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β -lactam antibiotics ( β - 内酰胺类抗生素）

β -lactam antibiotics ( β - 内酰胺类抗生素）. Penicillin nucleus. β - lactam is the square at the center. 二十世纪十大分子. 1900-1910: aspirin 1910-1920: isooctane （异辛烷，与汽车工业有关） 1920-1930: penicillin G 1930-1940: polyethene （英国 ICI 科学家偶尔得到， 1933 合成， 1939 年应用。大量用于雷达 cable insulation ）

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β -lactam antibiotics ( β - 内酰胺类抗生素）

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  1. β-lactam antibiotics(β-内酰胺类抗生素）

  2. Penicillin nucleus. β- lactam is the square at the center.

  3. 二十世纪十大分子 • 1900-1910: aspirin • 1910-1920: isooctane （异辛烷，与汽车工业有关） • 1920-1930: penicillin G • 1930-1940: polyethene （英国ICI科学家偶尔得到，1933合成，1939年应用。大量用于雷达cable insulation） • 1940-1950: nylon 6,6 (用于二战，代替丝织物) • 1950-1960: DNA • 1960-1970: progestin （黄体激素，contraceptives） • 1970-1980: DDT （对鸟、动物有害） • 1980-1990: fluoxetine, introduced by Eli Lilly in 1986. 到当时为止处方最多的抗抑郁药，在90多个国家应用。 • 1990-2000: carbon nanotubes

  4. Penicillins（青霉素类）

  5. Natural penicillins • Penicillin G • Pharmacokinetics: • destroyed easily by gastric acid • distribution widely and 5% across BBB when in meningitis • renal tubular excretion in prototype

  6. Antibacterial spectrum • Antibacterial spectrum: • Gram-positive cocci : Staphylococcus infections • Gram-negative cocci: Staphylococcus pneumoniae infection • Gram-positive bacilli: diphtheria（白喉），tetanus（破伤风） • Leptospira（螺旋体）: leptospirosis（钩端螺旋体病） • Actinomycetes（放线菌）：actinomycosis（放线菌病）

  7. 淋病奈瑟菌

  8. 放线菌

  9. 放线菌病

  10. Mechanism of penicillin • β-Lactam antibiotics work by binding to transpeptidase and then inhibiting the formation of peptidoglycan cross-links in the bacterial cell wall.

  11. Peptidoglycan（肽聚糖） is a 3D molecule Cross links are both horizontal and vertical between glycan chains stacked atop one another.

  12. Resistance to penicillins • Structural changes of penicillin binding protein (PBP) naturally • PBP production caused by sensitive or inter-bacterial gene recombination • Decrease of porin • Hydrolysis by β-lactamases

  13. Adverse effects • Allergic reactions • Allergic shock, 0.004%－0.04% • 10% cross-sensitivity between penicillin-derivatives, cephalosporins, and carbapenems • Inquiring history of β-lactam antibiotics use（没有用过青霉素要不要做皮试？） • Skin test before use • Seizure-like reaction when intrathecally administrated in large amount (>20000 U)(seizure model) (inhibition of GABA synthesis, …)

  14. Semi-synthetic penicillins Penicillin G Advantages disadvantages －－－－－－－－－－－－－－－－－－－－－－ high efficacy acid-irresistant low toxicity β-lactamase-irresistant cheap narrow spectrum easy to use high allergic reactions －－－－－－－－－－－－－－－－－－－－－－

  15. 6-aminopenicillanic acid (6-APA, 6-氨基青霉烷酸）

  16. Semi-synthetic penicillins • Penicillin V • resists destruction by gastric juice (oral route OK) • Still β-lactamase-irresistant • Less efficient when penicillin G is effective

  17. Semi-synthetic penicillins • β-lactamase-resistant penicillins • flucloxacillin（氟氯西林), oxacillin(苯唑西林), cloxacillin（氯唑西林） • β-lactamase-resistant • Less efficient when penicillin G is effective

  18. Semi-synthetic penicillins Wide-spectrum penicillins（广谱青霉素） • Ampicillin（氨苄西林），amoxicillin（阿莫西林） • wide spectrum (inhibiting grampositive and negative bacteria) • Acid-resistant • β-lactamase-irresistant

  19. Semi-synthetic penicillins antipseudomonal penicillins（抗铜绿假单胞菌青霉素） • Carbenicillin（羧苄西林），ticacillin（替卡西林），piperacillin（哌拉西林） • Antipseudomonal • β-lactamase-irresistant • Less efficient when penicillin G is effective

