基础医学各论III课件：26_2015抗生素

1、Part 2 -Lactam antibiotics,Beta-Lactam (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), a

2、nd inhibiting the synthesis of bacterial cell walls. (2)Activation of cell-wall autolytic enzy-me(自溶酶).,Penicillins,Comparison of the structure and composition of G+/ G- cell walls.,Penicillins,Penicillins (3)to make deficiency of porins, or enhance active efflux system, let penicillins does not rea

3、ch its target. (4) Lack of the autolysins,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: Meni

4、ngitis(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 penicilli

5、n 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

6、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.,Penicillins,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

7、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

8、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。,Box 发生青霉素过敏性休克的抢救,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 infectiv

9、e); 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),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

10、 gastric acid, and be well absorbed(60%) when it is given on an empty stomach. Its half-life(t) 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.,B. Semi-synthetic Penicillins:,Semisynthetic Penicillins,2. The penicil

11、linase-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-re

12、sistant staphylococcal infection.,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.,Semisynthetic Penicillins,4. Penicillin against Pseudomonas aeruginosa,Carbenicil

13、lin(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, usu

14、ally in combination with aminoglycoside (氨基苷类).,Semisynthetic Penicillins,4. 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,Semisynthetic Penicillins,. Cepha

15、rosporins(头孢菌素类),7-氨基头孢烷酸,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 stap

16、hyloccal -lactamase; (3)less active than second and third generation against certain G- microoganisms; (4)nonstable to G- bacilli -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,Cepharosporins,2. Second ge

17、neration: 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 to G- bacilli -lactamase; (2)somewhat less active than first generation against G+ cocci but more than third generation; (3)ac

18、tive 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- bacilli; (2)be highly resistant to -lactamas

19、e produced by G- bacilli; (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+ cocci; (6)less toxic to kidney.,Cepharosporins,4

20、. 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 (耐药肠杆菌), Pseudomonas and G+ cocci. (3)active against 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,. Other -lactam antibiotics,1

21、. 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.,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(

22、厄他培南) Broad spectrum: wide activity against gram-positive cocci (including some penicillin-resistant pneumococci), gram-negative rods, 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)Tiena

23、m(泰能), 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 aerob

24、ic 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.,. -lactamase inhibitors(-内酰胺酶抑制剂),Clavulanic acid(克拉

25、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.,. -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 prod

26、uced 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): irrever

27、sible inhibitor for beta-lactamases, active against inducible chromosomal beta-lactamases formed by Enterobacter, Pseudomonas, and Serratia.,Penicillin -Mechanism of resistance,The in vitro growth of Escherichiacoli in the presence of amoxicillin,with and without clavulanic acid.,amoxicillin+ clavul

28、anic 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,Part 3 Macrolides, Lincomycins high concentrations in secretions and body fluids; unable to cross cell membrane and BBB, able to cross the placenta. Tissue level is low except in the cortex of ki

29、dney and endolymph and perilymph of inner ear. iii) Metabolism and Elimination: excreted mainly by glomerular filtration. Accumulation occurs in renal failure with dose-related toxic effects.,Aminoglycosides,5. Clinical Uses mostly used against infection induced by aerobic G- bacilli . G- bacilli in

30、duced severe infection, such as sepsis(败血症), pneumonia and meningitis, almost always used in combination with b-lactam antibiotics (广谱半合成青霉素、三代头孢) and fluoroquinolones. G+ cocci severe infection: combined with vancomycin or -lactamase- resistant penicillins TB (streptomycin) and atypical mycobacteri

31、a分枝杆菌 (Amikacin),Aminoglycosides,7. Adverse reactions i) Ototoxicity （耳毒性） Caused by progressive destruction of vestibular and cochlear sensory cells (hearing loss irreversible!). Cochlear toxicity: tinnitus （耳鸣） and high frequency hearing loss KanamycinAmikacinSisomicinGentamicinTobramycin Vestibul

32、ar toxicity: vertigo, ataxia and loss of balance KanamycinStreptomycinSisomicinGentamicinTobramycin,Aminoglycosides,7. Adverse reactions ii) Nephrotoxicity consists of damage to the kidney tubules but reversible Neomycin KanamycinGentamicinStreptomycin or TobramycinAmikacin,Aminoglycosides,7. Advers

