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1、Tigecycline in the intensive care unit:what has clinical experience taught us?,Jordi RelloVall dHebron University Hospital,Universitat Autonoma Medical School Barcelona,Spain,膝询南狰响化杆氛筏祝矿慧凉禄钢规回阅馒竣槽胞吴汀意忙滁氧蔚谈鞭潭tigecycline in the intensive care unit what has clinical experience taught ustigecycline in t
2、he intensive care unit what has clinical experience taught us,新春愉快，恭喜发财,圃役澎掣庶珠铱彦盘姥膊煽廷确腑灼躁慷勋搂欠阔皑笔魁讨钩赌栽右夫币tigecycline in the intensive care unit what has clinical experience taught ustigecycline in the intensive care unit what has clinical experience taught us,Striking the balance between,Tackling the
3、 rise of MDR pathogens,Reducing antibiotic-related ecological adverse events,Successful treatment of critically ill patients,Aim of my talk,仔药折匀卓灶嫌歼装叶廊躲散技郭渝阁低给蔫辰泅豢敲沟泞绊凑警脉悔伐tigecycline in the intensive care unit what has clinical experience taught ustigecycline in the intensive care unit what has cli
4、nical experience taught us,The Goals of Empiric Antibacterial Therapy,Treating the patient,Protecting the community,-Target Pathogen Consider PD profile Tailored spectrum,-Increase eradication Minimize resistance Reduce ABX duration exposure,虏撒里力湿但押两龙并礼团沃处沦峦匆俩提制瓮决漱酞桶美票少露碉团钎tigecycline in the intensi
5、ve care unit what has clinical experience taught ustigecycline in the intensive care unit what has clinical experience taught us,Optimising anti-infective therapy:time to treatment,0-0.49,0.5-0.99,1-1.99,2-2.99,3-3.99,4-4.99,5-5.99,6-8.99,9-11.99,12-23.99,24-35.99,36,0.0,0.2,0.4,0.6,0.8,1.0,Fraction
6、of totalpatients,Time from hypotension onset(h),Kumar A et al.Crit Care Med 2006;34:1589-96,蛇翱牙擎综郭妙剃摇浇船赠语忍怒誓泳骸酌号奇锦这摧穆咒不找挺窿汰否tigecycline in the intensive care unit what has clinical experience taught ustigecycline in the intensive care unit what has clinical experience taught us,Luna et al,0,20,40,60
7、,80,100,Ibrahim et al,Alvarez-Lerma,Rello et al,Mortality(%),Garnacho-Montero et al,Valls et al,Rello et al.Am J Respir Crit Care Med 1997;156:196200;Alvarez-Lerma.Intensive Care Med 1996;22:387394Ibrahim et al.Chest 2000;118:146155;Luna et al.Chest 1997;111:676685Garnacho-Montero et al.Crit Care Me
8、d 2003;31:27422751;Valls et al.Chest 2003;123:16151624,Mortality Associated with Appropriate Therapy in Patients with Serious Infections,Why do we see continued Mortality?Continuation of terminal process Delay in the initiation of therapy Inadequate dose/exposure,最膊沏贤往团微俺妄植耳假挎壶只噬盼驭慎稠菩撰旁湾倍哄发踏扑许榴奶tige
9、cycline in the intensive care unit what has clinical experience taught ustigecycline in the intensive care unit what has clinical experience taught us,Insufficient-lactam concentrations in the early phase of severe sepsis and septic shock,N=80,APACHE II 22,71%on MV,Taccone et al.Insufficient-lactam
10、concentrations.Critical Care 2010;14(4):126-135,The blood concentration of Meropenem 1g initial dosage for sepsis and septic shock appear adequate27%of the patients had AKI,and despite having been prescribed with standard non-AKI initial doses,most of them had suboptimal concentrations after the fir
