Chemotherapeutic DrugsChemotherapeutic Drugs

Yun-Bi LuYun-Bi Lu, PhD, PhD

卢韵碧卢韵碧

Dept. of Pharmacology, Dept. of Pharmacology, School of Medicine, Zhejiang UniversitySchool of Medicine, Zhejiang University

yunbi@zju.edu.cnyunbi@zju.edu.cn

2013.12.19

According to the chemical structureAccording to the chemical structure ：：1.1. β-lactams (β-β-lactams (β- 内酰胺类内酰胺类 )) ；； Penicillins (Penicillins ( 青霉青霉

素类素类 )) ；； Cephalosporins (Cephalosporins ( 头孢菌素类头孢菌素类 ););

2.2. Aminoglycosides (Aminoglycosides ( 氨基糖苷类氨基糖苷类 ););

3.3. Macrolides (Macrolides ( 大环内酯类大环内酯类 ); Lincosamides (); Lincosamides ( 林林可胺类可胺类 ); Vancomycins (); Vancomycins ( 万古霉素类万古霉素类 ))

4.4. Tetracyclines (Tetracyclines ( 四环素类四环素类 ) ) ；； Chloramphenicol (Chloramphenicol ( 氯霉素氯霉素 ))

Antimicrobial drugsAntimicrobial drugs -Characteristics -Characteristics

Basic principle of clinical usage of antimicrobial agentsBasic principle of clinical usage of antimicrobial agents

5. Quinolones (5. Quinolones ( 喹诺酮类 喹诺酮类 ))

6. Sulphonamides (6. Sulphonamides ( 磺胺类 磺胺类 ))

7. Nitrofurans (7. Nitrofurans ( 硝基呋喃类硝基呋喃类 ))

8. Antimycobacterial agents (8. Antimycobacterial agents ( 抗结核分抗结核分支杆菌类 支杆菌类 ) )

9. others: 9. others:

Oxazolidinones (Oxazolidinones ( 恶唑烷酮类恶唑烷酮类 ) )

Streptogramins (Streptogramins ( 链阳菌素类链阳菌素类 ))

Basic principle of clinical usage of antimicrobial agentsBasic principle of clinical usage of antimicrobial agents

Chapter 39

-Lactam Antibiotics-Lactam Antibiotics

((-- 内酰胺类抗生素内酰胺类抗生素 ))

( 噻唑环 )

( 噻唑环 )

（青霉素类）

（头孢菌素类）

Classification Classification Penicillins Penicillins （青霉素类）（青霉素类） CepharosporinsCepharosporins （头孢菌素类）（头孢菌素类） Non-classical Non-classical β-Lactamsβ-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-lactamase inhibitors ((-- 内酰胺酶抑制剂内酰胺酶抑制剂 ))

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 penicillin1928 Fleming discovers penicillin

History of Antimicrobial TherapyHistory of Antimicrobial Therapy

1928

Sir Alexander Fleming The Nobel prize in Physiology or Medicine 1945

Discoverer of PenicillinCo-recipients: Florey and Chain

(They made it possible to produce large quantities)

                                           

19281928 found and named by Flemingfound and named by Fleming

19401940 the crude material was used on infected micethe crude material was used on infected mice

19411941 conduct therapeutic trials (10% purity)conduct therapeutic trials (10% purity)

19421942 USA (Yale Uni.) begin the first clinical trialUSA (Yale Uni.) begin the first clinical trial

19451945 the Noble Prize for Medicinethe Noble Prize for Medicine

19501950 the commercial cost became the commercial cost became

several $/100,000U several $/100,000U

1960 1960 …………

HistoryHistory

Mechanism of action

Mechanism of actionMechanism of action

Inhibit penicillin-binding proteins (Inhibit penicillin-binding proteins ( 青霉素结合蛋白青霉素结合蛋白 PBPs)PBPs)

Enhance the activity of cell autolytic enzyme(Enhance the activity of cell autolytic enzyme( 自溶酶自溶酶 ))

Mechanism of actionMechanism of action

PBPsPBPs ：分：分 22 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；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细菌种类不同含有不同的 PBPsPBPs ；同一种细菌可具有不同种的；同一种细菌可具有不同种的 PBPsPBPs 。。

the Role of Penicillins in Blocking the Role of Penicillins in Blocking Transpeptidase EnzymesTranspeptidase Enzymes

