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1、替加环素治疗下呼吸道感染的研究进展,解放军总医院呼吸科 佘丹阳,针对四环素类抗生素常见耐药机制设计的新型甘酰胺类抗生素,替加环素不受核糖体保护耐药机制的影响：与核糖体的亲和力比四环素类抗生素大5倍新的结合方式和结合区域可能会干扰核糖体保护蛋白的作用机制替加环素不受获得性外排耐药机制的影响：可能是无法将替加环素排出胞外、排出蛋白无法识别或是排出蛋白诱导不足。,J Antimicrob Chemother(2005)56,611614,替加环素与其他抗菌药物的抗菌谱比较,替加环素的药代动力学特点,浓度依赖性抗菌药物Linear pharmacokineticsCmax=0.87 g/mL Cmin
2、=0.13 g/mLAUC0-24h=4.7 gh/mL t=42 hoursVss=639 L,significant tissue uptake主要经胆道排泄肾功能减退者无需调整剂量透析无法清除轻中度肝功能异常无需调整剂量重度肝功能损害维持剂量减半不经过CYP450代谢，很少药物相互作用,Steady-State Serum Concentrations,0.01,0.1,1,10,0,2,4,6,8,10,12,Time Post-Dose(hr),Concentration log scale(g/mL),替加环素的组织分布(组织浓度/血清浓度),aPatients received
3、a single 100-mg IV dose of tigecycline prior to surgery.b Healthy subjects received a single 100-mg IV dose of tigecycline followed by 50 mg IV q12h.,替加环素的肺组织分布,Clinical Medicine:Therapeutics 2009:1 12751289,替加环素的临床应用范围,FDA批准的适应症复杂皮肤软组织感染复杂腹腔感染社区获得性细菌性肺炎适应症外使用：特殊MDR菌感染的靶向治疗MDR非发酵菌：鲍曼不动杆菌、嗜麦芽窄食单胞菌MDR
4、肠杆菌科细菌：碳青霉烯耐药的克雷伯菌MRSAVRE,替加环素治疗下呼吸道感染的研究现状,社区获得性细菌性肺炎FDA批准的适应症之一医院获得性肺炎现有的研究不支持标准剂量的替加环素做为HAP（尤其是VAP）的常规治疗选择最近的研究显示高剂量替加环素治疗非铜绿假单胞菌HAP（尤其是重症HAP或VAP）的疗效优于亚胺培南,替加环素在社区获得性肺炎治疗中的应用,替加环素对CAP常见致病原的体外抗菌活性,Infection and Drug Resistance 2011:4:77-86,替加环素治疗CAP的3期临床试验,multicenter,randomized,double-blind studi
5、es308 Study：conducted between June 2003 and July 2005 at 54 centers in 8 countries in North America,South America,and Mexico/Central America313 Study：conducted from January 2004 to January 2005 at 62 centers in 20 countries in Europe,Africa,and the Asia Pacific region随机分组治疗组：IV TGC(100 mg initially
6、followed by 50 mg bid)对照组：IV levofloxacin(500 mg every 24 h or 500 mg bid）duration of study therapy：7 to 14 days疗效判定：TOC:7 and 23 days after administration of the last dose of study medication,Diagnostic Microbiology and Infectious Disease 61(2008)329338,308 and 313 Study,病例入选情况,Diagnostic Microbiol
7、ogy and Infectious Disease 61(2008)329338,替加环素治疗CAP的3期临床试验：mITT基线特征,Diagnostic Microbiology and Infectious Disease 61(2008)329338,替加环素治疗CAP的3期临床试验：mITT人群基线病情严重程度,Diagnostic Microbiology and Infectious Disease 61(2008)329338,替加环素治疗CAP的3期临床试验：TOC疗效,Diagnostic Microbiology and Infectious Disease 61(200
