1、氨基糖苷類抗生素的定義和作用aminoglycosides鏈霉素 streptomycin妥布霉素 tobramycin卡那霉素kanamycin大觀霉素spectinomycin新霉素 neomycin慶大霉素gentamicin小諾霉素micronomicin阿司米星 astromicinsisomicin天然來(lái)源Selman A. Waksmanaminoglycosides半合成品阿米卡星 amikacin地貝卡星 dibekacin阿貝卡星 arbekacin 半合成品奈替米星 netilmicin依替米星 etilmicin異帕米星 isepamicinStructure of a

2、minoglycosidesIIIIIICommon Properties of Aminoglycosides氨基糖苷類的共性抗菌作用及機(jī)制細(xì)菌耐藥性體內(nèi)過(guò)程臨床應(yīng)用不良反應(yīng)aminoglycosidesantibacterial effects氨基糖苷類抗菌作用抗菌譜(antibacterial spectrum)：對(duì)需氧G-桿菌作用強(qiáng)大大部分對(duì)銅綠假單胞菌有效 除外 鏈霉素、大觀霉素、卡那霉素aminoglycosidesantibacterial effects氨基糖苷類抗菌作用抗菌譜(antibacterial spectrum)：對(duì)G+、G-球菌有一定抗菌作用少數(shù)對(duì)結(jié)核桿菌有抗菌作

3、用 鏈霉素、卡那霉素aminoglycosidesantibacterial effects氨基糖苷類抗菌作用抗菌特點(diǎn)：屬靜止期殺菌藥對(duì)需氧菌有效， 對(duì)厭氧菌無(wú)效（厭氧菌天然耐藥）G- cellenvelope氧依賴性主動(dòng)轉(zhuǎn)運(yùn)系統(tǒng)aminoglycosidesantibacterial effects氨基糖苷類抗菌作用抗菌特點(diǎn)：有濃度依賴性有初次接觸效應(yīng)（first exposure effect, FEE）aminoglycosidesantibacterial effects氨基糖苷類抗菌作用抗菌特點(diǎn)：有明顯的抗菌后效應(yīng)（postantibacterial effect, PAE）在堿性環(huán)

4、境中抗菌作用增強(qiáng)Aminoglycosides antibacterial mechanisms氨基糖苷類抗菌機(jī)制aminoglycosidesantibacterial mechanisms氨基糖苷類抗菌機(jī)制抑制細(xì)菌蛋白質(zhì)合成干擾細(xì)菌胞漿膜通透性aminoglycosidesTarget :核糖體30亞基細(xì)菌蛋白質(zhì)合成AP肽鏈延伸階段起始階段終止階段RAP轉(zhuǎn)肽酶轉(zhuǎn)位酶肽鏈延伸階段起始階段終止階段RAPAPaminoglycosidesaminoglycosdesantibacterial mechanisms氨基糖苷類抗菌機(jī)制抑制細(xì)菌蛋白質(zhì)合成起始階段：抑制70S始動(dòng)復(fù)合物形成肽鏈延伸階段：

5、造成RNA密碼錯(cuò)譯，合成無(wú)功能的蛋白質(zhì)終止階段：阻止肽鏈的脫落和核糖體循環(huán)aminoglycosdesantibacterial mechanisms氨基糖苷類抗菌機(jī)制aminoglycosides與核糖體30S亞基結(jié)合干擾細(xì)菌蛋白合成的全過(guò)程aminoglycosidesNEW REPORTBoris Francois, et al. Crystal structures of complexes between aminoglycosides and decoding A site oligonucleotides: role of the number of rings and posi

6、tive charges in the specific binding leading to miscoding. Nucleic Acids Research, 2005, 33(17):56775690細(xì)菌核糖體真核細(xì)胞核糖體aminoglycosdesantibacterial mechanisms氨基糖苷類抗菌機(jī)制干擾細(xì)菌胞漿膜的通透性破壞細(xì)菌體屏障保護(hù)作用G- cellenvelopeaminoglycosdesantibacterial mechanisms氨基糖苷類抗菌機(jī)制干擾細(xì)菌胞漿膜的通透性離子吸附作用插入異常膜蛋白aminoglycosdesantibacterial m

7、echanisms氨基糖苷類抗菌機(jī)制抑制細(xì)菌蛋白質(zhì)合成全過(guò)程干擾細(xì)菌胞漿膜的通透性aminoglycosidesresistance氨基糖苷類耐藥性耐藥機(jī)制：鈍化酶 modifying enzyme Acetylase,AC 乙?；窤denylase,AD 腺苷化酶Phosphorylase, P 磷酸化酶aminoglycosidesresistance氨基糖苷類耐藥性耐藥機(jī)制：鈍化酶 不完全交叉耐藥完全交叉耐藥膜對(duì)藥物通透性降低G- cellenvelopeaminoglycosidesresistance氨基糖苷類耐藥性耐藥機(jī)制：鈍化酶 膜對(duì)藥物通透性降低靶位改變 aminoglyco

8、sidesresistance氨基糖苷類耐藥性Jun-ichi Wachino, Kunikazu Yamane, et al. Novel Plasmid-Mediated 16S rRNA Methylase, RmtC, Found in a Proteus mirabilis Isolate Demonstrating Extraordinary High-Level Resistance against Various Aminoglycosides ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2006, 50(1): 178184 aminogly

