Part2 -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)

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)

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

1. Classification of Penicillins: (1)Nature penicillins: Penicillin G(苄青霉素, 简称青霉素) (2)oral penicillins: Penicillin V(青霉素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).

Mechanism of action Inhibit bacterial growth by interfering with a specific step in bacterial cell wall synthesis

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; Penicillins (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)

Penicillin -Mechanism of resistance

(2)to alter PBP, decreased affinity for the antibiotic; Penicillins (2)to alter PBP, decreased affinity for the antibiotic; (3)to make deficiency of porins, or enhance active efflux system, let penicillins does not reach its target, and inability to be effective. (4) Lack of the autolysins

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

5. Clinical Uses: (1)Streptococcal(链球菌) infections: such as: 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.

(3)Leptospira(螺旋体) infection: 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.

(1)Hypersensitivity reactions: Penicillins (1)Hypersensitivity reactions: Itching(痒), rashes, fever, serum sick-ness, angioneurotic oedema(血管神经性水肿). Anaphylactic shock (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.

7. ADME of Penicillin G: Be destroyed easily by p.o. 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.

8. Preparation of long-acting penicillin G: 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（口服耐酸青霉素）: 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 Pharyngitis(咽炎), etc.

2. The penicillinase-resistant penicillins(耐酶青霉素): 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, can be administrated by po, or im, iv ; and it is resistant to cleavage by penicillinase. It is used for treatment of penicillin G-resistance staphylococcal infection.

3. Broad spectrum penicillins（广谱青霉素）: Amipicillin(氨苄西林), Semisynthetic Penicillins 3. Broad spectrum penicillins（广谱青霉素）: Amipicillin(氨苄西林), Amoxicillin(阿莫西林) They have similar antibacterial activity and a broader spectrum. All can be destroyed by -lactamase. Pseudomonas aeruginosa(铜绿假单孢菌 ——绿脓杆菌)-resistance. Clinical Uses: Upper respiratory infections; Urinary tract infections; Meningitis; Salmonella infections.

4. Anti-pseudomonas penicillins Semisynthetic Penicillins 4. Anti-pseudomonas penicillins Carbenicillin(羧苄西林) Piperacillin(哌拉西林) Ticarcillin(替卡西林) With activity against Pseudomonas aeruginosa and some Proteus(变形杆菌).

Semisynthetic Penicillins Piperacillin(哌拉西林) They have the broadest antibacterial spectrum, and the most activity of the penicillins, with activity against Pseudo-monas aeruginosa, etc. Clinical Uses: 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) They are bacteriostatic drugs, and have narrow antibacterial spectrum, with activity against some G- bacilli.

Ⅱ. Cepharosporins (头孢菌素类)

Cepharosporins The well-accepted system of classification by “generations” is based on general features of anti-microbial activity.

Classification and Features: Cepharosporins 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 genera-tion against certain G+ microoganisms; (2)more impervious than second and third ge-neration to attack by staphyloccal -lactamase; (3)less active than second and third genera-tion against certain G- microoganisms; (4)non-stable to G- bacilli -lactamase; (5)more 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- bacilli and more impervious than first generation G- bacilli -lactamase; (2)somewhat less active than first generation against G+ cocci 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.

（头孢孟多） （头孢西丁）

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

（头孢哌酮） （头孢噻肟）

Cepharosporins 4. Fourth generation: Cefepime(头孢匹肟), Cefpirome(头孢匹罗), etc. (1)resistant to type 1 -lactamase; (2)more active than third generation against Enterbacter(耐肠杆菌); (3)less active than third generation against Pseudomonas.

Cepharosporins fourth

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

Ⅲ. Other -lactam antibiotics 1. Carbapenems(碳青霉烯类): Imipenem(亚胺培南) Imipenem is markered in combination with cilastatin(西司他丁)——Tienam(泰能), a drug that inhibits the degradation of imipenem by a renal tubular dipeptidase. It has the broadest antibacterial spec-trum and the most activity of all the anti-biotic.

2. 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.

Aztreonam(氨曲南) Carumonam(卡芦莫南) Other -lactam antibiotics 3. Monobectams(单环类): Aztreonam(氨曲南) Carumonam(卡芦莫南) For the treatment of aerobic G- bacilli infections. Narrow-spectrum antibiotic.

Latamoxef(拉氧头孢) Flomoxef(氟氧头孢) Other -lactam antibiotics 4. Oxacephalosporins(氧头孢烯类) Latamoxef(拉氧头孢) Flomoxef(氟氧头孢) Broad-spectrum antibiotic(anaerobic infections).

5. -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.

END OF CLASS