Pharmacokinetics, target attainment, and outcomes of piperacillin/tazobactam in critically ill patients receiving continuous infusion with therapeutic drug monitoring: a retrospective analysis

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OBJECTIVES: To provide real-world evidence on piperacillin exposure and outcomes in critically ill patients after the implementation of pharmacokinetics/pharmacodynamics-guided dosing in routine care. METHODS: This retrospective observational study included critically ill adults who received continuous piperacillin/tazobactam infusion between 2011 and 2019. Empiric doses were individualized using dosing software based on renal function and subsequently adjusted according to therapeutic drug monitoring (TDM) results. Drug exposure was defined as subtherapeutic (<32 mg/L), therapeutic (32-64 mg/L), extended (64-96 mg/L), or supratherapeutic (>96 mg/L). RESULTS: A total of 1538 critically ill patients with severe infections and sepsis of varying severity were included, and 3089 piperacillin serum concentrations were analysed. Median daily piperacillin dose was 8 g (interquartile range [IQR], 6-12 g), median steady-state concentration 55 mg/L (IQR, 38-73 mg/L), and median clearance 6.25 L/h (IQR, 4.0-9.8 L/h). At the first measurement, individualized empiric dosing resulted in 45.7% (704 of 1538) of patients being within the therapeutic range; after TDM-guided adjustment, target attainment increased to 62.4% (968 of 1551). Subtherapeutic and supratherapeutic concentrations were uncommon among all TDM samples collected during individualized dosing (<32 mg/L: 12.8%, 395 of 3089; <16 mg/L: 0.8%, 26 of 3089; >96 mg/L: 11%, 340 of 3089). Twenty-eight-day mortality was 18.2% (131 of 718) in patients within the therapeutic range, 27.0% (107 of 396) in those within the extended range, and 40.9% (101 of 247) in those with supratherapeutic concentrations (p 0.05). Women were associated with 1.74-fold higher odds of supratherapeutic concentrations (OR, 1.74; 95% CI, 1.38-2.19; p < 0.001; 176 of 2022 male vs. 152 of 1067 female with concentrations >96 mg/L). CONCLUSIONS: A multimodal approach combining individualized empiric dosing, TDM, and continuous infusion ensured target attainment while reducing drug consumption. These findings support the integration of individualized, pharmacokinetics/pharmacodynamics-guided dosing into routine care for critically ill patients and warrant further exploration of sex-related differences in exposure.

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