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01-03-2022 | Septicemia | Original

Effect of therapeutic drug monitoring-based dose optimization of piperacillin/tazobactam on sepsis-related organ dysfunction in patients with sepsis: a randomized controlled trial

Authors: Stefan Hagel, Friedhelm Bach, Thorsten Brenner, Hendrik Bracht, Alexander Brinkmann, Thorsten Annecke, Andreas Hohn, Markus Weigand, Guido Michels, Stefan Kluge, Axel Nierhaus, Dominik Jarczak, Christina König, Dirk Weismann, Otto Frey, Dominic Witzke, Carsten Müller, Michael Bauer, Michael Kiehntopf, Sophie Neugebauer, Thomas Lehmann, Jason A. Roberts, Mathias W. Pletz, the TARGET Trial Investigators

Published in: Intensive Care Medicine | Issue 3/2022

Abstract

Purpose

Insufficient antimicrobial exposure is associated with worse outcomes in sepsis. We evaluated whether therapeutic drug monitoring (TDM)-guided antibiotic therapy improves outcomes.

Methods

Randomized, multicenter, controlled trial from January 2017 to December 2019. Adult patients (n = 254) with sepsis or septic shock were randomly assigned 1:1 to receive continuous infusion of piperacillin/tazobactam with dosing guided by daily TDM of piperacillin or continuous infusion with a fixed dose (13.5 g/24 h if eGFR ≥ 20 mL/min). Target plasma concentration was four times the minimal inhibitory concentration (range ± 20%) of the underlying pathogen, respectively, of Pseudomonas aeruginosa in empiric situation. Primary outcome was the mean of daily total Sequential Organ Failure Assessment (SOFA) score up to day 10.

Results

Among 249 evaluable patients (66.3 ± 13.7 years; female, 30.9%), there was no significant difference in mean SOFA score between patients with TDM (7.9 points; 95% CI 7.1–8.7) and without TDM (8.2 points; 95% CI 7.5–9.0) (p = 0.39). Patients with TDM-guided therapy showed a lower 28-day mortality (21.6% vs. 25.8%, RR 0.8, 95% CI 0.5–1.3, p = 0.44) and a higher rate of clinical (OR 1.9; 95% CI 0.5–6.2, p = 0.30) and microbiological cure (OR 2.4; 95% CI 0.7–7.4, p = 0.12), but these differences did not reach statistical significance. Attainment of target concentration was more common in patients with TDM (37.3% vs. 14.6%, OR 4.5, CI 95%, 2.9–6.9, p < 0.001).

Conclusion

TDM-guided therapy showed no beneficial effect in patients with sepsis and continuous infusion of piperacillin/tazobactam with regard to the mean SOFA score. Larger studies with strategies to ensure optimization of antimicrobial exposure are needed to definitively answer the question.

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Evans L, Rhodes A, Alhazzani W et al (2021) Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. https://doi.org/10.1007/s00134-021-06506-yCrossRefPubMedPubMedCentral

Singer M, Deutschman CS, Seymour CW et al (2016) The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 315:801–810. https://doi.org/10.1001/jama.2016.0287CrossRefPubMedPubMedCentral

Roberts JA, Paul SK, Akova M et al (2014) DALI: defining antibiotic levels in intensive care unit patients: are current—lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis 58:1072–1083. https://doi.org/10.1093/cid/ciu027CrossRefPubMed

Lodise TP, Lomaestro B, Drusano GL (2007) Piperacillin–tazobactam for Pseudomonas aeruginosa infection: clinical implications of an extended-infusion dosing strategy. Clin Infect Dis 44:357–363. https://doi.org/10.1086/510590CrossRefPubMed

Tannous E, Lipman S, Tonna A et al (2020) Time above the MIC of piperacillin–tazobactam as a predictor of outcome in Pseudomonas aeruginosa bacteraemia. Antimicrob Agents Chemother. https://doi.org/10.1128/aac.02571-19CrossRefPubMedPubMedCentral

