Transcript 汤慧芳_大环内酯类&林可霉素

Content
Bacterial protein synthesis inhibitors
Part 1. Macrolides(大环内酯类), Lincomycin(林可
霉素类),
Part 2. Aminoglycosides(氨基糖苷类) and
Polymyxins(多黏菌素类)
Part 3. Tetracyclines(四环素类) and
Chloramphenicol(氯霉素)
Synthetic antimicrobial agents(人工合成抗菌药)
Bacterial protein synthesis inhibitors
Part1-1
Macrolides
History
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)
Macrolides
STRUCTURE:
(克拉霉素)
(红霉素)
(阿奇霉素)
• 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
Erythromycin (红霉素)
• Antimicrobial activity
– Gram-positive organisms: pneumococci（肺炎双球菌 ）,
streptococci（链球菌）, staphylococci（葡萄球菌） ,
diphtheriae （白喉）etc
– Gram-negative organisms:legionella（军团菌）,bacillus
pertussis(百日咳), brucella(布氏) ,
meningococci（脑膜炎球菌）, diplococcus gonorrhoeae （淋
病双球菌） etc
– Others: mycoplasma(支原体), chlamydia trachomatis(沙眼衣
原体), rickettsia(立克次体), spirochete (螺旋体 ),
anaerobes(厌氧菌) etc.
Typical therapeutic applications of macrolides.
Macrolides
Mechanism of action
• Target
50s ribosomal RNA
• Mechanism
Inhibition of
translocation of
mRNA
C: Chloramphenicol
M: Macrolides
T: Tertracyclines
Pharmokinetics
Macrolides
• Not stable at acid pH
• Metabolized in liver
• Excreted in bile
Drugs:
– erythromycin stearate(硬脂酸红霉素）
– erythromycin ethylsuccinate（琥乙红霉素，利君沙）
– erythromycin estolate（无味红霉素）
Macrolides
Mechanism of resistance
Modification of the ribosomal binding site
Production of esterase that hydrolyze
macrolides
Active efflux system
Adverse reactions
• Gastrointestinal effects
• Liver toxicity
• Superinfection(二重感染)
Macrolides
Macrolides
Second generation
• Advantage :
– Broader spectrum, higher activity
– Orally effective
– High blood concentration
– Longer t 1/2
– Less toxicity
– Mainly used in respitory tract
infection
Macrolides
Azithromycin (阿齐霉素）
• 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 respiratory tract
infection
Macrolides
Clarithromycin（甲红霉素,克拉霉素）
• Has the strongest activity on Grampositive bacteria, legionella
pneumophila(肺炎衣原体), chlamydia
pneumoniae (嗜肺军团菌)and H.p
• Good pharmacokinetic property
• Low toxicity
Third generation
Macrolides
• Ketolides(酮基大环内酯类)
• Ketolides are semisynthetic 14-membered-ring
macrolides, differing from erythromycin by
substitution of a 3-keto group for the neutral sugar Lcladinose.
• 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 (macrolides-lincomycinsstreptogramins, MLS)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.
Some properties of the macrolide antibiotics.
Lincomycin & Clindamycin
Part 1-2 Lincomycin (林可霉素)and Clindamycin（克林
霉素）
① Chloramphenicol
② Clindamycin
Macrolides
③ Tertracyclines
Mechanism
Binding to 50s ribosome subunit and inhibiting protein synthesis
Lincomycin & Clindamycin
• Antimicrobial activity
– Gram-positive organisms
– Bacteroide fragilis and other anaerobes
• Pharmacokinetics
– Absorbed well
– Penetrate well into most tissues including bone
Lincomycin & Clindamycin
• Clinical uses
– Severe anaerobic infection
– Acute or chronical suppurative osteomylitis（化脓性骨
髓炎）, arthritis caused by susceptive organisms
especially Staphylococci aureus（金黄色葡萄球菌）
• Adverse reactions
– Gastrointestinal effects: severe diarrhea and
pseudomembranous enterocolitis caused by Clostridium
difficile（难辨梭状芽孢杆菌）:
• vancomycin & metronidazole(甲硝唑)
– Impaired liver function , neutropenia(中性粒细胞减少)
Part 1-3
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
– 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.
• Mechanism of Resistance
– 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, grampositive anaerobic cocci, and grampositive 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
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.
• Pharmacokinetics
– Linezolid is 100% bioavailable after oral administration and has a
half-life 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.
• Clinical uses
–
–
–
–
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
Streptogramins
Part1-4 Streptogramins (链阳性菌素)
• Streptogramins are effective in the treatment of
Vancomycin-resistant Staphylococcus aureus (VRSA)
and Vancomycin-resistant enterococcus (VRE), two of
the most rapidly-growing strains of multidrugresistant bacteria.
• Members include:
–
–
–
–
Quinupristin/dalfopristin (喹奴普丁/达福普丁 )
Pristinamycin
Virginiamycin
NXL 103, a new oral streptogramin currently in phase II
trials (As of). It will be used to treat respiratory tract
infections.
Quinupristin/dalfopristin (喹奴普丁/达福
普丁 )
• A mixture of two streptogramins in a
ratio of thirty to seventy, respectively.
• They are derived from a streptomycete
and then chemically modified.
• The drug is normally reserved for the
treatment of vancomycin-resistant
Entero coccus faecium (VRE).
• Mechanism of action
• Each component of this combination drug binds to a separate
site on the 50S bacterial ribosome, forming a stable ternary
complex. Thus,they synergistically interrupt protein synthesis.
The combination drug is bactericidal and has a long
postantibiotic effect.
• Resistance
• Enzymatic processes commonly account for resistance to these
agents. For example, the presence of a ribosomal enzyme that
methylates the target bacterial 23S ribosomal RNA site can
interfere in quinupristin binding. In some cases, the enzymatic
modifi cation can change the action from bactericidal to
bacteriostatic. Plasmid-associated acetyltransferase inactivates
dalfopristin. An active efflux pump can also decrease levels of
the antibiotics in bacteria.
• Antibacterial spectrum
• The combination drug is active primarily against grampositive cocci, including those resistant to other
antibiotics (for example, methicillinresistant
staphylococci).
• Its primary use is in the treatment of E. faecium (屎肠
球菌) infections, including VRE strains. The drug is not
eff ective against Enterococcus faecalis(粪肠球菌).
Pharmacokinetics
• Quinupristin/dalfopristin is injected intravenously (the drug is
incompatible with a saline medium).
• The combination drug penetrates macrophages and polymorpho
nucleocytes, a property that is important, because VRE are
intracellular. Levels in the CSF are low. Both compounds undergo
metabolism.
• The products are less active than the parent in the case of
quinupristin and are equally active in the case of dalfopristin.
• Most of the parent drugs and metabolites are cleared through
the liver and eliminated via the bile into the feces. Urinary
excretion is secondary.
Adverse eff ects
1. Venous irritation
2. Arthralgia and myalgia: These have been reported when higher
levels of the drugs are employed.
3. Hyperbilirubinemia( 高胆红素血症): Total bilirubin is elevated in
about 25 percent of patients, resulting from a competition with
the antibiotic for excretion.
4. Interactions:
• Because of the ability of quinupristin/dalfopristin to inhibit the
cytochrome P450 (CYP3A4) isozyme, concomitant administration with drugs that are metabolized by this pathway may
lead to toxicities.
• A drug interaction with digoxin appears to occur by the same
mechanism as that caused by erythromycin.
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