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Master text styles,Second level,Third level,*,Click to edit Master title styleXxxxxxxxxxx Xxxxxxxxxxx,Click to edit Master text styles,Second level,Third level,*,Click to edit Master title styleXxxxxxxxxxx Xxxxxxxxxxx,Click to edit Master text styles,Second level,Third level,*,Click to edit Master title styleXxxxxxxxxxx Xxxxxxxxxxx,Click to edit Master text styles,Second level,Third level,*,Click to edit Master title styleXxxxxxxxxxx Xxxxxxxxxxx,Click to edit Master text styles,Second level,Third level,*,Click to edit Master title styleXxxxxxxxxxx Xxxxxxxxxxx,Click to edit Master text styles,Second level,Third level,*,Click to edit Master title styleXxxxxxxxxxx Xxxxxxxxxxx,Click to edit Master text styles,Second level,Third level,*,再认识阿奇霉素在儿童上呼吸道感染治疗中的应用,1,主要内容,不断变化的抗生素治疗环境,-,肺炎链球菌对大环内酯类药物的耐药问题,大环内酯类药物对儿童上呼吸道感染,（,URI,）持续有效的价值,阿奇霉素在呼吸道感染指南中的位置,2,肺炎链球菌对大环内酯类的耐药问题,亚特兰大肺炎链球菌对大环内酯类耐药的情况,(4148,个例),Gay et al:JID 2000;182;1417-1424,3,2001-2007,肺炎链球菌,对常用抗生素敏感性变化（,%,）,4,实验室：根据,NCCLS,折点判定标准，,SP,对大环内酯类高度耐药,临床：治疗常有效,（有报道用阿奇霉素治疗,75%,以上有效）,困惑：体外药敏与临床治疗结局的不一致性,如何评价,SP,对大环内酯类抗生素的,耐药现象是一个需要思考的问题。,2000,2002,年三地区,SP,对青霉素,耐药率,2000,2002,年三地区,SP,对红霉素,耐药率,5,体外药敏结果和临床治疗结局不一致,-,大环内酯类（阿奇霉素,),药物动力学特征感染组织高浓度,细胞内大环内酯类药物浓度高，阿奇霉素峰值浓度,80mg/L,阿奇霉素的组织穿透力受血清浓度驱动，更受白细胞趋化驱动,阿奇霉素在有,炎症和白细胞存在时阿奇霉素浓度即会戏剧性升高,白细胞趋化达感染部位，释放药物同时吞噬病原菌，在白细胞内清除细菌,阿奇霉素在吞噬细胞中浓集,吞噬细胞携带阿奇霉素并向感染,在感染部位,释放出阿奇霉素,6,浓度,(,g/mL),197.0,19.7 2.7,0.1,泰利霉素,0.16,1.6 0.2,10.0,青霉素,G,12.0,54 10.5,4.5,莫西沙星,4.8,28.8 4.8,6.0,左氟沙星,6.2,24.8 4.8,4.0,环丙沙星,517.0,51.7 4.3,0.1,阿奇霉素,I/E,比值*,细胞内,细胞外,药物,*孵育,1 h,多形核细胞对阿奇霉素（希舒美）的摄取,1Mandell GL,Coleman E.,AAC,.2001;45:1794-8,7,阿奇霉素浓度,(,g/mL),化脓性链球菌,(,皮下,),肺炎链球菌,(,肺,),攻击的细菌,(,感染部位,),32.0,24.0,16.0,8.0,2.0,1.0,0.0,非感染,感染,Retsema JA,Bergeron,JM,Girard D,et al.,JAC.,1993;31(suppl E):5-16.,金黄色葡萄球菌,(,大腿,),中性粒细胞将阿奇霉素（希舒美）输送到感染部位,8,希舒美高浓度、长时间持续存在于呼吸道组织及肺泡巨嗜细胞中,1,阿奇霉素（希舒美）具有卓越的组织穿透性,Foulds G et al.J Antimicrob Chemother.1990;25(Suppl