Antimicrobial Antimicrobial drugs in drugs in

Respiratory Infection

Huifang Tang Department of pharmacology

Zhejiang University, school of medicinetanghuifang@zju.edu.cn

Research building C4222012-3

IntroductionIntroduction

The key disorders of respiratory system:1. Disorders of the upper respiratory tract: r

hinitis( 鼻炎 ), tonsillitis( 扁桃体炎 ), angina( 咽峡炎 ), laryngitis( 喉炎 ), cold( 感冒 ), etc. ;

2. Bronchitis( 支气管炎 ), Pneumonia( 肺炎 );3. Chronic obstructive pulmonary disease (C

OPD, 慢性阻塞性肺疾病 , 慢阻肺 ); 4. Asthma( 支气管哮喘 , 哮喘 ); 5. Neoplasma: nasopharyngeal carcinoma

( 鼻烟癌 ), lung carcinoma( 肺癌 ), etc. 6. Pulmonary tuberculosis ( 肺结核 , PTB)

anti-microbial agentsanti-microbial agents

PartPart 1. 1. -Lactam antibiotics-Lactam antibioticsPart 2. Aminoglycosides Part 2. Aminoglycosides (( 氨基糖苷类氨基糖苷类 ) ) & polymyxins& polymyxins(( 多黏菌多黏菌

素类素类 ))Part 3. Macrolides Part 3. Macrolides (( 大环内酯类大环内酯类 )), lincomycins , lincomycins (( 林可霉素类林可霉素类 ),),

and vancomycins and vancomycins (( 万古霉素万古霉素 ))Part 4. Tetracyclines(Part 4. Tetracyclines( 四环素类四环素类 ))& chloramphenicol& chloramphenicol(( 氯霉素氯霉素 ))Part 5. Synthetic antimicrobial agentsPart 5. Synthetic antimicrobial agents(( 人工合成抗菌药人工合成抗菌药 ))Part 6. Antifungal agentsPart 6. Antifungal agentsPart 7. Antiviral agentsPart 7. Antiviral agentsPart 8. Antituberculous drugsPart 8. Antituberculous drugsPart 9. The drugs treated parasitic infectionsPart 9. The drugs treated parasitic infections

①①

②②

③③

④④

⑤⑤

Classification and mechanism of action

Contents

-Lactam Antibiotics （内酰胺类） Macrolides (( 大环内酯类大环内酯类 )) Quinolones （喹诺酮类） Tetracyclines(Tetracyclines( 四环素类四环素类 )) Antituberculous drugs （抗结核药）

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 )Ⅳ. -lactamase inhibitors( 内酰胺酶

抑制剂 )

1. Classification of Penicillins: (1)Nature penicillins: Penicillin G( 苄青霉素 , 简称青霉素 ) (2)Penicillinase-resistant penicillins: Oxacillin( 苯唑西林 ) (3)Broad-spectrum penicillins: Amoxicillin( 阿莫西林 ) (4)Anti-pseudomonas penicillins: Ticarcillin( 替卡西林 ) (5)Anti-G- bacilli penicillins: Mecillinam( 美西林 )

I. PenicillinsI. Penicillins

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 enzyme( 自溶酶 ).

PenicillinsPenicillins

1. Penicillins by oral administration（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.

Semi-syntheticSemi-synthetic PenicillinsPenicillins:

SemisyntheticSemisynthetic PenicillinsPenicillins

2. The penicillinase-resistant penicillins( 耐酶青霉素 ):

Oxacillin( 苯唑西林 ), Cloxacillin( 氯唑西林 ),

Dicloxacillin( 双氯西林 ) It is stable in an acidic medium, can be ad

ministrated 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 ), Piperacillin( 哌拉西林 ), etc.

They have similar antibacterial activity and a broader spectrum.

All can be destroyed by -lactamase.

SemisyntheticSemisynthetic PenicillinPenicillinss

Broad spectrum penicillinsBroad spectrum penicillins

(1)Ampicillin( 氨苄西林 ), Amoxicillin( 阿莫西林 )

Pseudomonas aeruginosa( 铜绿假单孢菌 ——绿脓杆菌 )-resistance. Clinical Uses: Upper respiratory infections; Urinary tr

act infections; Meningitis; Salmonella infections.