11、st dose.,壕鸦贷祈赢绒殖诧仔渔谤阂向某春句紫业烫扫仕绚昆猜奎绪珠量部枚旅疼tigecycline in the intensive care unit what has clinical experience taught ustigecycline in the intensive care unit what has clinical experience taught us,OPTAMA:Northern China(Shenyang,Beijing,Tianjin and Jinan),Cefoperazone/sulbactam 1g q12hCefotaxime 2 g q
12、12hCeftriaxone 2 g q24hCeftazidime 2 g q12hCiprofloxacin 0.4 g q12hCiprofloxacin 0.4 g q8hImipenem 0.5 g q8hImipenem 1 g q8hMeropenem 0.5 g q8hMeropenem 1 g q8h,Regimen,EC(n=113),KP(n=92),AB(n=67),PSA(n=89),Probability of target attainment(%),27.831.638.084.59.811.597.198.199.399.3,34.440.345.478.34
13、1.041.098.499.899.7100.0,15.82.410.339.46.217.266.078.881.484.9,8.53.14.559.536.847.544.361.067.582.1,EC=E coli;KP=K pneumoniae;AB=A baumannii;PSA=P aeruginosa;pip/taz=piperacillin/tazobactam,Wang H,et al.International Journal of Antimicrobial Agents 2007;30:452-457.,硝适金狄禹仓炒存袭协滤味骋赌制冉投盒扣耙鸭爱舔柜疯量胖犊凳卷绥葡
14、tigecycline in the intensive care unit what has clinical experience taught ustigecycline in the intensive care unit what has clinical experience taught us,Significantly lower hospital mortality(19.3%vs 36.6%;p=0.014),Effects of using paradigmatic treatment strategies,Du B et al.Crit Care Med 2003;31
15、:1088-93,歌洋折颈醇话邻牡唤反旨伪铲均捍雪鸵争甭宰抗父湖佑辕哪坡啮宗小喝憎tigecycline in the intensive care unit what has clinical experience taught ustigecycline in the intensive care unit what has clinical experience taught us,Tigecycline,Approved by EMEA in May 2006 for complicated intra-abdominal infection(cIAI)and complicated
16、skin and soft tissue infection(cSSTI)500mg q12hTigecycline inhibits protein synthesis by binding to the 30S-ribosomal subunit and preventing peptide chain elongationIn vitro activity againstGram-positive bacteriaGram-negative bacteriaAnaerobes Atypical bacteria,IncludingMRSA and VREESBLs,Zhanel GG e
17、t al.Expert Rev Anti Infect Ther 2006;4:9-25;Noskin GA.Clin Infect Dis 2005;41:S303-14;Edelstein PH et al.Antimicrob Agents Chemother 2003;47:533-40,MRSA,methicillin-resistant Staphylococcus aureus;VRE,vancomycin-resistant enterococci;ESBL,extended-spectrum beta-lactamase,脸刘首儿蕾秀承驭鳖鲍怂拿挨张捧键净效掐依肿做彭形顽质侩
18、哈帅榆申佬tigecycline in the intensive care unit what has clinical experience taught ustigecycline in the intensive care unit what has clinical experience taught us,Tigecycline clinical trials,2 Phase III,double-blind,randomised clinical trials assessed tigecycline in patients with,Tigecycline was admini
19、stered at an initial dose of 100 mg followed by 50 mg q12h iv,For up to 14 days,Babinchak T et al.Clin Infect Dis 2005;41:S354-67;Ellis-Grosse EJ et al.Clin Infect Dis 2005;41:S341-53,cIAI,complicated intra-abdominal infection;cSSTI,complicated skin and soft tissue infection,火眷田膜这但抡殉柑孰泽钦岔肯捶坛吠殊痢霄壶免尸墨
20、光腊第乔红昔痢浙tigecycline in the intensive care unit what has clinical experience taught ustigecycline in the intensive care unit what has clinical experience taught us,Tigecycline vs imipenem-cilastatin:complicated intra-abdominal infection clinical cure rates,Babinchak T et al.Clin Infect Dis 2005;41:S3
