1、对糖肽类抗生素临床应用的再认识,2,Folliculitis,Abscess,Cellulitis,Staphylococcus aureus Skin or Soft-Tissue Infections,Necrotizing pneumonia,Endocarditis,Osteomyelitis,Staphylococcus aureus Deep-Seated Infections,Intracranial infection,当前用于耐药革兰阳性菌的抗生素,药 名属类 MRS PRP VISA VRE毒付作用及其他 万古霉素糖肽YYXX肾毒替考拉宁糖肽YY溶血葡萄球菌弱夫西地酸 Y
2、Y利奈唑胺恶唑烷酮YYYY可贫血，血小板Quinupristin/链阳霉素YYYX粪肠球菌差 Dalfopristin副作用达托霉素环酯肽 YY 呼吸道感染差替加环素 四环素 YYYY ?oritavancin糖肽ly33328 YYYY 组织浓度不理想Telithromycin Ketolide YYYY 对MRSA弱,真的王牌 经得起时间的考验,抗G+球菌： 万古霉素 替考拉宁抗G-杆菌：多粘菌素抗真菌：两性霉素B,替考拉宁对葡萄球菌属的抗菌活性,*替考拉宁对金葡菌的抗菌活性比万古霉素强24倍*替考拉宁对凝固酶阴性葡萄球菌的抗菌活性与万古霉素相似,但对溶血葡萄球菌的抗菌作用较万古霉素差,S
3、pencer RC,Goering R, Int J Antimicrob Agents 1995;5:169-177,替考拉宁对链球菌属的抗菌活性,*替考拉宁对肺炎链球菌和化脓性链球菌等的抗菌活性较万古霉素稍强或相仿,Spencer RC,Goering R, Int J Antimicrob Agents 1995;5:169-177,替考拉宁对肠球菌属的抗菌活性,Spencer RC,Goering R, Int J Antimicrob Agents 1995;5:169-177,替考拉宁的抗菌活性,耐万古霉素肠球菌的耐药类型,替考拉宁对厌氧菌的抗菌活性,Glupczynski et
4、al. Eur J Clin Microbiol 1984;3:50-51,MRSA菌血症、自体瓣膜感染性心内膜炎糖肽类首选,MRSA菌血症：非复杂性（迅速转阴，迅速退热，无心内膜炎、迁涉灶、假体）： 万古霉素或达托霉素2周复杂性：万古霉素或达托霉素46周心内膜炎：万古霉素或达托霉素6周评估、处理菌血症的来源！菌血症者常规行心超检查！,万古霉素+利福平：6周万古霉素+庆大霉素：2周,MRSA人工瓣膜感染性心内膜炎推荐糖肽类,MRSA儿童菌血症、感染性心内膜炎首选糖肽类,万古霉素：15mg/kg q6h，26周鉴于替代药物疗效和安全性有限数据的考虑，不推荐利奈唑胺、克林霉素；达托霉素等选择也需慎
5、重,2011 IDSA糖肽类治疗MRSA菌血症与感染性心内膜炎推荐剂量,Liu C, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus Aureus Infections in Adults and Children. CID 2011:52.,MRSA肺炎的推荐抗菌治疗,重症CAP（进入ICU / 坏死或空洞浸润 / 脓胸） 经验性治疗 MRSA感染HA-MRSAC
6、A-MRSA伴脓胸MRSA肺炎，抗生素+引流儿童MRSA肺炎：万古霉素（克林霉素，替代利奈唑胺）,万古霉素利奈唑胺克林霉素,721天,Liu C, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus Aureus Infections in Adults and Children. CID 2011:52.,2011 IDSA糖肽类治疗MRSA肺炎推荐剂量,Liu C,
7、 et al. Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus Aureus Infections in Adults and Children. CID 2011:52.,MRSA骨关节感染,骨髓炎：清创引流+万古霉素或达托霉素、利奈唑胺、克林霉素（+利福平），8周化脓性关节炎：同骨髓炎，34周骨关节、脊柱植入物术后感染：早发：同骨髓炎 （+2周 利福平）迟发：取出植入物儿童：
8、万古霉素（克林霉素，达托霉素，利奈唑胺）,MRSA中枢神经系统感染,脑膜炎：万古霉素2周（+利福平） 替代治疗：利奈唑胺，TMP-SMX 引流管：取出，培养转阴后再置入脑脓肿、硬膜下积脓： 切开引流+万古霉素46周（+利福平） 替代治疗：利奈唑胺，TMP-SMX海绵窦栓塞：万古霉素46周（+利福平） 替代治疗：利奈唑胺，TMP-SMX儿童：万古霉素,万古霉素治疗失败怎么办？,Impact of Increasing Vancomycin Dosage,Recommended vancomycin trough level10 15 mg/L or 15 20 mg/LAchievable by
9、 15 mg/kg ever 12 hour Baddour LM, et al. Circulation 2005;111:e394 434 Gemmell CG, et al. J Antimicrob Agent 2006;57:589 608 Wang JT, et al. J Antimicrob Agent 2001;47:246Higher trough level?20 25 mg/L: no outcome differenceMore renal toxicityWysocki M, et al. Antimicrob Agents Chemother 2001;45:24
