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, Friedhelm Bach, Thorsten Brenner, Hendrik Bracht, Alexander Brinkmann, Thorsten Annecke, Andreas Höhn, Markus A. 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, Anke Braune, Karsten Schmidt, J. Motsch, Nadine Pinder, Daniel Richter, Peter Schlattmann, Andreas Ameln-Mayerhofer von, Markus Schappacher, Thomas Fuchs, Anka C. Röhr, Max Kurlbaum, Oliver Schreiner, Lars Hüter, Matthias Gründling, Stefan Angermair, Maria Deja, Frank Bloos, Sandra Fiedler, Hicham Chkirni
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.