Section 15. Infection disease and Anti-infective drugs ( 感染性疾病与抗感染药 )

1. Section 15. Infection disease and Anti-infective drugs (感染性疾病与抗感染药)

2. Charpter 2. Anti-infective drugs(抗感染药物) tanghuifang@zju.edu.cn 88208230 医学院科研C422

5. Contents Part 1.General considerations of anti-microbial agents Part2.-Lactam antibiotics Part 3. Macrolides, lincomycins, and vancomycins Part 4. Aminoglycosides & polymyxins Part 5. Tetracyclines & chloramphenicol Part 6. Synthetic antimicrobial agents Part 7. Antifungal agents Part 8. Antiviral agents Part 9. Antituberculous drugs Part 10. Clinical uses of antimicrobial agents Part 11. The drugs treated parasitic infections

6. Antimicrobial drugs classification According to bio-activity • Anti G+ antibiotic • Anti G- antibiotic • Broad-spectrum antibiotic • Anti mycobacterium（分支杆菌） antibiotic • Anti anaerobe（厌氧菌） antibiotic • β- lactamase inhibitor

7. According to the chemical structure： 1、β-lactams: Penicillins; Cephalosporins; 2、Aminoglycosides; 3、Macrolides; Lincosamides ;Vancomycins 4、Tetracyclines; Chloramphenicol 5、Quinolones 6、Sulphonamides 7、Nitrofurans 8、Antimycobacterial agents 9、others: Oxazolidinones; Streptogramins

8. History of Antimicrobial Therapy 1909 Ehrlich discovers Salvarsan（撒尔佛散，治疗梅毒特效剂） “Magic bullet” for treatment of syphilis（梅毒） 1928 Fleming discovers penicillin(青霉素) 1932 Domagk discovers sulfonamides（磺胺类药物） 1940s Penicillin and streptomycin （链霉素）used widely, cephalosporins （头孢菌素）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大环内酯类) 1956 Vancomycin （万古霉素）used for penicillin-resistant S. aureus 1957 Kanamycin（卡那霉素） discovered (aminoglycosides氨基苷类) 1962 Nalidixic acid （萘啶酸）discovered (quinolones喹诺酮类) 1980s Fluoroquinolones（氟喹诺酮类）, broad spectrum cephalosporins 2000s Newer agents to combat resistant pathogens

12. Part 1. General considerations of antimicrobial agents (抗微生物药物概论)

13. Contents 1.Overview 2. Term and definition 3. Classification and mechanism of antibacterial action 4. Bacterial resistance

14. 1. Overview: (1)Chemotherapy(化学治疗, 简称化疗) (2)Chemotherapeutic drugs: Antimicrobial drugs(抗微生物药); Antiparasitic durgs(抗寄生虫药); Antineoplastic drugs(抗肿瘤药). (3)Antimicrobial drugs: Antibacterial drugs(抗菌药); Antifungal drugs(抗真菌药); Antiviral drugs(抗病毒药).

15. Adverse effects The relationship of the host, microorganisms, antimicrobialdrugs. Resistance Pharmacokinetics Therapeutic Effects pathogenicity Immunological responses

16. Terminology 1. Antibacterial drugs(抗菌药) 2. Antibiotics(抗生素) 3. Bacteriostatic drugs(抑菌药) 4. Bactericidal drugs(杀菌药) 5. Antibacterial spectrum(抗菌谱) 6. Chemotherapetic index (化疗指数,CI) 7. Minimum inhibitory concentration (最小抑菌浓度, MIC) 8. Minimum bactericidal concentration (最小杀菌浓度, MBC) 9. Concentration Dependent killing 10. Post antibiotic effect (抗生素后效应,PAE) 11. Time-dependent killing

17. 2. Terms and definition: (1)Antibacterial drugs(抗菌药): Substances that can kill bacteria and/or inhibit its growth. including: ①Antibiotics(抗生素); ②Synthetic antimicrobial agents,such assulfonamides(磺胺类)andquinolones(喹诺酮类), etc.

18. Termsand definition (2)Antibiotics(抗生素): Substances produced by various species of microorganisms(bacteria, fungi, actinomyces, etc.), which can kill other microorganisms or inhibittheir growth.

19. Termsand definition (3)Chemotherapetic index: LD50/ED50,orLD5/ED95 (4)Antibacterialspectrum(抗菌谱); (5)Bacteriostatic drugs(抑菌药); (6)Bactericidal drugs(杀菌药);

20. Termsand definition agents

21. Termsand definition (7)Minimum inhibitory concent-ration(MIC); (8)Minimum bactericidal concen-tration(MBC): MBC ≥ MIC; if MBC > 32 times MIC  resistance.

22. Antimicrobial Susceptibility Testing 7. Minimum inhibitory concentration (MIC) 8. Minimum bactericidal concentration (MBC): 99.9% decrease in growth over 24 hours

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

24. Termsand definition 9. Concentration Dependent killing: situation in which the bactericidal activity of a drug depends by how much the drug concentration exceeds the Minimum inhibitory concentration of the organism in question. e.g. aminoglycosides and quinolones 10. Time-dependent killing: situation in which the bactericidal activity of a drug depends how long the drug concentration exceeds the Minimum inhibitory concentration of the organism in question. e.g. b-lactams and vancomycin 11. Post antibiotic affect (PAE) : Persistence of suppression of bacterial growth after limited exposure to an antimicrobial agent. e.g. aminoglycosides

25. Classification and mechanism of antibacterial action: (1) inhibit synthesis of bacte-rial cell walls; (2) act directly on the cell membrane of the microorganism and affect its permeability, and leading to leakage of intracellular compounds; (3) inhibit protein synthesis; (4) affect bacterial nucleic acid metabolism; (5) The antimetabolites of folic acid, that can block essential enzymes of folic acid synthetic metabolism.

