A multicenter study on the effect of continuous hemodiafiltration intensity on antibiotic pharmacokinetics

Darren M Roberts, Xin Liu, Jason A Roberts, Priya Nair, Louise Cole, Michael S Roberts, Jeffrey Lipman, Rinaldo Bellomo, RENAL Replacement Therapy Study Investigators, Darren M Roberts, Xin Liu, Jason A Roberts, Priya Nair, Louise Cole, Michael S Roberts, Jeffrey Lipman, Rinaldo Bellomo, RENAL Replacement Therapy Study Investigators

Abstract

Introduction: Continuous 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.

Methods: We 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.

Results: We 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.

Conclusions: In 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 registration: ClinicalTrials.gov NCT00221013. Registered 14 September 2005.

Figures

Figure 1
Figure 1
Marked variability but negative association between the saturation coefficients (Sd) of urea (significant) and creatinine (non-significant) and CRRT effluent flow rate. Urea: Pearson r = −0.2016, P = 0.0383, r2 = 0.04063, n = 106 pairs; creatinine: Pearson r = −0.1790, P = 0.0704, n = 103 pairs. CRRT, continuous renal replacement therapy.
Figure 2
Figure 2
Positive correlation between the saturation coefficient (Sd) of vancomycin with both urea and creatinine. Urea: Spearman r = 0.3817, P = 0.0074, n = 48 pairs; creatinine: Spearman r = 0.5297, P = 0.0001, n = 48 pairs.
Figure 3
Figure 3
Marked inter-individual and inter-occasion variability in the plasma concentration-time profile of meropenem over 12 hours following 17 doses of either 500 or 1,000 mg to 12 patients. Simulated concentration-time profiles using a single compartment equation are based on the trough concentration, time of infusion, and calculated systemic clearance and volume of distribution for each occasion (performed by using GraphPad Prism version 4.03 for Windows; GraphPad Software, San Diego, CA, USA).
Figure 4
Figure 4
Examples of inter-occasion variability in antibiotic pharmacokinetics. (a) Admission to the intensive care unit (ICU) after coronary artery bypass grafts and valve repair, requiring mechanical ventilation and vasopressors for hypotension (not attributed to sepsis). This patient received higher-intensity continuous renal replacement therapy (CRRT) and did not survive to hospital discharge. Meropenem (1 g) was administered on each occasion. (b) Admission to the ICU from the emergency department and subsequently diagnosis with Klebsiella sepsis associated with a soft tissue infection, complicated by edema and hypoalbuminemia (24 g/L). Treatment included mechanical ventilation, antibiotics, and dopamine infusion (decreasing requirements during admission, not required at the time of second samples). This patient received higher-intensity CRRT and was alive at 90 days post-admission. Ciprofloxacin (200 mg) was administered on both occasions. CL, clearance; Vd, volume of distribution.

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