{beta}-lactam dosage regimens in septic patients with augmented renal clearance [PublishAheadOfPrint]

Augmented renal clearance is commonly observed in septic patients and may result in insufficient β-lactam serum concentrations. The aims of this study were to evaluate potential correlations between drug concentrations or total body clearance of β-lactam antibiotics and measured creatinine clearance, and to quantify the need for drug dosage adjustments in septic patients with different levels of augmented renal clearance. We reviewed 256 antibiotic measurements (512 drug concentrations) from a cohort of 215 critically ill patients with a measured creatinine clearance ≥ 120 mL/min, and who received therapeutic drug monitoring of meropenem, cefepime, ceftazidime or piperacillin from October 2009 until December 2014 at Erasme Hospital. Population pharmacokinetic analysis of the data was performed using the Pmetrics software package for R. 55% of drug concentrations showed insufficient β-lactam serum concentrations to treat infections due to Pseudomonas aeruginosa. There were significant, yet weak correlations between measured creatinine clearance and trough concentrations of meropenem (r= -0.21, p=0.01), trough concentrations of piperacillin (r= -0.28, p= 0.0071), concentrations at 50% of the dosage interval (r= -0.41, p <0.0001), and total body clearance of piperacillin (r= 0.39, p= 0.0002). Measured creatinine clearance adequately explained changes in drug concentrations in population pharmacokinetic models for cefepime, ceftazidime, and meropenem, but not for piperacillin. Therefore, specific PK modelling can predict certain β-lactam concentrations based on renal function, but not on absolute values of measured creatinine clearance, easily available for clinicians. Currently, routine therapeutic drug monitoring is required to adjust daily regimens in critically ill patients receiving standard dosing regimens.

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