Piperacillin/tazobactam clearance predicted by non-creatinine based estimates of GFR in critically ill adults

Abstract

Background and objective

As a renally-eliminated beta-lactam antibiotic, estimated glomerular filtration rate (eGFR) is a central component of piperacillin/tazobactam pharmacokinetics. This study aimed to determine the optimal eGFR equation for inclusion in population pharmacokinetic models for piperacillin and tazobactam among critically ill adults.

Methods

The study included critically ill adults treated with piperacillin/tazobactam at a single academic medical center between 2018 and 2022. Excluded individuals had acute kidney injury, received kidney replacement therapy, or had extracorporeal membrane oxygenation at piperacillin/tazobactam initiation. Non-linear mixed effects population pharmacokinetic models using eGFR equations with creatinine, cystatin C, or both were developed and compared.

Results

Using 377 samples from 120 critically ill patients, we found that a two-compartment model with first-order elimination best fit the piperacillin data and a one-compartment model with first-order elimination best fit the tazobactam data. For piperacillin, the final population mean parameters (standard error) were 8.36 (0.55) L/h for CL and 12.96 (1.17) L for V1. The values for Q and V2 were fixed at 0.98 L/h and 18 L, respectively, due to low interindividual variation in these parameters. For tazobactam, the final population mean parameters were 8.12 (0.52) L/h for CL and 16.87 (1.44) L for V. Both final models identified eGFR_cystatinC expressed in mL/min as the eGFR equation that best predicted drug clearance as a covariate.

Conclusions

An eGFR equation that includes cystatin C improves the predictive performance of pharmacokinetic models for piperacillin/tazobactam in critically ill adults.