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ClassMRSAGram-FermentersESBLsP.aeruginosaAnaerobesAPPip/Tazo-+-+-+-
2、Imipenem/MEPM-+-+-+-Ertapanem-+-+-+-FQs-+-+-+-+-+ESC(Extended-spectrum ceph)-+-+-+-+-Tygacil+-+-+-+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，
3、很少药物相互作用Steady-State Serum ConcentrationsSteady-State Serum Concentrations0.010.010.10.11 110100 02 24 46 68 810101212Time Post-Dose(hr)Time Post-Dose(hr)Concentration log scale(Concentration log scale(g/mL)g/mL)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 s
4、urgery.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-
5、foldSynovial fluidb0.58-foldBonea0.35-fold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
6、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 studies308 Study：conducted between June 2003 and July 2005 at 54 centers in 8 countries in North America,South America,and
7、 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：
8、TOC:7 and 23 days after administration of the last dose of study medicationDiagnostic Microbiology and Infectious Disease 61(2008)329338 病例入选情况Diagnostic Microbiology 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
9、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(2008)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)Diagnosti
10、c 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.Agents Chemother.2011,55(3):1162TGC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):1162TGC治疗CAP等三类感染的荟萃分析：安全性Antimicrob.Agents Chemother
11、.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；28：10
12、79,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76.76%78.87%80.28%86.62%80.28%73.24%71.83%73.94%17.61%76.06%85.21%66.20%76.06%79.58%0.70%19.72%2.11%0.00%2.82%3.52%6.34%23.94%1.41%5.63%41.55%14.08%0.70%17.61%0.70%0.00%5.63%4.23%21.13%21.13%16.90%9.86%13.38%2.82%26.76%20.42%40.85%9.86%14.08%16.20%23.24%20.42%99.30%
13、74.65%95.77%0.00%10.00%20.00%30.00%40.00%50.00%60.00%70.00%80.00%90.00%100.00%MEMIMPTZPPIPFEPCROCAZCTXCFSSAMCIPLVXAMKGENPolymyxin BMINTGC耐药(%)中介(%)敏感(%)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8.33%8.33%14.58%66.67%29.17%70.83%35.42%66.67%22.92%56.25%47.92%12.50%41.67%39.58%0.00%0.00%2.08%12.50%22.92%0.00%18.
14、75%0.00%20.83%8.33%8.33%0.00%0.00%8.33%2.08%91.67%91.67%83.33%20.83%47.92%29.17%45.83%33.33%56.25%35.42%43.75%87.50%58.33%52.08%97.92%0.00%10.00%20.00%30.00%40.00%50.00%60.00%70.00%80.00%90.00%100.00%MEMIMPTZPPIPFEPCROCAZCTXCFSCIPLVXAMKGENMINTGC耐药(%)中介(%)敏感(%)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87.76%97
15、.96%87.76%87.76%87.76%87.76%77.55%63.27%87.76%95.92%95.92%100.00%8.16%12.24%65.31%91.84%12.24%2.04%12.24%12.24%12.24%12.24%18.37%12.24%12.24%4.08%4.08%0.00%91.84%71.43%34.69%8.16%100.00%100.00%100.00%100.00%0.00%10.00%20.00%30.00%40.00%50.00%60.00%70.00%80.00%90.00%100.00%OXAFOXAMCCROFEPETPIMPLVXMFX
16、ERMAZTCLISXTMINRFPGENVANTECLNZTGC耐药中介敏感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HAPHAP对照研究对照研究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100 mg；维持维持50 mg q12h若怀疑铜绿：加用头若怀疑铜绿：加用头孢他定孢他定2g Q8h1:1随机分组
17、亚胺培南亚胺培南-西司他丁西司他丁 500 mg1g IV q6h*若怀疑若怀疑MRSA：加用万：加用万古霉素古霉素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):14031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：
18、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AUCAUC/MIC/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
