Transcript Antimicrobial drugs in Respiratory Infection

Antimicrobial drugs in
Respiratory Infection
Huifang Tang
Department of pharmacology
Zhejiang University, school of medicine
[email protected]
Research building C422
2015-4
Introduction
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、腺病毒、流感病毒、
副流感病毒、SARS）
10%细菌
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。
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)
Drugs for respiratory infections
Part1 Antiviral drugs（抗病毒药）
 Part2 Antibacterial drugs（抗菌药）
 Part3 Antifungal drugs（抗真菌药）

Part1 Antiviral drugs （抗病毒药）
病毒侵入人体的过程
病毒吸附侵入
(attachment &
penetration)
病毒脱壳
(uncoating)
合成
核酸多聚酶
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)
Anti-influenza virus agents
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NA结合
抑制病毒
脱颗粒和扩散
神经氨酸酶
Anti-influenza virus agents

M2蛋白抑制剂--influenza A
Amantadine(金刚烷胺)

Neuraminidase(神经氨酸酶,NA)
inhibitors --influenza A &B
Oseltamivir(奥司他韦)；
zanamivir（扎那米韦）

广谱抗病毒药--DNA &RNA viurs
Ribavirin(利巴韦林, virazole病毒唑）
Part2
Antibacterial drugs （抗菌药）
-Lactam antibiotics
Aminoglycosides (氨基糖苷类) & polymyxins(多黏菌素类)
Macrolides ( 大 环 内 酯 类 ),
vancomycins (万古霉素)
lincomycins ( 林 可 霉 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
and
Classification and mechanism of action
①
④
⑤
③
②
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）
1、-Lactam Antibiotics
青霉素类
头孢菌素类
碳青霉烯类
β-Lactam Antibiotics
内酰胺酶抑制
剂
单环类
I. Penicillins
β-Lactam Antibiotics
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)
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).
β-Lactam Antibiotics
Semi-synthetic Penicillins:
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 for Penicillin G to
treat tonsilitis(扁桃体炎), or Pharyngitis(咽炎), etc.
Semisynthetic Penicillins
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 Gresistance staphylococcal infection.

Semisynthetic Penicillins
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.
Semisynthetic Penicillins
Broad spectrum penicillins
(1)Ampicillin(氨苄西林), Amoxicillin(阿莫西林)
Pseudomonas aeruginosa(铜绿假单孢菌
——绿脓杆菌)-resistance.
Clinical Uses:
Upper
respiratory
infections;
Urinary tract infections;
Meningitis;
Salmonella infections.
Semisynthetic Penicillins
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 Pseudomonas aeruginosa, etc.
Clinical Uses:
For the treatment of the patients with
severe infection caused by G- bacteria, usually in combination with aminoglycoside (氨
基苷类).
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).
Semisynthetic Penicillins
5. Anti-G- bacilli penicillins:
Mecillinam(美西林),
 Temocillin(替莫西林)


They are bacteriostatic drugs,
and
have
narrow
antibacterial
spectrum, with activity against some
G- bacilli.
耐 酸 青 霉 耐酶青霉素
素
广 谱 青 霉 抗绿脓广谱
素
窄谱 G－
抗 菌 谱 似 抗菌谱似青霉 抗菌谱广
青霉素
素
广、抗绿脓
大肠埃希菌
耐酸
耐酸
耐酸
多不耐酸
不耐酸
不耐酶
耐酶
不耐酶
不耐酶
不耐酶
作用弱
作用弱
作用强
作用强
G－杆菌强
青 霉 素 V 、苯唑西林、甲 氨 苄 西 林 、羧苄西林、替卡西 美西林、替莫
苯 氧 乙 基 氧西林、双氯 羟 氨 苄 西 林、呋苄西林、阿 西林、匹美西
青霉素
西林、氯唑西 林
洛西林、美洛西林 林
林、氟氯西林
与哌拉西林
主 要 用 于 用于耐青霉素 用 于 呼 吸
G+ 球 菌 引 的葡萄球菌所 道 、 尿 道
起 的 轻 度 致的感染等
感染等
感染
主要用于变形杆菌
和铜绿假单胞菌引
起的感染哌拉西林
主要用于治疗G－引
起的严重感染
用于大肠杆菌
和某些敏感菌
引起的尿路感
染与软组织感
染
II. Cepharosporins








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 generation against certain G+ microoganisms;
(2)more impervious than second and third generation to attack by staphyloccal -lactamase;
(3)less active than second and third genera-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
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+ cocci but more than third
generation;
(3)active against anaerobes(厌氧菌);
(4)lack activity against Pseudomonas;
(5)less toxic than first generation to kidney.
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 second
generation against G+ cocci;
(6)less toxic to kidney.
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.
Ⅲ. Other -lactam antibiotics
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 for the treatment
of anaerobic infections.
Other -lactam antibiotics
 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
spectrum and the most activity of all
the antibiotic.

