Part 2 β-Lactam antibiotics　

Classification of -Lactam Antibiotics Ⅰ. Penicillins(青霉素类) Ⅱ. Cepharosporins(头孢菌素类) Ⅲ. Other -lactam antibiotics: 1. Cephamycins(头霉素类) 2. Carbapenems(碳青霉烯类) 3. Monobectams(单环类) 4. Oxacephalosporins(氧头孢烯类) 5. -lactamase inhibitors(内酰胺酶抑制剂)

Sir Alexander Fleming The Nobel prize in Physiology or Medicine 1945                                             青霉素是抗菌素的一种，是从青霉菌培养液中提制的药物，是第一种能够治疗人类疾病的抗生素。青霉素的发现者是英国细菌学家弗莱明。1928年的一天，弗莱明在他的一间简陋的实验室里研究导致人体发热的葡萄球菌。由于盖子没有盖好，他发觉培养细菌用的琼脂上附了一层青霉菌。这是从楼上的一位研究青霉菌的学者的窗口飘落进来的。使弗莱明感到惊讶的是，在青霉菌的近旁，葡萄球菌不见了。这个偶然的发现深深吸引了他，他设法培养这种霉菌进行多次试验，证明青霉素可以在几小时内将葡萄球菌全部杀死。弗莱明据此发明了葡萄球菌的克星—青霉素。    1929年，弗莱明发表了学术论文，报告了他的发现，但当时未引起重视，而且青霉素的提纯问题也还没有解决。 　　1935年，英国牛津大学生物化学家钱恩和物理学家弗罗里对弗莱明的发现大感兴趣。钱恩负责青霉菌的培养和青霉素的分离、提纯和强化，使其抗菌力提高了几千倍同，弗罗里负责对动物观察试验。至此，青霉素的功效得到了证明。     由于青霉素的发现和大量生产，拯救了千百万肺炎、脑膜炎、脓肿、败血症患者的生命，及时抢救了许多的伤病员。青霉素的出现，当时曾轰动世界。为了表彰这一造福人类的贡献，弗莱明、钱恩、弗罗里于1945年共同获得诺贝尔医学和生理学奖。     第二次世界大战促使青霉素大量生产。1943年，已有足够青霉素治疗伤兵；1950年产量可满足全世界需求。青霉素的发现与研究成功，成为医学史的一项奇迹。 Sir Alexander Fleming The Nobel prize in Physiology or Medicine 1945 Discoverer of Penicillin Co-recipients: Florey and Chain (They made it possible to produce large quantities)

History 1929 penicillin is found and named by Fleming 1940 the crude material was used on infected mice 1941 conduct therapeutic trials (10% purity)， priceless /dose 1942 USA (Yale Uni.) begin the first clinical trial， $ 20 /dose 1945 the Noble Prize for Medicine 1950 the commercial cost became $ 0.55 /dose 1960 ……

Chemical structure of penicillins A. Nature Penicillins: (酰基侧链) (噻唑烷环) (青霉素类) (-内酰胺环) Chemical structure of penicillins

Core structures of beta-lactam antibiotic families (青霉素类) Core structures of beta-lactam antibiotic families (头孢菌素类)

(单环类) (碳青霉烯类) (亚胺培南——碳青霉烯类)

Penicillins 1. Classification of Penicillins: (1)Nature penicillins: Penicillin G(苄青霉素, 简称青霉素) (2)Acid resistant penicillin: penicillin V (3)Penicillinase-resistant penicillins: Oxacillin(苯唑西林) (4)Broad-spectrum penicillins: Amoxicillin(阿莫西林) (5)Anti-pseudomonas penicillins: Ticarcillin(替卡西林) (6)Anti-G- bacilli penicillins: Mecillinam(美西林)

2. Antimicrobial activity: Penicillins 2. Antimicrobial activity: The penicillin-susceptible bacteria: (1)G+ bacilli(革兰阳性杆菌); (2)Non-penicillinase-producing strains of most G+ cocci(大多数不产青霉素酶的球菌) and Nisseria (奈瑟菌属), etc. such as: Meningococcus(脑膜炎球菌), Gonococcus(淋球菌), etc. (3)Spirochetes(螺旋体), etc.

