Probability of pharmacokinetic/pharmacodynamic target attainment for different piperacillin/tazobactam dosing regimens in renally impaired patients in a non-intensive care unit setting.

Abstract

Aims: To optimize antibiotic therapy for pathogens classified as susceptible, increased exposure (I), an increased exposure of piperacillin/tazobactam (PTZ) is required. However, dosing recommendations are currently only available for patients with normal renal function. The aim of the study was to assess whether the recommended dosages of PTZ for patients with impaired renal function achieve adequate pharmacokinetic/pharmacodynamic (PK/PD) targets for pathogens classified as susceptible, increased exposure (I).

Methods: Overall, 49 patients with impaired renal function were included in this study (estimated glomerular filtration rate [eGFR] 20-40 mL/min: n = 20; eGFR <20 mL/min: n = 19; intermittent haemodialysis: n = 10). Peak, trough and between-dosing interval piperacillin concentrations were determined. The primary endpoint of the study was the probability of target attainment (PTA) for a conservative (fT 60% > minimal inhibitory concentration) and an aggressive PK/PD target (fT 100% > 4× minimal inhibitory concentration). First, a population pharmacokinetic model was developed followed by a model-based simulation.

Results: For the conservative PK/PD target, a PTA of >90% is achieved in all patients receiving intermittent short infusions, following the dosing recommendations outlined in the Summary of Product Characteristics (SmPC). For the more aggressive target, the PTA was <15% across all groups when using short infusions with SmPC dosing. Only continuous infusion with an increased daily dose in patients with eGFRs of 30 and 40 mL/min achieved a PTA of >90% in all patients.

Conclusions: Dosing according to the SmPC is only sufficient to achieve a conservative PK/PD target. In comparison, simulating an increased dosing with continuous administration attained an aggressive PK/PD target. Offering alternative dosing regimens may be of interest for severe infections with difficult to treat foci caused by Pseudomonas aeruginosa even in non-intensive care unit patients.