Piperacillin penetration into tissue of critically ill patients with sepsis--bolus versus continuous administration?

OBJECTIVE To describe a pharmacokinetic model of piperacillin concentrations in plasma and subcutaneous tissue when administered by bolus dosing and continuous infusion in critically ill patients with sepsis on days 1 and 2 of antibiotic therapy and to compare results against previous results for piperacillin from a cohort of patients with septic shock. DESIGN Prospective randomized controlled trial. SETTING Eighteen-bed intensive care unit at 918-bed tertiary referral hospital. PATIENTS Thirteen critically ill adult patients with known or suspected sepsis in whom the treating physician deemed piperacillin-tazobactam appropriate therapy were conveniently sampled. INTERVENTIONS Patients were randomized to receive different daily doses of piperacillin-tazobactam by bolus dosing or continuous infusion (continuous infusion--six patients; bolus dosing--seven patients). Serial plasma and tissue concentrations were determined on days 1 and 2 of treatment. Tissue concentrations of piperacillin were determined using a subcutaneously inserted microdialysis catheter. Separate pharmacokinetic models were developed for both bolus and continuous dosing. MEASUREMENTS AND MAIN RESULTS This is the first known article to report concurrent plasma and subcutaneous tissue concentrations of a beta-lactam antibiotic administered by bolus and continuous dosing in critically ill patients with sepsis. With a 25% lower piperacillin dose administered to the continuous infusion group, the infusion group had statistically significantly higher median plasma concentrations than the bolus group on day 2 (16.6 vs. 4.9 mg/L; p = 0.007). There was a trend to higher median plasma concentrations on day 1 in the bolus dosing group (8.9 vs. 4.9 mg/L; p = 0.078). Median tissue concentrations were not statistically different on day 1 (infusion group 2.4 mg/L vs. bolus group 2.2 mg/L; p = 0.48) and day 2 (infusion group 5.2 mg/L vs. bolus group 0.8 mg/L; p = 0.45). A two-compartment pharmacokinetic model was found to describe the data best. Tissue pharmacodynamic targets were achieved more successfully with infusion dosing. CONCLUSIONS Patients with sepsis do not seem to have the same level of impairment of tissue distribution as described for patients with septic shock. A 25% lower dose of piperacillin administered by continuous infusion seems to maintain higher trough concentrations compared with standard bolus dosing. It is likely that the clinical advantages of continuous infusion are most likely to be evident when treating pathogens with high minimum inhibitory concentration, although without therapeutic drug monitoring and subsequent dose adjustment, infusions may never achieve target concentrations of organisms with very high minimum inhibitory concentrations in a small number of patients.