Abstract
IntroductionContinuous renal replacement therapy (CRRT) may alter antibiotic pharmacokinetics and increase the risk of incorrect dosing. In a nested cohort within a large randomized controlled trial, we assessed the effect of higher (40 mL/kg per hour) and lower (25 mL/kg per hour) intensity CRRT on antibiotic pharmacokinetics.MethodsWe collected serial blood samples to measure ciprofloxacin, meropenem, piperacillin-tazobactam, and vancomycin levels. We calculated extracorporeal clearance (CL), systemic CL, and volume of distribution (Vd) by non-linear mixed-effects modelling. We assessed the influence of CRRT intensity and other patient factors on antibiotic pharmacokinetics.ResultsWe studied 24 patients who provided 179 pairs of samples. Extracorporeal CL increased with higher-intensity CRRT but the increase was significant for vancomycin only (mean 28 versus 22 mL/minute; P = 0.0003). At any given prescribed CRRT effluent rate, extracorporeal CL of individual antibiotics varied widely, and the effluent-to-plasma concentration ratio decreased with increasing effluent flow. Overall, systemic CL varied to a greater extent than Vd, particularly for meropenem, piperacillin, and tazobactam, and large intra-individual differences were also observed. CRRT dose did not influence overall (systemic) CL, Vd, or half-life. The proportion of systemic CL due to CRRT varied widely and was high in some cases.ConclusionsIn patients receiving CRRT, there is great variability in antibiotic pharmacokinetics, which complicates an empiric approach to dosing and suggests the need for therapeutic drug monitoring. More research is required to investigate the apparent relative decrease in clearance at higher CRRT effluent rates.Trial registrationClinicalTrials.gov NCT00221013. Registered 14 September 2005.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-015-0818-8) contains supplementary material, which is available to authorized users.
Highlights
Continuous renal replacement therapy (CRRT) may alter antibiotic pharmacokinetics and increase the risk of incorrect dosing
Sampling occurred at 179 time points in 24 patients: ciprofloxacin (19), meropenem (65), piperacillin-tazobactam (29), and vancomycin (66)
Key findings In this multicenter pharmacokinetic study of four antibiotics and tazobactam, the prescribed intensity of continuous renal replacement therapy (CRRT) did not adequately predict systemic clearance (CLs) from hemodiafiltration (CLHDF) or saturation coefficient in the effluent or diafiltrate (Sd), CLs, volume of distribution (Vd), or halflife. This did not appear to be explained by the age of the filter, hematocrit, or serum albumin concentration
Summary
Continuous renal replacement therapy (CRRT) may alter antibiotic pharmacokinetics and increase the risk of incorrect dosing. Key aspects of pharmacokinetics like antibiotic clearance (CL) and volume of distribution (Vd) are altered in critically ill patients with AKI because of loss or renal clearance, volume expansion, and interventions such as vasopressors and continuous renal replacement therapy (CRRT) [6,7]. Extracorporeal CL during CRRT is influenced by the physicochemical and pharmacokinetic properties of the antibiotic, blood flow, dialysate flow, and ultrafiltration rate and by membrane fouling and filter clotting [8]. These variables may lead to sub-therapeutic blood concentrations and contribute to treatment failure [9,10,11].
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