Other -lactam antibiotics
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.
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).
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.
β-内酰胺类抗生素的复方制剂
复方制剂
抗菌药
辅助药
优立新
氨苄西林
舒巴坦
奥格门汀
阿莫西林
克拉维酸
他唑星
哌拉西林
他唑巴坦
舒普深
头孢哌酮
舒巴坦
Macrolides
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)
Mechanism of action
Macrolides
Macrolides (M) bind to the 50S subunit and block transpeptidation
Antimicrobial spectrum




Macrolides
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).
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.
Macrolides
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
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
Clarithromycin（甲红霉素,克拉霉素）

Has the strongest activity on Gram-positive bacteria, legionella
pneumophila, chlamydia pneumoniae(衣 原 体 ) , Mycobacterium
avium complex and H.p

Good pharmacokinetic property

Low toxicity

The drug is also used for prophylaxis against and treatment of M
avium complex and as a component of drug regimens for ulcers
caused by H pylori.
Adverse effects






Macrolides
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.
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.
The drug can be used in community-acquired pneumonia including
infections caused by 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.
A dverse effects : hepatic dysfunctio , prolongation of the QTc
interval.
The drug is an inhibitor of the CYP3A4 drug-metabolizing system
3、 Quinolones
Quinolones
Generation
1 st (1962-1969)
Examples
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
fluoroquinolone
gemifloxacin (吉米沙星)
4 th (1997-)
Clinafloxacin 克林沙星
Moxifloxacin 莫西沙星
Quinolones
Classification of fluoroquinolone
1st generation : Norfloxacin
Spectrum: common pathogens that cause urinary tract infections.
2nd generation: Ciprofloxacin and ofloxacin
Spectrum: gram-negative bacteria and the gonococcus, many grampositive cocci, mycobacteria, and atypical pathgen (Mycoplasma ,
Chlamydophila ).
3rd-generation:levofloxacin , gemifloxacin,
and moxifloxacin
Respiratory 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.

Quinolones
Antimicrobial activity & spectrum
Quinolones
(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 multipleresistance strains.
（6）Bactericidal
concentration≥
bacteriostatic
concentration
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
chromosomal DNA during cell division.
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. so Use of
moxifloxacin in urinary tract infections is not recommended.


Half-lives : 3–8 h.
Clinical Uses


Quinolones
Levofloxacin has activity against most
organisms associated with community-acquired
pneumonia, including chlamydiae, mycoplasma,
and legionella species.
Gemifloxacin and moxifloxacin have the
widest spectrum of activity, which includes
b o t h gr a m - p osi t i v e a n d g r a m - ne g at i v e
organisms, atypical pneumonia agents, and
some anaerobic bacteria.
Toxicity





Quinolones
Gastrointestinal distress is the most common adverse
effect.
others: skin rashes, headache, dizziness, insomnia,
abnormal liver function tests, phototoxicity(光毒性),
and both tendinitis (腱炎)and tendon rupture(腱断裂).
The fluoroquinolones are not recommended for children or pregnant
women because they may damage growing cartilage and cause
arthropathy.
Fluoroquinolones may increase the plasma levels of theophylline and
other methylxanthines, enhancing their toxicity.
Newer fluoroquinolones (gemifloxacin, levofloxacin, moxifloxacin)
prolong the QTc interval.They should be avoided in patients with known
QTc prolongation and those on certain antiarrhythmic drugs or other
drugs that increase the QTc interval.
4. Sulfonamides

short-acting : sulfisoxazole

intermediate-acting: sulfamethoxazole

long-acting: sulfadoxine.