8、8)329338,替加环素治疗CAP的3期临床试验：基于基线致病原的临床治愈率（ME人群）,Diagnostic Microbiology and Infectious Disease 61(2008)329338,替加环素治疗CAP的3期临床试验：SAEs(mITT人群),Diagnostic Microbiology and Infectious Disease 61(2008)329338,替加环素在CAP中的应用,Clinical Medicine:Therapeutics 2009:1 12751289,TGC治疗CAP等三类感染的荟萃分析：CE人群成功率,Antimicrob.Ag
9、ents Chemother.2011,55(3):1162,TGC治疗CAP等三类感染的荟萃分析：MITT人群成功率,Antimicrob.Agents Chemother.2011,55(3):1162,TGC治疗CAP等三类感染的荟萃分析：安全性,Antimicrob.Agents Chemother.2011,55(3):1162,哪些CAP患者可能从替加环素治疗中获益？,存在MDR菌（PA除外）感染危险因素的CAP患者:优于氟喹诺酮类药物CA-MRSA肠球菌多药耐药革兰氏阴性肠道杆菌PA之外的其他非发酵菌细菌与非典型致病原的混合感染无法使用呼吸喹诺酮类药物的成人CAP患者合并肾功能不
10、全的CAP患者或有潜在肾功能减退的高龄CAP患者需要同时使用经P450酶代谢的药物的CAP患者长期口服华法令抗凝的患者长期口服免疫抑制剂（他克莫司、西罗莫司、环孢素等）的患者,替加环素在医院获得性肺炎治疗中的应用,TGC对HAP常见致病菌的体外抗菌活性,Clinical Therapeutics/2006；28：1079,中国大型教学医院呼吸科HAP临床调查鲍曼不动杆菌的抗生素敏感性,中国大型教学医院呼吸科HAP临床调查肠杆菌科细菌的抗生素敏感性,中国大型教学医院呼吸科HAP临床调查金黄色葡萄球菌的抗生素敏感性,替加环素与亚胺培南/西司他丁治疗HAP对照研究,311研究,311注册研究设计方案
11、(N=945),研究目的：比较替加环素与亚胺培南治疗HAP的疗效与安全性,研究设计：多中心，双盲，随机对照，期临床研究（2004.3-2006.12）,替加环素 首剂100 mg；维持50 mg q12h若怀疑铜绿：加用头孢他定2g Q8h,1:1随机分组,亚胺培南-西司他丁 500 mg1g IV q6h*若怀疑MRSA：加用万古霉素1g Q12h,或,5-14天,亚胺培南-西司他丁剂量取决于体重和肌酐清除率及对病情的判断,疗效判定人群CE人：临床可评估人群mITT：修正意向治疗人群,Freire AT et al.D Microbiolo Infect Dis.2010;68(2):140
12、,31个国家138个研究机构参与,TOC临床疗效：替加环素VS亚胺培南,CE人群未达到预期试验终点mITT人群达到非劣性终点,TOC临床疗效：替加环素VS亚胺培南,VAP治愈率：CE人群及mITT人群均未达到非劣性终点Non-VAP治愈率：CE人群及mITT人群均达到了非劣性终点,VAP未获得预期疗效的原因分析：病原学因素,体外敏感性并非治疗失败唯一原因！治愈率常常显著低于体外敏感率，部分体外敏感菌株感染并未获得理想疗效！,VAP未获得预期疗效的原因分析：PK/PD因素,VAP中替加环素清除较快，虽然Cmax变化不大，但AUC明显降低，导致AUC/MIC下降，无法获得理想疗效,1.PKPD,2
13、.病原学,3.进一步研究方向,VAP致病菌的敏感性较低（更高的MIC），AUC/MIC下降，从而导致治疗失败。但部分敏感菌株感染未能获得理想疗效提示致病菌敏感性降低非唯一的治疗失败因素,替加环素为浓度依赖性抗菌药物，具备线性药代动力学特性，增加剂量可能改变VAP的疗效 HAP2000研究,311研究结果的启示：VAP治疗中增加TGC剂量的必要性,1.Freire AT et al.D Microbiolo Infect Dis.2010;68(2):1402.Brink AJ et al.SAMJ,2010,100(6):3883.Crandon JL et al.Antimicrob Age
14、nts Chemother.2009;53:5060,替加环素AUC随剂量呈线性增加,Muralidharan G,et al.Antimicrob Agents Chemother.2005;49:220-229.,ECCMID Abstract:2757 Clinical Efficacy of Two High Tigecycline Dosage Regimens Versus Imipenem-Cilastatin in Hospital-Acquired Pneumonia:Results of a Randomized Phase II Clinical Trial(2000 S
15、tudy)Hassan Gandjini,Paul McGovern,M.D.,Jean Li Yan,Nataile Dartois,M.D.,2000 HAP STUDY,2000 HAP STUDY DESIGN,Global phase 2,multicenter,randomized,double-blind(third-party unblinded)study210 subjects in 3 cohorts70%VAP;30%non-VAPSubjects with Pseudomonas aeruginosa pathogen from the baseline cultur
