替加環(huán)素治療下呼吸道感染課件

1、替加環(huán)素治療下呼吸道感染的研究進(jìn)展解放軍總醫(yī)院呼吸科 佘丹陽(yáng)針對(duì)四環(huán)素類(lèi)抗生素常見(jiàn)耐藥機(jī)制設(shè)計(jì)的新型甘酰胺類(lèi)抗生素替加環(huán)素不受核糖體保護(hù)耐藥機(jī)制的影響：與核糖體的親和力比四環(huán)素類(lèi)抗生素大5倍新的結(jié)合方式和結(jié)合區(qū)域可能會(huì)干擾核糖體保護(hù)蛋白的作用機(jī)制替加環(huán)素不受獲得性外排耐藥機(jī)制的影響：可能是無(wú)法將替加環(huán)素排出胞外、排出蛋白無(wú)法識(shí)別或是排出蛋白誘導(dǎo)不足。J Antimicrob Chemother (2005) 56, 611614替加環(huán)素與其他抗菌藥物的抗菌譜比較ClassMRSAGram - FermentersESBLsP. aeruginosaAnaerobesAPPip/Tazo-+ -

2、 + - +-Imipenem/ MEPM-+ - + - +-Ertapanem-+ - +-+-FQs-+ - + - + - + -+ESC(Extended-spectrum ceph)-+ - +-+ - +-Tygacil+ - +-+ -+替加環(huán)素的藥代動(dòng)力學(xué)特點(diǎn)濃度依賴(lài)性抗菌藥物L(fēng)inear pharmacokineticsCmax = 0.87 g/mL Cmin = 0.13 g/mLAUC0-24h = 4.7 gh/mL t = 42 hoursVss = 639 L, significant tissue uptake主要經(jīng)膽道排泄腎功能減退者無(wú)需調(diào)整劑量透析無(wú)法清除

3、輕中度肝功能異常無(wú)需調(diào)整劑量重度肝功能損害維持劑量減半不經(jīng)過(guò)CYP450代謝，很少藥物相互作用Steady-State Serum Concentrations0.010.1110024681012Time Post-Dose (hr)Concentration log scale (g/mL)替加環(huán)素的組織分布(組織濃度/血清濃度)aPatients received a single 100-mg IV dose of tigecycline prior to surgery.b Healthy subjects received a single 100-mg IV dose of ti

4、gecycline 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-fold替加環(huán)素的臨床應(yīng)用范圍FDA批準(zhǔn)的適應(yīng)癥

5、復(fù)雜皮膚軟組織感染復(fù)雜腹腔感染社區(qū)獲得性細(xì)菌性肺炎適應(yīng)癥外使用：特殊MDR菌感染的靶向治療MDR非發(fā)酵菌：鮑曼不動(dòng)桿菌、嗜麥芽窄食單胞菌MDR腸桿菌科細(xì)菌：碳青霉烯耐藥的克雷伯菌MRSAVRE替加環(huán)素治療下呼吸道感染的研究現(xiàn)狀社區(qū)獲得性細(xì)菌性肺炎FDA批準(zhǔn)的適應(yīng)癥之一醫(yī)院獲得性肺炎現(xiàn)有的研究不支持標(biāo)準(zhǔn)劑量的替加環(huán)素做為HAP（尤其是VAP）的常規(guī)治療選擇最近的研究顯示高劑量替加環(huán)素治療非銅綠假單胞菌HAP（尤其是重癥HAP或VAP）的療效優(yōu)于亞胺培南替加環(huán)素對(duì)CAP常見(jiàn)致病原的體外抗菌活性Infection and Drug Resistance 2011:4:77-86替加環(huán)素治療CAP的3

6、期臨床試驗(yàn)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

7、 Asia Pacific region隨機(jī)分組治療組：IV TGC (100 mg initially followed by 50 mg bid) 對(duì)照組：IV levofloxacin(500 mg every 24 h or 500 mg bid）duration of study therapy ： 7 to 14 days療效判定：TOC: 7 and 23 days after administration of the last dose of study medicationDiagnostic Microbiology and Infectious Disease 61 (

