319 - Piperacillin-Associated Acute Kidney Injury is Associated with Higher Piperacillin Exposures

Poster Number: 319
Publication Number: 319.444

Sonya Tang Girdwood, Cincinnati Children's Hospital Medical Center, Fort Thomas, KY, United States; Denise Hasson, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States; J. Tim Caldwell, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States; Cara Slagle, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States; Shun Dong, Cincinnati Children's Hospital Medical Center, Erlanger, KY, United States; Lin Fei, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States; Peter Tang, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States; Alexander (Sander) A. Vinks, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States; Jennifer Kaplan, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States; Stuart L. Goldstein, Cincinnati Children's Hospital, Cincinnati, OH, United States

Background: Critically ill patients are at risk for antibiotic toxicity due to changes in drug pharmacokinetics (PK). Piperacillin/tazobactam (PTZ), a commonly used antibiotic, is associated with acute kidney injury (AKI) and is an ideal candidate for precision dosing. The relationship between piperacillin (PIP) concentrations and AKI remains unknown.

Objective: Estimate PIP exposures in critically ill patients given PTZ to identify PIP concentrations and clinical factors associated with increased risk of piperacillin-associated AKI (PTZ-AKI)

Design/Methods: We used a dataset of 149 critically ill patients admitted to one PICU, who received 1+ PTZ doses and had 1+ PIP concentrations measured by HPLC. Exclusion criteria were receipt of PTZ for < 24 hours, no free concentrations measured, initial PTZ given at another hospital, or receipt of CKRT, ECMO, or MARS™ therapy. PIP area under the curve (AUC), highest peak (C­max) and highest trough (Cmin) in the first 24 hours of PTZ therapy were estimated using MWPharm++ (Mediware, Czech Republic), Bayesian estimation, a PIP population PK model, and patient concentrations. PTZ-AKI was determined by 3 adjudicators based on: 1) AKI present for >24 hours after exposure to the first PTZ dose, 2) AKI meets KDIGO stage 2 or 3 criteria and 3) increase in serum creatinine (SCr) >0.5 mg/dL. Adjudicators rated the likelihood of PTZ-AKI using the Naranjo Adverse Drug Reaction Probability Scale. T-test of log-transformed PIP concentration measurements (AUC, Cmax, Cmin) was used to analyze differences between groups. Multivariable logistic regression was performed to identify patient and clinical predictors of PTZ-AKI (Table 1).

Results: 107/149 patients were included. Adjudicator consensus on PTZ-AKI presence was 82%; 16 patients (15%) met all 3 criteria and were rated as possibly or probably having PTZ-AKI. Patients with PTZ-AKI had higher weights (44.7 vs. 17.7 kg, p< 0.001) (Table 2). AUC and highest Cmin in the first 24 hours were higher in patients with PTZ-AKI (2042 vs. 1445 mg*hr/L, p=0.03; 50.1 vs. 10.7 mg/L, p< 0.001; Fig 1). Logistic regression showed that significant predictors of PTZ-AKI included higher Cmin (estimate 1.7, OR 5.4, p=0.009) and older age (estimate 0.13, OR 1.13, p=0.005).Conclusion(s): We used a robust adjudication process to show a relationship between PIP AUC and highest Cmin in the first 24 hours of PTZ therapy and PTZ-AKI, signifying that total piperacillin exposure early in the PTZ course is associated with AKI development. These data could serve as the foundation for implementation of precision dosing to reduce AKI incidence in patients given PTZ.  
Table 1: List of predictors included in multivariable logistic regressionAUC = area under the curve. Cmax = maximum concentration/peak; Cmin = minimum concentration/trough. KDIGO = Kidney Disease Improving Global Outcomes; PTZ = piperacillin/tazobactam
Table 2: Demographics and Hospitalization Characteristics of Patients.Comorbid condition is defined as a condition requiring subspecialty care or medication for treatment. PTZ-AKI = piperacillin-associated acute kidney injury. IQR = interquartile range