Penicillins 3. Mechanism of action: (1)Inhibiting transpeptidase(转肽酶, PBP, 青霉素结合蛋白), and inhibiting the synthesis of bacterial cell walls. (2)Activation of cell-wall autolytic enzy-me(自溶酶).

Comparison of the structure and composition of G+/ G- cell walls. Penicillins Comparison of the structure and composition of G+/ G- cell walls.

Penicillins Penicillins Penicillins & cephalosporins can inhibit the transpeptidase reaction in sen-sitive organism (敏感菌). Penicillins

4. Mechanism of resistance: (1)to produce penicillinase (-lactamase) by bacteria (青霉素酶) (酰胺酶) (青霉素裂解酸) (6-氨基青霉烷酸)

Penicillins (2) -lactamase rapidly bind to Penicillinase-resistant penicillins （药物停留在胞质膜外，陷阱机制or牵制机制） (3) Produce PBP with low affinity (3)to make deficiency of porins, or enhance active efflux system, let penicillins does not reach its target. (4) Lack of the autolysins

Antibiotic efflux pumps of G- bacteria. Penicillins Antibiotic efflux pumps of G- bacteria.

Penicillins 5. Clinical Uses: (1)Streptococcal(链球菌) infections: such as: Pharyngitis(咽炎), Scarlet fever(猩红热), Rheumatic fever(风湿热), Pneumonia(肺炎), Endocarditis(心内膜炎), etc. (2)Nisseria (奈瑟菌) infections: Meningitis(脑膜炎); Gonorrhea(淋病), etc.

Penicillins (3)Leptospira (螺旋体) infection: such as: Liptospirosis(钩端螺旋体病), Syphilis(梅毒), Recurrent fever(回归热). (4)G+ bacilli (G+ 杆菌) infection: such as: Diphtheria(白喉), Tetanus(破伤风), Anthrax(炭疽病), etc. (5)Staphylococcal (葡萄球菌) infection (generally resistant to penicillin G).

Penicillins 6. Adverse effects: Penicillins are among the safest of antibiotics, produce few direct toxic reactions, The most of the serious side effects are hypersensitivity reactions.

Penicillins (1)Hypersensitivity reactions: Itching(痒), rashes, fever, serum sickness,angioneurotic edema(血管神经性水肿). Anaphylactic shock (0.4-1.5/10 000). 防治措施： 1）仔细询问病史 2）避免滥用和局部用药、避免饥饿时注射 3）不在没有急救药物和设备时使用 4）初次使用、用药间隔3天以上、换批号必须皮试 5）现配现用，用药后观察30分钟 6）过敏性休克：肾上腺素、糖皮质激素、抗组胺药

Penicillins (1)Hypersensitivity reactions: Itching(痒), rashes, fever, serum sickness,angioneurotic edema(血管神经性水肿). Anaphylactic shock (0.4-1.5/10 000). (2)Other adverse reactions: Phlebitis(静脉炎), when i.v.; Local inflammatory reactions, in injection site when i.m.; Jarisch-Herxheimer reaction(赫氏反应) when treatment of syphilis, liptospirosis.

Box 发生青霉素过敏性休克的抢救 患者，女，48岁。因鼻咽癌住院行放射治疗25次，诉咽喉疼痛，发热，体查：T 38.8 ℃，急性面容，心肺（-），咽喉部明显充血红肿，无白膜覆盖诊断为放射性咽炎。无药物过敏史，青霉素皮试（-）。给予0.9%氯化钠注射液100 ml，青霉素320万u，bid。于用药第二天静脉滴入同批号青霉素约50 ml，患者即觉鼻咽喉发痒不适，打喷嚏、流清水样涕。考虑青霉素过敏反应即拔出针头。约数秒钟后患者自觉胸闷，测BP 67.5/37.5 mm Hg，P 120次/min，R 30次/min，出现痉挛性咳嗽，呼吸极度困难，烦躁不安，表情痛苦，眼睑、口唇轻度水肿，发红并迅速转发绀，脉洪数迅速转细弱面色苍白，四肢湿冷，神志不清。诊断：青霉素致迟发过敏性休克。立即给予皮下注射肾上腺素1 mg，肌注异丙嗪25 mg，肌注、静注地塞米松各10 mg、葡萄糖酸钙20 ml，同时吸氧等治疗，约30 min后症状逐渐缓解，测BP 127.5/67.5 mm Hg，P 82次/min，R 19次/min。观察2天，一般情况平稳，输液治疗后症状缓解，查体仅有咽喉部疼痛，其他无阳性体征，血常规恢复正常，无后遗症。