8、2008) 329338308 and 313 Study 病例入選情況Diagnostic Microbiology and Infectious Disease 61 (2008) 329338替加環(huán)素治療CAP的3期臨床試驗(yàn)：mITT人群基線(xiàn)病情嚴(yán)重程度Diagnostic Microbiology and Infectious Disease 61 (2008) 329338替加環(huán)素治療CAP的3期臨床試驗(yàn)：TOC療效Diagnostic Microbiology and Infectious Disease 61 (2008) 329338替加環(huán)素治療CAP的3期臨床試驗(yàn)：SAEs

9、(mITT人群)Diagnostic Microbiology and Infectious Disease 61 (2008) 329338替加環(huán)素在CAP中的應(yīng)用Clinical Medicine: Therapeutics 2009:1 12751289 TGC治療CAP等三類(lèi)感染的薈萃分析：CE人群成功率Antimicrob. Agents Chemother. 2011, 55(3):1162TGC治療CAP等三類(lèi)感染的薈萃分析：MITT人群成功率Antimicrob. Agents Chemother. 2011, 55(3):1162TGC治療CAP等三類(lèi)感染的薈萃分析：安全性A

10、ntimicrob. Agents Chemother. 2011, 55(3):1162哪些CAP患者可能從替加環(huán)素治療中獲益？存在MDR菌（PA除外）感染危險(xiǎn)因素的CAP患者: 優(yōu)于氟喹諾酮類(lèi)藥物CA-MRSA腸球菌多藥耐藥革蘭氏陰性腸道桿菌PA之外的其他非發(fā)酵菌細(xì)菌與非典型致病原的混合感染無(wú)法使用呼吸喹諾酮類(lèi)藥物的成人CAP患者合并腎功能不全的CAP患者或有潛在腎功能減退的高齡CAP患者需要同時(shí)使用經(jīng)P450酶代謝的藥物的CAP患者長(zhǎng)期口服華法令抗凝的患者長(zhǎng)期口服免疫抑制劑（他克莫司、西羅莫司、環(huán)孢素等）的患者TGC對(duì)HAP常見(jiàn)致病菌的體外抗菌活性Clinical Therapeutic

11、s/2006；28：1079, 中國(guó)大型教學(xué)醫(yī)院呼吸科HAP臨床調(diào)查鮑曼不動(dòng)桿菌的抗生素敏感性中國(guó)大型教學(xué)醫(yī)院呼吸科HAP臨床調(diào)查金黃色葡萄球菌的抗生素敏感性替加環(huán)素與亞胺培南/西司他丁治療HAP對(duì)照研究311研究311注冊(cè)研究設(shè)計(jì)方案(N=945)研究目的：比較替加環(huán)素與亞胺培南治療HAP的療效與安全性研究設(shè)計(jì)：多中心，雙盲，隨機(jī)對(duì)照，期臨床研究（2004.3-2006.12）替加環(huán)素 首劑100 mg ；維持50 mg q12h若懷疑銅綠：加用頭孢他定2g Q8h1:1隨機(jī)分組亞胺培南-西司他丁 500 mg1g IV q6h*若懷疑MRSA：加用萬(wàn)古霉素1g Q12h或5-14天亞胺培南

12、-西司他丁劑量取決于體重和肌酐清除率及對(duì)病情的判斷療效判定人群CE人：臨床可評(píng)估人群mITT：修正意向治療人群Freire AT et al. D Microbiolo Infect Dis. 2010; 68(2):14031個(gè)國(guó)家138個(gè)研究機(jī)構(gòu)參與TOC臨床療效：替加環(huán)素VS亞胺培南CE人群未達(dá)到預(yù)期試驗(yàn)終點(diǎn)mITT人群達(dá)到非劣性終點(diǎn)TOC臨床療效：替加環(huán)素VS亞胺培南VAP治愈率：CE人群及mITT人群均未達(dá)到非劣性終點(diǎn)Non-VAP治愈率：CE人群及mITT人群均達(dá)到了非劣性終點(diǎn)VAP未獲得預(yù)期療效的原因分析：病原學(xué)因素體外敏感性并非治療失敗唯一原因！治愈率常常顯著低于體外敏感率，部