Synthesis of Peptidoglycan Synthesis of Peptidoglycan

Mechanism of actionMechanism of action

Bacterial Resistance

（青霉素）

（链霉素）

（四环素）

（万古霉素）

1 Site of action of 1 Site of action of -lactamase-lactamase2 Site of action of amidase2 Site of action of amidaseA Thiazolidine ringA Thiazolidine ringB B -Lactam ring-Lactam ring

-lactamase-lactamase

（酰胺酶）（酰胺酶）（（ -- 内酰胺酶）内酰胺酶）

Mechanism of resistanceMechanism of resistance

Mechanism of resistanceMechanism 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 PBPs4. 改变膜通透性5. 增强药物外排6. 缺乏自溶酶

Mechanism of resistanceMechanism of resistance

β-lactamaseβ-lactamase

Altered PBPs decreased Altered PBPs decreased affinity for the antibioticaffinity for the antibiotic

Changes of PorinsChanges of Porins

Active efflux systemActive efflux system

Mechanism of action and resistanceMechanism of action and resistance

Classification Classification Penicillins Penicillins （青霉素类）（青霉素类） CepharosporinsCepharosporins （头孢菌素类）（头孢菌素类） Non-classical Non-classical β-Lactamsβ-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-lactamase inhibitors ((-- 内酰胺酶抑制剂内酰胺酶抑制剂 ))

Penicillins Penicillins （青霉素类）（青霉素类）

侧链 主核（ 6- 氨基青霉烷酸）

1. Natural penicillins 1. Natural penicillins （天然青霉素）（天然青霉素）— — penicillin Gpenicillin G

2. Semisynthetic penicillins 2. Semisynthetic penicillins （（半合成青霉素半合成青霉素））— — Oral penicillinsOral penicillins penicillin V (phenoxymethylpenicillin)penicillin V (phenoxymethylpenicillin)

— — Penicillinase-resistant penicillinsPenicillinase-resistant penicillins

methicillin methicillin 甲氧西林，甲氧西林， cloxacillin cloxacillin 氯唑西林 氯唑西林 dicloxacillin dicloxacillin 双氯西林双氯西林 , nafcillin, nafcillin 萘夫西林萘夫西林— — Extended-spectrum penicillinsExtended-spectrum penicillinsampicillin ampicillin 氨苄西林氨苄西林 , amoxicillin , amoxicillin 阿莫西林阿莫西林— — Anti-pseudomonas penicillinsAnti-pseudomonas penicillinscarbenicillin carbenicillin 羧苄西林，羧苄西林， piperacillin piperacillin 哌拉西林哌拉西林— — Anti-gram-negative bacilli penicillinsAnti-gram-negative bacilli penicillinsmecillinam mecillinam 美西林， 美西林， temocillin temocillin 替莫西林替莫西林

Penicillins Penicillins - Classification- Classification

Penicillins Penicillins - - penicillin Gpenicillin G (benzylbenzylpenicillin, penicillin, 苄青霉素苄青霉素 ))

PropertiesProperties

The activity of penicillin G was originally deThe activity of penicillin G was originally defined in units. Semisynthetic penicillins are fined in units. Semisynthetic penicillins are prescribed by weight (mg) rather than units. prescribed by weight (mg) rather than units.

Most penicillins are dispensed as the sodiuMost penicillins are dispensed as the sodium or potassium salt (m or potassium salt ( 钠盐或钾盐钠盐或钾盐 ) of the fre) of the free acid.e acid.

PropertiesProperties

In dry crystalline form, penicillin salts are In dry crystalline form, penicillin salts are

stable for long periods (e.g., for years at 4 stable for long periods (e.g., for years at 4 ºCºC). ).

Solutions lose their activity rapidly (e.g., 24 Solutions lose their activity rapidly (e.g., 24

hours at 20 ºC) and must be prepared fresh for hours at 20 ºC) and must be prepared fresh for

administration. administration.

Penicillins Penicillins - - penicillin Gpenicillin G

ADME ADME

Be given by Be given by imim ( ( 肌内注射肌内注射 ) or ) or i.v.gtti.v.gtt. (. ( 静滴静滴 ) ) widely distributed (even in CSF, when widely distributed (even in CSF, when

there is infection).there is infection). eliminated in the urine eliminated in the urine Long-acting Penicillin G(Long-acting Penicillin G( 混悬剂混悬剂 // 油剂油剂 ))

Benzathine penicillin (Benzathine penicillin ( 苄星青霉素）苄星青霉素） Procain penicillin (Procain penicillin ( 普鲁卡因青霉素）普鲁卡因青霉素）

Penicillins Penicillins - - penicillin Gpenicillin G

Penicillins Penicillins - - penicillin Gpenicillin G

Antimicrobial activityAntimicrobial activity

The penicillin-susceptible organisms are non-The penicillin-susceptible organisms are non-

penicillinase-producing strains of most coccipenicillinase-producing strains of most cocci

（球菌）（球菌） , gram-positive bacilli, gram-positive bacilli （杆菌）（杆菌） , and s, and s

pirochetespirochetes （螺旋体）（螺旋体） ..

