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Shi-Hong Zhang ( 张世红 ) , PhD

Drugs for respiratory infections. Shi-Hong Zhang ( 张世红 ) , PhD shzhang713@zju.edu.cn. 艾滋病. 结核. 疟疾. 麻疹. 腹泻. 急性呼吸道感染. Pathogens of respiratory infections.

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Shi-Hong Zhang ( 张世红 ) , PhD

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  1. Drugs for respiratory infections Shi-Hong Zhang(张世红), PhD shzhang713@zju.edu.cn

  2. 艾滋病 结核 疟疾 麻疹 腹泻 急性呼吸道感染

  3. Pathogens of respiratory infections • Bacteria: 球菌：肺炎链球菌、化脓性链球菌、葡萄球菌、卡他莫拉菌；杆菌：流血嗜血杆菌、肺炎克雷伯菌、铜绿假单胞菌、结核分枝杆菌、大肠杆菌、变形杆菌、棒状杆菌、梭杆菌等；非典型病原体：军团菌、衣原体、支原体等。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。 • Viruses: 鼻病毒、合胞体病毒、流感病毒；副流感病毒、人偏肺病毒；腺病毒；冠状病毒等。 • Fungi: 念珠菌、球孢子菌、曲霉菌、副球孢子菌、组织胞浆菌、芽生菌等。

  4. Drugs for respiratory infections • Anti-infective agents for the treatment of respiratory infections - Antibacterial drugs （antibiotics, 抗菌药） - Antifungal drugs （抗真菌药） - Antiviral drugs （抗病毒药）

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

  6. Antifungal agents Amphotercin B（两性霉素B） Flucytosine（氟胞嘧啶) Ketoconazole（酮康唑） Fluconazol（氟康唑） Itraconazole (伊曲康唑）

  7. Mechanism of action： • Inhibit the synthesis of ergosterol in fungal membrane, cause the leakage of intracellular substances • Promotes the penetration of other antifungal agents (两性霉素B) （疏水端） （亲水端）

  8. Action mechanisms of antibiotics 1. Inhibit synthesis of bacterial cell walls 2. Affect permeability of cell membrane and lead to leakage of intracellular compounds 3. Inhibit protein synthesis 4. Affect bacterial nucleic acid metabolism 5. Block essential enzymes of folate metabolism

  9. 大环内酯类 Action mechanisms of antibiotics

  10. β-Lactam antibiotics& other inhibitors of cell wall synthesis

  11. b-lactam ring amidase b-lactamase b-lactam ring amidase b-lactamase Source:Penicillium spp, 青霉菌 Source:Cephalosporium spp (now calledAcremonium spp.枝顶孢菌)

  12. Sir Alexander Fleming The Nobel prize in Physiology or Medicine 1945 Discoverer of Penicillin Co-recipients: Florey and Chain (They made it possible to produce large quantities)

  13. Penicillins • Action mechanisms • Inhibit the activity of peptidoglycan transpeptidase (PBP) • Increase the activity of cell wall autolytic enzyme C-terminal N-terminal

  14. Penicillins 1. Natural penicillins:penicillin G (benzylpenicillin), injection 2. Semi-synthetic penicillins - Oral penicillins(acid-resistant) penicillin V (phenoxymethylpenicillin) - Antistaphylococcal penicillins (-lactamase-resistant) methicillin甲氧西林，cloxacillin氯唑西林, dicloxacillin双氯唑西林, nafcillin萘夫西林 - Extended-spectrum penicillins(-lactamase-sensitive) ampicillin氨苄西林, amoxicillin阿莫西林, ineffective on staphylococci - Anti-pseudomonas penicillins carbenicillin羧苄西林，piperacillin哌拉西林, injection - Anti- G- bacilli penicillinsmecillinam美西林,temocillin替莫西林

  15. Penicillins Adverse effects of Penicillins: (1) Hypersensitivity reactions itch, rashes, fever, serum sickness , angioneurotic edema, anaphylactic shock (5-10/100,000). (2) Others phlebitis: i.v. inflammatory reactions at injection site, degeneration of nerve tissue (i.m.) central nervous system excitability (seizures). (3) Herxheimer reaction: cause by destroyed pathogens like spirochetes.

