure of streptomycin

41. Structures of several important aminoglycoside antibiotics.

44. Aminoglycosides • Spectrum of activity • Aminoglycosides are effective against aerobic gram-negative bacteria, especially in bacteremia, sepsis, or endocarditis.

45. Aminoglycosides Mechanism of action • The mechanism of Aminoglycosides is to inhibit protein synthesis in susceptiblemicroorganisms by interfering with the initiation complex of peptide formation. • inducing misreading of the code on the mRNA template, which causes incorporation of inappropriate amino acid into peptide. • by rupturing the polysomes into monosome, which become nonfunctional.

47. Inhibiting protein synthesis 氨基苷类 氨基苷类 氨基苷类 四环素类 氯霉素类 大环内酯类 林可霉素类

48. Mechanisms of resistance Three principal mechanisms have been established: (1) production of a transferase enzyme or enzymes inactivates the aminoglycoside by adenylylation, acetylation, or phosphorylation. This is the principal type of resistance encountered clinically. (Specific transferase enzymes are discussed below.) (2) There is impaired entry of aminoglycoside into the cell. This may be genotypic, ie, resulting from mutation or deletion of a porin protein or proteins involved in transport and maintenance of the electrochemical gradient; or phenotypic, eg, resulting from growth conditions under which the oxygen-dependent transport process described above is not functional. (3) The receptor protein on the 30S ribosomal subunit may be deleted or altered as a result of a mutation.

49. Aminoglycosides • Pharmacokinetics • poorly absorbed from the gastrointestinal tract. • must be given intramuscularly or intravemously for • systemic infection. • excreted almost entirely unchanged by glomerular filtration, which is greatly reduced in renal impairment, causing toxic blood levels.

50. Aminoglycosides • Adverse effects • Ototoxicity • Aminoglycosides are potentially toxic to branches • of the eighth cromial nerve. The evidence • indicates that the sensory receptor portions of the • inner ear ( hair cells of the cochlea) are affected • rather than the nerve itself. • cochlear damage(耳蜗损伤): • Kanamycin>Amikacin> sisomicin>gentamicin>tobramycin • vestibular impairment(前庭受损): • Kanamycin>Streptomycin>sisomicin> gentamicin> tobramycin