A):73-82.,时间,(h),平均浓度,(,g/ml,或,g/g),2,1,0.75,2.5,3.5,3.5,3.5,3,1,2,2,0.75,0.6,4,7,22.5,18,17,2,1.5,0,5,10,15,20,25,12,24,48,72,96,痰液,支气管黏液,上皮内液,肺泡巨噬细胞,9,阿奇霉素（希舒美）在靶组织中具有高而持久的有效药物浓度，确保病原菌的清除,扁桃体,前列腺,子宫颈,血 清,2,5,10,20,50,0,0.01,0.05,0.1,0.2,0.5,1,2,3,4,5,6,7,8,9,10(,天,),1.0,浓度,(mg/kg,或,mg/l),化脓性链球菌,(A,组,),肺炎链球菌,卡他莫拉菌,沙眼衣原体,肺炎支原体,流感嗜血杆菌,嗜肺军团菌,MIC,90,希舒美,500mg,每日一次，连服,3,天,The American Journal of Medicine Volume 91(suppl 3A),10,60,0,5,10,15,20,25,30,35,40,45,50,55,0.03,0.06,0.12,0.25,0.5,1,2,4,8,16,32,64,64,MIC(ug/mL),百分比,敏感,耐药,治疗成功,(,外泵机制,),治疗失败?,(,针对修饰机制,),是否应该以治疗结果来判定耐药性?,体外药敏结果和临床治疗结局不一致,-,怎样定义大环内酯类的耐药性?,大环内酯类的耐药判定点是否该移到这里,?,？,阿奇霉素,11,体外药敏结果和临床治疗结局不一致,临床疗效的重要性,现在的观点：,chest 1999,，体外药敏的局限性及临床疗效的重要性,青霉素耐药肺炎链球菌,(PRSP),和多重耐药肺炎链球菌,(MDRP),引起的社区获得性肺炎患者用大环内酯类抗生素治疗取成功，表明对这些患者的治疗建议不应当仅仅根据体外实验室结果，而应当根据临床实践的结果。,NCCLS,每年修订折奌判定标准主要就是根据临床实践,-,疗效的总结和反馈,Chest 1999;116:535-538,12,Zuckerman JM et al.Infect Dis Clin North Am.2000;14:449-462.,阿奇霉素可有效覆盖,典型菌,非典型菌,阿奇霉素不仅能覆盖非典型菌,对于某些革兰氏阴性菌具有较高的抗菌活性,13,阿奇霉素对革兰阳性、阴性菌具有广谱的抗菌活性,体外研究证实阿奇霉素对,呼吸道常见病原体有抗菌活性,对引起皮肤软组织感染、性传播疾病的常见病原体如沙眼衣原体、淋球菌及解脲脲原体阿奇霉素也具有抗菌活性,Roteema J,Girard A,Schody W,et al.spectrum and mode of action of azithromych(CP 62993),a new 15-membered-ring macrolids with improved potency against gram-negztive organisms.Amtimicrob.Agents chemother 1987;31:1939-47.,Bytander M.Hallander HO.In vitro comparison of the activity of doxycyline.tetracycline,erythromycin and a new macrolide,CP-62,993 against Mycoplasma pneumonize,Mycoplasma hominis and ureaplasma ureaslyticum.Scand J infect Dis 1988;53(Suppl):12-7.,流感嗜血杆菌,(,含产酶株）、肺炎链球菌（,PSSP,）、卡他莫拉菌、化脓性链球菌、和金黄色葡萄球菌（,MSSA,）,嗜肺军团菌、肺炎支原体、肺炎衣原体、沙眼衣原体,14,1990,至,20003/21,文献资料急性中耳炎,19,个对照研究,3421,例急性鼻窦炎,11,个对照研究,1742,例急性扁桃体咽炎,16,个对照研究,2447,例,阿奇霉素在上呼吸道感染的疗效和安全性,-,与其它抗生素随机对照研究的,Meta,分析,Ioannidis J.P.A,，,et al,J Antimicro Chemotherapy,BSAC,杂志，,2001,，,48,（,4,）：,677-689,15,临床失败率,各抗生素类似，相互间差异,2.0,急性中耳炎,odds,率,1.12,，,95%CI 0.81-1.54,急性鼻窦炎,odds,率,0.91,，,95%CI 0.60-1.39,急性扁桃体咽炎,odds,率,1.07,，,95%CI 0.59-1.94,中耳分离出细菌,399,株，细菌学清除率相互间无差异,odds,率,1.74,，,95%CI 0.71-4.31,阿奇霉素因副反应中断治疗,37/4870,（,0.8%,）,16,儿童呼吸道感染的治疗策略,经验
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