  16. Penicillins Prevention and treatment ofhypersensitivity reactions of penicillin G: (1) A detailed clinical history (2) Skin test (3) First aid treatment of allergic shock epinephrine and/or dopamine glucocorticoids (dexamethasone) anti-histamines (promethazine)

  17. Cephalosporins

  18. Cephalosporins

  19. Cephalosporins

  20. Cephalosporins 吡

  21. First Second Third Gram-positive Gram-negative Good Pseudomonas - - + Anearobes - + + Beta-lactamase sensitive No Kidney toxicity Almost no Well penetration Yes Small summary Good yes yes no

  22. Macrolides （大环内酯类） • First generation: • - Erythromycin(红霉素) • -Medecamycin(麦迪霉素) • - Spiramycin(螺旋霉素) • Second generation: • - Clarithromycin(克拉霉素) • - Azithromycin(阿奇霉素) • - Acetylmedecamycin(乙酰麦迪霉素) • Third generation: • - Telithromycin(替利霉素)

  23. General properties of macrolides 1. 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).

  24. General properties of Macrolides 2. Mechanism of action: • Inhibit the formation of functional 70S ribosome • Prevent the transfer of peptidyl-tRNA • Destroy ribosome and cause dissociation of peptidyl-tRNA from the ribosome

  25. General properties of macrolides 3. Clinical Uses: (1) Streptococcus (链球菌)infections (2) Legionnaire’s disease (军团菌病) (3) Mycoplasma (支原体) infections (4) Chlamydia (衣原体) infections (5) Diphtheria(白喉)/Pertussis (百日咳)

  26. General properties of macrolides 4. Adverse effects: (1) GI effects: nausea, vomiting, abdominal cramps, etc. (2) Liver toxicity: Cholestatic hepatitis （胆汁淤积性肝炎）. (3) Auditory impairment. (4) Allergic reaction (5) Cardiac arrhythmias

  27. Lincomycin & Clindamycin 林可霉素和克林霉素 • Resemble erythromycin in antibacterial, spectrum, activity, mechanism and resistance. • Clinical Uses: • aerobic G+ cocci infection • severe anaerobic infection • combination with pyrimethamine (乙氨嘧啶) for AIDS-related toxoplasmosis(弓形体病)& pneumocystis carinii pneumonia (卡氏肺囊虫肺炎).

  28. Vancomycins - Vancomycin 万古霉素 - Norvancomycin 去甲万古霉素 - Teicoplanin 替考拉宁 • Antibacterial activity (Narrow spectrum) • bactericidal for G+ bacteria (especially G+ ococci, including MRSA & MRSE耐甲氧西林表皮葡萄球菌） • Intravenous administration, widely distributed in the body, including CSF when the meninges is inflamed

  29. Aminoglycosides 氨基糖苷类抗生素

  30. Aminoglycosides Natural Synthesized • Streptomycin链霉素 • Gentamicin庆大霉素 • Micronomicin小诺米星 • Sisomicin西索米星 • Astromicin阿司米星 • Neomycin新霉素 • Kanamycin卡那霉素 • Tobramycin妥布霉素 • Amikacin阿米卡星，丁胺卡那霉素 • Netilmicin奈替米星 • B kanamycin卡那霉素B • Arbekacin阿贝卡星 • Dibekacin地贝卡星 • Etilmicin依替米星 • Isepamicin异帕米星

  31. Aminoglycosides 1. Antimicrobial activity: i) Rapid-acting bactericidal to resting bacteria ii) Broad-spectrum: G- bacilli, G+ organisms (including MRSA - netilmicin) , TB , ineffective for anaerobic strains. iii) More active in alkaline environment iv) Unabsorbable in GI tract v) Concentration-dependent activity and duration of post antibiotic effect (PAE) vi) First exposure effect (FEE)

  32. Aminoglycosides 2. Mechanism of action Inhibit the whole process of protein synthesis i) Interfere with the initiation complex of peptide formation (30S or 70S). ii) Induce misreading of mRNA, which causes the incorporation of incorrect amino acid into peptide, resulting nonfunctional or toxic protein. iii) Inhibit the release of peptide chain from ribosome Iv) Disrupt the normal cycle of ribosome, make the ribosome exhausted.

  33. Aminoglycosides 3. Clinical Uses: • mostly used against infection induced by aerobicG-bacteria (bacilli, enteric) . • in severe infection, such as sepsis (败血症), pneumonia and meningitis, almost always used in combination with b-lactam antibiotics and fluoroquinolones. • TB (streptomycin and kanamycin) and atypical mycobacteria (Amikacin)

  34. Aminoglycosides 4. Adverse reactions i) Ototoxicity (耳毒性) Caused by progressive destruction of vestibular and cochlear sensory cells (irreversible!!). Cochlear toxicity: tinnitus （耳鸣） and high frequency hearing loss Kanamycin>Amikacin>Sisomicin>Gentamicin>Tobramycin Vestibular toxicity: vertigo, ataxia and loss of balance Kanamycin>Streptomycin>Sisomicin>Gentamicin>Tobramycin

  35. Aminoglycosides 4. Adverse reactions ii) Nephrotoxicity consists of damage to the kidney tubules but reversible Neomycin> Amikacin >Kanamycin>Gentamicin>Streptomycin or Tobramycin> iii) Neuromuscular blockade (paralysis) iv) Allergic reaction: skin rashes, fever, eosinophiliay,anaphylactic shock, etc.