Bacteriostatic inhibitors of folic acid synthesis.

competitive inhibitors of dihydropteroate synthase

Trimethoprim—a selective inhibitor of bacterial
dihydrofolate reductase
Inhibitory effects of sulfonamides and trimethoprim on folic acid synthesis.
Pharmacokinetic features





Modest tissue penetration
Bind to plasma proteins at sites shared by bilirubin(胆
红素) and by other drugs.
Hepatic metabolism
Excretion: both intact drug and acetylated
metabolites in the urine. Solubility may be decreased
in acidic urine, resulting in precipitation of the drug
or its metabolites.
Solubility limitation: a combination of 3 separate
sulfonamides (triple sulfa) has been used to reduce
the likelihood that any one drug will precipitate.
Clinical Use
Trimethoprim-sulfamethoxazole (TMP-SMZ)
Effective orally in the treatment of urinary tract infections and
in respiratory, ear, and sinus infections caused by Haemophilus
influenzae(流感嗜血杆菌) and Moraxella catarrhalis(卡他莫拉菌).
In the immunocompromised patient, TMP-SMZ is used for
infections due to Aeromonas hydrophila (嗜水气单胞菌)and is the
drug of choice for prevention and treatment of pneumocystis
pneumonia(肺孢子菌肺炎).
An intravenous formulation is available for patients unable to take
the drug by mouth and is used for treatment of severe
pneumocystis pneumonia and for gram-negative sepsis.
TMP-SMZ is also the drug of choice in nocardiosis(诺卡氏菌病), a
possible backup drug for cholera(霍乱), typhoid fever(伤寒), and
shigellosis(志贺氏菌), and has been used in the treatment of
infections caused by methicillin-resistant staphylococci and Listeria
monocytogenes.
5. 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)

Tigecycline (替加环素) --甘氨酰四环素类中的首个药品
新型的广谱活性的静脉注射用抗生素
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.
Tetracyclines
Pharmacokinetics






Oral absorption is variable, especially for the older
drugs, and may be impaired by foods and multivalent
cations (calcium, iron, aluminum).
Wide tissue distribution and cross the placental
barrier.
Undergo enterohepatic cycling.
Doxycycline is excreted mainly in feces; the other
drugs are eliminated primarily in the urine.
The half-lives of doxycycline and minocycline are
longer than those of other tetracyclines.
Tigecycline, formulated only for IV use, is eliminated
in the bile and has a half-life of 30–36 h.
Mechanism of action
Tetracyclines
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)
Clinical Uses



Tetracyclines
Primary uses—Tetracyclines are recommended in the
treatment of infections caused by Mycoplasma
pneumoniae (in adults).
Doxycycline is currently an alternative to macrolides
in the initial treatment of community-acquired
pneumonia.
Secondary uses—Tetracyclines are also used in the
treatment of respiratory infections caused by
susceptible organisms, for prophylaxis against
infection in chronic bronchitis.
Toxicity

Gastrointestinal disturbances

Bony structures and teeth

Hepatic toxicity

Tetracyclines
Renal toxicity: One form of renal tubular
acidosis, Fanconi’s syndrome

Photosensitivity

Vestibular toxicity(前庭毒性)
6. Aminoglycosides(氨基糖苷类)
• Natural Aminoglycosides
•
链霉素(streptomycin)
•
新霉素(neomycin)
•
妥布霉素(tobramycin)
•
卡那霉素(kanamycin)
•
大观霉素(spectinomycin)
• Semisynthetic Aminoglycosides
(amikacin)
阿米卡星
•
庆大霉素(gentamicin)
西索米星(sisomicin)
小诺米星(micronomicin)
奈替米星(netilmicin)
Mechanism of action
Pharmacokinetics


Poorly absorbed from the gastrointestinal
tract.
Systemic infection:
must be given intramuscularly or intravemously
for excreted almost entirely unchanged by
glomerular filtration, which is greatly reduced in
renal impairment, causing toxic blood levels.
Adverse effects

Ototoxicity

Nephrotoxicity

Neuromuscular blockade

Skin Reactions
Supplyment
Linezolid
Oxazolidinones(恶唑烷酮类)--- Linezolid (利奈唑
胺)

Linezolid is a member of the oxazolidinones, a new class of
synthetic antimicrobials.

