Population pharmacokinetics of piperacillin and tazobactam in critically ill patients undergoing continuous renal replacement therapy: application to pharmacokinetic/pharmacodynamic analysis

Abstract

Population pharmacokinetic models have been developed and validated for piperacillin and tazobactam. Based on the pharmacokinetic/pharmacodynamic analysis, dosing recommendations are given considering the residual renal function of the patient and the MIC for the isolated bacteria.

Pharmacokinetic/pharmacodynamic analysis to evaluate ceftaroline fosamil dosing regimens for the treatment of community-acquired bacterial pneumonia and complicated skin and skin-structure infections in patients with normal and impaired renal function

“…Normally, exposure of antimicrobials that are eliminated mainly in urine, such as cephalosporins, is higher in patients with renal insufficiency than in patients with normal renal function [26,27] and therefore the probability to reach the pharmacodynamic target significantly increases. This means that patients with normal renal function have more risk of underdosage.…”

Beta-lactam dosing in critically ill patients with septic shock and continuous renal replacement therapy

“…In this context, CRRT represents a particular challenge in terms of dosing, especially for hydrophilic antibiotics, as concentrations may vary depending on the degree of extraction, which in turn depends on the CRRT modality, on drug physicochemistry and, presumably, on CRRT intensity [7]. Moreover, residual renal function is usually variable, difficult to assess and rarely considered when dosing, despite its relevant contribution to antibiotic CL in patients undergoing CRRT that has been described for meropenem and piperacillin among others [26,29,32]. Finally, the patient’s condition evolves throughout the ICU stay so the influence of the previously mentioned factors may vary over time, making it difficult to generalize recommendations only based on CRRT modality and intensity.…”

“…Other studies include septic and polytrauma patients requiring CRRT [25,32]. Of note, one of these studies overcame the admission diagnosis-driven variability by developing a population pharmacokinetics model.…”

“…These data suggest that different CRRT intensities may translate into different drug CL and therefore into different dose requirements. Importantly, one must also highlight that most of the published studies use CRRT intensities in the lower range of the area of best practice (1 to 2 l/hour; 14.3 to 28.5 ml/kg/hour for a 70 kg adult) [16,17,19-21,27,29,30,32,34,35,49,50], while the actual tendency in the clinical setting may be using CRRT intensities in the higher range (>30 ml/kg/hour), especially for septic patients [41,46]. In fact, a recent study by Varghese and colleagues studied the pharmacokinetics of piperacillin/tazobactam in critically ill patients with anuria/oliguria and CRRT at a median intensity of 38.5 ml/kg/hour, and reported higher drug CL (median 5.1 (interquartile range 4.2 to 6.2) l/hour) compared with other studies that used lower CRRT intensities (see Table 3 and 4) [38].…”

Pharmacokinetics of piperacillin in critically ill patients receiving continuous venovenous haemofiltration: A randomised controlled trial of continuous infusion versus intermittent bolus administration

“…Although numerous piperacillin pharmacokinetic studies have been conducted in critically ill patients concurrently treated with variable modes and doses of continuous RRT (CRRT) [9][10][11][12][13][14][15][16], none have evaluated CI administration. The only related paper was based on simulation and it concluded that CI administration of piperacillin could be beneficial in this context [17]. Therefore, evaluating the use of CI of piperacillin during CRRT will inform ICU clinicians regarding its application.…”