Chemotherapeutic Drugs Yun-Bi Lu, PhD 卢韵碧 Dept. of Pharmacology, School of Medicine, Zhejiang University

According to the chemical structure ： 1.β-lactams (β- 内酰胺类 ) ； Penicillins ( 青霉素 类 ) ； Cephalosporins ( 头孢菌素类 ); 2. Aminoglycosides ( 氨基糖苷类 ); 3. Macrolides ( 大环内酯类 ); Lincosamides ( 林 可胺类 ); Vancomycins ( 万古霉素类 ) 4. Tetracyclines ( 四环素类 ) ； Chloramphenicol ( 氯霉素 ) Chloramphenicol ( 氯霉素 ) Antimicrobial drugs -Characteristics Basic principle of clinical usage of antimicrobial agents

5. Quinolones ( 喹诺酮类 ) 6. Sulphonamides ( 磺胺类 ) 7. Nitrofurans ( 硝基呋喃类 ) 8. Antimycobacterial agents ( 抗结核分 支杆菌类 ) 9. others: Oxazolidinones ( 恶唑烷酮类 ) Oxazolidinones ( 恶唑烷酮类 ) Streptogramins ( 链阳菌素类 ) Streptogramins ( 链阳菌素类 ) Basic principle of clinical usage of antimicrobial agents

Chapter 39  -Lactam Antibiotics (  - 内酰胺类抗生素 )

( 噻唑环 ) （青霉素类） （头孢菌素类）

Classification  Penicillins （青霉素类）  Cepharosporins （头孢菌素类）  Non-classical β-Lactams Cephamycins （头霉素类） Carbapenems （碳青霉烯类） Monobectams （单环  - 内酰胺类） Oxacephalosporins( 氧头孢烯类 )   -lactamase inhibitors (  - 内酰胺酶抑制剂 )

Paul Ehrlich introduced an arsenic-containing chemical called salvarsan ( 阿斯凡纳明 ) to treat syphilis ( 梅毒 ) (1910). –“Magic bullet” for treatment of syphilis Chemotherapy 1928 Fleming discovers penicillin

History of Antimicrobial Therapy 1928

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)

1928 found and named by Fleming 1928 found and named by Fleming 1940 the crude material was used on infected mice 1940 the crude material was used on infected mice 1941 conduct therapeutic trials (10% purity) 1941 conduct therapeutic trials (10% purity) 1942 USA (Yale Uni.) begin the first clinical trial 1942 USA (Yale Uni.) begin the first clinical trial 1945 the Noble Prize for Medicine 1945 the Noble Prize for Medicine 1950 the commercial cost became 1950 the commercial cost became several $/100,000U several $/100,000U 1960 …… 1960 …… History

Mechanism of action

 Inhibit penicillin-binding proteins ( 青霉素结合蛋白 PBPs)  Enhance the activity of cell autolytic enzyme( 自溶酶 )

Mechanism of action PBPs ：分 2 类，大分子量具有转肽酶和转糖基酶活性，小分子量具有羧肽酶活性； 细菌种类不同含有不同的 PBPs ；同一种细菌可具有不同种的 PBPs 。

the Role of Penicillins in Blocking Transpeptidase Enzymes Synthesis of Peptidoglycan Mechanism of action

Bacterial Resistance （青霉素） （链霉素） （四环素） （万古霉素）

1 Site of action of  -lactamase 2 Site of action of amidase A Thiazolidine ring B  -Lactam ring  -lactamase （酰胺酶） （  - 内酰胺酶） Mechanism of resistance

陷阱 / 牵制机制 trapping mechanism 1. 产生水解酶 2. 与药物结合 3. 改变 PBPs 4. 改变膜通透性 5. 增强药物外排 6. 缺乏自溶酶

Mechanism of resistance β-lactamase Altered PBPs decreased affinity for the antibiotic Changes of Porins Active efflux system

Mechanism of action and resistance

Classification  Penicillins （青霉素类）  Cepharosporins （头孢菌素类）  Non-classical β-Lactams Cephamycins （头霉素类） Carbapenems （碳青霉烯类） Monobectams （单环  - 内酰胺类） Oxacephalosporins( 氧头孢烯类 )   -lactamase inhibitors (  - 内酰胺酶抑制剂 )