33、e reactions iii) Neuromuscular blockade (paralysis) generally occurred after intra-pleural or intra-peritoneal instillation of large doses of aminoglycosides Treatment: Calcium salt or inhibitor of cholinesterase (neostigmine) . NeomycinStreptomycinAmikacin or Kanamycin GentamicinTobramycin,Aminogly

34、cosides,7. Adverse reactions iv) Allergic reaction skin rashes, fever, angioneurotic edema, anaphylactic shock, etc.,Aminoglycosides,1. ADME i) Absorption: im ii) Distribution: mainly at extracellular fluid, can cross the BBB when meninges is inflamed. iii) Excretion: 90% from kidney 2.Clinical uses

35、 i) plague鼠疫(耶尔森菌) and tularemia土拉菌病(兔热病): combination with an oral tetracycline. ii) tuberculosis: as a first-line agent iii) bacterial endocarditis: (enterococcal, viridans streptococcal, etc.), streptomycin and penicillin produce a synergistic bactericidal effect.,Streptomycin,3. Adverse reaction

36、s i) Allergic reaction skin rashes, fever, anaphylactic shock ii) Ototoxicity: disturbance of vestibular function, deafness of newborn iii) Neuromuscular blockade (paralysis)：avoided in Myasthenia Gravis, avoided combining with anesthetics, scoline iv) Nephrotoxicity,Streptomycin,1. ADME Gentamicin

37、can accumulate in cortex of the kidney . 2.Clinical use : i) serious G- bacillary infections (sepsis, pneumonia, etc.). ii) infection induced by enterococcus, viridans streptococcus, staphylococcus etc. (in combination with other antibiotics, e.g. b-lactams) iii) prevent the infection induced by ope

38、ration (e.g., gastrointestinal operation) iv) local application,Gentamicin,1. Features 抗肺炎杆菌、肠杆菌、变形杆菌、绿脓杆菌较gentamicin强 Only effective to staphylococcus in G+ cocci 2. Adverse reactions Ototoxicity less toxic to cochlear and vestibular Nephrotoxicity less renal tubular damage,Tobramycin,1.Antibacteri

39、al activity: the broadest in the group. - effective against G- bacilli and staphylococcus aureus - ineffective to other G+ cocci - tolerance to modifying enzyme of enteric G- bacilli and pseudomonas 2.Clinical uses : - treatment of G- bacillary infections which are resistant to gentamicin and tobram

40、ycin. - most strains resistant to Amikacin found also resistant to other aminoglycosides. - combination with b-lactams, produce a synergistic bactericidal effect.,Amikacin,1. Broad spectrum, especially strong effect against aerobic G- bacilli. Effective against MRSA and strains resistant to other am

41、inoglycosides. 2. Tolerant to many aminoglycosides- inactivating enzymes. 3. Less toxic,Netilmicin,Polymyxins 多粘菌素,1.Notice: because of the extreme toxicity, they are now rarely used. 2.Antibacterial activity: narrow spectrum (G- bacilli), slow active, bactericidal. Not active to G+ organisms, G- co

42、ccus, Bacterooides fragilis(脆弱杆菌）, proteusbacillus vulgaris（变形杆菌）, serratia plymuthica（沙雷菌属）,Polymyxins,3. Mechanism of action: they interact with phospholipids (are surface-active) and penetrate into and disrupt the structure of cell membranes. 4. Clinical uses: substitute of -lactams and aminoglyc

43、osides, to treat infection of pseudomonas aeruginosa (铜绿假单胞菌属) and other G- bacilli, local application. 卫生部在2010年印发了产NDM1泛耐药肠杆菌科细菌感染诊疗指南（试行版）: 轻、中度感染：敏感药物单用即可，如氨基糖苷类、喹诺酮类、磷霉素等，也可以联合用药，如氨基糖苷类联合环丙沙星、环丙沙星联合磷霉素等。无效患者可以选用替加环素、多粘菌素。,Mechanism of Polymyxins action,Polymyxins,6. Adverse reaction: (1) Nephro