19、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
20、,2010,100(6):3883.Crandon JL et al.Antimicrob Agents 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 ECCMID Abstract:2757 Clinical Efficacy of Two High Tigecycline Dosage Regimens Versus Imipenem-Cilastatin in Hospital-Acquired Pneumonia:
21、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 2000 HAP STUDY DESIGNnGlobal phase 2,multicenter,randomized,double-blind(third-party unblinded)studyn210 subjects in 3 cohortsn70%VAP;30%non-VAPnSubjects with
22、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 therapy2000 HAP INCLUSION CRITERIAnHAP in this trial is defined as pneumonia with onset of symp
23、toms 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
24、 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 character2000 HAP TEST ARTICLE ADMINISTRATION TigecyclineTigecycline IV IV*150 mg load then 75 mgq12h150 mg l
25、oad then 75 mgq12h TigecyclineTigecycline IV IV*200 mg load then 100 q12h200 mg load then 100 q12hImipenem-cilastatinImipenem-cilastatin IV IV*1 g q8h1 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*
26、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 cure2000 HAP DEMOGRAPHICS(MITT)TGC 75 MG(N=36)n(%)TGC 100MG(N=35)n(%)IMI
27、PENEM(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)7.478.948.562000 H
28、AP EFFICACY(TOC)Tigecycline n/N(%)Imipenem n/N(%)Difference (70%CI)CE PopulationTGC 7516/23(69.6)18/24(75.0)-5.4(-21.6,10.9)TGC 10017/20(85.0)10.0(-6.1,24.8)c-mlTT PopulationTGC 7519/36(52.8)18/34(52.9)-0.2(-14.3,14.0)TGC 10025/35(71.4)18.5(4.3,31,8)2000 HAP VS.311 HAP EFFICACY Clinical Responses wi
29、th 70%Confidence IntervalsCure Rate(%)311 Study2000 Study2000 HAP EFFICACY AT TEST-OF-CURETGC 75mg n/N(%)TGC 100mg n/N(%)IMIPENEM n/N(%)Non-VAP11/16(68.8)11/13(84.6)11/15(73.3)VAP5/7(71.4)6/7(85.7)7/9(77.8)APACHE1514/17(82.4)13/16(81.3)14/17(82.4)APACHE152/6(33.3)4/4(100)4/7(57.1)替加环素大剂量组具有较高的治愈率n=2
30、0 n=23 n=24n=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 7 916 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
31、.4)3(8.6)7(20.6)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 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 Antimic
32、robial 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-resi
33、stant: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-resistant56144AkcamTu
34、rkey;2000200474 A.baumannii,MDR1000.0125-20.19SouliGreece;20032005100 A.baumannii;resistant to 2 antibiotic classes;(imipenem-resistant:94,colistin-resistant:3)990.1241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)Sei
35、fertEurope 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.baum
36、annii900.008 to 82Navon-VeneziaIsrael;2003;Etest82 A.baumannii;resistant to 3 antibiotic classes;(imipenem-resistant:22)221-12832中国大型教学医院呼吸科HAP临床调查TGCTGC对对112112株株CRABCRAB的抗菌活性的抗菌活性29.46%94.64%74.11%100.00%49.11%14.29%5.36%5.36%21.43%85.71%20.54%0.00%10.00%20.00%30.00%40.00%50.00%60.00%70.00%80.00%90.00%100.00%CFSAMSTGCMINPB敏感中介耐药替加环素治疗34例CRAB 感染的临床疗效Gordon NC.Journal of Antimicrobial Chemotherapy(2009)63,775780人有了知识，就会具备各种分析能力，明辨是非的能力。所以我们要勤恳读书，广泛阅读，古人说“书中自有黄金屋。”通过阅读科技书籍，我们能丰富知识，培养逻辑思维能力；通过阅读文学作品，我们能提高文学鉴赏水平，培养文学情趣；通过阅读报刊，我们能增长见识，扩大自己的知识面。有许多书籍还能培养我们的道德情操，给我们巨大的精神力量，鼓舞我们前进。
