Pathogen-based target attainment of optimized continuous infusion dosing regimens of piperacillin-tazobactam and meropenem in surgical ICU patients: a prospective single center observational study

Abstract

Background: Several studies have indicated that commonly used piperacillin-tazobactam (TZP) and meropenem (MEM) dosing regimens lead to suboptimal plasma concentrations for a range of pharmacokinetic/pharmacodynamic (PK/PD) targets in intensive care unit (ICU) patients. These targets are often based on a hypothetical worst-case scenario, possibly overestimating the percentage of suboptimal concentrations. We aimed to evaluate the pathogen-based clinically relevant target attainment (CRTA) and therapeutic range attainment (TRA) of optimized continuous infusion dosing regimens of TZP and MEM in surgical ICU patients. Methods: A single center prospective observational study was conducted between March 2016 and April 2019. Free plasma concentrations were calculated by correcting total plasma concentrations, determined on remnants of blood gas samples by ultra-performance liquid chromatography with tandem mass spectrometry, for their protein binding. Break points (BP) of identified pathogens were derived from epidemiological cut-off values. CRTA was defined as a corrected measured total serum concentration above the BP and calculated for increasing BP multiplications up to 6 × BP. The upper limit of the therapeutic range was set at 157.2 mg/L for TZP and 45 mg/L for MEM. As a worst-case scenario, a BP of 16 mg/L for TZP and 2 mg/L for MEM was used. Results: 781 unique patients were included with 1036 distinctive beta-lactam antimicrobial prescriptions (731 TZP, 305 MEM) for 1003 unique infections/prophylactic regimens (750 TZP, 323 MEM). 2810 samples were available (1892 TZP, 918 MEM). The median corrected plasma concentration for TZP was 86.4 mg/L [IQR 56.2–148] and 16.2 mg/L [10.2–25.5] for MEM. CRTA and TRA was consistently higher for the pathogen-based scenario than for the worst-case scenario, but nonetheless, a substantial proportion of samples did not attain commonly used PK/PD targets. Conclusion: Despite these pathogen-based data demonstrating that CRTA and TRA is higher than in the often-used theoretical worst-case scenario, a substantial proportion of samples did not attain commonly used PK/PD targets when using optimised continuous infusion dosing regimens. Therefore, more dosing optimization research seems warranted. At the same time, a ‘pathogen-based analysis’ approach might prove to be more sensible than a worst-case scenario approach when evaluating target attainment and linked clinical outcomes.