13、分體外敏感菌株感染并未獲得理想療效！VAP未獲得預(yù)期療效的原因分析：PK/PD因素VAP中替加環(huán)素清除較快，雖然Cmax變化不大，但AUC明顯降低，導(dǎo)致AUC/MIC下降，無(wú)法獲得理想療效1. PKPD2. 病原學(xué)3. 進(jìn)一步研究方向VAP致病菌的敏感性較低（更高的MIC），AUC/MIC下降，從而導(dǎo)致治療失敗。但部分敏感菌株感染未能獲得理想療效提示致病菌敏感性降低非唯一的治療失敗因素替加環(huán)素為濃度依賴(lài)性抗菌藥物，具備線(xiàn)性藥代動(dòng)力學(xué)特性，增加劑量可能改變VAP的療效 HAP2000研究311研究結(jié)果的啟示：VAP治療中增加TGC劑量的必要性1. Freire AT et al. D Micro

14、biolo Infect Dis. 2010; 68(2):1402.Brink AJ et al. SAMJ,2010,100(6):3883.Crandon JL et al.Antimicrob Agents Chemother. 2009;53:5060替加環(huán)素AUC隨劑量呈線(xiàn)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 Versu

15、s 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 2000 HAP STUDY DESIGNGlobal phase 2, multicenter, randomized, double-blind (third-party unblind

16、ed) study210 subjects in 3 cohorts70% VAP; 30% non-VAPSubjects with Pseudomonas aeruginosa pathogen from the baseline culture 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 therapy2000 HAP INCLUSION C

17、RITERIAHAP 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)VAP in this trial is defined as pneumonia with onset of symptoms 48 hours after endotracheal intubation or 48 hours after extubationPresence of a

18、 new or evolving infiltrate on a chest x-ray filmPresence of fever or leukocytosis2 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 ADMINI

19、STRATION Tigecycline IV*150 mg load then 75 mgq12h Tigecycline IV*200 mg load then 100 q12hImipenem-cilastatin IV*1 g q8h 1:1:1 Randomization *Tigecycline Adjunctive Rx: ceftazidime 2 g IV q8h and aminoglycoside (tobramycin 7mg/kg daily or amikacin 20mg/kg daily) *Imipenem-cilastatin Adjunctive Rx:

20、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 (%)IMIPENEM(N=34)n (%)Age(Mean Yea

21、rs)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 HAP EFFIC

22、ACY (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 Resp

23、onses with 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

24、(57.1)替加環(huán)素大劑量組具有較高的治愈率n=20 n=23 n=24n=35 n=36 n=34大劑量替加環(huán)素治療重癥HAP的優(yōu)勢(shì)尤其明顯13 16 15 7 7 916 17 17 4 6 7大劑量組的不良反應(yīng)并未隨著劑量上升而增加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 (

25、29.4)Discontinued4 (11.1)3 (8.6)3 (8.8)Deaths7 (19.4)3 (8.6)7 (20.6)2000 HAP CONCLUSIONSNumerically 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 for tigecycline替加環(huán)素在治療

26、特殊耐藥菌感染中的應(yīng)用替加環(huán)素對(duì)多藥耐藥腸桿菌科細(xì)菌的累積敏感率Journal of Antimicrobial Chemotherapy (2008) 62, 895904替加環(huán)素治療MDR腸桿菌科細(xì)菌肺部感染的臨床報(bào)道Journal of Antimicrobial Chemotherapy (2008) 62, 895904替加環(huán)素對(duì)MDR-AB的體外抗菌活性AuthorCountry; collectionperiod;Number of isolates% susceptibleMICdistribution(mg/L)MIC90 (mg/L)MezzatestaItaly; 200

27、32004107 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;