1. Antimicrobial drugs in Respiratory Infection
Huifang Tang
Department of pharmacology
Zhejiang University, school of medicine
Research building C422
2012-3

2. Introduction The key disorders of respiratory system:
1. Disorders of the upper respiratory tract: rhinitis(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 (COPD, 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)

3. anti-microbial agents
Part 1. -Lactam antibiotics
Part 2. Aminoglycosides (氨基糖苷类) & polymyxins(多黏菌素类)
Part 3. Macrolides (大环内酯类), lincomycins (林可霉素类), and vancomycins (万古霉素)
Part 4. Tetracyclines(四环素类)& chloramphenicol(氯霉素)
Part 5. Synthetic antimicrobial agents(人工合成抗菌药)
Part 6. Antifungal agents
Part 7. Antiviral agents
Part 8. Antituberculous drugs
Part 9. The drugs treated parasitic infections

4. Classification and mechanism of action① ④ ⑤ ③ ②

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

6. 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)

7. I. Penicillins 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)

8. 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).

9. Phenoxymethylpenicillin (苯氧甲基青霉素, Penicillin V)
Semi-synthetic Penicillins:
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.

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

11. Piperacillin(哌拉西林), etc.
Semisynthetic Penicillins
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.

12. Broad spectrum penicillins
Semisynthetic Penicillins
Broad 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 tract infections; Meningitis; Salmonella infections.

13. Broad spectrum Penicillins
Semisynthetic Penicillins
Broad spectrum Penicillins
(2)Piperacillin(哌拉西林),Mezlocillin(美洛西林)
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, us-ually in combination with aminoglycoside (氨基苷类).

14. 4.Anti-pseudomonas penicillins
Carbenicillin(羧苄西林)
Ticarcillin(替卡西林)
With activity against Pseudomonas aeruginosa and some Proteus(变形杆菌).

15. 5. Anti-G- bacilli penicillins:
Semisynthetic Penicillins
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.

16. II. Cepharosporins 1. First generation:
Cefazolin(头孢唑林), Cefradine(头孢拉定), Cefalexin(头孢氨苄), etc.
(1)more active than second and third genera-tion against certain G+ microoganisms;
(2)more impervious than second and third ge-neration to attack by staphyloccal -lactamase;
(3)less active than second and third genera-tion against certain G- microoganisms;
(4)non-stable to G- bacilli -lactamase;
(5)more activity against certain Pseudomonas (铜绿假单孢菌), anaerobes(厌氧菌), etc;
(6)certain kinds have kidney toxicity.

17. Cepharosporins 2. Second generation:
Cefuroxime(头孢呋辛), Cefamandole(头孢孟多), Cefaclor(头孢克洛), etc.
(1)more active than first generation against certain G- bacilli and more impervious than first generation G- bacilli -lactamase;
(2)somewhat less active than first generation against G+ cocci but more than third generation;
(3)active against anaerobes(厌氧菌);
(4)lack activity against Pseudomonas;
(5)less toxic than first generation to kidney.

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

19. Cepharosporins 4. Fourth generation:
Cefepime(头孢匹肟), Cefpirome(头孢匹罗), etc.
(1)resistant to type 1 -lactamase;
(2)more active than third generation against Enterbacter(耐肠杆菌);
(3)less active than third generation against Pseudomonas.

20. Ⅲ. Other -lactam antibiotics
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.

21. 2. Carbapenems(碳青霉烯类): Imipenem(亚胺培南)
Other -lactam antibiotics
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.

22. Aztreonam(氨曲南) Carumonam(卡芦莫南)
Other -lactam antibiotics
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.

23. Latamoxef(拉氧头孢) Flomoxef(氟氧头孢)
Other -lactam antibiotics
4. Oxacephalosporins(氧头孢烯类)
Latamoxef(拉氧头孢)
Flomoxef(氟氧头孢)
Broad-spectrum antibiotic(anaerobic infections).

24. Ⅳ. -lactamase inhibitors (-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.

25. History of Macrolides 1952 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)

26. 14碳环大环内酯类： 16碳环大环内酯类： 15碳环大环内酯类： Macrolides 红霉素(erythromycin)
克拉霉素(clarithromycin)
罗红霉素(roxithromycin)
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 (acetylspiramycin)
麦迪霉素(medecamycin)

27. 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 pneumonia(肺炎支原体)
H.p infection

28. 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

29. Azithromycin (阿齐霉素,丽珠奇乐）
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

30. Roxithromycin （罗红霉素，严迪）
Macrolides
Roxithromycin （罗红霉素，严迪）
France
The highest blood concentration
F 72%~85%
Respiratory tract infection and soft tissue infection
Low adverse effects

31. Clarithromycin（甲红霉素,克拉霉素）
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

32. Third generation -- Ketolides(酮基大环内酯类)
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 pneumoniae, 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.

33. Classification Quinolones Generation Examples
1 st ( ) Nalidixic acid, 萘啶酸
2 nd ( ) Pipemidic acid 吡哌酸
Cinoxacin 西诺沙星
3 rd ( ) 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”

34. Quinolones Antimicrobial activity & spectrum Quinolones
(1) Bactericidal and have significant PAE.
(2)Excellent activity against aerobic gram-negative bacteria, some agents have activity against Pesudomonas.
(3) Several newer agents with improved activity against aerobic gram-positive bacteria.

