大环内酯类药物

1、Chapter 38Macrolides, Lincomycins and Polymycins大环内酯类药物大环内酯类药物v14元大环内酯类元大环内酯类：红霉素、罗红霉素、克拉霉素、地红霉素v15元大环内酯类元大环内酯类：阿奇霉素v16元大环内酯类元大环内酯类：螺旋霉素、乙酰螺旋霉素、麦迪霉素、麦白霉素、罗他霉素、柱晶白霉素、交沙霉素、米欧卡霉素Macrolides vFirst generation ： 1950serythromycinvSecond generation：1970sclaithromycin azithromycinvThird generation：Common pr

2、operties of MacrolidesAntibacterial activityvFirst generationMost G+ organisms: pneumococci, streptococci, staphylococci , diphtheriae etcPart G- organisms:legionella（军团菌）（军团菌）,bacillus pertussis(百日咳百日咳), brucella(布氏布氏) etcOthers: mycoplasma(支原体支原体), chlamydia trachomatis(沙眼衣原体沙眼衣原体), rickettsia(立克次

3、体立克次体), spirochete ,anaerobes etc. vSecond generationMore active on G- organismsMechanism of actionvTarget 50s ribosomal RNAvMechanism inhibition of translocation of mRNAMechanism of resistancevProduction of inactivating enzymesvModification of the ribosomal binding sitevActive efflux systemvMLSRPha

4、rmokinetics vAbsorptionErythromycin: not stable at acid pHNew macrolides: stable povDistribution vMetabolism: Erythromycin&clarithromycin: in livervExcretion Erythromycin& azithromycin: bileClarithromycin: kidneyCommomly used macrolidesErythromycin vAntimicrobial activityGram-positive organisms: pne

5、umococci, streptococci, staphylococci , diphtheriae etcGram-negative organisms:legionella（军团（军团菌）菌）,bacillus pertussis(百日咳百日咳), brucella(布氏布氏) , meningococci, diplococcus gonorrhoeae etcOthers: mycoplasma(支原体支原体), chlamydia trachomatis(沙眼衣原体沙眼衣原体), rickettsia(立克次体立克次体), spirochete ,anaerobes etc. Er

6、ythromycinvClinical uses vAs penicillin substitute in penicillin-allergic or resistant patients with infections caused by staphylococci, streptococci and pneumococcivPertussis，diphtheriaevLegionella and mycoplasma pneumoniavH.p infectionErythromycinvAdverse reactionsGastrointestinal effectsLiver tox

7、icityCardiotoxicity Erythromycin vErythromycin lactobionate(乳糖酸红霉素）乳糖酸红霉素）verythromycin estolate（无味红霉素（无味红霉素)verythromycin stearate(硬脂酸红霉素）硬脂酸红霉素）verythromycin ethylsuccinate（琥乙红霉素，（琥乙红霉素， 利君沙利君沙） New macrolides antibioticsvAdvantage :Broader spectrum, higher activityOrally effectiveHigh blood conce

8、ntrationLonger t 1/2Less toxicityMainly used in respiratory tract infectionClarithromycin（甲红霉素（甲红霉素,克拉霉素）克拉霉素）vHas the strongest activity on Gram-positive bacteria, legionella pneumophila, chlamydia pneumoniae and H.pvGood pharmacokinetic propertyvLow toxicityAzithromycin (阿齐霉素阿齐霉素,丽珠奇乐）丽珠奇乐）vHas th

9、e strongest activity against mycoplasma pneumoniae（肺炎支原体）（肺炎支原体）vMore effective on Gram-negative bacteriavWell toleratedvT1/2 :3548h once dailyvMainly used in respitory tract infectionRoxithromycin （罗红霉素，严迪）（罗红霉素，严迪） v1987 FrancevThe highest blood concentration vF 72%85%vRespiratory tract infection

10、and soft tissue infectionvLow adverse effectsLincomycin and ClindamycinvAntimicrobial activityGram-positive organismsBacteroide fragilis and other anaerobesvMechanism Binding to 50s ribosome subunit and inhibiting protein synthesisvPharmacokineticsAbsorbed wellPenetrate well into most tissues includ

11、ing bone ClindaycinvClinical uses Severe anaerobic infection Acute or chronical suppurative osteomylitis , arthritis caused by susceptive organisms especially Staphylococci aureusvAdverse reactionsGastrointestinal effects: severe diarrhea and pseudomembranous enterocolitis caused by Clostridium diff

12、icile :vancomycin & metronidazoleOther :Impaired liver function , neutropeniaPolypeptide antibioticsvVancomycin & TeicoplaninvPolymyxinsvbactitracinVancomycin vMechanism of actionInhibit cell wall synthesisvAntimicrobial spectrum:Narrow spectrum, active only against gram-positive bacteria paticularl

13、y staphylococcivPharmacokineticsPoorly absorbed from intestinal tract, ivExcreted from glomerular filtration 90%VancomycinvClinical uses Infection caused by MRSA, MRSE and penicillin-resistant pneumococcusTreatment of antibiotic-associated enterocolitis caused by clostridium difficile povAdverse rea

14、ctionOtotoxicity & nephrotoxicityRed-man syndromeTeicoplanin vSimilar to vancomycin in mechanism and antimicrobial spectrumvCan be given im as well as ivvLess adverse reactionsPolymyxins vActive only against gram-negative rods, particularly P.aeruginosavMechanism:increase permeability of cell membranevMainly used in P.aeruginosa infection when ot