Part4Part4Macrolides(Macrolides( 大环内酯类大环内酯类 ), ), Lincomycin(Lincomycin( 林可霉素类林可霉素类 ), ), and Vancomycin(and Vancomycin( 万古霉素万古霉素 ))

Huifang Tang tanghuifang@zju.edu.cn

Part4-1 MacrolidesMacrolides

History1952 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

(( 红霉红霉素素 ))

(( 克拉霉克拉霉素素 ))

(( 阿奇霉阿奇霉素素 ))

STRUCTURE:

• 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)

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

Macrolides

C: ChloramphenicChloramphenicol ol

M: MacrolidesMacrolides

T: Tertracyclines

Pharmokinetics

• 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

Clinical uses

• 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

Macrolides

Adverse reactions

• Gastrointestinal effects• Liver toxicity• Superinfection( 二重感染 )

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 Gram-positive bacteria, legionella pneumophila( 肺炎衣原体 ), chlamydia pneumoniae ( 嗜肺军团菌 )and H.p

• Good pharmacokinetic property• Low toxicity

Macrolides

Third generation • 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 L-cladinose.

• 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-lincomycins-streptogramins, 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.

Macrolides

Part 4-2 Lincomycin (林可霉素 )and Clindamycin（克林霉素）

Lincomycin & Clindamycin

① Chloramphenicol Chloramphenicol

② ClindamycinClindamycin MacrolidesMacrolides

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

• 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 )

Lincomycin & Clindamycin

Part 4-3 ----------last choice

Vancomycin ( 万古霉素 )& Teicoplanin （替考拉宁）

Vancomycin

Vancomycin ( 万古霉素 )• Mechanism of action--Inhibit cell wall synthesis

Vancomycin

transpeptidatranspeptidasese

vancomycivancomycinn

-Lactam -Lactam antibioticsantibiotics

• Antimicrobial spectrum:– Narrow spectrum, active only against

gram-positive bacteria paticularly staphylococci

• Pharmacokinetics– Poorly absorbed from intestinal tract, iv– Excreted from glomerular filtration

90%

Vancomycin( 万古霉素 )

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

Vancomycin

Part 4-4Oxazolidinones( 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 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.

• 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

• Adverse reaction– 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

Linezolid

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 multidrug-resistant 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.

Streptogramins

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.

Daptomycin

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