35. Quinolones Antimicrobial activity & spectrum Quinolones
(4) They also are effective against Chlamydia spp.（衣原体）, Legionella pneumophila(军团菌) ,anaerobic bacteria, mycobacteria(分枝杆菌).
(5) Some agents have limited activity against multiple-resistance strains.
（6）Bactericidal concentration≥ bacteriostatic concentration

36. Quinolones Mechanism of actions Quinolones
Topoisomerases : enzymes that control and modify the topological states of DNA in cells.
Topoisomerase I， III catalyse merely the relaxation of DNA
Topoisomerase II （DNA gyrase） catalyse the supercoiling of DNA
Topoisomerase IV involved in the separation process of the DNA daughter chains after chromosome duplication.

37. Quinolones Mechanism of actions Quinolones
The quinolone antibiotics target bacterial
DNA gyrase (gram-negative bacteria)
Topoisomerase IV (gram- positive bacteria).

38. Clinical Uses Respiratory tract infections. Quinolones
Have inferior activity against streptococci链球菌and should not be used as primary therapy for common upper respiratory tract infections.
Alternatives for treatment of acute exacerbation of chronic bronchitis in patients with obstructive pulmonary disease who are intolerant of or have developed resistance to first-line antibiotics.
Antibiotics with activity against Streptococcus pneumoniae, Haemophilus influenzae流感(嗜血)杆菌, and Moraxella catarrhalis卡他莫拉菌.

39. Tetracyclines Clinical used tetracyclines: Tetracycline(四环素);
Demeclocycline(地美环素, 去甲金霉素);
Metacycline(美他环素, 甲烯土霉素);
Doxycycline(多西环素, 强力霉素);
Minocycline(米诺环素, 美满霉素).
(Antimicrobial activity enhanced from up to down)

40. Antimicrobial spectrum
Tetracyclines
Antimicrobial spectrum
Broad-spectrum antibiotic
(1) Active against a wide range of aerobic and anaerobic gram-positive and gram-negative bacteria.
(2) Effective against Rickettsia(立克次体）,Coxiella burnetii（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.

41. Mechanism of action Tetracyclines
①Chloramphenicol
②Macrolides, Clindamycin
③Tetracyclines
Inhibits binding of 30S subunit with A site
Interfering with the binding of aminoacyl-tRNA with aminoacyl site(A site)

42. Antituberculous Drugs
Main Antituberculous Drugs:
First-line agents:
Isoniazid(异烟肼),
Rifampin(利福平),
Ethambutol(乙胺丁醇),
Streptomycin(链霉素),
Pyrazinamide(吡嗪酰胺),
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), Ofloxacin(氧氟沙星), etc.

43. Isoniazid(异烟肼, Rimifon, 雷米封, INH, Isonicotinylhydrazide)
1. Antituberculous activity:
Bacteriostatic for resting tubercle bacilli, and bactericidal for actively growing tubercle bacilli.
Remarkable selectivity to tubercle bacilli (0.025 ~ 0.05 mg/ml, and to other microorganisms 500 mg/ml).

44. Isoniazid
2. Mechanism of action:
Inhibiting synthesis of mycolic acids(分枝菌酸) of tubercle bacilli, the mycolic acids are essential com-ponents of mycobacterial cell walls:

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

46. Rifampicin(RPF, 利福平) 1. Antibacterial activity:
Rifampicin is a broad-spectrum antimicrobial activity;
It is a bactericidal for tubercle bacilli;
It can readily penetrates most tissues and into phagocytes;
Resistance mutants occurs easily if used as a single drug.

47. 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).

48. Ethambutol(乙胺丁醇) Ethambutol 1. Antimycobacterial actvity:
Nearly all strain of tubercle bacilli are sensitive.
Be bactericidal to intercellular and extrecellular tubercle bacilli.
Resistance to ethambutol developed very slowly in 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.

49. Streptomycin(链霉素)
Streptomycin is the first effective drug to treat tuberculosis.
It is bacteriostatic for the tuber-cle bacillus.
Resistance to streptomycin deve-loped easily when it is used alone.
Given simultaneously with other antibacterial drugs to prevent emer-gence of toxic reaction & resistance occurrence.

50. 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.

51. 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.

52. Other antituberculous drugs
Rifapentine(利福喷汀) and Rifadin(利福定)
Ethionamide(乙硫异烟胺)
Amikacin(阿米卡星)
Capreomycin(卷曲霉素)
Fluoroquinolones(氟喹酮类)

53. 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).

54. 对呼吸道感染具有较好药代动力学的抗菌药物
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；
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；
半合成四环素类如二甲胺四环素、多西环素、万古霉素等。

55. 推荐阅读 美国成人社区获得性肺炎诊断治疗指南（2007） 2005 ATS/CDC/IDSA美国肺结核的控制
2011年美国感染病学会耐甲氧西林金黄色葡萄球菌(MRSA)感染治疗指南要点
2011年美国胸科学会（ATS）发布了新版成人肺部真菌感染治疗指南
儿童侵袭性肺部真菌感染诊治指南2009版

56. END OF CLASS