10、60 7,万古霉素治疗失败怎么办？,清创引流替代一：达托霉素+（庆大霉素，利福平，利奈唑胺，SMZco）替代二：奎奴普丁/达福普丁， SMZco，利奈唑胺，特拉万星,台湾传染病协会推荐替考拉宁为MRSA-HAP的经验性治疗,Guidelines on antimicrobial therapy of pneumonia in adults in Taiwan, revised 2006. J Microbiol Immunol Infect. 2007; 40(3): 279-283.,推荐替考拉宁作为MRSA感染的迟发性HAP和VAP的经验性治疗用药对于存在多重耐药危险因素和任何严重疾病的迟
11、发性HAP (肺炎发生于入院第5天或以后)，推荐替考拉宁联合其他抗生素作为MRSA感染的经验性治疗用药对于 VAP，推荐替考拉宁联合其他抗生素作为MRSA感染的经验性治疗用药,台湾成人肺炎抗生素治疗指南 (2007)台湾传染病协会 (IDST),亚洲HAP工作组专家共识推荐替考拉宁为MRSA-HAP的一线用药,Song JH, et al. Am J Infect Control. 2008; 36(4): S83-S92.,亚洲HAP工作组专家共识 (2008),推荐万古霉素和替考拉宁作为治疗MRSA感染HAP的一线用药万古霉素具有肾毒性和耳毒性等副作用，治疗时需要严密监测其血药浓度；替考拉
12、宁严重不良反应少，无需监测血药浓度为避免耐药菌株选择抗生素，利奈唑胺应作为治疗MRSA感染HAP的二线用药,英国MRSA感染预防和治疗指南推荐MRSA感染选用糖肽类治疗,Gould FK, et al. Journal of Antimicrobial Chemotherapy. 2009; 63:849861.,英国MRSA感染预防和治疗指南(2008),无并发症的菌血症推荐使用糖肽类抗生素，疗程至少14 d 证据级别,严重皮肤软组织感染和/或菌血症高危因素的住院患者，可考虑使用使用糖肽类抗生素 证据级别A,糖肽类分子结构,万古霉素,替考拉宁,组织浓度(% of serum concentr
13、ation),1986-2007年265篇论文，RCT46篇，符合荟萃分析标准24篇。粒细胞减少伴发热和非粒细胞减少伴发热各12篇，病例数1872例结论：替考拉宁疗效与万古霉素相似（万古霉素MIC1.5），而不良反应（肾毒性）少于万古霉素,Syetitsky S, et al.Comparative efficacy and safety of vancomycin versus teicoplanin: systematic review and meta-analysis. Antimicrob Agents Chemother. 2009;53:4069-79.,替考拉宁与万古霉素的疗效
14、与安全性: 荟萃分析,Vancomycin Teicoplanin,- 64%,p0.05,Hahn-Ast C et al. Infection 2008;36:548.,替考拉宁肾毒性发生率低于万古霉素,Nephrotoxicity of glycopeptides,Definations: 50% rise in creatinine,J Chemother 2000;12(supp 5):21-5,29/49,32/42,Hahn-Ast C et al. Infection 2008;36:548.,2/11,11/19,%,Overall,Overall,Pneumonia,Pne
15、umonia,替考拉宁 vs 万古霉素-肺部感染,Overall vs Pneumonia Clinical Efficacy in Febrile Neutropenia,C.Tascini. et.al. Journal of Chemotherapy. 2009;21:311-316.,利奈唑胺与替考拉宁治疗G+菌感染的回顾性研究,菌血症及肺炎是两组患者最常见的感染类型,C.Tascini. et al. Journal of Chemotherapy. 2009;21:311-316.,临床有效率(%),32/37,12/15,15/22,7/10,15/16,11/14,13/16,
16、9/14,13/14,8/13,利奈唑胺治疗各部位感染的临床有效率与替考拉宁无统计学差异,C.Tascini. et al. Journal of Chemotherapy. 2009;21:311-316.,研究结果,Time,MIC90,Log Concentration,24h-AUC,Trough level: 15-20 mg/L24 h-AUC: 800 g h/mL (teicolanin)24 h-AUIC (AUC24/MIC): At least an AUC24/MIC 125，Better an AUC24/MIC 345 or 400,Glycopeptides Ti
17、me-dependent Bacterial Killing,MIC,Dose,Dose,Cmax,TMIC,Teicoplanin Pharmacokinetics,Teicoplanin can be given by the IV or IM routeLong serum half life (88182 hrs)90% bound to serum albuminExcreted through the kidneys, 80% of the dose being recovered in urine and 3 % in stool in 16 days,4.98,7.64,9.4
18、,一,一,Teicoplanin Levels in Critically Ill Patients202 Patients,J Antimicrob Chemother 2003;51: 9715.,An appropriate loading dose of teicoplanin (6 mg/kg every 12 h for at least three doses) was administered only in 38.6% of cases 41.2% with normal renal function 8.7% with moderately impaired renal f