26. Classification and mechanism of action ① ④ ⑤ ③ ②

27. Classification and mechanism of action • (1)Inhibiting synthesis of bacterial cell walls: UDP-乙酰胞壁酸-5肽 双糖十肽聚合物

28. Classification and mechanism of action -Lactam antibiotics vancomycin transpeptidase

29. Classification and mechanism of action (2)Affecting permeability of membrane: ①Ionic-adsorbed(streptomycin); ②binding to ergosterol(amphotercin B); ③Inhibiting the synthesis of ergosterol (imidazoles); ④Surface-active agent, that interact strongly with phospholipids(polymixins).

30. Classification and mechanism of action (3)Inhibiting protein synthesis: affecting the function of 30S, or 50S ribosomalsubunitstocauseareversibleinhibition of protein synthesis (strepto-mycin, erythromycin, etc.). binding to the 30S ribosomal subunit and altering protein synthesis, which eventually leads to cell death (strepto-mycin, etc.).

31. Classification and mechanism of action (4)Affecting bacterial nucleic acid metabolism: quinolones, etc.

32. Classificationandmechanismofaction

33. Classificationandmechanismofaction (5)Blocking enzymes of folate metabolism: Pteridine(蝶啶)+PABA(对氨苯甲酸) Dihydropteroate synthase Blocked bysulfonamides Dihydropteroic acid(二氢蝶酸) Glutaminic acid Dihydrofolic acid(二氢叶酸) NADPH Dihydrofolate reductasease Blocked bytrimethoprim NADP Tetrahydrofolic acid(四氢叶酸)

34. Bacterial Resistance

35. 4. Bacterial resistance: (1)Category of resistance: ①Intrinsic resistance: Inherent features ，usually expressed by chromosomal genes ②Acquired resistance: • emerge from previously sensitive bacterial populations • Caused by mutations in chromosomal genes • Or by acquisition of plasmids or transposons

36. Bacterial Resistance (2)Mechanism of bacterial resistance: ①to produce inactivated enzyme; ②to inhance active efflux system: ③the drug does not reach its target; ④ the target is altered;

37. OM Penicillinase b-lactam Inactive IM Penicillin Acetylation Phosphorylation Kanamycin Adenylyation Resistance: mechanisms, pathways 2. Active efflux e.g. Tetracycline resistance 1A. Enzymatic inactivation e.g. b-lactamase 3. Decreased permeability e.g. Porin mutations - cephalosporin 4. Target alteration Streptomycin resistance penicillin binding proteins 1B. Enzymatic modification e.g. Aminoglycoside modification

38. Bacterial Resistance Mechanismofbacterialresistance ①To produce inactivated enzyme: 1)Production of aminoglycoside modify-ingenzymes, suchas deactivatedenzyme to streptomycin; 2)Production of -lactamase, such as penicillinase; 3)Production of inactivated enzymes to other antibiotics, etc.

39. BacterialResistance Mechanismofbacterialresistance ②To enhance active efflux system:

40. BacterialResistance Mechanismofbacterialresistance • ③The drug does not reach its target: • Absence of, mutation in, or loss of the appropriate porins(膜孔蛋白) channel can slow the rate of drug entry into the cell, or prevent entry altogether, reducing the effectivedrugconcentrationat thetarget site.

41. Bacterial Resistance Mechanismofbacterialresistance • Porin channel(膜孔蛋白通道)

42. BacterialResistance Mechanismofbacterialresistance ④ The target is altered: Mutationof the natural target(such as resistance to fluoroquinolone). Target modification(ribosomal protec-tion type of resistance to macrolides and tetracyclines). Substitution with a resistant alternat-ive to the natural, susceptible target (such asmethicillinresistance in staphy-lococci).

43. BacterialResistance The transfer of resistance genes: ①Mutations; ②Transduction; ③Transformation; ④Conjugation.

44. Bacterial Resistance The transfer of resistance genes ①Mutations(突变): which may occur in the gene encoding. 1)The target protein; 2)The protein involved in drug transport; 3)Act on regulatory gene or promoter(启动子)affecting expression of the target, a transport protein, or an inactivating enzyme. suchas aminoglycosides,quinolones,etc.

45. BacterialResistance Thetransferofresistancegenes

46. Mutations May occur in the gene encoding i) The target protein ii) A protein involved in drug transport iii) A protein important for drug activation iv) A regulatory gene or promoter affecting expression of the target, a transport protein, or an inactivating enzyme.

47. BacterialResistance Thetransferofresistancegenes ②Transduction(转导): acquisition of bacterial DNA from bac-teriophage(噬菌体) that has incorporated DNAfromaprevioushostbacteriumwith-in its outer protein coat. Some phages can carry plasmids that code for penicillinase, or genes encod-ing resistance to erythromycin, tetracy-cline, or chioramphenicol.

48. Transduction

49. BacterialResistance Thetransferofresistancegenes

50. Bacterial Resistance Thetransferofresistancegenes ③Transformation(转化): Uptake and incorporation of DNA that is free in the environment into the host genome by homologous recombination.