AAC Accepts, published online ahead of print on 26 October 2009

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Antimicrob. Agents Chemother. doi:10.1128/AAC.00296-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Identification of Optimal Renal Dosage Adjustments for Traditional and Extended Infusion Piperacillin/Tazobactam Dosing Regimens in Hospitalized Patients

N Patel, M H Scheetz, G L Drusano, and T P Lodise^*

Albany College of Pharmacy and Health Sciences, Albany, NY; Midwestern College of Pharmacy, Department of Pharmacy Practice, Downers Grove, IL; Northwestern Memorial Hospital, Department of Pharmacy, Chicago, IL; Ordway Research Institute, Albany, NY

^* To whom correspondence should be addressed. Email: lodiset{at}acp.edu.

This study examined the effect of varying levels of renal impairment on the probability of achieving 50% fT>MIC for traditional and extended infusion piperacillin/tazobactam (TZP) dosing strategies. It also identified the optimal renal dosage adjustments for traditional and extended infusion dosing schemes that yielded isometric probability of target attainment (PTA) and exposure profiles for the TZP renal dosing strategies relative to 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 (9999 subjects) was performed for the traditional dosing scheme (4.5 g, infused over 30 minutes, every 6 hours) and the extended infusion TZP dosing scheme (3.375 g, infused over 4 hours, every 8 hours). The fraction of simulated subjects who achieved 50% fT > MIC was calculated for the range of piperacillin minimum inhibitory concentrations (MICs) from 0.25 to 32 mg/L 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/L when stratified by CL_CR. In contrast, the PTA for the extended infusion TZP regimen exceeded 80% for MIC values < 8 mg/L across all CL_CR strata. All regimens were associated with suboptimal PTA for MIC values 32 mg/L, irrespective of CL_CR. The CL_CR adjustments for traditional and extended infusion TZP dosing regimens should be considered at CL_CR 20 mL/minute.