  36. Synthetic antimicrobial agents • Quinolones 喹诺酮类 • Sulfonamides 磺胺类 • Other synthetic antimicrobials • Trimethoprim (甲氧苄啶), Nitrofurans (硝基呋喃)

  37. Classification Quinolones • Quinolones (1st generation): • Highly protein bound • Mostly used in urinary tract infections • Fluoroquinolones (2nd, 3rd and 4th generation) • Modified 1st generation quinolones • Not highly protein bound • Wide distribution to urine and other tissues; limited CSF penetration. • Spectrum extended to Gram+, some atypical, and broad anaerobic coverage

  38. http://jac.oxfordjournals.org/cgi/reprint/46/suppl_3/17

  39. Quinolones Classification Withdrawn from the market: fleroxacin 氟罗沙星 temafloxacin替马沙星 trovafloxacin曲伐沙星 grepafloxacin格帕沙星 enoxacin 依诺沙星 sparfloxacin 司帕沙星 gatifloxacin加替沙星

  40. Fluoroquinolones 1. Antimicrobial activity & spectrum: • bactericidal and have significant PAE. • show both time-dependent and a combination of time- and concentration- dependent killing (3) against aerobic G- bacteria, pseudomonas, aerobic G+bacteria, chlamydia (衣原体), legionella pneumophila (军团菌), anaerobic bacteria, mycobacteria (分支杆菌), multiple-resistance strains.

  41. DNA gyrase (G-) Topoisomerase IV (G+) Fluoroquinolones 2. Mechanism of action

  42. Fluoroquinolones 3. Adverse reactions • Gastrointestinal effects: nausea, vomiting • CNS side effects: headache, dizziness, confusion, insomnia, delerium, hallucinations, seizure (rare). • Cardiovascular: torsades de pointes (rare) • Allergic reaction, phototoxicity (光毒性) • Hepatotoxicity（肝毒性） • Nephrotoxicity （肾毒性） • Joint/cartilage toxicity, Tendinopathy(肌腱病) • Achilles tendon rupture （跟腱断裂） • Neurologic: polyneuropathy (rare) **Limited FDA approval for children (under 18)

  43. Ciprofloxacin Fluoroquinolones Spectrum: Gram- aerobic rods, and Legionella pneumophila, and other atypicals. Poor activity against Strep. pneumonia. Indications: -- Respiratory infections -- Intra-abdominal infections -- Uncomplicated/complicated UTIs -- Anthrax (炭疽) exposure and prophylaxis Unique Qualities: -- Increased effects of warfarin

  44. Levofloxacin Fluoroquinolones Spectrum: Gram+ (excluding MRSA) , Gram- and Legionella pneumophila, atypical resp. pathogens, Mycobacterium tuberculosis, anaerobes Indications: -- Chronic bronchitis and community-acquired pneumonia -- Skin and soft tissue infections (SSTIs) -- Intra-abdominal infections

  45. Moxifloxacin Fluoroquinolones Spectrum: Gram+ (excluding MRSA) & atypicals (L. pneumophila, C pneumonia & M. pneumonia), Mycobacterium tuberculosis, gram-negative anaerobes, Gram- aerobes Indications: Chronic bronchitis, community-acquired pneumonia Bacterial conjunctivitis (细菌性结膜炎) Sinusitis

  46. Gerhard Domagk Nobel Laureate 1939 Sulfonamides

  47. Sulfonamides 2,4-Diaminoazobenzen-4’-sulfonamide Prontosil 4 - 氨磺酰 – 2，4 – 二胺偶氮苯 对氨基苯甲酸

  48. Mechanism of action Pteridine(蝶啶)+PABA (对氨基苯甲酸) Dihydropteroate Synthase 二氢蝶酸合成酶 Blocked by sulfonamides Dihydropteroic acid(二氢蝶酸) glutamate Dihydrofolic acid(二氢叶酸) NADPH+H+ Dihydrofolate Reductase 二氢叶酸还原酶 Blocked by trimethoprim NADP+ Tetrahydrofolic acid(四氢叶酸)

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