Penicillins 7. ADME of Penicillin G: Be destroyed easily by p.o. Administration by i.m. or i.v. gtt. Widely distributed (even in CSF, when menings is infective); Eliminated in the urine, 90% secreted from renal tubule.

Penicillins 8. Preparation of long-acting penicillin G: Benzathine penicillin G(苄星青霉素) Procain penicillin(普鲁卡因青霉素)

Phenoxymethylpenicillin (苯氧甲基青霉素, Penicillin V) B. Semi-synthetic Penicillins: 1. Penicillins by oral administration（耐酸青霉素）: Phenoxymethylpenicillin (苯氧甲基青霉素, Penicillin V) It is resistant to gastric acid, and be well absorbed(60%) when it is given on an empty stomach. Its half-life(t½) is longer than that of penicillin G. A satisfactory substitute for Penicillin G to treat tonsilitis(扁桃体炎), or Pharyn-gitis(咽炎), etc.

Semisynthetic Penicillins 2. The penicillinase-resistant penicillins(耐酶青霉素): Methicillin(甲氧西林), Oxacillin(苯唑西林), Cloxacillin(氯唑西林), Dicloxacillin(双氯西林) It is stable in an acidic medium (except methicillin), can be administrated by po, or im, iv ; and it is resistant to cleavage by penicillinase. It is used for treatment of penicillin G-resistant staphylococcal infection.

Semisynthetic Penicillins Amipicillin(氨苄西林),Amoxicillin(阿莫西林) 3. Broad spectrum penicillins（广谱青霉素）: Amipicillin(氨苄西林),Amoxicillin(阿莫西林) They have better antibacterial activity to G- bacterial than penicillin G. All can be destroyed by -lactamase.

4. Penicillin against Pseudomonas aeruginosa Semisynthetic Penicillins 4. Penicillin against Pseudomonas aeruginosa Carbenicillin(羧苄西林), piperacillin (哌拉西林) With activity against Pseudomonas aeruginosa (铜绿假单孢菌 ——绿脓杆菌) and some Proteus (变形杆菌). Piperacillin has boardest spectrum and highest antibacterial activity among semi-synthetic Penicillins For the treatment of the patients with severe infection caused by G- bacteria, usually in combination with aminoglycoside (氨基苷类).

5. Anti-G- bacilli penicillins: Semisynthetic Penicillins 5. Anti-G- bacilli penicillins: Mecillinam(美西林), Temocillin(替莫西林) Narrow antibacterial spectrum: have activity against some G- bacilli. Temocillin is effective to bacteria producing -lactamase

Ⅱ. Cepharosporins (头孢菌素类) 理化特性、生物活性、作用机制、临床应用和青霉素类似 对-内酰胺酶稳定 抗菌谱广 杀菌力强 过敏反应少

B. Classification and Features: Cepharosporins B. Classification and Features: 1. First generation: Cefazolin(头孢唑林), Cefradine(头孢拉定), Cefalexin(头孢氨苄), etc. (1)more active than second and third generation against certain G+ microoganisms (except MRSA); (2)more impervious than second and third generation to attack by staphyloccal -lactamase; (3)less active than second and third generation against certain G- microoganisms; (4)nonstable to G- microoganisms -lactamase; (5) Lack activity against certain Pseudomonas (铜绿假单孢菌), anaerobes(厌氧菌), etc; (6)certain kinds have kidney toxicity.

Cepharosporins 2. Second generation: Cefuroxime(头孢呋辛), Cefamandole(头孢孟多), Cefaclor(头孢克洛), etc. (1)more active than first generation against certain G- microoganisms and more impervious than first generation to G- microoganisms -lactamase; (2)somewhat less active than first generation against G+ microoganisms but more than third generation; (3)active against anaerobes(厌氧菌); (4)lack activity against Pseudomonas; (5)less toxic than first generation to kidney.

