1. Drugs for respiratory infections
Shi-Hong Zhang(张世红), PhD

2. 麻疹 疟疾 结核 腹泻
艾滋病
急性呼吸道感染
The main leading infectious causes of death in the world include: acute respiratory infections, HIV/AIDS, diarrheal diseases, tuberculosis, malaria, measles(麻疹).

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）
抗菌药：各类。。。。
抗病毒：利巴韦林，干扰素，奥司他韦（达菲).
抗真菌：两性霉素B，酮康唑，氟康唑

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

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

11. Vancomycin/Tichoplanin: 万古霉素/替考拉宁
Bacitracin: 杆菌肽
Imipenem/cilastatin:亚胺培南/西司他丁， meropanem：美罗培南
Monobactam：单环beta内酰胺类：aztreonam 氨曲南

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

13. Sir Alexander Fleming The Nobel prize in Physiology or Medicine 1945
                                           
Sir Alexander Fleming
青霉素是抗菌素的一种，是从青霉菌培养液中提制的药物，是第一种能够治疗人类疾病的抗生素。青霉素的发现者是英国细菌学家弗莱明。1928年的一天，弗莱明在他的一间简陋的实验室里研究导致人体发热的葡萄球菌。由于盖子没有盖好，他发觉培养细菌用的琼脂上附了一层青霉菌。这是从楼上的一位研究青霉菌的学者的窗口飘落进来的。使弗莱明感到惊讶的是，在青霉菌的近旁，葡萄球菌不见了。这个偶然的发现深深吸引了他，他设法培养这种霉菌进行多次试验，证明青霉素可以在几小时内将葡萄球菌全部杀死。弗莱明据此发明了葡萄球菌的克星—青霉素。 1929年，弗莱明发表了学术论文，报告了他的发现，但当时未引起重视，而且青霉素的提纯问题也还没有解决。
　　1935年，英国牛津大学生物化学家钱恩和物理学家弗罗里对弗莱明的发现大感兴趣。钱恩负责青霉菌的培养和青霉素的分离、提纯和强化，使其抗菌力提高了几千倍同，弗罗里负责对动物观察试验。至此，青霉素的功效得到了证明。
    由于青霉素的发现和大量生产，拯救了千百万肺炎、脑膜炎、脓肿、败血症患者的生命，及时抢救了许多的伤病员。青霉素的出现，当时曾轰动世界。为了表彰这一造福人类的贡献，弗莱明、钱恩、弗罗里于1945年共同获得诺贝尔医学和生理学奖。
    第二次世界大战促使青霉素大量生产。1943年，已有足够青霉素治疗伤兵；1950年产量可满足全世界需求。青霉素的发现与研究成功，成为医学史的一项奇迹。
The Nobel prize in Physiology or Medicine 1945
Discoverer of Penicillin
Co-recipients: Florey and Chain
(They made it possible to produce large quantities)

14. Penicillins Action mechanisms
Inhibit the activity of peptidoglycan transpeptidase (PBP)
Increase the activity of cell wall autolytic enzyme
C-terminal
N-terminal
glycosyltransfer (GT), and transpeptidation (TP)。 5个氨基酸的多肽+多糖组成肽聚糖(peptidoglycan).

15. 5个氨基酸的多肽(丙氨酸/谷氨酸/赖氨酸/丙氨酸/丙氨酸)+多糖组成肽聚糖(peptidoglycan），N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM)。转肽反应使末端一个丙氨酸脱落，经多糖连接与临近肽链形成交联。青霉素可与TP亚区结合，抑制转肽酶活性

16. 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 penicillins mecillinam美西林, temocillin替莫西林
天然、抗绿脓杆菌青霉素类不耐酸，仅能注射给药。其余各类均有口服品种

17. 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.

18. Penicillins
Prevention and treatment of hypersensitivity 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)

19. Cephalosporins
第一代头孢菌素对葡萄球菌产生的酶比较稳定，但对G-菌产生的酶不稳定

20. Cephalosporins

21. Cephalosporins

22. Cephalosporins 吡
β-lactamase

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

24. 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)

25. 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).

26. 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

27. 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)

28. 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

29. 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).
对引起吸入性肺炎、肺脓肿、阻塞性肺炎的厌氧菌有强大杀灭作用

30. 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

31. Aminoglycosides
氨基糖苷类抗生素

32. 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
第三代氨基糖苷类阿米卡星和奈替米星对耐头孢菌素和甲氧西林的菌株也有效

33. 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)
仍是抗G-杆菌：铜绿假单胞菌，大肠埃希菌，变形杆菌，肠杆菌，志贺菌，枸橼酸菌的重要药物，尤其是抗耐头孢菌素和甲氧西林菌株、结核的用途。

34. 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.

35. Aminoglycosides 3. Clinical Uses:
mostly used against infection induced by aerobic G- 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)

36. 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

37. 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.

