part2 - -lactam antibiotics. classification of -lactam antibiotics Ⅰ. penicillins( 青霉素类...

Part2 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 )

(( 青霉素青霉素类类 ))

(( 头孢菌素类头孢菌素类 ))

Core Core structures of structures of beta-lactam beta-lactam antibiotic antibiotic familiesfamilies

(( 单环类单环类 ))

(( 碳青霉烯碳青霉烯类类 ))

(( 亚胺培南亚胺培南————碳青霉烯类碳青霉烯类 ))

• ChemicalChemical structurestructure of of penicillinspenicillins

ⅠⅠ. . PenicillinsPenicillins( 青霉素类 )

( 酰基侧链 ) ( 噻唑烷环 )

((-- 内酰胺环内酰胺环 ))

(( 青霉素类青霉素类 ))

A. NatureA. Nature PenicillinsPenicillins:

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 )

PenicillinsPenicillins

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.

PenicillinsPenicillins

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 ).

PenicillinsPenicillins

Mechanism of actionMechanism 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.

PenicillinsPenicillins

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

PenicillinsPenicillins

PenicillinPenicillins s

4. Mechanism of resistance:

PenicillinsPenicillins

(( 酰胺酶酰胺酶 ))(( 青霉素青霉素

酶酶 ))

(6-(6- 氨基青霉烷氨基青霉烷酸酸 ))

(( 青霉素裂解酸青霉素裂解酸 ))

(1)to produce penicillinase(-lactamase) by bacteria;

Penicillin -Penicillin -Mechanism of resistanceMechanism of resistance

(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

PenicillinsPenicillins

Antibiotic efflux pumps of G- bacteria.

PenicillinsPenicillins

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.

PenicillinsPenicillins

(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).

PenicillinsPenicillins

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.

PenicillinsPenicillins

(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.

PenicillinsPenicillins

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.

PenicillinsPenicillins

8. Preparation of long-acting penicillin G:

Benzathine penicillin G( 苄星青霉素 )

Procain penicillin( 普鲁卡因青霉素 )

PenicillinsPenicillins

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.

B. Semi-syntheticB. Semi-synthetic PenicillinsPenicillins:

SemisyntheticSemisynthetic PenicillinsPenicillins

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 ),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.

SemisyntheticSemisynthetic PenicillinsPenicillins

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 ).

SemisyntheticSemisynthetic PenicillinsPenicillins

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 ).

SemisyntheticSemisynthetic PenicillinsPenicillins

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.

SemisyntheticSemisynthetic PenicillinsPenicillins

Ⅱ. CepharosporinsCepharosporins( 头孢菌素类 )

CepharosporinsCepharosporins

• The well-accepted system of classification by “generations”

is based on general features of anti-microbial activity.

Classification and Features:

CepharosporiCepharosporinsns

• 1. First generation:1. First generation: • Cefazolin(Cefazolin( 头孢唑林头孢唑林 ), Cefradine(), Cefradine( 头孢拉定头孢拉定 ), ),

Cefalexin(Cefalexin( 头孢氨苄头孢氨苄 ), ), etc.etc.• (1)more active than second and third genera-(1)more active than second and third genera-

tion against certain G+ microoganisms;tion against certain G+ microoganisms;• (2)more impervious than second and third(2)more impervious than second and third ge-ge-

neration to attack by staphyloccal neration to attack by staphyloccal -lactamase;-lactamase;• (3)less active than second and third(3)less active than second and third genera-genera-

tion against certain G- microoganisms;tion against certain G- microoganisms;• (4)non-stable to G- bacilli (4)non-stable to G- bacilli -lactamase;-lactamase;• (5)more activity against certain (5)more activity against certain PseudomonasPseudomonas

(( 铜绿假单孢菌铜绿假单孢菌 ), anaerobes(), anaerobes( 厌氧菌厌氧菌 ), ), etcetc; ; • (6)certain kinds have kidney toxicity.(6)certain kinds have kidney toxicity.

CepharosporiCepharosporinsns

2. Second generation:2. Second generation: Cefuroxime(Cefuroxime( 头孢呋辛头孢呋辛 ), ), Cefamandole(Cefamandole( 头孢孟多头孢孟多 ), Cefaclor(), Cefaclor( 头头孢克洛孢克洛 ), ), etc.etc. (1)more active than first generation (1)more active than first generation against certain Gagainst certain G-- bacilli and more bacilli and more impervious than first generation Gimpervious than first generation G-- bacilli bacilli -lactamase;-lactamase; (2)somewhat less active than first (2)somewhat less active than first generation against Ggeneration against G++ coccicocci butbut moremore than thirdthan third generation;generation; (3)active(3)active againstagainst anaerobes(anaerobes( 厌氧菌厌氧菌 );); (4)lack activity against (4)lack activity against PseudomonasPseudomonas; ; (5)less toxic than first generation to (5)less toxic than first generation to kidney.kidney.

（头孢西丁（头孢西丁））

（头孢孟多（头孢孟多））

CepharosporiCepharosporinsns

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

（头孢哌酮（头孢哌酮））

（（头孢噻头孢噻肟肟））

CepharosporiCepharosporinsns

4. Fourth generation:4. Fourth generation: Cefepime(Cefepime( 头孢匹肟头孢匹肟 ), Cefpirome(), Cefpirome( 头头孢匹罗孢匹罗 ), ), etc.etc. (1)resistant to type 1 (1)resistant to type 1 -lactamase;-lactamase;

(2)more active than third generation (2)more active than third generation against Enterbacter(against Enterbacter( 耐肠杆菌耐肠杆菌 ););

(3)less active than third generation (3)less active than third generation against against PseudomonasPseudomonas..

fourth

CepharosporiCepharosporinsns

1st 2st 3st 4st1st 2st 3st 4st 抗菌谱 抗菌谱 G+ G+

G- G- 强强酶稳定性 好酶稳定性 好 肾毒性肾毒性半衰期 长半衰期 长

血脑屏障通透性血脑屏障通透性 好 好

OtherOther -lactam-lactam antibioticsantibiotics

• 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.

Ⅲ. OtherOther -lactamlactam antibioticsantibiotics

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.

OtherOther --lactamlactam antibioticsantibiotics

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.

Other Other -lactam -lactam antibioticsantibiotics

4. Oxacephalosporins( 氧头孢烯类 )

Latamoxef( 拉氧头孢 ) Flomoxef( 氟氧头孢 )

Broad-spectrum antibiotic(anaerobic infections).

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

•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 CLASSEND OF CLASS