Cepharosporins 3. Third generation: Ceftazidime(头孢他啶), Ceftriaxone(头孢曲松), etc. (1)far more active than first and second generation against G- microoganisms; (2)be highly resistant to -lactamase produced by G- microoganisms; (3)with the extended spectrum against anaerobes and Pseudomonas; (4)well absorbed, penetration into tissue, blood and body cavity as well in sufficient concentration; (5)less active than first and second generation against G+ microoganisms; (6)less toxic to kidney.

Cepharosporins 4. Fourth generation: Cefepime(头孢匹肟), Cefpirome(头孢匹罗), etc. (1)resistant to type 1 -lactamase; (2)has high activity on both G+ and G- microoganisms. (3)active against Pseudomonas and anaerobes

1st 2st 3st 4st 抗菌谱 G+ 强 G- 酶稳定性 好 肾毒性 大 半衰期 长 血脑屏障通透性 好

Ⅲ. Other -lactam antibiotics 1. Cephamycins(头霉素类): Cefoxitin (头孢西丁) It has the similar antibacterial activity and spectrum to the second generation cepharosporins, also can be used for the treatment of anaerobic infections （> 3rd cephalosporins）. highly resistant to -lactamase. Widely distributed, especially in CSF.

Other -lactam antibiotics 2. Carbapenems(碳青霉烯类): Imipenem(亚胺培南) Meropenem(美罗培南) Panipenem(帕尼培南) Ertapenem(厄他培南) Broad spectrum: wide activity against gram-positive (including some penicillin-resistant pneumococci), gram-negative microorganisms and anaerobes. With the exception of ertapenem, the carbapenems are active against Pseudomonas and Acinetobacter (不动杆菌) species.

Imipenem(亚胺培南)+cilastatin(西司他丁)—Tienam(泰能), cilastatin is a drug that inhibits the degradation of imipenem by a renal tubular dipeptidase. Panipenem(帕尼培南)+betamipron (倍他米隆)-Carbenin(克倍宁) CNS side effects at large dose.

Other -lactam antibiotics 3. Monobectams(单环类): Aztreonam(氨曲南) Carumonam(卡芦莫南) Narrow-spectrum antibiotic. For the treatment of aerobic G- bacilli infections (铜绿假单胞菌), resistant to -lactamase.

Other -lactam antibiotics 4. Oxacephalosporins(氧头孢烯类) Latamoxef(拉氧头孢) Flomoxef(氟氧头孢) Broad-spectrum antibiotic (similar to third generation of Cepharosporins). High concentration in CSF.

Ⅳ. -lactamase inhibitors (-内酰胺酶抑制剂) Clavulanic acid(克拉维酸) Sulbactam(舒巴坦) Tazobactam(三唑巴坦) Binding to -lactamases and inactivate them, thus preventing the destruction of -lactam antibiotics which are substrates for -lactamases.

Ⅳ. -lactamase inhibitors (-内酰胺酶抑制剂) Clavulanic acid (克拉维酸):most active against plasmid-encoded beta-lactamases such as those produced by staphylococci, gonococci, E coli, and H influenzae, but not good inhibitors of inducible chromosomal beta-lactamases formed by Morganii, Pseudomonas, and Serratia. Sulbactam (舒巴坦): active against both plasmid-encoded beta-lactamases and chromosomal beta-lactamases. Tazobactam (三唑巴坦): irreversible inhibitor for beta-lactamases, active against inducible chromosomal beta-lactamases formed by Enterobacter, Pseudomonas, and Serratia.

Penicillin -Mechanism of resistance

amoxicillin+ clavulanic acid = augmentin (奥格门汀) The in vitro growth of Escherichia coli in the presence of amoxicillin, with and without clavulanic acid. amoxicillin+ clavulanic acid = augmentin (奥格门汀)

阿莫西林+ 克拉维酸 = 奥格门汀augmentin 氨苄西林+舒巴坦 = 优立新unasyn 替卡西林+克拉维酸 =替门汀/特美汀 timentin