tigecycline in the intensive care unit what has clinical experience taught us 课件

1、 Tigecycline in the intensive care unit: what has clinical experience taught us? Jordi Rello Vall dHebron University Hospital, Universitat Autonoma Medical School Barcelona, Spain 新春愉快，恭喜发财 Striking the balance between Tackling the rise of MDR pathogens Reducing antibiotic- related ecological advers

2、e events Successful treatment of critically ill patients Aim of my talk 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 Opt

3、imising anti-infective therapy: time to treatment Adequate antimicrobial therapy should start within 1 hour 0.0 0.2 0.4 0.6 0.8 1.0 Fraction of total patients Time from hypotension onset (h) Survival fraction Cumulative effective antimicrobial initiation Kumar A et al. Crit Care Med 2019;34:1589-96

4、Luna et al 0 20 40 60 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 2019;156:196200; Alvarez-Lerma. Intensive Care Med 2019;22:387394 Ibrahim et al. Chest 2000;118:146155; Luna et al. Chest 2019;111:676685 Garna

5、cho-Montero et al. Crit Care Med 2019;31:27422751; Valls et al. Chest 2019;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 / exp

6、osure 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 concentrations. Critical Care 2019;14(4):126-135 ?The blood concentration of Meropenem 1g initial dosage for sepsis and septic shock appear

7、 adequate ?27% 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 q12h Cefotaxime 2 g q12h Ceftriaxon

8、e 2 g q24h Ceftazidime 2 g q12h Ciprofloxacin 0.4 g q12h Ciprofloxacin 0.4 g q8h Imipenem 0.5 g q8h Imipenem 1 g q8h Meropenem 0.5 g q8h Meropenem 1 g q8h Regimen EC (n=113) KP (n=92) AB (n=67) PSA (n=89) Probability of target attainment (%) 27.8 31.6 38.0 84.5 9.8 11.5 97.1 98.1 99.3 99.3 34.4 40.3

9、 45.4 78.3 41.0 41.0 98.4 99.8 99.7 100.0 15.8 2.4 10.3 39.4 6.2 17.2 66.0 78.8 81.4 84.9 8.5 3.1 4.5 59.5 36.8 47.5 44.3 61.0 67.5 82.1 EC = E coli ; KP = K pneumoniae; AB = A baumannii ; PSA = P aeruginosa; pip/taz = piperacillin/tazobactam Wang H, et al. International Journal of Antimicrobial Age

10、nts 2019;30:452-457. Tigecycline Approved by EMEA in May 2019 for complicated intra-abdominal infection (cIAI) and complicated skin and soft tissue infection (cSSTI) 500mg q12h Tigecycline inhibits protein synthesis by binding to the 30S-ribosomal subunit and preventing peptide chain elongation In v

11、itro activity against Gram-positive bacteria Gram-negative bacteria Anaerobes Atypical bacteria Including MRSA and VRE ESBLs Zhanel GG et al. Expert Rev Anti Infect Ther 2019;4:9-25; Noskin GA. Clin Infect Dis 2019;41:S303-14; Edelstein PH et al. Antimicrob Agents Chemother 2019;47:533-40 MRSA, meth

12、icillin-resistant Staphylococcus aureus; VRE, vancomycin-resistant enterococci; ESBL, extended-spectrum beta-lactamase Tigecycline in the ICU Only a few investigations have been undertaken assessing tigecycline in critically ill patients These include early experience with tigecycline for VAP and ba

13、cteremia 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 pathogens treated with tigecycline Schafer JJ et al. Pharmacotherapy 2019;27:980-7; Swoboda S et al. J Antimicr

14、ob Chemother 2019;61:729-33; Anthony KB et al. Clin Infect Dis 2019;46:567-70 ICU, intensive care unit; MDR, multi-drug resistant Spanish clinical experience with tigecycline in critically ill patients 113 patients A multicentre retrospective observational study 13 Spanish ICUs Baseline characterist

15、ics Patients Total, n (%) Sex, n (%) Male Female Median (range) age, years Apache, mean SD SOFA points, mean SD Diagnostic group, n (%) Medical Surgical Trauma Underlying disease, n (%) Hypertension Cancer COPD Diabetes mellitus 113 (100) 80 (71) 33 (29) 61 (44-72) 19.6 7.3 7.9 3.8 64 (57) 36 (32) 1

