替加环素治疗下呼吸道感染培训课件

替加环素治疗下呼吸道感染替加环素与其他抗菌药物的抗菌谱比较ClassMRSAGram-FermentersESBLsP.aeruginosaAnaerobesAPPip/Tazo-+-+-+-Imipenem/MEPM-+-+-+-Ertapanem-+-+-+-FQs-+-+-+-+-+ESC(Extended-spectrum ceph)-+-+-+-+-Tygacil+-+-+-+2替加环素治疗下呼吸道感染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=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 Concentrations0.010.1110024681012Time Post-Dose(hr)Concentration log scale(g/mL)3替加环素治疗下呼吸道感染替加环素的组织分布(组织浓度/血清浓度)aPatients received 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.Tissue/FluidConcentration Increase in Tissue vs SerumGallbladdera38-foldColona2.1-foldSkin Blister fluida26%lower than serumAlveolar cellsb78-foldEpithelial lining fluidb32%greater than serumLunga8.6-foldSynovial fluidb0.58-foldBonea0.35-fold4替加环素治疗下呼吸道感染替加环素的肺组织分布Clinical Medicine:Therapeutics 2009:1 12751289 5替加环素治疗下呼吸道感染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肠杆菌科细菌：碳青霉烯耐药的克雷伯菌MRSAVRE6替加环素治疗下呼吸道感染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7替加环素治疗下呼吸道感染替加环素在社区获得性肺炎治疗中的应用8替加环素治疗下呼吸道感染替加环素对CAP常见致病原的体外抗菌活性Infection and Drug Resistance 2011:4:77-869替加环素治疗下呼吸道感染替加环素治疗CAP的3期临床试验multicenter,randomized,double-blind studies308 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 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 medicationDiagnostic Microbiology and Infectious Disease 61(2008)329338308 and 313 Study10替加环素治疗下呼吸道感染 病例入选情况Diagnostic Microbiology and Infectious Disease 61(2008)32933811替加环素治疗下呼吸道感染替加环素治疗CAP的3期临床试验：mITT基线特征Diagnostic Microbiology and Infectious Disease 61(2008)32933812替加环素治疗下呼吸道感染替加环素治疗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)32933813替加环素治疗下呼吸道感染替加环素治疗CAP的3期临床试验：TOC疗效Diagnostic Microbiology and Infectious Disease 61(2008)32933814替加环素治疗下呼吸道感染替加环素治疗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)32933815替加环素治疗下呼吸道感染替加环素治疗CAP的3期临床试验：SAEs(mITT人群)Diagnostic Microbiology and Infectious Disease 61(2008)32933816替加环素治疗下呼吸道感染替加环素在CAP中的应用Clinical Medicine:Therapeutics 2009:1 12751289 17替加环素治疗下呼吸道感染TGC治疗CAP等三类感染的荟萃分析：CE人群成功率Antimicrob.Agents Chemother.2011,55(3):116218替加环素治疗下呼吸道感染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):116219替加环素治疗下呼吸道感染TGC治疗CAP等三类感染的荟萃分析：安全性Antimicrob.Agents Chemother.2011,55(3):116220替加环素治疗下呼吸道感染哪些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21替加环素治疗下呼吸道感染替加环素在医院获得性肺炎治疗中的应用22替加环素治疗下呼吸道感染TGC对HAP常见致病菌的体外抗菌活性Clinical