Clinical Uses Clinical Uses

(1) Streptococcal(1) Streptococcal （链球菌） （链球菌） infections (pharyngitisinfections (pharyngitis 咽炎咽炎 , scarlet , scarlet

feverfever 猩红热猩红热 , pneumonia, pneumonia 肺炎肺炎 , arthritis , arthritis

关节炎关节炎 , endocarditis, endocarditis 心内膜炎心内膜炎 , , etcetc.).)

(2) Meningococcal(2) Meningococcal （脑膜炎球菌）（脑膜炎球菌） infections infections

Penicillins Penicillins - - penicillin Gpenicillin G

Clinical Uses Clinical Uses

(3) Leptospira(3) Leptospira （螺旋体感染） （螺旋体感染） infection(Syphilisinfection(Syphilis 梅梅毒，毒， typhinia typhinia 回归热回归热 ); and Actinomycosis ); and Actinomycosis （放线菌病）（放线菌病）

(4) Gram-positive bacilli infection(4) Gram-positive bacilli infection

（（ diphtheria diphtheria 白喉）白喉） , combinated with antitoxin , combinated with antitoxin

(5) Staphylococcal (5) Staphylococcal （葡萄球菌）（葡萄球菌） infection (generallinfection (generally resistant to penicillin G), Pneumococcaly resistant to penicillin G), Pneumococcal （肺（肺炎球菌）炎球菌） infection , Gonococcalinfection , Gonococcal （淋球菌） （淋球菌） infinfectionection

Penicillins Penicillins - - penicillin Gpenicillin G

Adverse effects Adverse effects

(1) Hypersensitivity reactions(1) Hypersensitivity reactions

itching, rashes, fever, serum sickness, angioneurotic oitching, rashes, fever, serum sickness, angioneurotic o

edemaedema （血管神经性水肿）（血管神经性水肿） , anaphylactic shock , anaphylactic shock （过敏（过敏性休克）性休克） (0.4-1.5/10, 000(0.4-1.5/10, 000 ，， 0.1/10,000).0.1/10,000).

(2) Others(2) Others

Phlebitis (Phlebitis ( 静脉炎静脉炎 ); injection site inflammatory reaction); injection site inflammatory reaction

s; degeneration of nerve tissue; and central nervous ss; degeneration of nerve tissue; and central nervous s

ystem excitability.ystem excitability.

(3) Herxheimer reaction((3) Herxheimer reaction( 赫氏反应赫氏反应 ))

Penicillins Penicillins - - penicillin Gpenicillin G

Treatment/prevention for Adverse effects Treatment/prevention for Adverse effects

(1)(1) 询问病史询问病史 // 过敏史过敏史 ;;

(2)(2) 避免滥用与局部应用避免滥用与局部应用 ;;

(3)(3) 避免饥饿时注射避免饥饿时注射 ;;

(4)(4) 不可在无急救药物与抢救设备条件下使用不可在无急救药物与抢救设备条件下使用 ;;

(5)(5) 初次使用、用药间隔初次使用、用药间隔 33 天以上、换用不同批次药物需做皮试，天以上、换用不同批次药物需做皮试，皮试阳性者禁用；皮试阳性者禁用；

(6)(6) 注射液需现配现用注射液需现配现用 ;;

(7)(7) 患者注射后需留观患者注射后需留观 30min30min ，无反应者方可离开，无反应者方可离开 ;;

(8)(8) 一 旦 发 生 过 敏 性 休 克 ，一 旦 发 生 过 敏 性 休 克 ， First aid treatmentFirst aid treatment Epinephrine ( Epinephrine (sc.sc.), Glucocorticoids, Anti-histamines.), Glucocorticoids, Anti-histamines.

Penicillins Penicillins - - penicillin Gpenicillin G

药物相互作用 药物相互作用 (1)(1)药动学：抑制药动学：抑制 ββ-- 内酰胺类的肾小管分泌，内酰胺类的肾小管分泌，

如丙磺舒如丙磺舒 ;;

(2)(2)药效学：协同作用药效学：协同作用 -- 氨基糖苷类药物， 氨基糖苷类药物， 拮抗作用 拮抗作用 -- 抑菌药抑菌药

(3)(3)配伍禁忌：不可与重金属配伍，不可与其他配伍禁忌：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。基酸营养液增强其抗原性。

Penicillins Penicillins - - penicillin Gpenicillin G

Antibacterial spectrum(Antibacterial spectrum( 抗菌谱抗菌谱 ))• Narrow?Narrow?• Broad?Broad?

