Antimicrobial drugs in Respiratory Infection

1. Antimicrobial drugs in Respiratory Infection Huifang Tang Department of pharmacology Zhejiang University, school of medicine tanghuifang@zju.edu.cn

2. The key disorders of respiratory system: 1. Disorders of the upper respiratory tract(上呼吸道感染): rhinitis(鼻炎), tonsillitis(扁桃体炎), angina(咽峡炎), laryngitis(喉炎), cold(感冒), etc. ; 病原体：90%病毒（鼻病毒、呼吸道合胞病毒、腺病毒、流感病毒、副流感病毒、SARS） 10%细菌 Introduction

3. 2. Disorders of the lower respiratory tract(下呼吸道感染)： Bronchitis(支气管炎), Pneumonia(肺炎); 病原体：70-80%细菌 G+：肺炎链球菌、金黄色葡萄球菌； G-： 肺炎克雷伯杆菌、流感嗜血杆菌、绿脓杆菌、大肠杆菌、变形杆菌； 厌氧杆菌：棒状杆菌、梭形杆菌 病毒、真菌、原虫、支原体、衣原体 院外获得性下呼吸道感染以革兰氏阳性球菌为主(主要为肺炎球菌) ，其次为革兰氏阴性杆菌(最常见的为肺炎克雷伯杆菌) 。 院内获得性感染约 60%为革兰氏阴性杆菌,其中最多的是绿脓杆菌。

4. 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)

5. Drugs for respiratory infections Part1 Antiviral drugs（抗病毒药） Part2 Antibacterial drugs（抗菌药） Part3 Antifungal drugs（抗真菌药）

6. 病毒侵入人体的过程 病毒吸附侵入(attachment & penetration) 合成病毒 核酸\蛋白质 病毒颗粒 装配成熟(assembly) 从细胞内 释放(release) Part1 Antiviral drugs （抗病毒药） 合成 核酸多聚酶 病毒脱壳(uncoating)

7. 金刚烷胺 金刚乙胺 Anti-influenza virus agents 阻断M2蛋白 阻止病毒脱壳 及其RNA的释放 抑制 核苷酸合成 血凝素 奥司他韦 扎那米韦 利巴韦林 选择性NA结合 抑制病毒 脱颗粒和扩散 神经氨酸酶

8. Anti-influenza virus agents • Neuraminidase(神经氨酸酶,NA) inhibitors --influenza A &B • Oseltamivir(奥司他韦): oral • zanamivir（扎那米韦）: intravenous, inhaled • Peramivir (帕拉米韦): intravenous, • Laninamivir(拉尼米韦): inhaled • Influenza A neuraminidases form two groups on phylogenetic analysis: group 1 (N1, N4, N5, and N8) and group 2 (N2, N3, N6, N7, and N9). • Circulating influenza viruses including avian influenzas H7N9 and H5N1 are susceptible to neuraminidase inhibitors, and ovesrvational clinical data show reduced mortality with timely oseltamivir therapy in H5N1 disease.

9. M2蛋白抑制剂--influenza A • Amantadine(金刚烷胺) • Rimantadine (金刚乙胺) • Most circulating or threatening influenza viruses at present are adamantane-resistant, including avian A H7N9, pandemic H1N1, avian H10N8, and seasonal H3N2 viruses • adamantane resistance is variable in avian H5N1 viruses, and many isolates have been susceptible. • a dual regimen of an adamantane and neuraminidase inhibitor would be a reasonable initial treatment regimen for serious influenza when the infecting strain is probably susceptible to both drug classes.

10. 广谱抗病毒药--DNA &RNA viurs • Ribavirin(利巴韦林, virazole病毒唑）: • Aerosolised and intravenous • Combinations of ribavirin with neuraminidase inhibitors have shown variable interactions. •  Peramivir and ribavirin showed synergistic activity for an H1N1 virus in vitro and enhanced survival effects when given orally in combination compared with suboptimum doses of either agent. • Several oseltamivir and ribavirin dose combinations increased survival, reduced lung consolidation, and reduced lung viral titres in influenza B compared with suboptimum doses of single agents, whereas one dosing regimen of oseltamivir and ribavirin showed no greater effects than ribavirin alone for mice injected with A/New Caledonia/20/99 H1N1

11. Triple-combination antiviral drug (TCAD) treatment • Three available agents : • amantadine+ ribavirin+ oseltamivir • Influenza A viruses that are susceptible • Resistant to the adamantanes or oseltamivir at baseline, including adamantane-resistant 2009 pandemic H1N1 virus.