Penicillins （青霉素类） 侧链 主核 （ 6- 氨基青霉烷酸）

1. Natural penicillins （天然青霉素） — penicillin G 2. Semisynthetic penicillins （半合成青霉素） — Oral penicillins penicillin V (phenoxymethylpenicillin) penicillin V (phenoxymethylpenicillin) — Penicillinase-resistant penicillins methicillin 甲氧西林， cloxacillin 氯唑西林 methicillin 甲氧西林， cloxacillin 氯唑西林 dicloxacillin 双氯西林, nafcillin 萘夫西林 dicloxacillin 双氯西林, nafcillin 萘夫西林 — Extended-spectrum penicillins ampicillin 氨苄西林, amoxicillin 阿莫西林 — Anti-pseudomonas penicillins carbenicillin 羧苄西林， piperacillin 哌拉西林 — Anti-gram-negative bacilli penicillins mecillinam 美西林， temocillin 替莫西林 Penicillins - Classification

Penicillins - penicillin G benzylpenicillin, 苄青霉素 ) Penicillins - penicillin G (benzylpenicillin, 苄青霉素 ) Properties  The activity of penicillin G was originally defined in units. Semisynthetic penicillins are prescribed by weight (mg) rather than units.  Most penicillins are dispensed as the sodium or potassium salt ( 钠盐或钾盐 ) of the free acid.

Properties In dry crystalline form, penicillin salts are stable for long periods (e.g., for years at 4 ºC ). Solutions lose their activity rapidly (e.g., 24 hours at 20 ºC) and must be prepared fresh for administration. Penicillins - penicillin G

ADME  Be given by im ( 肌内注射 ) or i.v.gtt. ( 静滴 )  widely distributed (even in CSF, when there is infection). there is infection).  eliminated in the urine  Long-acting Penicillin G( 混悬剂 / 油剂 ) Benzathine penicillin ( 苄星青霉素） Benzathine penicillin ( 苄星青霉素） Procain penicillin ( 普鲁卡因青霉素） Procain penicillin ( 普鲁卡因青霉素） Penicillins - penicillin G

Antimicrobial activity The penicillin-susceptible organisms are non- penicillinase-producing strains of most cocci （球菌）, gram-positive bacilli （杆菌）, and spirochetes （螺旋体）.

Clinical Uses Clinical Uses (1) Streptococcal （链球菌） infections (pharyngitis 咽炎, scarlet infections (pharyngitis 咽炎, scarlet fever 猩红热, pneumonia 肺炎, arthritis fever 猩红热, pneumonia 肺炎, arthritis 关节炎, endocarditis 心内膜炎, etc.) 关节炎, endocarditis 心内膜炎, etc.) (2) Meningococcal （脑膜炎球菌） infections infections Penicillins - penicillin G

Clinical Uses (3) Leptospira （螺旋体感染） infection(Syphilis 梅 毒， typhinia 回归热 ); and Actinomycosis （放 线菌病） (4) Gram-positive bacilli infection （ diphtheria 白喉）, combinated with antitoxin （ diphtheria 白喉）, combinated with antitoxin (5) Staphylococcal （葡萄球菌） infection (generally resistant to penicillin G), Pneumococcal （肺炎球菌） infection, Gonococcal （淋球菌） infection Penicillins - penicillin G

Adverse effects Adverse effects (1) Hypersensitivity reactions itching, rashes, fever, serum sickness, angioneurotic oedema （血管神经性水肿）, anaphylactic shock （过敏 性休克） ( /10, 000 ， 0.1/10,000). itching, rashes, fever, serum sickness, angioneurotic oedema （血管神经性水肿）, anaphylactic shock （过敏 性休克） ( /10, 000 ， 0.1/10,000). (2) Others Phlebitis ( 静脉炎 ); injection site inflammatory reactions; degeneration of nerve tissue; and central nervous system excitability. Phlebitis ( 静脉炎 ); injection site inflammatory reactions; degeneration of nerve tissue; and central nervous system excitability. (3) Herxheimer reaction( 赫氏反应 ) Penicillins - penicillin G

