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常用术语 抗菌药物作用机制 抗菌药物的耐药性 抗菌药物的合理应用 药物滥用与食品安全

抗菌药物概论. 常用术语 抗菌药物作用机制 抗菌药物的耐药性 抗菌药物的合理应用 药物滥用与食品安全. I. Chemotherapy. The Birth of Modern Chemotherapy: Dreams of a “Magic Bullet”. Louis Pasteur 1822-1895. Robert Koch 1843-1910. Rebecca Lancefield 1896-1981. I. Chemotherapy.

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常用术语 抗菌药物作用机制 抗菌药物的耐药性 抗菌药物的合理应用 药物滥用与食品安全

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  1. 抗菌药物概论 常用术语 抗菌药物作用机制 抗菌药物的耐药性 抗菌药物的合理应用 药物滥用与食品安全

  2. I. Chemotherapy The Birth of Modern Chemotherapy: Dreams of a “Magic Bullet” Louis Pasteur 1822-1895 Robert Koch 1843-1910 Rebecca Lancefield 1896-1981

  3. I. Chemotherapy • Paul Ehrlich introduced an arsenic-containing chemical called salvarsan （阿斯凡纳明）to treat syphilis （梅毒） (1910). • “Magic bullet” for treatment of syphilis 1928 Fleming discovers penicillin

  4. History of Antimicrobial Therapy I. Chemotherapy 1928

  5. History of Antimicrobial Therapy 1928 Fleming discovers penicillin (青霉素) 1932 Domagk discovers sulfonamides （磺胺类） 1940s Penicillin and streptomycin （链霉素）used widely, cephalosporins （头孢霉素）discovered 1947 Chloramphenicol （氯霉素）discovered, first broad spectrum agent 1950s Tetracycline（四环素）in use 1952 Erythromycin（红霉素）discovered (macrolides，大环内脂类) 1956 Vancomycin（万古霉素）used for penicillin-resistant S. aureus 1957 Kanamycin（卡那霉素）discovered (aminoglycosides，氨基糖苷类) 1962 Nalidixic acid（奈啶酸）discovered (quinolones，喹诺酮类) 1980s Fluoroquinolones（氟喹诺酮）, broad spectrum cephalosporins（广谱头孢类） 2000s Newer agents to combat resistant pathogens I. Chemotherapy

  6. History of Antimicrobial Therapy I. Chemotherapy Endless way ……………… MRSA，NAM-1 Superbug……drug resistance

  7. II. Chemotherapeutic agents

  8. II. Chemotherapeutic agents Host Factors： patient’s age, gender, constitution, hepatic, renal function Adverse effects Resistance Pharmacokinetics Therapeutic Effects pathogenicity Immunological responses

  9. II. Chemotherapeutic agents Ideal antimicrobial drugs • High sensitivity • Nontoxic or low-toxic (safety) • Nonresistance • Satisfied pharmacokinetic properties • Good price

  10. Antibacterial drugs (抗菌药) kill bacteria and arresting its growth Antibiotics(抗生素) and synthetic antimicrobial agents(人工合成抗菌药物) such as sulfonamides(磺胺类) and quinolones (喹诺酮类). Antibiotics (抗生素) Produced by various species of microorganisms (bacteria, fungi , actinomycetes), such as penicillin (青霉素) Suppress the growth of other microorganisms. II. Chemotherapeutic agents

  11. Antibacterial spectrum（抗菌谱） Narrow? Broad? Chemotherapetic index (CI)（化疗指数） CI= LD50 / ED50 CI= LD5 / ED95 II. Chemotherapeutic agents

  12. II. Chemotherapeutic agents • Bacteriostatic drugs （抑菌药） • inhibit the growth of microorganisms • e.g. Sulfonamides, Tetracycline • Bactericidal drugs （杀菌药） • kill microorganisms • e.g. Penicillin, Aminoglycosides

  13. Minimum inhibitory concentration (MIC) 最低抑菌浓度 Minimum bactericidal concentration (MBC) 最低杀菌浓度 Post antibiotic effect (PAE) 抗生素后效应 Resistance （耐药性） Cross Resistance （交叉耐药性） First expose effect （首次接触效应） II. Chemotherapeutic agents

  14. II. Chemotherapeutic agents 最低抑菌浓度 最低杀菌浓度

  15. II. Chemotherapeutic agents Incubate 18 to 24 hr at 37℃ Measure diameters of nongrowth zones Disk diffusion method for testing bacteria for susceptibility to specific antimicrobial drugs.

