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Part4
Macrolides(大环内酯类),
Lincomycin(林可霉素类), and
Vancomycin(万古霉素)
Huifang Tang
[email protected]
Part4-1
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.
Macrolides
Mechanism of action
• Target
50s ribosomal RNA
• Mechanism
inhibition of translocation of mRNA
Macrolides
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）
Clinical uses
Macrolides
• As penicillin substitute in penicillin-allergic or
resistant patients with infections caused by
staphylococci, streptococci and pneumococci
• Pertussis(百日咳)，diphtheriae(白喉)
• Legionella (军团菌)and mycoplasma
pneumonia(肺炎支原体)
• H.p infection
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.
Lincomycin & Clindamycin
Part 4-2 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
• 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)
Vancomycin
Part 4-3 ----------last choice
Vancomycin (万古霉素)
& Teicoplanin（替考拉宁）
Vancomycin (万古霉素)
Vancomycin
• Mechanism of action--Inhibit cell wall synthesis
-Lactam antibiotics
vancomycin
transpeptidase
Vancomycin
Vancomycin(万古霉素)
• Antimicrobial spectrum:
– Narrow spectrum, active only against grampositive bacteria paticularly staphylococci
• Pharmacokinetics
– Poorly absorbed from intestinal tract, iv
– Excreted from glomerular filtration 90%
Vancomycin
Vancomycin(万古霉素)
• Clinical uses
– Infection caused by MRSA, MRSE and
penicillin-resistant pneumococcus
– Treatment of antibiotic-associated
enterocolitis caused by clostridium
difficile po
• Adverse reaction
– Ototoxicity & nephrotoxicity
– Red-man syndrome
Vancomycin
Teicoplanin(替考拉宁)
• Similar to vancomycin in mechanism and
antimicrobial spectrum
• Can be given im as well as iv
• Less adverse reactions
Part 4-4
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.
• Antimicrobial spectrum:
– It is active against gram-positive organisms including staphylococci,
streptococci, enterococci, gram-positive 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.
• 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.
• 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
Part4-5 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.
Daptomycin
Part4-6 lipopeptide antibiotic
• Daptomycin(达托霉素)
• Mechanism of action
– disruption of the bacterial membrane
through the formation of transmembrane
channels, resulting in a loss of membrane
potential leading to inhibition of protein,
DNA and RNA synthesis, which results in
bacterial cell death.
Daptomycin
Antimicrobial spectrum:
• Daptomycin is unable to permeate the outer
membrane of Gram-negative bacteria, thus its
spectrum is limited to Gram-positive
organisms only.
• Daptomycin has activity against Staphylococci
(including MRSA, VISA, and VRSA),
Enterococci (both E. faecalis and E.faecium,
including VRE), and Streptococci (including
DRSP), as well as most other aerobic and
anaerobic Gram-positive bacteria.
Let’s have a rest!