Chemotherapetic index (CI)(Chemotherapetic index (CI)( 治疗指数治疗指数 ))

• CI= LDCI= LD50 50 / ED/ ED50 50

• CI= LDCI= LD5 5 / ED/ ED9595

Chemotherapeutic agents

Bactericidal vs Bacterostatic

Chemotherapeutic agents

1. Pencillins1. Pencillins for Oral administritionfor Oral administrition

Phenoxymethylpenicillin (Phenoxymethylpenicillin ( 苯氧甲基青霉素苯氧甲基青霉素 , , Penicillin V)Penicillin V)

It is It is resistant to gastric acidresistant to gastric acid, and be well ab, and be well absorbed (60%) when it is given on an empty ssorbed (60%) when it is given on an empty stomach. tomach.

Its half-life is longer than that of penicillin G.Its half-life is longer than that of penicillin G.

Penicillins Penicillins -- Semisynthetic Penicillins Semisynthetic Penicillins

2. The Penicillinase-resistant Penicillins2. The Penicillinase-resistant Penicillins

Methicillin(Methicillin( 甲氧西林甲氧西林 )) ，， Oxacillin(Oxacillin( 苯唑西林苯唑西林 )) ，， CloCloxacillinxacillin （氯唑西林），（氯唑西林）， DicloxacillinDicloxacillin （双氯西林） （双氯西林）

stable in an acidic mediumstable in an acidic medium （（ exp. Methicillin exp. Methicillin ）） , , and and resistant toresistant to cleavage by cleavage by β-lactamaseβ-lactamase. .

used for treatment of Penicillin G-resistance staphused for treatment of Penicillin G-resistance staphylococcal infection.ylococcal infection.

Methicillin-resistant strains of staphylococcus aurMethicillin-resistant strains of staphylococcus aureus (MRAS)eus (MRAS) ： ： new PBPs new PBPs

Penicillins Penicillins -- Semisynthetic Penicillins Semisynthetic Penicillins

3. Broad-spectrum Penicillins3. Broad-spectrum Penicillins Amipicillin(Amipicillin( 氨苄西林氨苄西林 )) ，， Amoxicillin(Amoxicillin( 阿莫西阿莫西

林）林） Pseudomonas aeruginosa(Pseudomonas aeruginosa( 铜绿假单胞菌铜绿假单胞菌 ))-resi-resi

stancestance ；； cancan be destroyed byβ-lactamase. 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 Penicillins -- Semisynthetic Penicillins Semisynthetic Penicillins

4. Broad spectrum Penicillins against 4. Broad spectrum Penicillins against PseudomonPseudomonas aeruginosaas aeruginosa

CarbenicillinCarbenicillin （羧苄西林），（羧苄西林）， PiperacillinPiperacillin （哌拉西林） （哌拉西林） with activity against with activity against Pseudomonas aeruginosa Pseudomonas aeruginosa and sand s

ome ome Proteus Proteus (( 变形杆菌）变形杆菌） etcetc..

Clinical Uses Clinical Uses

severe infection caused by gram-negative bacteria, ussevere infection caused by gram-negative bacteria, usually in combination with aminoglycosideually in combination with aminoglycoside （ 氨 基 苷（ 氨 基 苷类）类） . .

Penicillins Penicillins -- Semisynthetic Penicillins Semisynthetic Penicillins

5. Penicillins 5. Penicillins against gram-negative rodagainst gram-negative rod

Mecillinam( Mecillinam( 美西林）美西林） TemocillinTemocillin （替莫西林）（替莫西林） • They have narrow antibacterial spectruThey have narrow antibacterial spectru

mm..

Penicillins Penicillins -- Semisynthetic Penicillins Semisynthetic Penicillins

Cephalosporins(Cephalosporins( 头孢菌头孢菌素素 ))

More stable to -lactase

Broader spectrum

Higher anti-bacteria strength

Less hypersensitivity

Lower toxicity

7- 氨基头孢烷酸

1. 1. ClassificationClassification

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

CephalosporinsCephalosporins

Based on: Spectrum, stable to -lactase, effect on G-negative bacteria and the toxicity to kidney.