44、toxicity (22%) (2) Neurotoxicity (3) Allergic reaction (4) other reactions,Part 5 Tetracyclines & Chloramphenicol 四环素和氯霉素,Part A Tetracyclines,Divided into: Crude products (Naturally occurring) - Tetracycline (四环素) - Chlortetracycline (金霉素) - Oxytetracycline(土霉素) - Demeclocycline(地美环素) Semisynthetic

45、 derivatives - Doxycycline(多西环素) - Minocycline(米诺环素) - Meclocycline(甲氯环素) - Lymecycline(赖甲环素) - Methacycline(美他环素) - Rolitetracycline(吡甲四环素) - tigecycline (替加环素 ) (glycylcyline, 2005 approved),Tetracyclines,1. Antimicrobial activity: (1) Bacteriostatic (2) Bactericidal (at high concentration ) (3) M

46、inocyclineDoxycyclineTetracycline,Tetracyclines,2. Antimicrobial spectrum: (1)Broad spectrum: active against a wide range of aerobic and anaerobic gram-positive and gram-negative bacteria (对肠球菌、变形杆菌、绿脓杆菌不敏感). (2)Effective against Rickettsia (立克次体), spirochetes (螺旋体), Pneumoniae (支原体), Chlamydia (衣原体

47、), and Plasmodium (疟原虫). (3) Ineffective against fungi (eg. candida albicans白色念珠菌), virus.,Tetracyclines,3. Mechanism of action: (1) Enter bacteria by passive diffusion through porins or active transport by an energy-dependent system. (2) Inhibit protein synthesis in susceptible microorganisms (bind

48、 to A site and block combination of tRNA with 30S subunit). (3) Increase the permeability of the cell membrane,Tetracyclines,Tetracyclines, Chloramphenicol, Macrolides,4. Resistance Mechanism: (1) Decreased intracellular accumulation due to increased efflux by a active transport protein pump. (2) Ri

49、bosome protection that interfere with the tetracycline binding to the ribosome. (3) Enzyme inactivation of tetracycline.,Tetracyclines,5. ADME of Tetracyclines: (1) Absorption largely differ from each other after oral administration (doxycycline and minocycline 95-100%). Absorption are impaired by f

50、ood (except doxycycline and minocycline). (2) Distributed widely to tissue and body fluid except for CSF (minocycline exclusive). (3) Excreted mainly in bile and urine.,Tetracyclines,5. ADME of Tetracyclines: (4) Able to penetrate the placenta and are also excreted in the milk. (5) As a result of ch

51、elation with calcium, tetracyclines are bound to- and damage- growing bones and teeth.,Tetracyclines,6.Clinical Uses (1)Rickettsial (立克次体) infections. (2)Mycoplasma (支原体) infections: M. pneumonia and M.urealyticum (肺炎支原体/溶脲支原体). (3)Chlamydia(衣原体) infection：Chlamydia psittaci, pneumonia, rachomatis (

52、鹦鹉热/肺炎/沙眼衣原体). (4)Leptospira (螺旋体) infection：Borrelia burgdorferi, recurrentis, treponema pallidum (伯氏疏/回归热/梅毒螺旋体) infection. (5)Bacterial infection: Calymmatobacterium granulomatis, Vibrio cholerae, brucellosis (肉芽肿鞘杆菌/霍乱弧菌/布鲁菌) infection.,Tetracyclines,7. Adverse reactions (1)Gastrointestinal effe

53、cts. (2)Superinfections. (3)Deposition of the drugs in growing teeth and bones. (4)Hepatic toxicity and renal toxicity. (5)Photosensitivity(光敏反应). (6)Vestibular toxicity.,Tetracyclines,8. Drug interaction,Tetracyclines,Part B Chloramphenicol (氯霉素),p 1246 p776pharm,Chemical structure,1. Antimicrobial

54、 activity: (1) Possesses a wide antimicrobial spectrum aerobic and anaerobic, G- G+, rickettsia (立克次体), spirochetes (螺旋体), mycobacteria (支原体) but not chlamydia (衣原体), virus, fungi (2) Primarily bacteriostatic, bactericidal to certain species.,Chloramphenicol,2. Mechanism of action Inhibit protein synthesis in susceptible bacteria, and to a lesser extent in mammalian cell (because mitochondrial rib