Daniel C Richter1, Otto Frey2, Anka Röhr2, Jason A Roberts3,4,5,6, Andreas Köberer7, Thomas Fuchs7, Nikolaos Papadimas8, Monika Heinzel-Gutenbrunner9, Thorsten Brenner10, Christoph Lichtenstern10, Markus A Weigand10, Alexander Brinkmann11. 1. Department of Anesthesiology and Critical Care, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. daniel.richter@med.uni-heidelberg.de. 2. Department of Clinical Pharmacy, Heidenheim Hospital, Schloßhaustraße 100, 89522, Heidenheim, Germany. 3. University of Queensland Centre for Clinical Research, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia. 4. Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, The University of Queensland, 20 Cornwall St, Woolloongabba, Brisbane, QLD, 4102, Australia. 5. Royal Brisbane and Women's Hospital, Brisbane, Australia. 6. Royal Brisbane and Women's Hospital, Herston, 4029, QLD, Australia. 7. Department of Anesthesiology, Heidenheim Hospital, Schloßhaustraße 100, 89522, Heidenheim, Germany. 8. Department of Urology, Heidenheim Hospital, Schloßhaustraße 100, 89522, Heidenheim, Germany. 9. MH-Statistical Consulting, Bienenweg 8, 35041, Marburg, Germany. 10. Department of Anesthesiology and Critical Care, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. 11. Department of Anesthesiology, Heidenheim Hospital, Schloßhaustraße 100, 89522, Heidenheim, Germany. alexander.brinkmann@kliniken-heidenheim.de.
Abstract
PURPOSE: Standard dosing and intermittent bolus application (IB) are important risk factors for pharmacokinetic (PK) target non-attainment during empirical treatment with β-lactams in critically ill patients, particularly in those with sepsis and septic shock. We assessed the effect of therapeutic drug monitoring-guided (TDM), continuous infusion (CI) and individual dosing of piperacillin/tazobactam (PIP) on PK-target attainment in critically ill patients. METHODS: This is a retrospective, single-center analysis of a database including 484 patients [933 serum concentrations (SC)] with severe infections, sepsis and septic shock who received TDM-guided CI of PIP in the intensive care unit (ICU) of an academic teaching hospital. The PK-target was defined as a PIP SC between 33 and 64 mg/L [fT > 2-4 times the epidemiological cutoff value (ECOFF) of Pseudomonas aeruginosa (PSA)]. RESULTS: PK-target attainment with standard dosing (initial dose) was observed in 166 patients (34.3%), whereas only 49 patients (10.1%) demonstrated target non-attainment. The minimum PK-target of ≥ 33 mg/L was overall realized in 89.9% (n = 435/484) of patients after the first PIP dose including 146 patients (30.2%) with potentially harmful SCs ≥ 100 mg/L. Subsequent TDM-guided dose adjustments significantly enhanced PK-target attainment to 280 patients (62.4%) and significantly reduced the fraction of potentially overdosed (≥ 100 mg/L) patients to 4.5% (n = 20/449). Renal replacement therapy (RRT) resulted in a relevant reduction of PIP clearance (CLPIP): no RRT CLPIP 6.8/6.3 L/h (median/IQR) [SCs n = 752, patients n = 405], continuous veno-venous hemodialysis (CVVHD) CLPIP 4.3/2.6 L/h [SCs n = 160, n = 71 patients], intermittent hemodialysis (iHD) CLPIP 2.6/2.3 L/h [SCs n = 21, n = 8 patients]). A body mass index (BMI) of > 40 kg/m2 significantly increased CLPIP 9.6/7.7 L/h [SC n = 43, n = 18 patients] in these patients. Age was significantly associated with supratherapeutic PIP concentrations (p < 0.0005), whereas high CrCL led to non-target attainment (p < 0.0005). Patients with target attainment (33-64 mg/L) within the first 24 h exhibited the lowest hospital mortality rates (13.9% [n = 23/166], p < 0.005). Those with target non-attainment demonstrated higher mortality rates (≤ 32 mg/L; 20.8% [n = 10/49] ≥ 64 mg/L; 29.4% [n = 79/269]). CONCLUSION: TDM-guided CI of PIP is safe in critically ill patients and improves PK-target attainment. Exposure to defined PK-targets impacts patient mortality while lower and higher than intended SCs may influence the outcome of critically ill patients. Renal function and renal replacement therapy are main determinants of PK-target attainment. These results are only valid for CI of PIP and not for prolonged or intermittent bolus administration of PIP.