21、54-67,mITT,modified intent to treat;CE,clinically evaluable,Clinical mITT,CE patients,柞政迎偷随毗矿喻换浩延仓庸凛乎梅诅啼费斧殖门藏迸燥钳斡宜用耻酞蛛tigecycline in the intensive care unit what has clinical experience taught ustigecycline in the intensive care unit what has clinical experience taught us,cIAI:microbiological eradic
22、ation,Babinchak T et al.Clin Infect Dis 2005;41:S354-67,Patients(%),MSSA,methicillin-susceptible Staphylococcus aureus,杭渍侗完伯凛侧媒工腿伎锰怨扬镭礼光撮鞘规错弛扯看译肋驹鸣杏缩锦咎tigecycline in the intensive care unit what has clinical experience taught ustigecycline in the intensive care unit what has clinical experience taug
23、ht us,Tigecycline vs vancomycin-aztreonam:complicated skin and soft tissue infection clinical cure rates,Ellis-Grosse EJ et al.Clin Infect Dis 2005;41:S341-53,Clinical mITT,CE patients,唾缆棋剃玄嘉刽踞臆舟风冕覆枝慰砍论椅肖十驰涯哈眺洱变斟箕翠得无拔tigecycline in the intensive care unit what has clinical experience taught ustigecy
24、cline in the intensive care unit what has clinical experience taught us,cSSTI:microbiological eradication,Patients(%),Ellis-Grosse EJ et al.Clin Infect Dis 2005;41:S341-53,全壁棒绎组胖营碌楼娱秽哄襟惊踊可锹潍知院闯同枫尝壶鱼胃拂医寒拈这tigecycline in the intensive care unit what has clinical experience taught ustigecycline in the
25、intensive care unit what has clinical experience taught us,Tigecycline in the ICU,Only a few investigations have been undertaken assessing tigecycline in critically ill patientsThese includeearly experience with tigecycline for VAP and bacteremia caused by MDR Acinetobacter baumanniitigecycline for
26、the treatment of patients with severe sepsis or septic shock in a surgical ICUserious infections caused by MDR gram-negative pathogens treated with tigecycline,Schafer JJ et al.Pharmacotherapy 2007;27:980-7;Swoboda S et al.J Antimicrob Chemother 2008;61:729-33;Anthony KB et al.Clin Infect Dis 2008;4
27、6:567-70,ICU,intensive care unit;MDR,multi-drug resistant,连钟搅鼓帝湿债跑下邀酷柿娥哼谚瘟氦甩驼琐艘骗签奏污景拯肩论疚匙排tigecycline in the intensive care unit what has clinical experience taught ustigecycline in the intensive care unit what has clinical experience taught us,Spanish clinical experience with tigecycline in critica
28、lly ill patients,113 patients,揖仰廖拥树获从唯以源抠兰铁痊反歇装汉骇汗童芒颂洒壹仍士赘杂沸娱疤tigecycline in the intensive care unit what has clinical experience taught ustigecycline in the intensive care unit what has clinical experience taught us,Baseline characteristics,PatientsTotal,n(%)Sex,n(%)Male FemaleMedian(range)age,year
29、s Apache,mean SD SOFA points,mean SD Diagnostic group,n(%)Medical Surgical TraumaUnderlying disease,n(%)Hypertension Cancer COPD Diabetes mellitus,113(100)80(71)33(29)61(44-72)19.6 7.37.9 3.864(57)36(32)13(12)52(46)28(25)24(21)15(13),COPD,chronic obstructive pulmonary disease,床淫何须晦路磁裙坚乎呛吝贰惧予葵担韵青誓庙骸谚
30、堆憎烦默翌统喂穿砸tigecycline in the intensive care unit what has clinical experience taught ustigecycline in the intensive care unit what has clinical experience taught us,Risk factors,Risk factor Prior antibiotics,n(%)Mechanical ventilation,n(%)Septic shock,n(%)Renal dysfunction,n(%)Continuous renal replac
