tigecyclineintheintensivecareunitwhathasclinicalexperiencetaughtus

1、tigecycline in the intensive care unit: what has clinical experience taught us?jordi rellovall dhebron university hospital,universitat autonoma medical school barcelona, spain 新春愉快，恭喜發(fā)財(cái)striking the balance betweentackling the rise of mdr pathogensreducing antibiotic-related ecological adverse events

2、successful treatment of critically ill patientsaim of my talktreating the patientprotecting the community- target pathogen consider pd profile tailored spectrum- increase eradication minimize resistance reduce abx duration exposureoptimising anti-infective therapy: time to treatmentadequate antimicr

3、obial therapy should start within 1 hour0-0.490.5-0.991-1.992-2.993-3.994-4.995-5.996-8.999-11.9912-23.9924-35.99360.00.20.40.60.81.0fractionof totalpatientstime from hypotension onset (h)survival fractioncumulative effective antimicrobial initiationkumar a et al. crit care med 2006;34:1589-96rello

4、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 med 2003;31:27422751; valls et al. chest 2003;123:16151624mortality associated with appropriate t

5、herapy in patients with serious infectionswhy do we see continued mortality? continuation of terminal process delay in the initiation of therapy inadequate dose / exposuren=80, apache ii 22, 71% on mvthe blood concentration of meropenem 1g initial dosage for sepsis and septic shock appear adequate27

6、% of the patients had aki, and despite having been prescribed with standard non-aki initial doses, most of them had suboptimal concentrations after the first dose.optama: northern china(shenyang, beijing, tianjin and jinan)cefoperazone/sulbactam 1g q12hcefotaxime 2 g q12hceftriaxone 2 g q24hceftazid

7、ime 2 g q12hciprofloxacin 0.4 g q12hciprofloxacin 0.4 g q8himipenem 0.5 g q8himipenem 1 g q8hmeropenem 0.5 g q8hmeropenem 1 g q8hregimenec (n=113)kp (n=92)ab (n=67)psa (n=89)probability of target attainment (%)27.831.638.084.59.811.597.198.199.399.334.440.345.478.341.041.098.499.899.7100.015.82.410.

8、339.46.217.266.078.881.484.98.53.14.559.536.847.544.361.067.582.1ec = e coli; kp = k pneumoniae; ab = a baumannii; psa = p aeruginosa; pip/taz = piperacillin/tazobactamwang h, et al. international journal of antimicrobial agents 2007;30:452-457.significantly lower hospital mortality (19.3% vs 36.6%;

9、 p=0.014)but there was a 277.7% increase in cefepime useeffects of using paradigmatic treatment strategies26.6% reduction in use of 3rd-generation cephalosporinssignificant decrease in reduced susceptibility of gram-negative bacilli to 3rd-generation cephalosporinsis associated with lower mortality

10、rate by multivariate logistic regression analysisdu b et al. crit care med 2003;31:1088-93tigecyclineapproved by emea in may 2006 for complicated intra-abdominal infection (ciai) and complicated skin and soft tissue infection (cssti) 500mg q12htigecycline inhibits protein synthesis by binding to the

11、 30s-ribosomal subunit and preventing peptide chain elongationin vitro activity against gram-positive bacteria gram-negative bacteria anaerobes atypical bacteria includingmrsa and vreesblszhanel gg et al. expert rev anti infect ther 2006;4:9-25; noskin ga.clin infect dis 2005;41:s303-14; edelstein p

12、h et al. antimicrob agents chemother 2003;47:533-40 mrsa, methicillin-resistant staphylococcus aureus; vre, vancomycin-resistant enterococci; esbl, extended-spectrum beta-lactamasetigecycline clinical trials2 phase iii, double-blind, randomised clinical trials assessed tigecycline in patients withci

13、ai compared withimipenem-cilastatin(500 / 500 mg) q6h ivcssti compared with vancomycin-aztreonam (1 / 2 g) q12h ivtigecycline was administered at an initial dose of 100 mg followed by 50 mg q12h ivfor up to 14 daysbabinchak t et al. clin infect dis 2005;41:s354-67; ellis-grosse ej et al. clin infect

14、 dis 2005;41:s341-53ciai, complicated intra-abdominal infection; cssti, complicated skin and soft tissue infection tigecycline vs imipenem-cilastatin: complicated intra-abdominal infection clinical cure ratesbabinchak t et al. clin infect dis 2005;41:s354-67 mitt, modified intent to treat; ce, clini

