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Antimicrobial drugs in Respiratory Infection

Antimicrobial drugs in Respiratory Infection. Huifang Tang Department of pharmacology Zhejiang University, school of medicine tanghuifang@zju.edu.cn Research building C422 2012-3. Introduction. The key disorders of respiratory system:

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Antimicrobial drugs in Respiratory Infection

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  1. Antimicrobial drugs in Respiratory Infection Huifang Tang Department of pharmacology Zhejiang University, school of medicine tanghuifang@zju.edu.cn 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 Part1. -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 action ① 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. 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.

  10. 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.

  11. 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.

  12. SemisyntheticPenicillins 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.

  13. SemisyntheticPenicillins 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).

  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. SemisyntheticPenicillins 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.

  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 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.

  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+coccibutmorethan thirdgeneration; (3)activeagainstanaerobes(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 secondgeneration 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-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.

  21. 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 spec-trumandthemostactivityofalltheanti-biotic.

  22. 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.

  23. 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. Macrolides 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： 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) Macrolides

  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. Macrolides Second generation macrolides antibiotics • Advantage : • Broaderspectrum, higheractivity • Orallyeffective • High blood concentration • Longer t 1/2 • Less toxicity • Mainly used in respritory tract infection

  29. 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. 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

  31. 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. 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. Quinolones Classification 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 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 Quinolones 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.

  35. Quinolones Quinolones Antimicrobial activity & spectrum (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 Quinolones • Mechanism of actions • Topoisomerases :enzymes that control and modify the topological states of DNA in cells. • Topoisomerase I， IIIcatalyse merely the relaxation of DNA • Topoisomerase II （DNA gyrase）catalyse the supercoiling of DNA • Topoisomerase IVinvolved in the separation process of the DNA daughter chains after chromosome duplication.

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

  38. Quinolones ClinicalUses Respiratory tract infections. • 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. 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. Tetracyclines Mechanism of action Mechanism of action: 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), 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), Ofloxacin(氧氟沙星), etc.

  43. Isoniazid(异烟肼, Rimifon, 雷米封,INH, Isonicotinylhydrazide) • 1. Antituberculous activity: • Bacteriostaticfor resting tubercle bacilli,andbactericidalfor 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. 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: • Rifampicincanbindstronglytothe bsubunit ofbacterialDNA-dependent RNA ploymerase, toinhibitbacterialRNAsynthesis selectively. • It is no effect to RNA ploymerase of mammal cell(哺乳动物的细胞).

  48. Ethambutol Ethambutol(乙胺丁醇) • 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 antibacterialdrugstopreventemer-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.

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