Classification and FeaturesClassification and Features

Cefadroxil头孢羟氨苄Cephalothin头孢噻吩Cephapirin头孢匹林

No sensitivity to MRSA

Classification and FeaturesClassification and Features

Cefonicid 头孢尼西Ceforanide 头孢雷特

Classification and FeaturesClassification and Features

Cefoperazone 头孢哌酮

Cefotaxime

Ceftizoxime

Cefixime

Cefodizime

Classification and FeaturesClassification and Features

5th generation ？ Ceftobiprole and Ceftaroline

powerful antipseudomonal characteristics and appears to be less susceptible to development of resistance

Other β-lactam antibiotics Other β-lactam antibiotics

Stable to Stable to -lactase, however sensitive to metalloenzyme-lactase, however sensitive to metalloenzyme （金属酶）（金属酶） ..

in combination with cilastatinin combination with cilastatin （西司他丁）（西司他丁） , a drug that inhibits the , a drug that inhibits the

degradation of imipenem by a renal tubular dipeptidase (degradation of imipenem by a renal tubular dipeptidase ( 二肽酶二肽酶 ).).

Central nervous side effectsCentral nervous side effects

1. Carbapenems1. Carbapenems （碳青霉烯类）（碳青霉烯类）

Imipenem Imipenem

(( 亚胺培南亚胺培南 //亚胺硫霉亚胺硫霉素素 ))

2. Cephamycins2. Cephamycins （头霉素类）（头霉素类） Cefoxitin (Cefoxitin ( 头孢西丁头孢西丁 )) ，， CefmetazoleCefmetazole （头孢美唑）（头孢美唑）

has the similar antibacterial activity and spehas the similar antibacterial activity and spectrum to the 2ctrum to the 2ndnd generation generation CephalosporinsCephalosporins 。。

Very sensitive to anaerobic infectionsVery sensitive to anaerobic infections （厌氧（厌氧菌）菌） ..

Other β-lactam antibiotics Other β-lactam antibiotics

33. Oxacephalosporins(. Oxacephalosporins( 氧头孢烯类氧头孢烯类 ))

LatamoxefLatamoxef （拉氧头孢） （拉氧头孢） FlomoxefFlomoxef （氟氧头孢）（氟氧头孢）

Broad-spectrum antibiotic (anaerobic infeBroad-spectrum antibiotic (anaerobic infe

ctions) , has the similar antibacterial activctions) , has the similar antibacterial activ

ity and spectrum to the 3ity and spectrum to the 3rdrd generation generation CepCep

halosporins.halosporins.

High concentration in CSFHigh concentration in CSF

Other β-lactam antibiotics Other β-lactam antibiotics

Other β-lactam antibiotics Other β-lactam antibiotics

Narrow-spectrum antibiotic.Narrow-spectrum antibiotic. For the treatment of aerobic gram-negativFor the treatment of aerobic gram-negativ

e bacilli infections or e bacilli infections or Pseudomonas aerugPseudomonas aeruginosa inosa ..

No effect on anaerobic or gram-positive No effect on anaerobic or gram-positive Less cross anaphylaxisLess cross anaphylaxis

4. Monobectams4. Monobectams （单环类）（单环类）

Aztreonam Aztreonam （氨曲南） （氨曲南） CarumonamCarumonam （卡芦莫南）（卡芦莫南）

• Clavulanic acid(Clavulanic acid( 克拉维酸克拉维酸 ))

• Sulbactam(Sulbactam( 舒巴坦舒巴坦 ))

• Tazobactam(Tazobactam( 三唑巴坦三唑巴坦 ))

• Binding to Binding to -lactamases and inactiv-lactamases and inactivate them.ate them.

-lactamase inhibitors (-lactamase inhibitors (-- 内酰胺酶抑制剂内酰胺酶抑制剂 ))

Compound Preparation of Compound Preparation of -lactamase -lactamase Inhibitors : Inhibitors : • 优立新 优立新 unsaynunsayn = = 阿莫西林 阿莫西林 + + 舒巴坦舒巴坦 (2:1)(2:1)

I. Mechanism of action and resistanceI. Mechanism of action and resistance

II. ClassificationII. Classification

Penicillins Penicillins （青霉素类）（青霉素类） CepharosporinsCepharosporins （头孢菌素类）（头孢菌素类） Non-classical Non-classical β-Lactamsβ-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-lactamase inhibitors ((-- 内酰胺酶抑制剂内酰胺酶抑制剂 )) Compound Preparation of Compound Preparation of -lactamase inhibitor-lactamase inhibitor

ss

Summary II

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