  16. III. Mechanism of action

  17. IV. Bacterial Resistance

  18. Intrinsic resistance – Inherent features ，usually expressed by chromosomal genes Acquired resistance – Emerge from previously sensitive bacterial populations – Caused by mutations in chromosomal genes – Or by acquisition of plasmids or transposons IV. Bacterial Resistance

  19. The drug is not active. The target is altered. The drug does not reach its target. IV. Bacterial Resistance Bacterial Resistance- Mechanisms

  20. Production of aminoglycoside-modifying enzymes and b-lactamase; IV. Bacterial Resistance 1.The drug is not active.

  21. IV. Bacterial Resistance 2.The target is altered Mutation of the natural target (quinolone resistance) Substitution with a resistant alternative to the native, susceptible target (methicillin甲氧西林 resistance)

  22. Target modification (ribosomal protection type of resistance to macrolides and tetracyclines) IV. Bacterial Resistance 2.The target is altered

  23. Absence, mutation or loss of the appropriate transporteror porins (膜孔蛋白） IV. Bacterial Resistance 3.The drug does not reach its target

  24. Active efflux system (主动排出系统) Efflux transporter（转运子） Accessory protein （附加蛋白） Outer membrane channel（外膜蛋白） IV. Bacterial Resistance 3.The drug does not reach its target

  25. Active efflux system（主动排出系统 ） IV. Bacterial Resistance Outer membrane channel Accessory protein transporter

  26. Mutations 突变 Transduction 转导 Transformation 转化 Conjugation 接合 IV. Bacterial Resistance The transfer of Resistance genes • From human  human • From bacteria  bacteria • Intracellular

  27. Mutations 突变 IV. Bacterial Resistance

  28. Transduction 转导 IV. Bacterial Resistance

  29. Transformation 转化 IV. Bacterial Resistance • Conjugation 接合

  30. IV. Bacterial Resistance Multi-drug resistance (MDR) • Methicillin-resistant staphylococcus aureus, MRSA • 甲氧西林耐药金黄色葡萄球菌 • Methicillin-resistant coagulase • negative staphylococci, MRCNS • 甲氧西林凝固酶阴性葡萄球菌 • PBP-2a （a 78kD new PBP）

  31. IV. Bacterial Resistance Multi-drug resistance MDR • Penicillin-resistant streptococcus pneumoniae, • PRSP，青霉素耐药肺炎链球菌 • PBP-1a, PBP-2a, PBP-2x, PBP-2b （78-100 kD） • Active efflux system （express mef(A)对大环内酯类） • Vancomycin-resistant Enterococcus, VRE • 万古霉素耐药肠球菌 • PBP avidity ↓ • van-A, van-B, van C-1, van C-2, van D, van E

  32. IV. Bacterial Resistance Multi-drug resistance MDR • 4. The 3rd generation-cephalosporins -resistant • Extended spectrumβ-lactamases, ESBL • 超广谱β- 内酰胺酶 • Class I chromosone mediated β-lactamases • I类染色体介导的β- 内酰胺酶 • E.g. 大肠埃希菌、克雷伯肺炎杆菌、阴沟肠杆菌

  33. IV. Bacterial Resistance Multi-drug resistance MDR • Carbapenem (碳青霉烯) –resistant：对亚胺培南的铜绿假单胞菌敏感 • OprD porin • Metalβ-lactamases （金属β- 内酰胺酶） • 6. Quinolone-resistant escherichia coli（大肠埃希菌）, AREC • Active efflux system • Cross-resistance superbug or super bacterium

  34. Basic principle of clinical usage of antimicrobial agents Antimicrobial drugs -Characteristics Some laboratory techniques that are useful in the diagnosis of microbial diseases

  35. According to bio-activity Anti G+ antibiotic Anti G- antibiotic Broad-spectrum antibiotic Anti mycobacterium antibiotic Anti anaerobe antibiotic - lactamase inhibitor Basic principle of clinical usage of antimicrobial agents Antimicrobial drugs -Characteristics

  36. According to the chemical structure： -lactams (-内酰胺类）；Penicillins（青霉素类）；Cephalosporins（头孢菌素类）; Aminoglycosides(氨基糖苷类); Macrolides（大环内酯类）; Lincosamides（林可胺类）;Vancomycins（万古霉素类） Tetracyclines（四环素类）； Chloramphenicol (氯霉素) Basic principle of clinical usage of antimicrobial agents Antimicrobial drugs -Characteristics

  37. 5. Quinolones (喹诺酮类 ) 6. Sulphonamides (磺胺类 ) 7. Nitrofurans (硝基呋喃类) 8. Antimycobacterial agents (抗结核分支杆菌类 ) 9. others: Oxazolidinones（恶唑烷酮类） Streptogramins（链阳菌素类） Basic principle of clinical usage of antimicrobial agents

  38. 参考书目：

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