38. 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)

39. 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
Quinolones highly protein bound so best activity is in protein-free compartment (i.e. urinary tract); fluoro group attached to central ring

40. Generation Drug Names Spectrum
1st
nalidixic acid 萘啶酸pipemidic acid吡哌酸
cinoxacin西诺沙星
Gram- but not Pseudomonas species
2nd
norfloxacin诺氟沙星ciprofloxacin 环丙沙星ofloxacin 氧氟沙星*lomefloxacin洛美沙星
Gram- (including Pseudomonas species), some Gram+ (S. aureus) and some atypicals
3rd
levofloxacin 左氧氟沙星
balofloxacin巴罗沙星
pazufloxacin帕珠沙星
tosufloxacin妥舒沙星
Same as 2nd generation with extended Gram+ and atypical coverage
4th
besifloxacin贝西沙星
garenoxacin格林沙星
sitafloxacin西他沙星
*moxifloxacin莫西沙星
gemifloxacin吉米沙星
prulifloxacin普卢利沙星
Same as 3rd generation with broad anaerobic coverage

41. Classification Quinolones 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

42. 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.

43. Fluoroquinolones 2. Mechanism of action DNA gyrase (G-)
Topoisomerase IV (G+)
DNA gyrase (G-)
拓扑异构酶包括I、II、III、IV四种，其中II又称DNA 回旋酶。在G+菌中主要为IV，阴性菌中主要为II

44. 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)

45. 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
Not inclusive list of indications; patients at risk for tendon effects (>60 yo, renal failure, dialysis, concomitant corticosteroid therapy, dyslipidemia); weakest quinolone against MRSA

46. 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

47. 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
L. Pneumophila 嗜肺军团菌，M pneumonia 支原体肺炎，C pneumonia 衣原体肺炎

48. Sulfonamides Gerhard Domagk Nobel Laureate 1939

49. 2,4-Diaminoazobenzen-4’-sulfonamide
Sulfonamides
2,4-Diaminoazobenzen-4’-sulfonamide
Prontosil
4 - 氨磺酰 – 2，4 – 二胺偶氮苯
对氨基苯甲酸

50. Pteridine(蝶啶)+PABA (对氨基苯甲酸)
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)

51. Sulfonamides 1. Antimicrobial activity:
A wide antimicrobial spectrum: effective against G- and G+ bacteria, nocardia, chlamydia, pneumocystis carinii; ineffective to Rickettsia.
Only bacteriostatic effect.

52. Sulfonamides Adverse reactions Hypersensitivity reaction
Urinary tract disturbances: Sulfonamide crystalluria （磺胺结晶尿）
Hematopoietic system （造血系统）disturbances
Kernicterus （核黄疸，胆红素脑病）
Hepatitis （肝炎）
GI effects
Kernicterus: occurs in newborns where sulfonamides displace bilirubin from its binding site on serum albumin, and the excess bilirubin penetrates into the CNS to cause brain damage.

53. Combination agents: Co-trimoxazole
1) Features
Trimethoprim in combination with Sulfamethoxazole (1:5,eg,160mg:800mg for p.o.) exerts a synergistic effects (bactericidal effect).
Sequential blocking of essential enzymes of folate metabolism.
The ADME of the two agents is similar.

54. Combination agents: Co-trimoxazole
2) Clinical Uses
Chronic and recurrent infections in the urinary tract
Bacterial respiratory infections
GI infections (e.g. induced by Salmonella, cholera and traveler diarrhea)
pneumocystis carinii pneumonia

55. Combination agents: Co-trimoxazole
3) Adverse reactions
Trimethoprim(TMP): megaloblastic anemia, due to the lack of folic acid
Sulfamethoxazole (SMZ ) induced adverse reactions
Drug interactions: warfarin, phenytoin, etc.

60. Antituberculous drugs
First line agents: Isoniazid (INH异烟肼), rifampicin (RIF 利福平), pyrazinamide (PZA 吡嗪酰胺) , ethambutol (EMB 乙胺丁醇) and streptomycin (SM 链霉素).
Second line agents:
Fluoroquinolones: Ofloxacin (OFX氧氟沙星), levofloxacin (LEV左氧氟沙 星), moxifloxacin (MOX莫西沙星) and ciprofloxacin (CIP环丙沙星).
Injectable antituberculosis drugs: Kanamycin (KAN卡那霉素), amikacin (AMK阿米卡星) and capreomycin (CAP卷曲霉素).
Less-effective second-line antituberculosis drugs: P-aminosalicylic acid (PAS对氨基水杨酸), Ethionamide (ETH乙硫异烟胺), Cycloserine (CS环丝 氨酸).
结核的治疗原则是早期用药、联合用药、适量、坚持全程规律用药。常用方案为：短期强化（一线药物联合强化治疗6个月异烟肼+利福平+吡嗪酰胺两个，继以异烟肼+利福平四个月，异烟肼耐药的可加用链霉素和乙胺丁醇。对体质差的可用12月一疗程，后半年用一个药物巩固疗效。对多药耐药的，可延长至两年。