PURPOSE: Standard dosing and intermittent bolus application (IB) are important risk factors for pharmacokinetic (PK) target non-attainment during empirical treatment with β-lactams in critically illpatients, particularly in those with sepsis and septic shock. We assessed the effect of therapeutic drug monitoring-guided (TDM), continuous infusion (CI) and individual dosing of piperacillin/tazobactam (PIP) on PK-target attainment in critically illpatients. METHODS: This is a retrospective, single-center analysis of a database including 484 patients [933 serum concentrations (SC)] with severe infections, sepsis and septic shock who received TDM-guided CI of PIP in the intensive care unit (ICU) of an academic teaching hospital. The PK-target was defined as a PIP SC between 33 and 64 mg/L [fT > 2-4 times the epidemiological cutoff value (ECOFF) of Pseudomonas aeruginosa (PSA)]. RESULTS: PK-target attainment with standard dosing (initial dose) was observed in 166 patients (34.3%), whereas only 49 patients (10.1%) demonstrated target non-attainment. The minimum PK-target of ≥ 33 mg/L was overall realized in 89.9% (n = 435/484) of patients after the first PIP dose including 146 patients (30.2%) with potentially harmful SCs ≥ 100 mg/L. Subsequent TDM-guided dose adjustments significantly enhanced PK-target attainment to 280 patients (62.4%) and significantly reduced the fraction of potentially overdosed (≥ 100 mg/L) patients to 4.5% (n = 20/449). Renal replacement therapy (RRT) resulted in a relevant reduction of PIP clearance (CLPIP): no RRT CLPIP 6.8/6.3 L/h (median/IQR) [SCs n = 752, patients n = 405], continuous veno-venous hemodialysis (CVVHD) CLPIP 4.3/2.6 L/h [SCs n = 160, n = 71 patients], intermittent hemodialysis (iHD) CLPIP 2.6/2.3 L/h [SCs n = 21, n = 8 patients]). A body mass index (BMI) of > 40 kg/m2 significantly increased CLPIP 9.6/7.7 L/h [SC n = 43, n = 18 patients] in these patients. Age was significantly associated with supratherapeutic PIP concentrations (p < 0.0005), whereas high CrCL led to non-target attainment (p < 0.0005). Patients with target attainment (33-64 mg/L) within the first 24 h exhibited the lowest hospital mortality rates (13.9% [n = 23/166], p < 0.005). Those with target non-attainment demonstrated higher mortality rates (≤ 32 mg/L; 20.8% [n = 10/49] ≥ 64 mg/L; 29.4% [n = 79/269]). CONCLUSION: TDM-guided CI of PIP is safe in critically illpatients and improves PK-target attainment. Exposure to defined PK-targets impacts patientmortality while lower and higher than intended SCs may influence the outcome of critically illpatients. Renal function and renal replacement therapy are main determinants of PK-target attainment. These results are only valid for CI of PIP and not for prolonged or intermittent bolus administration of PIP.
Authors: Ashlan J Kunz Coyne; Mohammad Alshaer; Anthony M Casapao; Veena Venugopalan; Carmen Isache; Jason Ferreira; Christopher A Jankowski Journal: Antimicrob Agents Chemother Date: 2022-09-08 Impact factor: 5.938
Authors: Ute Chiriac; Otto R Frey; Anka C Roehr; Andreas Koeberer; Patrick Gronau; Thomas Fuchs; Jason A Roberts; Alexander Brinkmann Journal: Medicine (Baltimore) Date: 2021-06-04 Impact factor: 1.817
Authors: Adam G Stewart; David L Paterson; Barnaby Young; David C Lye; Joshua S Davis; Kellie Schneider; Mesut Yilmaz; Rumeysa Dinleyici; Naomi Runnegar; Andrew Henderson; Sophia Archuleta; Shirin Kalimuddin; Brian M Forde; Mark D Chatfield; Michelle J Bauer; Jeffrey Lipman; Tiffany Harris-Brown; Patrick N A Harris Journal: Open Forum Infect Dis Date: 2021-08-02 Impact factor: 3.835