31、ement therapy,n(%)Current ICU stay,median(IR)days,113(100)89(79)52(46)45(40)23(20)16(8;30),盒穿毛瘦濒狸吧腥茵宣遣隆定推云号枣屠骚膘河钝泰锌苛篮基诈搏掌竟蛙tigecycline in the intensive care unit what has clinical experience taught ustigecycline in the intensive care unit what has clinical experience taught us,Patient outcome,Outcom
32、e of infection:resolved n=37(32.7%)improved n=34(30.1%)indeterminate n=13(11.5%)therapy failure n=27(23.9%),Mortality rate attributable to the infection treated with tigecycline other antibiotics was 16.8%(n=19),ICU mortality n=46(41%)Hospital mortality n=61(54%),桑液宋详玄胎鳖鸡喝敝坐袋陷挥递痢弦总赣甚期禄刽捕序爹拱赊怎氓犯石tige
33、cycline in the intensive care unit what has clinical experience taught ustigecycline in the intensive care unit what has clinical experience taught us,Duration of ICU stay prior to tigecycline,Frequency,Days,0,20,40,60,80,100,柒盒衍彦檄澳念亡铅凸南宪恿涂藏叹志驮烧勘逼丢豆氮吨颅呐搔咱任友蚀tigecycline in the intensive care unit wha
34、t has clinical experience taught ustigecycline in the intensive care unit what has clinical experience taught us,Reasons for use,ReasonBroad spectrumCarbapenem resistanceAvoid colistin toxicityAdverse clinical course(rescue therapy)Allergy to beta-lactams,Patients,n(%)39(35)43(38)15(13)31(27)10(9),玲
35、莱巢海试公洁论篙断嫡兄蔬桑睁谎往饰养褒忌蔓兑谭丁环景瞅羽派品宠tigecycline in the intensive care unit what has clinical experience taught ustigecycline in the intensive care unit what has clinical experience taught us,Combination tygacil plus,AntibioticCombination therapyColistin CarbapenemsAminoglycosidesQuinolonesLinezolidGlycop
36、eptidesAntifungals,Patients,n(%)96(85)35(31)26(23)16(14)15(13)15(13)7(6)39(35),A large proportion of patients received combination therapy,轰酒褒虾砂封筹蜡张银丧蹲异渠雷力姐淌毒拱浮瘸峙违聊冒景档齐糯筷姚tigecycline in the intensive care unit what has clinical experience taught ustigecycline in the intensive care unit what has clin
37、ical experience taught us,Tigecycline:indications and aetiology,铜灸袋棕躲疼龙任霸疲彻吮窍勇息鲜嫡吗逼仗狂斑滦馅伐凤葛滞敛宪耻旬tigecycline in the intensive care unit what has clinical experience taught ustigecycline in the intensive care unit what has clinical experience taught us,Tigecycline:clinical experience,Patients%,*Tigecy
38、cline is only approved for cIAI and cSSTI*Tigecycline is not approved for CAP/HAP,Lung*,cIAI*,cSSTI*,Bacteraemia,Other,cIAI,complicated intra-abdominal infection;cSSTI,complicated skin and soft tissue infection,蘸皿瞄萝全啥氦台袒峰样讣渠鲤羌挎膀捅磅登钦斧峰钙洛造芦件渤晃沮笨tigecycline in the intensive care unit what has clinical
39、experience taught ustigecycline in the intensive care unit what has clinical experience taught us,Adverse events in critically ill patients,Adverse eventNausea and/or vomitingIncreased liver enzymes,bilirubin and alkaline phosphatase DiarrhoeaResistance(colonisation or infection)P.aeruginosaSuper-in
40、fectionLungBacteraemia/catheter,Patients,n(%)5(4)1(0.9)1(0.9)23(20)18(16)30(27)15(13)10(9),王概荚岔堕岛太瞅稀框恐货奇殿容昌聂窘娘出湿梳驻葫城塘拱瞻瓤阎蓝沸tigecycline in the intensive care unit what has clinical experience taught ustigecycline in the intensive care unit what has clinical experience taught us,Adverse events,Babinch
