Identification of optimal renal dosage adjustments for traditional and extended-infusion piperacillin-tazobactam dosing regimens in hospitalized patients.

Abstract

This study examined the effect of various levels of renal impairment on the probability of achieving free drug concentrations that exceed the MIC for 50% of the dosing interval (50% fT > MIC) for traditional and extended-infusion piperacillin-tazobactam (TZP) dosing strategies. It also identified optimal renal dosage adjustments for traditional and extended-infusion dosing schemes that yielded probability of target attainment (PTA) and exposure profiles that were isometric to those of the parent regimens. Data from 105 patients were analyzed using the population pharmacokinetic modeling program BigNPAG. To assess the effect of creatinine clearance (CL(CR)) on overall clearance, TZP clearance was made proportional to the estimated CL(CR). A Monte Carlo simulation (9,999 subjects) was performed for the traditional dosing scheme (4.5 g infused during 30 min every 6 h) and the extended-infusion TZP dosing scheme (3.375 g infused during 4 h every 8 h). The fraction of simulated subjects who achieved 50% fT > MIC was calculated for the range of piperacillin MICs from 0.25 to 32 mg/liter and stratified by CL(CR). The traditional TZP regimen displayed the greatest variability in PTA across MIC values, especially for MIC values exceeding 4 mg/liter, when stratified by CL(CR). In contrast, the PTA for the extended-infusion TZP regimen exceeded >or=80% for MIC values of <or=8 mg/liter across all CL(CR) strata. All regimens were associated with suboptimal PTA for MIC values of >or=32 mg/liter irrespective of the CL(CR). The CL(CR) adjustments for traditional and extended-infusion TZP dosing regimens should be considered at a CL(CR) of <or=20 ml/min.