16、3 (12) 52 (46) 28 (25) 24 (21) 15 (13) COPD, chronic obstructive pulmonary disease Risk factors Risk factor Prior antibiotics, n (%) Mechanical ventilation, n (%) Septic shock, n (%) Renal dysfunction, n (%) Continuous renal replacement therapy, n (%) Current ICU stay, median (IR) days 113 (100) 89

17、(79) 52 (46) 45 (40) 23 (20) 16 (8; 30) Patient outcome Outcome 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

18、=46 (41%) Hospital mortality n=61 (54%) Duration of ICU stay prior to tigecycline F r e q u e n c y Days 0 20 40 60 80 100 Reasons for use Reason Broad spectrum Carbapenem resistance Avoid colistin toxicity Adverse clinical course (rescue therapy) Allergy to beta-lactams Patients, n (%) 39 (35) 43 (

19、38) 15 (13) 31 (27) 10 (9) Combination tygacil plus Antibiotic Combination therapy Colistin Carbapenems Aminoglycosides Quinolones Linezolid Glycopeptides Antifungals 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 the

20、rapy Tigecycline: indications and aetiology Tigecycline: clinical experience Patients % *Tigecycline 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

21、infection Adverse events in critically ill patients Adverse event Nausea and / or vomiting Increased liver enzymes, bilirubin and alkaline phosphatase Diarrhoea Resistance (colonisation or infection) P. aeruginosa Super-infection Lung Bacteraemia / catheter Patients, n (%) 5 (4) 1 (0.9) 1 (0.9) 23 (

22、20) 18 (16) 30 (27) 15 (13) 10 (9) Pathophysiology of MODS: Effects on Drug Vd and CL Sepsis-mediated altered blood flow may have important effects on drug delivery to tissues High frequency of Renal Dysfunction and Hepatic Dysfunction Initial phase of sepsis, increased Vd and CL are common, and dos

23、ing must be adjusted “front -loaded” dosing and especially applies to hydrophilic drugs whose Vd dramatically increases in this scenario Vd of hydrophilic antibiotics is increased in obese patients due to the increased interstitial fluid, connective tissue, and muscle mass also present in obesity. T

24、herefore, obesity must be a factor to consider for initial dosing Ulldemolins M, Roberts J, Lipman J, Rello J. CHEST 2019 Vd changing in ICU sepsis patient Joao Goncalves-Pereira ,et al.Critical Care 2019, 15:R206 Effect of SIRS on Volume of distribution Ulldemolins 30% non-VAP ?Subjects with Pseudo

25、monas aeruginosa pathogen from the baseline culture were withdrawn from the study ?The primary efficacy endpoint is the clinical response in the CE population at the TOC assessment, 10 to 21 days post therapy 2000 HAP Study Design Tigecycline IV* 150 mg load then 75 mgq12h Tigecycline IV* 200 mg loa

26、d then 100 q12h Imipenem-cilastatin IV* 1 g q8h 1 : 1 : 1 R a n d o m i z a t i o n ? *Tigecycline Adjunctive Rx: ceftazidime 2 g IV q8h and aminoglycoside (tobramycin 7mg/kg daily or amikacin 20mg/kg daily) ? *Imipenem-cilastatin Adjunctive Rx: vancomycin 15 mg/kg IV q12 and aminoglycoside(tobramyc

27、in 7mg/kg daily or amikacin 20 mg/kg daily) 7-14 days 10-21 days after LDOT LDOT Visit TOC Visit LDOT: Last dose of therapy; TOC: test of cure Test of cure When dosage raised, Efficacy Improves Cure Rate% Severe pts benefit most from dosage escalation Cure Rate% Safety Profiles Remain Good TGC 75 MG (N = 36) n (%) TGC 100MG (N = 35) n (%) IMIPENEM (N=34) n (%) TEAEs 31 (86.1) 27 (77.1) 28 (82.4) Nausea 2 (5.6) 4 (11.4) 1 (2.9) Vomiting 4 (11.1) 2 (5.7) 4 (11.8) SAEs 12 (33.3) 9 (25.7) 10 (29.4) Discontinued 4 (11.1) 3 (8.6) 3 (8.8) Deaths 7 (19.4) 3 (8.6) 7 (