Taccone FS, Laterre P-F, Dugernier T et al (2010) Insufficient β-lactam concentrations in the early phase of severe sepsis and septic shock. Crit Care 14:R126. https://doi.org/10.1186/cc9091CrossRefPubMedPubMedCentral

Huttner A, Harbarth S, Hope WW et al (2015) Therapeutic drug monitoring of the β-lactam antibiotics: what is the evidence and which patients should we be using it for?: Figure 1. J Antimicrob Chemother. https://doi.org/10.1093/jac/dkv201CrossRefPubMedPubMedCentral

Roberts JA, Abdul-Aziz M-H, Davis JS et al (2016) Continuous versus intermittent β-lactam infusion in severe sepsis. A meta-analysis of individual patient data from randomized trials. Am J Respir Crit Care Med 194:681–691. https://doi.org/10.1164/rccm.201601-0024OCCrossRefPubMed

Carrié C, Legeron R, Petit L et al (2018) Higher than standard dosing regimen are needed to achieve optimal antibiotic exposure in critically ill patients with augmented renal clearance receiving piperacillin–tazobactam administered by continuous infusion. J Crit Care 48:66–71. https://doi.org/10.1016/j.jcrc.2018.08.026CrossRefPubMed

10.

Dhaese SAM, Thooft ADJ, Farkas A et al (2019) Early target attainment of continuous infusion piperacillin/tazobactam and meropenem in critically ill patients: a prospective observational study. J Crit Care 52:75–79. https://doi.org/10.1016/j.jcrc.2019.04.013CrossRefPubMed

11.

Abdul-Aziz MH, Alffenaar J-WC, Bassetti M et al (2020) Antimicrobial therapeutic drug monitoring in critically ill adult patients: a position paper. Intensive Care Med 46:1127–1153. https://doi.org/10.1007/s00134-020-06050-1CrossRefPubMedPubMedCentral

12.

van Lent-Evers NA, Mathôt RA, Geus WP et al (1999) Impact of goal-oriented and model-based clinical pharmacokinetic dosing of aminoglycosides on clinical outcome: a cost-effectiveness analysis. Ther Drug Monit 21:63–73. https://doi.org/10.1097/00007691-199902000-00010CrossRefPubMed

13.

Rybak MJ, Le J, Lodise TP et al (2020) Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: a revised consensus guideline and review by the American Society of Health-system Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists. Clin Infect Dis 71:1361–1364. https://doi.org/10.1093/cid/ciaa303CrossRefPubMed

14.

De Waele JJ, Carrette S, Carlier M et al (2014) Therapeutic drug monitoring-based dose optimisation of piperacillin and meropenem: a randomised controlled trial. Intensive Care Med 40:380–387. https://doi.org/10.1007/s00134-013-3187-2CrossRefPubMed

15.

Machado AS, Oliveira MS, Sanches C et al (2017) Clinical outcome and antimicrobial therapeutic drug monitoring for the treatment of infections in acute burn patients. Clin Ther 39:1649-1657.e3. https://doi.org/10.1016/j.clinthera.2017.06.008CrossRefPubMed

16.

Richter DC, Frey O, Röhr A et al (2019) Therapeutic drug monitoring-guided continuous infusion of piperacillin/tazobactam significantly improves pharmacokinetic target attainment in critically ill patients: a retrospective analysis of four years of clinical experience. Infection 47:1001–1011. https://doi.org/10.1007/s15010-019-01352-zCrossRefPubMed

17.

Roberts JA, Ulldemolins M, Roberts MS et al (2010) Therapeutic drug monitoring of beta-lactams in critically ill patients: proof of concept. Int J Antimicrob Agents 36:332–339. https://doi.org/10.1016/j.ijantimicag.2010.06.008CrossRefPubMed

18.

Sime FB, Roberts MS, Tiong IS et al (2015) Can therapeutic drug monitoring optimize exposure to piperacillin in febrile neutropenic patients with haematological malignancies? A randomized controlled trial. J Antimicrob Chemother 70:2369–2375. https://doi.org/10.1093/jac/dkv123CrossRefPubMed

19.