15、cally evaluableclinical mittce patientsimipenem-cilastatintigecyclineciai: microbiological eradication babinchak t et al. clin infect dis 2005;41:s354-67patients (%)mssa, methicillin-susceptible staphylococcus aureustigecycline vs vancomycin-aztreonam: complicated skin and soft tissue infection clin

16、ical cure rates ellis-grosse ej et al. clin infect dis 2005;41:s341-53clinical mittce patientsvancomycin-aztreonamtigecyclinecssti: microbiological eradication patients (%) ellis-grosse ej et al. clin infect dis 2005;41:s341-53tigecycline in the icu only a few investigations have been undertaken ass

17、essing tigecycline in critically ill patients these include early experience with tigecycline for vap and bacteremia caused by mdr acinetobacter baumannii tigecycline for the treatment of patients with severe sepsis or septic shock in a surgical icu serious infections caused by mdr gram-negative pat

18、hogens treated with tigecyclineschafer 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;46:567-70icu, intensive care unit; mdr, multi-drug resistant spanish clinical experience with tigecycline in critically ill pa

19、tients113 patients a multicentre retrospective observational study13 spanish icus baseline characteristicspatientstotal, n (%)sex, n (%) male femalemedian (range) age, years apache, mean sd sofa points, mean sd diagnostic group, n (%) medical surgical traumaunderlying disease, n (%) hypertension can

20、cer copd diabetes mellitus113 (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 diseaserisk factorsrisk factor prior antibiotics, n (%)mechanical ventilation, n (%)septic shock, n (%)renal dysfunction, n (%)continuous ren

21、al replacement therapy, n (%)current icu stay, median (ir) days113 (100)89 (79)52 (46)45 (40) 23 (20)16 (8; 30) patient outcomeoutcome 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 wit

22、h tigecycline other antibiotics was 16.8% (n=19)icu mortality n=46 (41%)hospital mortality n=61 (54%)duration of icu stay prior to tigecyclinefrequencydays020406080100reasons for usereasonbroad spectrumcarbapenem resistanceavoid colistin toxicityadverse clinical course (rescue therapy)allergy to bet

23、a-lactamspatients, n (%) 39 (35)43 (38)15 (13)31 (27)10 (9)combination tygacil plusantibioticcombination therapycolistin carbapenemsaminoglycosidesquinoloneslinezolidglycopeptidesantifungalspatients, n (%) 96 (85)35 (31)26 (23)16 (14)15 (13)15 (13)7 (6)39 (35)a large proportion of patients received

24、combination therapytigecycline: indications and aetiologytigecycline: clinical experiencepatients %*tigecycline is only approved for ciai and cssti*tigecycline is not approved for cap/haplung*ciai*cssti*bacteraemiaotherciai, complicated intra-abdominal infection; cssti, complicated skin and soft tis

25、sue infection adverse events in critically ill patientsadverse eventnausea and / or vomitingincreased liver enzymes, bilirubin and alkaline phosphatase diarrhoearesistance (colonisation or infection)p. aeruginosasuper-infectionlungbacteraemia / catheterpatients, n (%)5 (4)1 (0.9)1 (0.9)23 (20) 18 (1

26、6)30 (27)15 (13)10 (9)adverse eventstigecycline was well toleratedmild to moderate in severitymost common were nausea and vomitingbabinchak t et al. clin infect dis 2005;41:s354-67; ellis-grosse ej et al. clin infect dis 2005;41:s341-53pharmacodynamic goal not achieved in 16/19 (84%)8/16 (50%): orga

27、nism 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 breakpointmohr jf, et al. diagn micro infect dis 2004;48:125-30.do we deliver effective doses in critically ill patients: empir

28、ic therapypathophysiology of mods: effects on drug vd and clsepsis-mediated 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-l

29、oaded” dosing and especially applies to hydrophilic drugs whose vd dramatically 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 fac

30、tor to consider for initial dosingulldemolins m, roberts j, lipman j, rello j. chest 2011 vd changing in icu sepsis patientjoao goncalves-pereira ,et al.critical care 2011, 15:r206 effect of sirs on volume of distributionulldemolins & rello. clin pharm biotechnol 2011 clinical efficacy of two high t

31、igecycline 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.aac, published online ahead of print on 28 january 20132000 hap study designng

32、lobal 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 pop

33、ulation at the toc assessment, 10 to 21 days post therapy2000 hap study design 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

34、 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 days10-21 days after ldotldotvisittocvisitldot: last dose of therapy; toc: test of curetest of curewhen dosage raised, efficacy improvescure rate%severe pts benefit most from dosage escalationcure rate%safety profiles remain goo