19、unction 2.2% of patients with totally impaired renal functionHypoalbuminaemic in 74.5% More rapid distribution and higher clearance,J Antimicrob Chemother 2003;51: 9715.,4.24,6.47,10.8,6.11,11.22,8.66,Teicoplanin Levels in Critically Ill PatientsLoading Dose Is Needed,6 mg/kg every 12 h for three do
20、ses,4.98,7.64,9.4,一,一,Teicoplanin Levels in Critically Ill Patients202 Patients,J Antimicrob Chemother 2003;51: 9715.,Niwa T et al. Int J Antimicrob Agents 2010;35:507-10.,Kanazawa N et al. J Infect Chemother 2011;17:297-300.,Matsumoto K et al. J Infect Chemother 2010;16:193-9.,Ahn BJ, et al. Yonsei
21、 Med J 2011;52:616-23.,Clinical Response vs. Trough Teicoplanin Levels Ctrough 13 mg/L on 4th Day (N=69),Matsumoto K et al. J Infect Chemother 2010;16:193-9.,83%,20%,Teicoplanin Dosing for MRSA Infections,Teicoplanin a total dose of 36 mg/kg during the first 3 days and a trough concentration of 13 m
22、g/L on the fourth day,9%,88%,36 mg/kg was recommended to achieve Ctrough 13 mg/L,Matsumoto K et al. J Infect Chemother 2010;16:193-9.,13,Serum Level of Teicoplanin,12mg/kg q12h x 3 doses, followed by 12 mg/kg 24h x 1 dose,6mg/kg q12h x 3 doses, followed by 6 mg/kg 24h x 1 dose,Maintenance dose: both
23、 6 mg/kg.day,Wang JT, et al. Manuscript prepared,Recommended Teicoplanin Loading Doses,A loading dose of 400 mg q12h for three doses followed by 400mg once daily: None achieved the optimal teicoplanin trough concentration within 3 days800 mg and 400 mg 12 h apart on Day 1 and 600 mg and 400 mg 12 h
24、apart on Day 2, followed by a high maintenance dose of 400 mg95% of patients (21/22) showed the optimal concentration800mg on Day 1 followed by 400mg on Days 2 and 3 is recommended as the initial loading doses to achieve the optimal trough concentration promptly,Niwa T et al. Int J Antimicrob Agents
25、 2010;35:507-10.,Slide 43 of 45,Recommended Teicoplanin Loading Doses,说明书对于剂量的规定：,肾功能正常的成人和老年人 ：中度感染，如皮肤和软组织感染、泌尿系统感染、呼吸道感染 ：负荷量 ：第一天400 mg，静脉注射1次。维持量 ：静脉或肌肉注射200 mg，每日1次。严重感染，如骨和关节感染、败血症、心内膜炎 ：负荷量 ：静脉注射400 mg，每12小时给药1次，连续3次。维持量 ：静脉或肌肉注射400 mg，每日1次。某些临床情况，如严重烧伤感染或金黄色葡萄球菌心内膜炎病人，替考拉宁维持量可能需要达到12 mg/kg。
26、,肾功能不全患者替考拉宁剂量调整,无尿长期血透患者替考拉宁剂量调整,替考拉宁不能被血透滤过血药谷浓度应维持在10mg/l以上以往：负荷剂量6mg/kg，每12小时注射三次，之后每72小时重复注射一次推荐：每次10mg/kg，每隔48-72小时注射一次,PapaioannouMG,et al. Inter J Antimicrob Agents 2002; 19: 233-236,CRRT患者替考拉宁剂量调整,无尿CRRT患者的CLCRRT与健康志愿者的CL相当或略高，推荐：负荷量：6mg/kg q12h 3-4剂维持量：3-6mg/kg24对低蛋白，高通量超滤，有残余肾功能者，还需加大剂量，有必要监测血药浓度,Clin Pharmacokinet 2007; 46 (12): 997-1038,