Treatment/prevention for Adverse effects (1) 询问病史 / 过敏史 ; (2) 避免滥用与局部应用 ; (3) 避免饥饿时注射 ; (4) 不可在无急救药物与抢救设备条件下使用 ; (5) 初次使用、用药间隔 3 天以上、换用不同批次药物需做皮试， 皮试阳性者禁用； (6) 注射液需现配现用 ; (7) 患者注射后需留观 30min ，无反应者方可离开 ; (8) 一旦发生过敏性休克， First aid treatment Epinephrine (sc.), Glucocorticoids, Anti-histamines. Penicillins - penicillin G

药物相互作用 (1) 药动学：抑制 β - 内酰胺类的肾小管分泌，如 丙磺舒 ; (2) 药效学：协同作用 - 氨基糖苷类药物， 拮抗作用 - 抑菌药 (3) 配伍禁忌：不可与重金属配伍，不可与其他 抗生素混合后静脉滴注给药（易浑浊）；氨 基酸营养液增强其抗原性。 Penicillins - penicillin G

Antibacterial spectrum( 抗菌谱 ) Narrow?Narrow? Broad?Broad? Chemotherapetic index (CI)( 治疗指数 ) CI= LD 50 / ED 50CI= LD 50 / ED 50 CI= LD 5 / ED 95CI= LD 5 / ED 95 Chemotherapeutic agents

Bactericidal vs Bacterostatic Chemotherapeutic agents

1. Pencillins for Oral administrition 1. Pencillins for Oral administrition  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 is longer than that of penicillin G. Penicillins -Semisynthetic Penicillins Penicillins - Semisynthetic Penicillins

2. The Penicillinase-resistant Penicillins  Methicillin( 甲氧西林 ) ， Oxacillin( 苯唑西林 ) ， Cloxacillin （氯唑西林）， Dicloxacillin （双氯西林）  stable in an acidic medium （ exp. Methicillin ）, and resistant to cleavage by β-lactamase.  used for treatment of Penicillin G-resistance staphylococcal infection.  Methicillin-resistant strains of staphylococcus aureus (MRAS) ： new PBPs Penicillins -Semisynthetic Penicillins Penicillins - Semisynthetic Penicillins

3. Broad-spectrum Penicillins Amipicillin( 氨苄西林 ) ， Amoxicillin( 阿莫西林） Amipicillin( 氨苄西林 ) ， Amoxicillin( 阿莫西林） Pseudomonas aeruginosa( 铜绿假单胞菌 )- resistance ； can be destroyed byβ-lactamase. Pseudomonas aeruginosa( 铜绿假单胞菌 )- resistance ； can be destroyed byβ-lactamase. Clinical Uses Clinical Uses Upper respiratory infections Upper respiratory infections Urinary tract infections Urinary tract infections Meningitis Meningitis Salmonella infections Salmonella infections Penicillins -Semisynthetic Penicillins Penicillins - Semisynthetic Penicillins

4. Broad spectrum Penicillins against Pseudomonas aeruginosa 4. Broad spectrum Penicillins against Pseudomonas aeruginosa Carbenicillin （羧苄西林）， Piperacillin （哌拉西林） Carbenicillin （羧苄西林）， Piperacillin （哌拉西林） with activity against Pseudomonas aeruginosa and some Proteus ( 变形杆菌） etc. with activity against Pseudomonas aeruginosa and some Proteus ( 变形杆菌） etc. Clinical Uses Clinical Uses severe infection caused by gram-negative bacteria, usually in combination with aminoglycoside （氨基苷 类）. severe infection caused by gram-negative bacteria, usually in combination with aminoglycoside （氨基苷 类）. Penicillins -Semisynthetic Penicillins Penicillins - Semisynthetic Penicillins

5. Penicillins against gram-negative rod 5. Penicillins against gram-negative rod Mecillinam( 美西林） Mecillinam( 美西林） Temocillin （替莫西林） Temocillin （替莫西林） They have narrow antibacterial spectrum.They have narrow antibacterial spectrum. Penicillins -Semisynthetic Penicillins Penicillins - Semisynthetic Penicillins

