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Randomized Controlled Trial
. 2022 Mar;48(3):311-321.
doi: 10.1007/s00134-021-06609-6. Epub 2022 Feb 1.

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

Stefan Hagel  1   2 , Friedhelm Bach  3 , Thorsten Brenner  4   5 , Hendrik Bracht  6 , Alexander Brinkmann  7 , Thorsten Annecke  8   9 , Andreas Hohn  8   10 , Markus Weigand  5 , Guido Michels  11 , Stefan Kluge  12 , Axel Nierhaus  12 , Dominik Jarczak  12 , Christina König  12 , Dirk Weismann  13 , Otto Frey  14 , Dominic Witzke  3 , Carsten Müller  15 , Michael Bauer  16 , Michael Kiehntopf  17 , Sophie Neugebauer  18   17 , Thomas Lehmann  19 , Jason A Roberts  20   21   22 , Mathias W Pletz  23   18 ; TARGET Trial Investigators
Collaborators, Affiliations
Randomized Controlled Trial

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

Stefan Hagel et al. Intensive Care Med. 2022 Mar.

Erratum in

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.

Keywords: Sepsis; Therapeutic drug monitoring; β-Lactams.

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Conflict of interest statement

SH report grants from the Federal Ministry of Education and Research (BMBF), lecture fees from Pfizer, MSD, InfectoPharm, Advanz and Philips, support for attending meetings from Pfizer and Advanz. AB reports lecture fees from MSD Sharp & Dohme GmbH, Pfizer Pharma GmbH, Fresenius Medical Care (FMC), Labor Volkmann (Karlsruhe). TB reports lecture fees from CSL Behring GmbH, Schöchl medical education GmbH, Biotest AG, Baxter Deutschland GmbH, Boehringer Ingelheim Pharma GmbH, Astellas Pharma GmbH, B. Braun Melsungen AG, MSD Sharp & Dohme GmbH, support for participation in a Data Safety and Monitoring Board for Baxter Deutschland GmbH and and research funding from Deutsche Forschungsgemeinschaft (DFG), Dietmar Hopp Stiftung, Stiftung Universitätsmedizin Essen. Heidelberger Stiftung Chirurgie, Innovationsfonds des Gemeinsamen Bundesausschusses (G-BA). SN reports grants from the Center for Sepsis Control and Care (CSCC) by the Ministry of Education and Research (BMBF), Grant-no. 01EO1502. SK reports grants from Ambu, Daiichi Sankyo, ETView Ltd, Fisher & Paykel, Pfizer and Xenios, consulting fees from Bayer, Fresenius, Gilead, MSD and Pfizer, lecture fees from Astra, C.R.Bard, Baxter, Biotest, Cytosorbents, Daiichi Sankyo, Fresenius, Gilead, Mitsubishi Tanabe Pharma, MSD, Pfizer, Philips and Zoll. MW reports lecture fees from MSD, Gilead, Shionogi, Pfizer, support for participation in a Data Safety and Monitoring Board for MSD, Gilead, Shionogi, Eumedica, Biotest. All other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Flowchart of patient recruitment, inclusion and randomization. TZP = piperacillin/tazobactam; ICU = intensive care unit
Fig. 2
Fig. 2
Kaplan–Meier analysis. Overall survival rates at day 28 among patients with piperacillin TDM-guided therapy (TDM) and patients in the control group (control). Number of patients at risk for each group included in the analysis along the x-axis scale
Fig. 3
Fig. 3
Attainment of piperacillin target concentration in percent up to day 5 after randomization in patients with piperacillin TDM-guided therapy (TDM, right columns) and patients in the control group (control, left column). Within range (green), above range (blue) or below range (red) per the target range on a given day
See this image and copyright information in PMC

Comment in

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