shi-hong zhang( 张世红 ), phd [email protected] drugs for respiratory infections
TRANSCRIPT
麻疹疟疾结核腹泻艾滋病急性呼吸道感染
• 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。
Pathogens of respiratory infectionsPathogens of 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）
Drugs for respiratory infections
利巴韦林
金刚烷胺金刚乙胺
奥司他韦扎那米韦
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 神经氨酸酶
血凝素
Antiviral drugsAntiviral drugs
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）
Mechanism of action
：1. Inhibit the synthesis of
ergosterol in fungal
membrane, cause the
leakage of intracellular
substances
2. Promotes the penetration
of other antifungal agents (
两性霉素 B)（疏水端） （亲水端）
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
Action mechanisms of antibiotics
Action mechanisms of antibioticsAction mechanisms of antibiotics
大环内酯类
β-Lactam antibiotics &
other inhibitors of cell wall synthesis
amidase
-lactamase
-lactam ring
amidase
-lactamase
-lactam ring
Source: Penicillium spp, 青霉菌
Source: Cephalosporium spp
(now called Acremonium spp.枝顶孢菌 )
Sir Alexander Fleming The Nobel prize in Physiology or Medicine 1945
Discoverer of PenicillinCo-recipients: Florey and Chain
(They made it possible to produce large quantities)
Penicillins
Action mechanisms• Inhibit the activity of peptidoglycan transpeptidase (PBP)• Increase the activity of cell wall autolytic enzyme
C-terminal
N-terminal
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
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.
Penicillins 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)
Penicillins Penicillins
Cephalosporins
Cephalosporins
Cephalosporins
吡
Cephalosporins
Good
yes
yes
no
First Second Third
Gram-positive
Gram-negative Good
Pseudomonas - - +
Anearobes - + +
Beta-lactamase sensitive No
Kidney toxicity Almost no
Well penetration Yes
Small summary
• 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 )
Macrolides （大环内酯类）
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 ).
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
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 )
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
General properties of macrolides
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 ).
Lincomycin & Clindamycin 林可霉素和克林霉素
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
AminoglycosidesAminoglycosides 氨基糖苷类抗生素
• 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
Aminoglycosides
Natural Synthesized
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)
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.
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-lactam antibiotics and fluoroquinolones.
• TB (streptomycin and kanamycin) and atypical
mycobacteria (Amikacin)
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
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.
Aminoglycosides
• Quinolones 喹诺酮类
Synthetic antimicrobial agents
• Sulfonamides 磺胺类• Other synthetic antimicrobials
Trimethoprim ( 甲氧苄啶 ), Nitrofurans ( 硝基呋喃 )
Classification• 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
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
http://jac.oxfordjournals.org/cgi/reprint/46/suppl_3/17
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
Classification
Quinolones
1. Antimicrobial activity & spectrum:
(1) bactericidal and have significant PAE.
(2) 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.
Fluoroquinolones
2. Mechanism of action2. Mechanism of action
Topoisomerase IV (G+)
DNA gyrase (G-)
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)
Fluoroquinolones
CiprofloxacinSpectrum: 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
Fluoroquinolones
LevofloxacinSpectrum: 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
Fluoroquinolones
MoxifloxacinSpectrum: 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
Fluoroquinolones
Sulfonamides
Gerhard DomagkNobel Laureate 1939
Sulfonamides
2,4-Diaminoazobenzen-4’-sulfonamideProntosil
4 - 氨磺酰 – 2 ， 4 – 二胺偶氮苯
对氨基苯甲酸
Pteridine( 蝶啶 )+PABA ( 对氨基苯甲酸 )
Blocked by sulfonamides
Dihydropteroic acid( 二氢蝶酸 )
Dihydrofolic acid( 二氢叶酸 )
glutamate
Tetrahydrofolic acid( 四氢叶酸 )
Blocked by trimethoprim
NADPH+H+
NADP+
DihydropteroateSynthase 二氢蝶酸合成酶
DihydrofolateReductase 二氢叶酸还原酶
Mechanism of action
Sulfonamides
1. Antimicrobial activity:
• A wide antimicrobial spectrum: effective
against G- and G+ bacteria, nocardia, chlamydia,
pneumocystis carinii; ineffective to Rickettsia.
• Only bacteriostatic effect.
• 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
Adverse reactions
Sulfonamides
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.
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
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.
Combination agents: Combination agents: Co-trimoxazole
• 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 ).
Antituberculous drugsAntituberculous drugs