9、cosidespharmacokinetics氨基糖苷類體內(nèi)過(guò)程吸收absorption：口服用于腸道術(shù)前消毒或腸道感染注射用于全身感染/非腸道感染aminoglycosidespharmacokinetics氨基糖苷類體內(nèi)過(guò)程分布distribution：主要分布在細(xì)胞外液不易進(jìn)入細(xì)胞內(nèi)不易進(jìn)入腦脊液易透過(guò)胎盤屏障腎臟和內(nèi)耳淋巴液中濃度高aminoglycosidespharmacokinetics氨基糖苷類體內(nèi)過(guò)程消除elimination：以原形從腎臟排出，尿中藥物濃度高堿性尿中作用增強(qiáng)腎功能不良時(shí)慎用aminoglycosidesclinical uses氨基糖苷類臨床應(yīng)用需氧-桿菌引

10、起的全身感染銅綠假單胞菌感染+球菌感染結(jié)核桿菌感染aminoglycosidesadverse reactions氨基糖苷類不良反應(yīng)四大毒性aminoglycosidesadverse reactions氨基糖苷類不良反應(yīng)耳毒性 ototoxicity腎毒性 nephrotoxicity神經(jīng)肌肉接頭阻滯 neuromuscular blockade過(guò)敏反應(yīng) allergyaminoglycosidesadverse reactions氨基糖苷類不良反應(yīng)ototoxicity： 第八對(duì)腦神經(jīng)的損害前庭功能損害發(fā)生率：neomycin kanamycin streptomycin gentamic

11、in,amikacin, tobramycin netilmicinaminoglycosidesadverse reactions氨基糖苷類不良反應(yīng)ototoxicity： 第八對(duì)腦神經(jīng)的損害耳蝸功能受損：耳鳴、聽力減退、永久性耳聾。其發(fā)生率：neomycin kanamycin amikacin gentamicin tobramycin netilmicin streptomycinaminoglycosidesadverse reactions氨基糖苷類不良反應(yīng)ototoxicity： 可能機(jī)制耳蝸內(nèi)淋巴液中藥物濃度過(guò)高g/mlHOURS816240Plasma concentrati

12、ons after intravenous administration of gentamicin as single dose or as three divided doses during 24h.引起耳毒性的閾濃度單次給藥一日三次給藥aminoglycosidesadverse reactions氨基糖苷類不良反應(yīng)ototoxicity： 可能機(jī)制耳蝸內(nèi)淋巴液中藥物濃度過(guò)高毛細(xì)胞損傷線粒體基因突變Nucleic Acids Res. 2005; 33(3): 11321139線粒體12S rRNAaminoglycosidesadverse reactions氨基糖苷類不良反應(yīng)Pro

13、phylaxis of ototoxicity：嚴(yán)格控制適應(yīng)證，兒童，老人，孕婦更應(yīng)慎重用藥期間注意發(fā)現(xiàn)早期毒性，及早停藥有條件時(shí)監(jiān)測(cè)聽力避免與其他的耳毒性藥合用（呋塞米，依他尼酸、萬(wàn)古霉素類、順鉑等）避免合用鎮(zhèn)靜催眠藥aminoglycosidesadverse reactions氨基糖苷類不良反應(yīng)nephrotoxicity：表現(xiàn)：蛋白尿，管型尿、血尿、腎功能不良發(fā)生率：neomycin kanamycin gentamicin tobramycin amikacinstreptomycin netilmicin機(jī)制： 損傷腎近曲小管上皮細(xì)胞aminoglycosidesadverse r

14、eactions氨基糖苷類不良反應(yīng)nephrotoxicity：預(yù)防：長(zhǎng)期應(yīng)用要定期檢查腎功能腎功能不良的患者慎用或禁用避免與其他腎毒性藥物合用 萬(wàn)古霉素、多粘菌素、兩性霉素B、第一代頭孢菌素類等aminoglycosidesadverse reactions氨基糖苷類不良反應(yīng)neuromuscular blockade：與劑量、給藥途徑、用藥種類有關(guān)多在胸、腹腔給藥時(shí)產(chǎn)生大量、快速靜脈滴注時(shí)易引起發(fā)生率：neomycinstreptomycinamikacin ， kanamycin gentamicin tobramycin aminoglycosidesadverse reactions

15、氨基糖苷類不良反應(yīng)neuromuscular blockade：發(fā)生機(jī)制aminoglycosidesaminoglycosidesadverse reactions氨基糖苷類不良反應(yīng)neuromuscular blockade：治療措施 鈣劑、新斯的明GuineaPig 豚 鼠aminoglycosidesadverse reactions氨基糖苷類不良反應(yīng)allergy：以鏈霉素過(guò)敏反應(yīng)最明顯過(guò)敏反應(yīng)發(fā)生率不如青霉素G高，但休克死亡率高于青霉素皮試準(zhǔn)確性不如青霉素治療：腎上腺素+鈣劑aminoglycosidesadverse reactions氨基糖苷類不良反應(yīng)耳毒性 ototoxicity腎毒性 nephrotoxicity神經(jīng)肌肉接頭阻滯 neuromuscular bl