Reinhart K, Brunkhorst FM, Bone H-G et al (2010) Prevention, diagnosis, therapy and follow-up care of sepsis: 1st revision of S-2k guidelines of the German Sepsis Society (Deutsche Sepsis-Gesellschaft e.V. (DSG)) and the German Interdisciplinary Association of Intensive Care and Emergency Medicine (Deutsche Interdisziplinäre Vereinigung für Intensiv- und Notfallmedizin (DIVI)). Ger Med Sci 8:Doc14. https://doi.org/10.3205/000103CrossRefPubMedPubMedCentral

20.

Hagel S, Fiedler S, Hohn A et al (2019) Therapeutic drug monitoring-based dose optimisation of piperacillin/tazobactam to improve outcome in patients with sepsis (TARGET): a prospective, multi-centre, randomised controlled trial. Trials 20:330. https://doi.org/10.1186/s13063-019-3437-xCrossRefPubMedPubMedCentral

21.

Bergeron N, Dubois MJ, Dumont M et al (2001) Intensive Care Delirium Screening Checklist: evaluation of a new screening tool. Intensive Care Med 27:859–864. https://doi.org/10.1007/s001340100909CrossRefPubMed

22.

European Medicines Agency (2012) Reflection paper for laboratories that perform the analysis or evaluation of clinical trial samples, EMA/INS/GCP/532137/2010

23.

Moreno R, Vincent JL, Matos R et al (1999) The use of maximum SOFA score to quantify organ dysfunction/failure in intensive care. Results of a prospective, multicentre study. Working Group on Sepsis related Problems of the ESICM. Intensive Care Med 25:686–696. https://doi.org/10.1007/s001340050931CrossRefPubMed

24.

Brunkhorst FM, Oppert M, Marx G et al (2012) Effect of empirical treatment with moxifloxacin and meropenem vs meropenem on sepsis-related organ dysfunction in patients with severe sepsis: a randomized trial. JAMA 307:2390–2399. https://doi.org/10.1001/jama.2012.5833CrossRefPubMed

25.

Mouton JW, Muller AE, Canton R et al (2018) MIC-based dose adjustment: facts and fables. J Antimicrob Chemother 73:564–568. https://doi.org/10.1093/jac/dkx427CrossRefPubMed

26.

Felton TW, Ogungbenro K, Boselli E et al (2018) Comparison of piperacillin exposure in the lungs of critically ill patients and healthy volunteers. J Antimicrob Chemother 73:1340–1347. https://doi.org/10.1093/jac/dkx541CrossRefPubMed

Title: Effect of therapeutic drug monitoring-based dose optimization of piperacillin/tazobactam on sepsis-related organ dysfunction in patients with sepsis: a randomized controlled trial
Authors: Stefan Hagel
Friedhelm Bach
Thorsten Brenner
Hendrik Bracht
Alexander Brinkmann
Thorsten Annecke
Andreas Hohn
Markus Weigand
Guido Michels
Stefan Kluge
Axel Nierhaus
Dominik Jarczak
Christina König
Dirk Weismann
Otto Frey
Dominic Witzke
Carsten Müller
Michael Bauer
Michael Kiehntopf
Sophie Neugebauer
Thomas Lehmann
Jason A. Roberts
Mathias W. Pletz
the TARGET Trial Investigators
Publication date: 01-03-2022
Publisher: Springer Berlin Heidelberg
Keywords: Septicemia
Septicemia
Antibiotic
Piperacillin
Published in: Intensive Care Medicine / Issue 3/2022
Print ISSN: 0342-4642
Electronic ISSN: 1432-1238
DOI: https://doi.org/10.1007/s00134-021-06609-6

ACC 2024 Congress

Springer Medicine

Effect of therapeutic drug monitoring-based dose optimization of piperacillin/tazobactam on sepsis-related organ dysfunction in patients with sepsis: a randomized controlled trial

Abstract

Purpose

Methods

Results

Conclusion

ACC 2024 Congress

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

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