12. Favipiravir(法匹拉韦) • 日本埃博拉药物 • 一种能有效对抗甲型和乙型流感以及其他RNA病毒的口服RNA多聚酶抑制剂,该药与神经氨酸酶抑制剂或金刚烷胺类药物无交叉耐药性。 • Spectrum: • Influenza A, B, and C viruses including adamantane-resistant or oseltamivir-resistant variants

13. Part2 Antibacterial drugs （抗菌药） -Lactam antibiotics Macrolides (大环内酯类), lincomycins (林可霉素类), and vancomycins (万古霉素) Aminoglycosides (氨基糖苷类) & polymyxins(多黏菌素类) Tetracyclines(四环素类)& chloramphenicol(氯霉素) Synthetic antimicrobial agents(人工合成抗菌药) Quinolones Sulfonamides Antifungal agents Antituberculous drugs

14. Classification and mechanism of action ① ④ ⑤ ③ ②

15. Contents 1、-Lactam Antibiotics（内酰胺类） 2、Macrolides (大环内酯类) 3、Quinolones（喹诺酮类） 4、Sulfonamides (磺胺类) 5、Tetracyclines(四环素类) 6、Aminoglycosides(氨基糖苷类) 7、Antituberculous drugs（抗结核药）

16. β-Lactam Antibiotics 1、-Lactam Antibiotics 内酰胺酶抑制剂 青霉素类 头孢菌素类 碳青霉烯类 单环类

17. β-Lactam Antibiotics 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)

18. β-Lactam Antibiotics 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).

19. β-Lactam Antibiotics Semi-syntheticPenicillins: 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 forPenicillin Gto treat tonsilitis(扁桃体炎), or Pharyngitis(咽炎), etc.

20. SemisyntheticPenicillins 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.

21. SemisyntheticPenicillins 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.

22. Broad spectrum penicillins (1)Ampicillin(氨苄西林), Amoxicillin(阿莫西林) Pseudomonasaeruginosa(铜绿假单孢菌 ——绿脓杆菌)-resistance. Clinical Uses: Upper respiratory infections; Urinary tract infections; Meningitis; Salmonella infections. SemisyntheticPenicillins

23. 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 severeinfectioncausedbyG-bacteria, us-uallyincombinationwithaminoglycoside (氨基苷类). SemisyntheticPenicillins

24. 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).

25. 5. Anti-G- bacilli penicillins: Mecillinam(美西林), Temocillin(替莫西林) They are bacteriostatic drugs, and havenarrowantibacterialspectrum, with activity against some G- bacilli. SemisyntheticPenicillins

27. 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 thirdge-neration to attack by staphyloccal -lactamase; (3)less active than second and thirdgenera-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. Cepharosporins

28. 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+coccibutmorethan thirdgeneration; (3)activeagainstanaerobes(厌氧菌); (4)lack activity against Pseudomonas; (5)less toxic than first generation to kidney.

29. Cepharosporins 3. Third generation: Ceftazidime(头孢他啶), Ceftriaxone(头孢曲松), etc. (1)far more active than first and second generation against G- bacilli; (2)be highly resistant to -lactamase produced by G- bacilli; (3)with the extended spectrum against anaerobes 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 secondgeneration against G+ cocci; (6)less toxic to kidney.

30. 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.

31. Ⅲ. Other-lactamantibiotics 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 forthe treatment of anaerobic infections.

32. Other-lactamantibiotics • 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 spectrumandthemostactivityofalltheantibiotic.

33. Other-lactamantibiotics 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.

34. 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).

35. 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.

36. β-内酰胺类抗生素的复方制剂

37. 2、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) 2000s- Telithromycin(替利霉素) Macrolides

38. Macrolides Mechanism of action Macrolides (M) bind to the 50S subunit and block transpeptidation

39. Macrolides Antimicrobial spectrum • G+ organisms: • -Cocci: streptococcus pyogenesand pneumoniae (化脓性和肺炎链球菌) • - Bacilli: Diphtheria白喉, Pertussis百日咳 • Atypical pathogens: • - Mycoplasma pneumoniae (肺炎支原体) • - Legionella pneumophila (军团菌) • - Chlamydia pneumoniae(衣原体).

40. Pharmacokinetics • Good oral bioavailability ( azithromycin absorption is impeded by food). • Widely Distribution (Azithromycin is unique in that the levels achieved in tissues and in phagocytes are considerably higher than those in the plasma). • Fairly rapidly elimination • erythromycin (via biliary excretion) :half-lives of 2 • clarithromycin (via hepatic metabolism and urinary excretion of intact drug) : half-lives 6 h. • Azithromycin is eliminated slowly (half-life 2–4 days), mainly in the urine as unchanged drug.