SemisyntheticSemisynthetic PenicillinPenicillinss

Broad spectrum PenicillinsBroad spectrum Penicillins

(2)Piperacillin( 哌拉西林 ),Mezlocillin( 美洛西林 ) They have the broadest antibacterial spect

rum, and the most activity of the penicillins, with activity against Pseudo-monas aeruginosa, etc.

Clinical Uses: For the treatment of the patients with seve

re infection caused by G- bacteria, us-ually in combination with aminoglycoside ( 氨基苷类 ).

SemisyntheticSemisynthetic PenicillinPenicillinss

4.Anti-pseudomonas penicillins

Carbenicillin( 羧苄西林 )Ticarcillin( 替卡西林 ) With activity against Pseudomon

as aeruginosa and some Proteus( 变形杆菌 ).

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 PenicillinPenicillinss

II. CepharosporinsII. Cepharosporins 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 ), Cefalex), Cefalex

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

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

tion to attack by staphyloccal tion to attack by staphyloccal -lactamase;-lactamase; (3)less active than second and third(3)less active than second and third genera-tion agenera-tion a

gainst certain G- microoganisms;gainst 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 ( ( 铜铜

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

CepharosporinsCepharosporins

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( 头孢克洛头孢克洛 ), ), etc.etc. (1)more active than first generation against c(1)more active than first generation against certain Gertain G-- bacilli and more impervious than first bacilli and more impervious than first generation Ggeneration G-- bacilli bacilli -lactamase;-lactamase; (2)somewhat less active than first generation (2)somewhat less active than first generation against Gagainst 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 kidney.(5)less toxic than first generation to kidney.

CepharosporinsCepharosporins3. Third generation:3. Third generation: Ceftazidime(Ceftazidime( 头孢他啶头孢他啶 ), Ceftriaxone(), Ceftriaxone( 头孢曲松头孢曲松), ), etc.etc. (1)far more active than first and second gene-(1)far more active than first and second gene-ration against Gration against G-- bacilli; bacilli; (2)be highly resistant to (2)be highly resistant to -lactamase produce-lactamase produced by Gd by G-- bacilli; bacilli; (3)with the extended spectrum against anae-r(3)with the extended spectrum against anae-robes and obes and PseudomonasPseudomonas;; (4)well absorbed, penetration into tissue, blo-(4)well absorbed, penetration into tissue, blo-od and body cavity as well in sufficient concen-od and body cavity as well in sufficient concen-tration;tration; (5)less active than first and second(5)less active than first and second generatiogeneration against Gn against G++ cocci; cocci; (6)less toxic to kidney.(6)less toxic to kidney.

CepharosporinsCepharosporins

4. Fourth generation:4. Fourth generation: Cefepime(Cefepime( 头孢匹肟头孢匹肟 ), Cefpirome(), Cefpirome( 头孢匹头孢匹罗罗 ), ), etc.etc. (1)resistant to type 1 (1)resistant to type 1 -lactamase;-lactamase; (2)more active than third generation against En(2)more active than third generation against Enterbacter(terbacter( 耐肠杆菌耐肠杆菌 );); (3)less active than third generation against (3)less active than third generation against PsePseudomonasudomonas..

Ⅲ. OtherOther -lactamlactam antibioticsantibiotics

1. 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 -lactam-lactam antibioticsantibiotics

2. 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.

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 antibiotics-lactam antibiotics

4. Oxacephalosporins( 氧头孢烯类 )Latamoxef( 拉氧头孢 ) Flomoxef( 氟氧头孢 )

Broad-spectrum antibiotic(anaerobic infections).

ⅣⅣ. . -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 inact

ivate them, thus preventing the destruction of -lactam antibiotics which are substrates for -lactamases.