Therapeutics/2006；28：1079,23替加环素治疗下呼吸道感染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24替加环素治疗下呼吸道感染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25替加环素治疗下呼吸道感染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26替加环素治疗下呼吸道感染替加环素与亚胺培南替加环素与亚胺培南/西司他丁治疗西司他丁治疗HAP对照研究对照研究311研究研究27替加环素治疗下呼吸道感染311注册研究设计方案(N=945)研究目的：比较替加环素与亚胺培南治疗研究目的：比较替加环素与亚胺培南治疗HAP的疗效与安全性的疗效与安全性研究设计：多中心，双盲，随机对照，研究设计：多中心，双盲，随机对照，期临床研究期临床研究（2004.3-2006.122004.3-2006.12）替加环素替加环素首剂首剂100mg；维持维持50mgq12h若怀疑铜绿：加用头若怀疑铜绿：加用头孢他定孢他定2gQ8h1:1随机分组亚胺培南亚胺培南-西司他丁西司他丁500mg1gIVq6h*若怀疑若怀疑MRSA：加用万：加用万古霉素古霉素1gQ12h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):14031个国家138个研究机构参与28替加环素治疗下呼吸道感染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29替加环素治疗下呼吸道感染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30替加环素治疗下呼吸道感染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！31替加环素治疗下呼吸道感染VAP未获得预期疗效的原因分析：PK/PD因素32替加环素治疗下呼吸道感染VAPVAP中替加环素清除中替加环素清除较快，虽然较快，虽然CmaxCmax变化变化不大，但不大，但AUCAUC明显降明显降低，导致低，导致AUC/MICAUC/MIC下下降，无法获得理想疗降，无法获得理想疗效效1.PKPD2.病原学3.进一步研究方向VAPVAP致病菌的敏感性较致病菌的敏感性较低（更高的低（更高的MICMIC），），AUC/MICAUC/MIC下降，从而导下降，从而导致治疗失败。但部分敏致治疗失败。但部分敏感菌株感染未能获得理感菌株感染未能获得理想疗效提示致病菌敏感想疗效提示致病菌敏感性降低非唯一的治疗失性降低非唯一的治疗失败因素败因素替加环素为浓度依赖替加环素为浓度依赖性抗菌药物，具备线性抗菌药物，具备线性药代动力学特性，性药代动力学特性，增加剂量可能改变增加剂量可能改变VAPVAP的疗效的疗效 HAP2000HAP2000研究研究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 Agents Chemother.2009;53:506033替加环素治疗下呼吸道感染替加环素AUC随剂量呈线性增加 Muralidharan G,et al.Antimicrob Agents Chemother.2005;49:220-229.34替加环素治疗下呼吸道感染 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 Study)Hassan Gandjini,Paul McGovern,M.D.,Jean Li Yan,Nataile Dartois,M.D.2000 HAP STUDY 35替加环素治疗下呼吸道感染2000 HAP STUDY DESIGNnGlobal phase 2,multicenter,randomized,double-blind(third-party unblinded)studyn210 subjects in 3 cohortsn70%VAP;30%non-VAPnSubjects with Pseudomonas aeruginosa pathogen from the baseline culture were withdrawn from the studynThe primary efficacy endpoint is the clinical response in the CE population at the TOC assessment,10 to 21 days post therapy36替加环素治疗下呼吸道感染2000 HAP INCLUSION CRITERIAnHAP in this trial is defined as pneumonia with onset of symptoms 48 hours after admission or 7 days after discharge from hospital(3 days duration)nVAP in this trial is defined as pneumonia with onset of symptoms 48 hours after endotracheal intubation or 48 hours after extubationnPresence of a new or evolving infiltrate on a chest x-ray filmnPresence of fever or leukocytosisn2 of the following clinical signs and symptoms:cough,dyspnea,or tachypnea,pleuritic chest pain,ausculatatory findings,hypoxemia,purulent sputum secretion or change in sputum character37替加环素治疗下呼吸道感染2000 HAP TEST ARTICLE ADMINISTRATION Tigecycline IV*150 mg load then 75 mgq12h Tigecycline IV*200 mg load then 100 q12hImipenem-cilastatin IV*1 g q8h 1:1:1 Randomizationn*Tigecycline Adjunctive Rx:ceftazidime 2 g IV q8h and aminoglycoside (tobramycin 7mg/kg daily or amikacin 20mg/kg daily)n*Imipenem-cilastatin Adjunctive Rx:vancomycin 15 mg/kg IV q12 and aminoglycoside(tobramycin 7mg/kg daily or amikacin 20 mg/kg daily)7-14 days10-21 days after LDOTLDOTVisitTOCVisitLDOT:Last dose of therapy;TOC:test of cureTest of