16、e were withdrawn from the studyThe primary efficacy endpoint is the clinical response in the CE population at the TOC assessment,10 to 21 days post therapy,2000 HAP INCLUSION CRITERIA,HAP in this trial is defined as pneumonia with onset of symptoms 48 hours after admission or 7 days after discharge
17、from hospital(3 days duration)VAP in this trial is defined as pneumonia with onset of symptoms 48 hours after endotracheal intubation or 48 hours after extubationPresence of a new or evolving infiltrate on a chest x-ray filmPresence of fever or leukocytosis2 of the following clinical signs and sympt
18、oms:cough,dyspnea,or tachypnea,pleuritic chest pain,ausculatatory findings,hypoxemia,purulent sputum secretion or change in sputum character,2000 HAP TEST ARTICLE ADMINISTRATION,Tigecycline IV*150 mg load then 75 mgq12h,Tigecycline IV*200 mg load then 100 q12h,Imipenem-cilastatin IV*1 g q8h,1:1:1 Ra
19、ndomization,*Tigecycline Adjunctive Rx:ceftazidime 2 g IV q8h and aminoglycoside(tobramycin 7mg/kg daily or amikacin 20mg/kg daily)*Imipenem-cilastatin Adjunctive Rx:vancomycin 15 mg/kg IV q12 and aminoglycoside(tobramycin 7mg/kg daily or amikacin 20 mg/kg daily),7-14 days,10-21 days after LDOT,LDOT
20、Visit,TOCVisit,LDOT:Last dose of therapy;TOC:test of cure,Test of cure,2000 HAP DEMOGRAPHICS(MITT),2000 HAP EFFICACY(TOC),2000 HAP VS.311 HAP EFFICACY,Clinical Responses with 70%Confidence Intervals,Cure Rate(%),311 Study,2000 Study,2000 HAP EFFICACY AT TEST-OF-CURE,替加环素大剂量组具有较高的治愈率,n=20 n=23 n=24,n
21、=35 n=36 n=34,大剂量替加环素治疗重症HAP的优势尤其明显,13 16 15,7 7 9,16 17 17,4 6 7,大剂量组的不良反应并未随着剂量上升而增加,2000 HAP CONCLUSIONS,Numerically higher efficacy at the tigecycline 100 mg twice daily dose was observed in the treatment of HAP The safety profile observed in this study was similar to the known safety profile fo
22、r tigecycline,替加环素在治疗特殊耐药菌感染中的应用,替加环素对多药耐药肠杆菌科细菌的累积敏感率,Journal of Antimicrobial Chemotherapy(2008)62,895904,替加环素治疗MDR肠杆菌科细菌肺部感染的临床报道,Journal of Antimicrobial Chemotherapy(2008)62,895904,替加环素对MDR-AB的体外抗菌活性,替加环素对MDR-AB的体外抗菌活性,中国大型教学医院呼吸科HAP临床调查TGC对112株CRAB的抗菌活性,替加环素治疗34例CRAB 感染的临床疗效,Gordon NC.Journal of Antimicrobial Chemotherapy(2009)63,775780,谢 谢,