History of Macrolides1952 Erythromycin(红霉素 )1970s Acetylspiramycin(乙酰螺旋霉素 ) Medecamycin(麦迪霉素 ) josamycin(交沙霉素 )1980s Clarithromycin (克拉霉素 ) Roxithromycin(罗红霉素 ) Azithromycin(阿奇霉素 )

Macrolides

14 碳环大环内酯类： 红霉素 (erythromycin) 克拉霉素 (clarithromyc

in) 罗红霉素 (roxithromy

cin) 15 碳环大环内酯类：

阿奇霉素 (azithromycin)

16 碳环大环内酯类： 吉他霉素 (kitasamycin) 交沙霉素 (josamycin) 乙酰螺旋霉素 (acetylsp

iramycin) 麦迪霉素 (medecamycin)

Macrolides

Clinical uses

As penicillin substitute in penicillin-allergic or resistant patients with infections caused by staphylococci, streptococci and pneumococci

Pertussis( 百日咳 ) ， diphtheriae( 白喉 ) Legionella ( 军团菌 )and mycoplasma pneumoni

a( 肺炎支原体 ) H.p infection

Macrolides

Second generation macrolides antibiotics

Advantage : Broader spectrum, higher activity Orally effective High blood concentration Longer t 1/2 Less toxicity Mainly used in respritory tract infection

Macrolides

Azithromycin ( 阿齐霉素 ,丽珠奇乐）

Has the strongest activity against mycoplasma pneumoniae （肺炎支原体）

More effective on Gram-negative bacteria Well tolerated T1/2 :35~48h once daily Mainly used in respitory tract infection

Macrolides

Roxithromycin （罗红霉素，严迪） 1987 France The highest blood concentration F 72%~85% Respiratory tract infection and soft

tissue infection Low adverse effects

Macrolides

Clarithromycin （甲红霉素 ,克拉霉素）

Has the strongest activity on Gram-positive bacteria, legionella pneumophila, chlamydia pneumoniae and H.p

Good pharmacokinetic property Low toxicity

Macrolides

Third generation-- Ketolides( 酮基大环内酯类 )

Telithromycin ( 泰利霉素 ) It is active in vitro against Streptococcus pyogenes, S pn

eumoniae, S aureus, H influenzae, Moraxella catarrhalis, mycoplasmas, Legionella, Chlamydia, H pylori, N gonorrhoeae, B fragilis, T gondii, and nontuberculosis mycobacteria.

Many macrolide-resistant strains are susceptible to ketolides because the structural modification of these compounds renders them poor substrates for efflux pump-mediated resistance and they bind to ribosomes of some bacterial species with higher affinity than macrolides.

Macrolides

Generation Examples1 st (1962-1969) Nalidixic acid, 萘啶酸2 nd (1969-1979) Pipemidic acid 吡哌酸

Cinoxacin 西诺沙星3 rd (1980-1996) Norfloxacin 诺氟沙星

Levofloxacin 左氧氟沙星 Ciprofloxacin 环丙沙星

Ofloxacin 氧氟沙星sparfloxacin 司帕沙星

4 th (1997-) Grepafloxacin 格帕沙星Clinafloxacin 克林沙星Gatifloxacin 加替沙星Moxifloxacin 莫西沙星

Respiratory fluoroquinolone ” 呼吸喹诺酮”

Classification

Quinolones

Antimicrobial activity & spectrumAntimicrobial activity & spectrum(1) Bactericidal and have significant PAE. (1) Bactericidal and have significant PAE. (2)Excellent activity against aerobic gram-ne(2)Excellent activity against aerobic gram-ne

gative bacteria, some agents have activity gative bacteria, some agents have activity against Pesudomonas. against Pesudomonas.

(3) Several newer agents with improved activ(3) Several newer agents with improved activity against aerobic gram-positive bacteria.ity against aerobic gram-positive bacteria.

QuinolonesQuinolonesQuinolones

Antimicrobial activity & spectrumAntimicrobial activity & spectrum(4) They also are effective against Chlamydia s(4) They also are effective against Chlamydia s

pp.pp. （衣原体）（衣原体） , Legionella pneumophila(, Legionella pneumophila( 军军团菌团菌 ) ,anaerobic bacteria, mycobacteria() ,anaerobic bacteria, mycobacteria( 分分枝杆菌枝杆菌 ).).

(5) Some agents have limited activity against (5) Some agents have limited activity against multiple-resistance strains.multiple-resistance strains.