cure38替加环素治疗下呼吸道感染2000 HAP DEMOGRAPHICS(MITT)TGC 75 MG(N=36)n(%)TGC 100MG(N=35)n(%)IMIPENEM(N=34)n(%)Age(Mean Years)60.3161.4664.85Sex(Male)23(63.89)19(54.29)29(85.29)Race(White)20(55.56)25(71.43)17(50.00)Weight(Mean kg)71.8170.6273.61Diagnosis-VAP13(36.11)12(34.29)16(47.06)APACHE II 1512(33.33)9(25.71)11(32.35)Prior Abx Failure4(11.11)12(34.29)5(14.71)Rx(Mean Days)7.478.948.5639替加环素治疗下呼吸道感染2000 HAP VS.311 HAP EFFICACY Clinical Responses with 70%Confidence IntervalsCure Rate(%)311 Study2000 Study41替加环素治疗下呼吸道感染替加环素大剂量组具有较高的治愈率n=20 n=23 n=24n=35 n=36 n=3443替加环素治疗下呼吸道感染大剂量替加环素治疗重症HAP的优势尤其明显13 16 15 7 7 916 17 17 4 6 744替加环素治疗下呼吸道感染大剂量组的不良反应并未随着剂量上升而增加TGC 75 MG(N=36)n(%)TGC 100MG(N=35)n(%)IMIPENEM(N=34)n(%)TEAEs31(86.1)27(77.1)28(82.4)Nausea2(5.6)4(11.4)1(2.9)Vomiting4(11.1)2(5.7)4(11.8)SAEs12(33.3)9(25.7)10(29.4)Discontinued4(11.1)3(8.6)3(8.8)Deaths7(19.4)3(8.6)7(20.6)45替加环素治疗下呼吸道感染2000 HAP CONCLUSIONSnNumerically higher efficacy at the tigecycline 100 mg twice daily dose was observed in the treatment of HAPn The safety profile observed in this study was similar to the known safety profile for tigecycline46替加环素治疗下呼吸道感染替加环素在治疗特殊耐药菌感染中的应用47替加环素治疗下呼吸道感染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)62,89590448替加环素治疗下呼吸道感染替加环素治疗MDR肠杆菌科细菌肺部感染的临床报道Journal of Antimicrobial Chemotherapy(2008)62,89590449替加环素治疗下呼吸道感染替加环素对替加环素对MDR-ABMDR-AB的体外抗菌活性的体外抗菌活性AuthorCountry;collectionperiod;Number of isolates%susceptibleMICdistribution(mg/L)MIC90(mg/L)MezzatestaItaly;20032004107 A.baumanni MDR90%;(meropenem-resistant:58)930.2542InsaUSA;2003200677 AB;resistant to b-lactams(including carbapenems),sulbactam,aminoglycosides,fluoroquinolones800.0948NRCurcioglobal isolatesArgentina;631 A.baumannii;resistant to Aminoglycosides cephalosporins,95NRNRSong Korea;2002200643 A.baumannii;carbapenem-resistant56144AkcamTurkey;2000200474 A.baumannii,MDR1000.0125-20.19SouliGreece;20032005100 A.baumannii;resistant to 2 antibiotic classes;(imipenem-resistant:94,colistin-resistant:3)990.124150替加环素治疗下呼吸道感染替加环素对替加环素对MDR-ABMDR-AB的体外抗菌活性的体外抗菌活性AuthorCountry;collectionperiod;Number of isolates%susceptibleMICdistribution(mg/L)MIC90(mg/L)SeifertEurope andUSA;9003215 A.baumannii;MDR;(imipenem-resistant:7,colistin-resistant:6)850.06 to324Pachon-IbanezSpain38 A.baumannii;Imipenem-resistant89NRNRThamlikitkulThailand;200205148 A.baumannii;resistant to all b-lactams,quinolonesand aminoglycosides97NRNRGarrisona,MWTEST 2004 to 07582 MDR A.baumannii900.008 to 82Navon-VeneziaIsrael;2003;Etest82 A.baumannii;resistant to 3 antibiotic classes;(imipenem-resistant:22)221-1283251替加环素治疗下呼吸道感染中国大型教学医院呼吸科HAP临床调查TGC对对112株株CRAB的抗菌活性的抗菌活性52替加环素治疗下呼吸道感染替加环素治疗34例CRAB 感染的临床疗效Gordon NC.Journal of Antimicrobial Chemotherapy(2009)63,77578053替加环素治疗下呼吸道感染谢谢 谢谢54替加环素治疗下呼吸道感染