Mechanism of action

Mechanism of Resistance
Linezolid inhibits protein synthesis by preventing formation of the
ribosome complex that initiates protein synthesis. Its unique binding
site, located on 23S ribosomal RNA of the 50S subunit, results in no
cross-resistance with other drug classes.
Resistance is caused by mutation of the linezolid binding site on 23S
ribosomal RNA.
Linezolid

Antimicrobial spectrum:
It is active against gram-positive
organisms
including
staphylococci,
streptococci, enterococci, gram-positive
anaerobic cocci, and gram-positive rods
such as corynebacteria and Listeria
monocytogenes.
It is primarily a bacteriostatic agent
except for streptococci for which it is
bactericidal.
There is modest in vitro activity against
Mycobacterium tuberculosis.

Adverse reaction

Pharmacokinetics

Clinical uses
Linezolid
The principal toxicity of linezolid is hematologic—reversible and
generally mild.
Thrombocytopenia(血小板减少症) is the most common manifestation
(seen in approximately 3% of treatment courses), particularly when the
drug is administered for longer than 2 weeks.
Neutropenia may also occur, most commonly in patients with a
predisposition to or underlying bone marrow suppression.
Linezolid is 100% bioavailable after oral administration and has a halflife of 4–6 hours. It is metabolized by oxidative metabolism, yielding
two inactive metabolites.
It is neither an inducer nor an inhibitor of cytochrome P450 enzymes.
Peak serum concentrations average 18 g/mL following a 600 mg oral
dose. The recommended dose for most indications is 600 mg twice daily,
either orally or intraveneously.
Vancomycin-resistant E faecium infections;
nosocomial pneumonia(医院获得性肺炎);
community-acquired pneumonia(社区获得性肺炎);
skin infections
院外呼吸道感染：
以青霉素为首选，但近年来细菌耐药性有较大变化，如
肺炎球菌对苯唑西林、氨苄西林耐药率达50%，对红霉
素及克林霉素耐药率达50-70%,
金黄色葡萄球菌及表皮葡萄球菌对青霉素耐药率达97%
以上，对红霉素及克林霉素耐药率达70%
但对复方新诺明、喹诺酮类耐药率低，特别是新一代喹
诺酮类药物。故复方新诺明和喹诺酮类合用常常可以获
得理想疗效。
院内下呼吸道感染：
首选氨苄青霉素、羟氨苄或二代头孢菌素
合并厌氧菌感染时可加用甲硝唑或克林霉素。
Antituberculous Drugs
7. 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.
Antitubercular Drug Regimens








Standard regimens—3-drug regimen INH+rifampin+pyrazinamide
If the organisms are fully susceptible (and the patient is HIVnegative), pyrazinamide can be discontinued after 2 mo and treatment
continued for a further 4 mo with a 2-drug regimen.
Alternative regimens— INH + rifampin for 9 mo
or INH + ETB for 18 mo.
Intermittent (2 or 3 × weekly) high-dose 4-drug regimens are also
effective.
Resistance—If resistance to INH is higher than 4%, the initial drug
regimen should include ethambutol or streptomycin.
resistant only to INH : RIF + pyrazinamide + ethambutol or
streptomycin. 6 mo
Multidrug-resistant organisms (resistant to both INH and rifampin) :
3 or more drugs to which the organism is susceptible for a period of
more than 18 mo, including 12 mo after sputum cultures become
negative.
Part3 Antifungal drugs （抗真菌药）
1、Antibiotic (抗生素类):
Amphotericin B(两性霉素B ); Nystatin（制霉菌素）
Griseofulvin(灰黄霉素)
2、Azole (唑类) :
Imidazoles （咪唑类）：ketoconazole(酮康唑),
Triazoles（三唑类）: Itraconazole(伊曲康唑),
3、Allylamine(丙烯胺类):
Terbinafine （特比萘芬）
4、Pyrimidine (嘧啶类) :
Flucytosine (氟胞嘧啶)
5、Echinocandins(棘白菌素类)
Caspofungin(卡泊芬净)
Mechanism of action
4.嘧啶类
3.丙烯胺类
1.抗生素类
2.唑类
5.棘白菌素类
推荐阅读

美国成人社区获得性肺炎诊断治疗指南（2007）

2005 ATS/CDC/IDSA美国肺结核的控制

2011年美国感染病学会耐甲氧西林金黄色葡萄球菌
(MRSA)感染治疗指南要点

2011年美国胸科学会（ATS）发布了新版成人肺部
真菌感染治疗指南

儿 童 侵 袭 性 肺 部 真 菌 感 染 诊 治 指 南 2009 版
http://www.idsociety.org/Index.aspx
END OF CLASS