（（ 66 ）） Bactericidal concentration≥ bacteriostBactericidal concentration≥ bacteriostatic concentrationatic concentration

QuinolonesQuinolonesQuinolones

Mechanism of actionsMechanism of actions Topoisomerases :Topoisomerases : enzymes that control and moenzymes that control and mo

dify the topological states of DNA in cells.dify the topological states of DNA in cells. • Topoisomerase ITopoisomerase I ， ， IIIIII catalyse merely the relcatalyse merely the rel

axation of DNAaxation of DNA• Topoisomerase II Topoisomerase II （（ DNA gyraseDNA gyrase ）） catalyse tcatalyse t

he supercoiling of DNAhe supercoiling of DNA• Topoisomerase IVTopoisomerase IV involved in the separation involved in the separation

process of the DNA daughter chains after chroprocess of the DNA daughter chains after chromosome duplication.mosome duplication.

QuinolonesQuinolonesQuinolones

Mechanism of actions Mechanism of actions

The quinolone antibiotics target bacteriaThe quinolone antibiotics target bacterial l

• DNA gyrase (gram-negative bacteria) DNA gyrase (gram-negative bacteria) • Topoisomerase IV (gram- positive bactTopoisomerase IV (gram- positive bact

eria).eria).

QuinolonesQuinolonesQuinolones

Respiratory tract infections.Respiratory tract infections. Have inferior activity against streptococciHave inferior activity against streptococci 链链

球菌球菌 and should not be used as primary theraand should not be used as primary therapy for common upper respiratory tract infectpy for common upper respiratory tract infections. ions.

Alternatives for treatment of acute exacerbatAlternatives for treatment of acute exacerbation of chronic bronchitis in patients with obstion of chronic bronchitis in patients with obstructive pulmonary disease who are intoleranructive pulmonary disease who are intolerant of or have developed resistance to first-line t of or have developed resistance to first-line antibiotics.antibiotics.

Antibiotics with activity against StreptococcAntibiotics with activity against Streptococcus pneumoniae, Haemophilus influenzaeus pneumoniae, Haemophilus influenzae 流感流感(( 嗜血嗜血 )) 杆菌杆菌 , and Moraxella catarrhalis, and Moraxella catarrhalis 卡他莫卡他莫拉菌拉菌 . .

ClinicalClinical UsesUsesQuinolones

Clinical used tetracyclines:Clinical used tetracyclines: Tetracycline(Tetracycline( 四环素四环素 ); ); Demeclocycline(Demeclocycline( 地美环素地美环素 , , 去甲金霉素去甲金霉素 ); ); Metacycline(Metacycline( 美他环素美他环素 , , 甲烯土霉素甲烯土霉素 ); ); Doxycycline(Doxycycline( 多西环素多西环素 , , 强力霉素强力霉素 ); ); Minocycline(Minocycline( 米诺环素米诺环素 , , 美满霉素美满霉素 ). ). ((Antimicrobial activity enhanced from up to Antimicrobial activity enhanced from up to

downdown))

Tetracyclines

Broad-spectrum antibiotic(1) Active against a wide range of aerobic and anaerobic gr

am-positive and gram-negative bacteria. (2) Effective against Rickettsia(立克次体） ,Coxiella burnet

ii（螺旋体） ,Mycoplasma pneumoniae（支原体） ,Chlamydia (衣原体 ), and Plasmodium （疟原虫） .

(3) They are not active against fungi,virus.

Antimicrobial spectrum

Tetracyclines

Mechanism of action:①Chloramphenicol②Macrolides, Clinda

mycin③Tetracyclines

•Inhibits binding of 30S subunit with A site•Interfering with the binding of aminoacyl-tRNA with aminoacyl site(A site)

Mechanism of action

Tetracyclines

Main Antituberculous Drugs:Antituberculous Drugs

First-line agents: Isoniazid( 异烟肼 ), 1945 Rifampin( 利福平 ), 1965 Ethambutol( 乙胺丁醇 ), 1959 Streptomycin( 链霉素 ), 1944 Pyrazinamide( 吡嗪酰胺 ), 1952 Second-line agents: Para-aminosalicylic( 对氨水杨酸 ), Ethionamide( 乙硫异烟胺 ) Amikacin( 阿米卡星 ) Capreomycin( 卷曲霉素 ) Fluoroquinolones: Ciprofloxacin( 环丙沙星 ), Ofloxac

in( 氧氟沙星 ), etc.