Cephalosporins( 头孢菌素 )  More stable to  -lactase  Broader spectrum  Higher anti-bacteria strength  Less hypersensitivity  Lower toxicity 7- 氨基头孢烷酸

1. Classification 1. Classification The well-accepted system of classification by “generations” is based on general features of antimicrobial activity. The well-accepted system of classification by “generations” is based on general features of antimicrobial activity. Cephalosporins Based on: Spectrum, stable to  -lactase, effect on G- negative bacteria and the toxicity to kidney.

Classification and Features Cefadroxil 头孢羟氨苄 Cephalothin 头孢噻吩 Cephapirin 头孢匹林 No sensitivity to MRSA

Classification and Features Cefonicid 头孢尼西 Ceforanide 头孢雷特

Classification and Features Cefoperazone 头孢哌酮 Cefotaxime Ceftizoxime Cefixime Cefodizime

Classification and Features 5 th generation ？ Ceftobiprole and Ceftaroline powerful antipseudomonal characteristics and appears to be less susceptible to development of resistance

Other β-lactam antibiotics  Stable to  -lactase, however sensitive to metalloenzyme （金属酶）.  in combination with cilastatin （西司他丁）, a drug that inhibits the degradation of imipenem by a renal tubular dipeptidase ( 二肽酶 ).  Central nervous side effects 1. Carbapenems （碳青霉烯类） Imipenem ( 亚胺培南 / 亚胺硫霉素 )

2. Cephamycins （头霉素类） 2. Cephamycins （头霉素类） Cefoxitin ( 头孢西丁 ) ， Cefmetazole （头孢美唑） Cefoxitin ( 头孢西丁 ) ， Cefmetazole （头孢美唑） has the similar antibacterial activity and spectrum to the 2 nd generation Cephalosporins 。 has the similar antibacterial activity and spectrum to the 2 nd generation Cephalosporins 。 Very sensitive to anaerobic infections （厌氧 菌）. Very sensitive to anaerobic infections （厌氧 菌）. Other β-lactam antibiotics

3. Oxacephalosporins( 氧头孢烯类 ) 3. Oxacephalosporins( 氧头孢烯类 ) Latamoxef （拉氧头孢） Latamoxef （拉氧头孢） Flomoxef （氟氧头孢） Flomoxef （氟氧头孢）  Broad-spectrum antibiotic (anaerobic infections), has the similar antibacterial activity and spectrum to the 3 rd generation Cephalosporins.  High concentration in CSF Other β-lactam antibiotics

 Narrow-spectrum antibiotic.  For the treatment of aerobic gram- negative bacilli infections or Pseudomonas aeruginosa.  No effect on anaerobic or gram-positive  Less cross anaphylaxis 4. Monobectams （单环类） Aztreonam （氨曲南） Carumonam （卡芦莫南）

Clavulanic acid( 克拉维酸 )Clavulanic acid( 克拉维酸 ) Sulbactam( 舒巴坦 )Sulbactam( 舒巴坦 ) Tazobactam( 三唑巴坦 )Tazobactam( 三唑巴坦 ) Binding to  -lactamases and inactivate them.Binding to  -lactamases and inactivate them.  -lactamase inhibitors (  - 内酰胺酶抑制剂 ) Compound Preparation of  -lactamase Inhibitors : 优立新 unsayn = 阿莫西林 + 舒巴坦 (2:1) 优立新 unsayn = 阿莫西林 + 舒巴坦 (2:1)

I. Mechanism of action and resistance II. Classification  Penicillins （青霉素类）  Cepharosporins （头孢菌素类）  Non-classical β-Lactams Cephamycins （头霉素类） Carbapenems （碳青霉烯类） Monobectams （单环  - 内酰胺类） Oxacephalosporins( 氧头孢烯类 )   -lactamase inhibitors (  - 内酰胺酶抑制剂 )  Compound Preparation of  -lactamase inhibitors Summary II

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