41. Clinical uses As penicillin substitute in penicillin-allergic or resistant patients with infections caused by staphylococci（金葡菌）, streptococci (链球菌)and pneumococci （肺炎球菌） Pertussis(百日咳)，diphtheriae(白喉) Legionella (军团菌)and mycoplasma pneumonia(肺炎支原体) H.p infection Macrolides

42. Azithromycin (阿齐霉素） Strongest activity against mycoplasma pneumoniae（肺炎支原体） More active against Moraxella catarrhalis(卡他莫拉菌),Haemophilus influenzae(流感嗜血杆菌), Neisseria(奈 瑟 菌 属) More effective on Gram-negative bacteria Well tolerated T1/2 :35~48h once daily Mainly used in respitory tract infection: a 4-day course of treatment has been effective in community-acquired pneumonia. Macrolides

43. Clarithromycin（甲红霉素,克拉霉素） Has the strongest activity on Grampositive bacteria, legionella pneumophila, chlamydia pneumoniae(衣原体), Mycobacterium avium complex and H.p Good pharmacokinetic property Low toxicity The drug is also usedfor prophylaxis against and treatment of M avium complex andas a component of drug regimens for ulcers caused by H pylori. Macrolides

44. Macrolides Adverse effects • Gastrointestinal irritation (common) via stimulation of motolin receptors : nausea, vomiting, abdominal cramps, etc. • Allergic reaction: skin rashes, and eosinophilia, • Hepatitis: A hypersensitivity-based acute cholestatic hepatitis（胆汁淤积性肝炎）may occur with erythromycin estolate. • Auditory impairment(听觉障碍) • Cardiac arrhythmias • Inhibitor of hepatic cytochrome P450: increase the plasma levels of many drugs, including anticoagulants, carbamazepine, cisapride, digoxin, and theophylline. • The lactone ring structure of azithromycin is slightly different from that of other macrolides, and drug interactions are uncommon because azithromycin does not inhibit hepatic cytochrome P450.

45. 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. The drug can be usedin community-acquired pneumonia including infections causedby multidrug-resistant organisms. 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. Adverseeffects : hepatic dysfunctio,prolongationof the QTc interval. The drug is an inhibitor of the CYP3A4drug-metabolizing system Macrolides

46. Generation Examples 1 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 gemifloxacin (吉米沙星) 4 th (1997-) Clinafloxacin 克林沙星 Moxifloxacin 莫西沙星 3、 Quinolones Quinolones fluoroquinolone

47. Quinolones Classification of fluoroquinolone 1st generation : Norfloxacin • Spectrum: common pathogens that cause urinary tract infections. 2nd generation: Ciprofloxacin and ofloxacin • Spectrum: gramnegative bacteria and the gonococcus, many gram-positive cocci, mycobacteria, and atypical pathgen (Mycoplasma , Chlamydophila ). 3rd-generation:levofloxacin,gemifloxacin, and moxifloxacinRespiratory fluoroquinolone ”呼吸喹诺酮” • Spectrum: slightly less active than ciprofloxacin and ofloxacin against gram-negative bacteria but have greater activity against gram-positive cocci, including S pneumoniae and some strains of enterococci and methicillin-resistant Staphylococcus aureus (MRSA). • The broadest-spectrum fluoroquinolones introduced to date, with enhanced activity against anaerobes.

48. Antimicrobial activity & spectrum (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. (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 Quinolones Quinolones

49. Quinolones Quinolones • Mechanism of actions • The quinolone antibiotics target bacterial • Topoisomerase II-DNA gyrase (gram-negative bacteria) : • block the relaxation of supercoiledDNA • Topoisomerase IV (gram- positive bacteria). • interferes with the separation of replicated chromosomalDNA during cell division.

50. Pharmacokinetics • Good oral bioavailability (antacids containing multivalent cations may interfere) • Good penetration to most body tissues. • norfloxacin does not achieve adequate plasma levels for use in most systemic infections. • Elimination via active tubular secretion (excepte for moxifloxacin): which can be blocked by probenecid(丙磺舒). • Dosage reductions are usually needed in renal dysfunction except for moxifloxacin which is eliminated partly by hepatic metabolism and also by biliary excretion. soUse of moxifloxacin in urinary tract infections is not recommended. • Half-lives : 3–8 h.