  20. Semi-synthetic penicillins • Anti-Gram negative bacterial penicillins（抗G-杆菌青霉素） • Mecillinam（美西林）, temocillin（替莫西林） β-lactamase resistant and effective against Gram negative bacteria

  21. Cephalosporins（头孢菌素类）

  22. Cephalosporins（头孢菌素类） • 1948，Italian Giuseppe Brotzu • Sardinia, sewer • Cephalosporium acremonium (头孢菌） • Culture effective against Salmonella typhi （伤寒沙门菌） • Cephalosporin C isolated in Oxford, weak activity

  23. 7-aminocephalosporanic acid（7-ACA, 7-氨基头孢烯酸）

  24. cephalosporins • General characters: • Wide antibacterial spectrum • High efficacy • Low allergic rate • Partial cross-sensitivity to penicillin (lesser from third generation on) • Certain extent of β-lactamase resistance

  25. cephalosporins Classification, based mainly on antibacterial properties: • First generation: cefazolin（头孢唑啉），cephalexin（头孢氨苄）：potent against G+; renal toxicity • Second generation: cefuroxime（头孢呋辛），cefacolor（头孢克洛）：against G+ & G－; low renal toxicity • Third generation: ceftriaxone（头孢曲松），cefoperazone（头孢哌酮）：less against G+,more potent against G－; very low renal toxicity • Fourth generation: cefepime（头孢吡肟）: potent both against G+ & G－; no renal toxicity • 各代头孢菌素都在临床应用!!!

  26. Carbapenems（碳青霉烯类）

  27. Other β-lactam penicillins • Imipenem（亚胺培南）

  28. imipenem

  29. Imipenem 亚胺培南 • extremely broad spectrum • high efficacy • β-lactamase resistant • hydrolyzed easily by renal dehydropeptidase; co-administered with silastatin（西司他丁）, the enzyme inhibitor

  30. Meropenem（美罗培南） • Dehydropeptidase-resistant • Even wider antibacterial spectrum than imipenem

  31. Cephamycins（头霉素类）

  32. Cephamycins • ≈second generation of cephalosporin • Cefoxitin 头孢西丁；Cefmetazole （头孢美唑）

  33. Oxacephems（氧头孢烯类）

  34. Oxacephems（氧头孢烯类） • Latamoxef（拉氧头孢） • wide antibacterial spectrum like third generation of cephalosporins • Strong anti-anaerobic bacterial effect • prolonged bleeding time (even lethal) • No longer available in US

  35. Monocyclic β-lactam antibiotic 单环β-内酰胺抗生素

  36. Monocyclic β-lactam antibiotic • strong activity against susceptible gram-negative bacteria including Pseudomonas aeruginosa. • like aminoglycosides, but no renal toxicity Aztreonam 氨曲南

  37. β-lactamase inhibitors and compound preparation β-内酰胺酶抑制剂及复方制剂

  38. Clavulanic acid 克拉维酸

  39. β-lactamase inhibitor • clavulanic acid（克拉维酸）; sulbactam（舒巴坦）；tazobactam（他唑巴坦） • similarity in chemical structure allows the molecule to act as a competitive inhibitor of β-lactamases to conferβ-lactam antibiotics antibacterial activity • co-administered with β-lactam antibiotics: • clavulanic acid + amoxicillin • sulbactam + cefoperazone

  40. Glycopeptide antibiotics 糖肽类 and Other antibiotics

  41. Vancomycin（万古霉素） Borneo婆罗洲丛林土壤 Eli Lilly, EC Kornfeld

  42. vancomycin • Glycopeptide; preventing incorporation of N-acetylmuramic acid (NAM)- and N-acetylglucosamine (NAG)-peptide subunits into the peptidoglycan matrix • Only effective against gram＋bacteria including MRSA • Traditionally, drug of “last resort” • VRSA:vancomycin-resistant Staphylococcus aureus • VRE: vancomycin-resistant enterococci

  43. Scanning electron micrographs of vancomycin-resistant Enterococcus

  44. vancomycin • Severe ototoxicity and nephrotoxicity, etc. • being replaced by linezolid（利奈唑胺）and daptomycin（达托霉素）

  45. norvancomycin 去甲万古霉素; teicoplanin 替考拉宁 • ≈vancomycin with lower toxicity

  46. Daptomycin 达托霉素

  47. daptomycin • Eli Lilly; Cubist company • Novel cyclic lipopeptide antibiotic 环脂肽抗生素 • Strong activity against Gram-positive organisms, even multi-resistant bacteria

  48. Fosfomycin 磷霉素

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