Isoniazid( 异烟肼 , Rimifon, 雷米封 ,

INH, Isonicotinylhydrazide) 1. Antituberculous activity: Bacteriostatic for resting tubercle bacilli, and bact

ericidal for actively growing tubercle bacilli. Remarkable selectivity to tubercle bacilli (0.025 ~

0.05 mg/ml, and to other microorganisms 500 mg/ml).

Isoniazid

2. Mechanism of action:Inhibiting synthesis of mycolic ac

ids( 分枝菌酸 ) of tubercle bacilli, the mycolic acids are essential com-ponents of mycobacterial cell walls:

Isoniazid

* NAD: nicotinamide-adenine dinucleotide* NAD: nicotinamide-adenine dinucleotide (( 烟酰胺腺嘌呤二核苷酸烟酰胺腺嘌呤二核苷酸 , , 辅酶Ⅰ辅酶Ⅰ ))

**

Rifampicin(RPF, 利福平 )1. Antibacterial activity: Rifampicin is a broad-spectrum antimicr

obial activity; It is a bactericidal for tubercle bacilli; It can readily penetrates most tissues

and into phagocytes; Resistance mutants occurs easily if us

ed as a single drug.

2. Mechanism of action: Rifampicin can bind strongly to the b subunit

of bacterial DNA-dependent RNA ploymerase, to inhibit bacterial RNA synthesis selectively.

It is no effect to RNA ploymerase of mammal cell( 哺乳动物的细胞 ).

Ethambutol( 乙胺丁醇 ) 1. Antimycobacterial actvity: Nearly all strain of tubercle bacilli are sensitive. Be bactericidal to intercellular and extrecellular t

ubercle bacilli. Resistance to ethambutol developed very slowly i

n vitro. The mechanism of action is involved in inhibition

of RNA synthesis. 2. Clinical uses: Treatment for tuberculosis of various forms when

given concurrently with isoniazid.

Ethambutol

Streptomycin( 链霉素 ) Streptomycin is the first effective drug to

treat tuberculosis. It is bacteriostatic for the tuber-cle bacillu

s. Resistance to streptomycin deve-loped ea

sily when it is used alone. Given simultaneously with other antibact

erial drugs to prevent emer-gence of toxic reaction & resistance occurrence.

Pyrazinamide( 吡嗪酰胺 ) Presenting bactericidal activity only

at a sightly acidic pH in vitro. Well absorbed from the GI tract, and

it is widely distributed through-out the body.

Tubercle bacilli develops resist-ance to pyrazinamide fairly readily, but there is no cross-resistance with other anti-mycobacterial drugs.

Para-aminosalicylic acid(PAS, 对氨水杨酸 )

A folate synthesis antagonist, it is structurally similar to PABA.

Well absorbed after oral admi-nistration, and widely distributed in tissues and body fluid except the CSF.

PAS is used in combination with other drugs. PAS alone is of little value in the treatment of tubercu-losis.

Other antituberculous drugsRifapentine( 利福喷汀 ) and Rifadi

n( 利福定 )Ethionamide( 乙硫异烟胺 )Amikacin( 阿米卡星 )Capreomycin( 卷曲霉素 )Fluoroquinolones( 氟喹酮类 )

The principle for using antituberculous drugs

1. Treatment should be initiated with antituberculous drugs early.

2. Treatment should be initiated with combination of antituberculous drugs.

3. Treatment should be continued for a suitable time( at least 6-9 months).

对呼吸道感染具有较好药代动力学的抗菌药物

1. 大环内酯类 ( 如红霉素、罗红霉素、麦迪霉素、乙酰螺旋霉素等 ) 、喹诺酮类、氯霉素、甲硝唑、利福平、 SMZ-TMP ；

2. 其次为氨基糖苷类，如庆大霉素、妥布霉素、丁胺卡那霉素、卡那霉素、链霉素、乙基丙松霉素等；

3. 半合成四环素类如二甲胺四环素、多西环素、万古霉素等。

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