1. Macrolides(大环内酯类), Lincomycin(林可霉素类), and Vancomycin(万古霉素)
Huifang Tang

2. History of 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)

3. STRUCTURE:
(克拉霉素)
(红霉素)
(阿奇霉素)

4. 14碳环大环内酯类： 16碳环大环内酯类： 15碳环大环内酯类： 红霉素(erythromycin) 吉他霉素(kitasamycin)
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)

5. Erythromycin (红霉素) Antimicrobial activity Macrolides
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.

6. Mechanism of action Target 50s ribosomal RNA Mechanism
Macrolides
Mechanism of action
Target
50s ribosomal RNA
Mechanism
inhibition of translocation of mRNA

7. Macrolides
C: Chloramphenicol
M: Macrolides
T: Tertracyclines

8. Pharmokinetics Not stable at acid pH Metabolized in liver
Macrolides
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）

9. 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

10. Mechanism of resistance
Macrolides
Mechanism of resistance
Modification of the ribosomal binding site
Production of esterase that hydrolize macrolides
Active efflux system

11. Adverse reactions Gastrointestinal effects Liver toxicity
Macrolides
Adverse reactions
Gastrointestinal effects
Liver toxicity
Superinfection(二重感染)

12. Second generation Advantage : Broader spectrum, higher activity
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

13. 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 respitory tract infection

14. Clarithromycin（甲红霉素,克拉霉素）
Macrolides
Clarithromycin（甲红霉素,克拉霉素）
Has the strongest activity on Gram-positive bacteria, legionella pneumophila, chlamydia pneumoniae and H.p
Good pharmacokinetic property
Low toxicity

15. 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 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 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.

16. Part 2 Lincomycin (林可霉素)and Clindamycin（克林霉素）
Lincomycin & Clindamycin
Part 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

17. Antimicrobial activity
Gram-positive organisms
Bacteroide fragilis and other anaerobes
Pharmacokinetics
Absorbed well
Penetrate well into most tissues including bone

18. 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
Impaired liver function , neutropenia

19. Part 3 ----------last choice Vancomycin (万古霉素) & Teicoplanin（替考拉宁）

20. Vancomycin (万古霉素) Mechanism of action Inhibit cell wall synthesis
Antimicrobial spectrum:
Narrow spectrum, active only against gram-positive bacteria paticularly staphylococci
Pharmacokinetics
Poorly absorbed from intestinal tract, iv
Excreted from glomerular filtration 90%

21. 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

22. 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

23. Part 4 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 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.

24. Adverse reaction Pharmacokinetics Clinical uses
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
It is approved for vancomycin-resistant E faecium infections; nosocomial pneumonia; community-acquired pneumonia; and skin infections, complicated or uncomplicated. It should be reserved for treatment of infections caused by multiply drug-resistant gram-positive bacteria.

25. Part5 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 2008[update]). It will be used to treat respiratory tract infections.

26. Part6 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.

27. 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.

28. Let’s have a rest!