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.


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 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.


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


PenicillinPenicillins s

4. Mechanism of resistance:


(( 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


Antibiotic efflux pumps of G- bacteria.


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: 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).


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: 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. 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:

Benzathine penicillin G( 苄星青霉素 )

Procain penicillin( 普鲁卡因青霉素 )


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.


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 ).


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:

• 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. 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.


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））


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））


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


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

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

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