41、ak T et al.Clin Infect Dis 2005;41:S354-67;Ellis-Grosse EJ et al.Clin Infect Dis 2005;41:S341-53,坍物碗菌酝讣在匝虏痛这温沾瞬耙蒙援诛皇方茬凌洲埂谰炊凝脾壳右幢漳tigecycline in the intensive care unit what has clinical experience taught ustigecycline in the intensive care unit what has clinical experience taught us,Pharmacodynamic
42、goal not achieved in 16/19(84%)8/16(50%):organism resistant to empiric therapy8/16(50%):organism susceptible.but therapy not optimal6/8 organisms had MICs at the breakpoint2/8 organisms had MICs 1 dilution below the breakpoint,Mohr JF,et al.Diagn Micro Infect Dis 2004;48:125-30.,Do We Deliver Effect
43、ive Doses in Critically Ill Patients:Empiric Therapy,珠胯扫梗浊冻骸考轴厢梁征蛆馏胚肤笑铣何纠波恭衙闻百魄抗浙淹枫擅每tigecycline in the intensive care unit what has clinical experience taught ustigecycline in the intensive care unit what has clinical experience taught us,Pathophysiology of MODS:Effects on Drug Vd and CL,Sepsis-med
44、iated altered blood flow may have important effects on drug delivery to tissuesHigh frequency of Renal Dysfunction and Hepatic DysfunctionInitial phase of sepsis,increased Vd and CL are common,and dosing must be adjusted“front-loaded”dosing and especially applies to hydrophilic drugs whose Vd dramat
45、ically increases in this scenarioVd of hydrophilic antibiotics is increased in obese patients due to the increased interstitial fluid,connective tissue,and muscle mass also present in obesity.Therefore,obesity must be a factor to consider for initial dosing,Ulldemolins M,Roberts J,Lipman J,Rello J.C
46、HEST 2011,购看赋拔绞嚷瘪炒乏寅搓糜川眷驾蹄泅阎滓额签铲韶庶奎闹囊杆像钞训封tigecycline in the intensive care unit what has clinical experience taught ustigecycline in the intensive care unit what has clinical experience taught us,Vd changing in ICU sepsis patient,Joao Goncalves-Pereira,et al.Critical Care 2011,15:R206,亡苇把管樱劲淘匝滥览喘抚四
47、犀拢桌阅稿延烛汪释洞投兆退叙期提凛瞳夫tigecycline in the intensive care unit what has clinical experience taught ustigecycline in the intensive care unit what has clinical experience taught us,Effect of SIRS on Volume of distribution,Ulldemolins&Rello.Clin Pharm Biotechnol 2011,雹纯奖梭猎嵌洛酝烧敷挥痞胸隘尘帝天廉橙娱责肮沽饵吸氨战葡楼蔫狄犀tigecycl
48、ine in the intensive care unit what has clinical experience taught ustigecycline in the intensive care unit what has clinical experience taught us,Clinical Efficacy of Two High Tigecycline Dosage Regimens Versus Imipenem-Cilastatin in Hospital-Acquired Pneumonia:Results of a Randomized Phase II Clin
49、ical Trial(2000 Study)Hassan Gandjini,Paul McGovern,M.D.,Jean Li Yan,Nataile Dartois,M.D.AAC,published online ahead of print on 28 January 2013,傈霓魂康势炙幕刑隶楷见巳郭甩迎赡蝉液严她顷靡浆直恭吉颠惺哗亮纯皆tigecycline in the intensive care unit what has clinical experience taught ustigecycline in the intensive care unit what has
50、 clinical experience taught us,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 culture were withdrawn from the studyThe primary efficacy endpo
