(W-121) Model-informed simulations to determine optimal Piperacillin-Tazobactam Dosing regimens in Pediatric Perioperative Care: Effect of body size and renal function

Kei Irie, NA – RESEARCH ASSOCIATE, Division of Translational and Clinical Pharmacology, Cincinnati Children's Hospital Medical Center; Carter McIntire, NA – Research Assistant, Hospital Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati; Julie Luna Torres, NA – Research Assistant, Hospital Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati; Rhonda Jones, NA – Research Assistant, Critical Care Medicine, Cincinnati Children's Hospital Medical Center; Abigayle Gibson, NA – Research Assistant, Critical Care Medicine, Cincinnati Children's Hospital Medical CentER; Tomoyuki Mizuno, NA – ASSOC PROF, Division of Translational and Clinical PharmacologY, Cincinnati Children's Hospital Medical Center; Sonya Tang Girdwood, NA – ASSISTANT PROFESSOR, Hospital Medicine, Cincinnati Children's Hospital Medical Center

Objectives: Current global standards recommend a pediatric intraoperative dosing regimen for piperacillin/tazobactam (PTZ) to be 90-112.5 mg/kg (80-100 mg/kg as piperacillin (PIP)) administered every 2 hours (Q2H)¹. However, concerns regarding potential for nephrotoxicity from high piperacillin levels and the complexity of maintaining Q2H dosing schedule have prompted the need for new dosing guidelines. This study aims to provide new dosing recommendations for peri-operative pediatric patients, accounting for body size and renal function, with model-based simulations using a previously developed PK model for this population.

Methods: Based on a population PK model built by our research group², this study utilized Pop PK model-based simulations to determine tailored dosing regimens that ensure therapeutic target attainment while minimizing nephrotoxic risk. Simulations stratified patients into groups based on creatinine clearance and body weight groups to customize doses according to the patient's renal function and body weight; these ranged from 20-29 mL/min/1.73 m² ,30-59 mL/min/1.73 m², 60-89 mL/min/1.73 m², 90-129 mL/min/1.73 m² and ≥130 mL/min/1.73 m² ;10-29 kg, 30-49 kg, 50-69 kg and ≥70 kg. Target attainment was defined as concentrations above 1x and 4x minimum inhibitory concentration (MIC) for 100% of the time, with 1 and 4x MIC values set at 8 mg/L and 32 mg/L, respectively, for Enterococcus and Enterobacterales. The strategy focused on determining the minimum doses necessary for PD target attainment to minimize the risk of nephrotoxicity.

Result: In our study, the lowest effective PIP dose for pediatric perioperative patients Q2H was found to be 6 mg/kg for certain subgroups and the highest effective dose for 4x MIC levels reached 55 mg/kg, which is significantly lower than current guidelines suggest. For continuous infusion, dosing ranged from a loading dose of 10 mg/kg followed by 1.0 to 2.5 mg/kg/hour for 1x MIC and up to 20 mg/kg loading dose followed by a maintenance dose as high as 9.25 mg/kg/hour for 4x MIC.

Conclusion: This study leverages Pop PK model-based simulations to establish tailored dosing guideline for PTZ in pediatric perioperative patients. Findings show that effective Q2H dosages can be substantially lower than current guideline suggested, reducing nephrotoxicity risks while ensuring therapeutic levels. Furthermore, continuous infusion strategies mitigate practical challenges associated with frequent dosing intervals. Future research will involve a larger, prospective study to validate these proposed dosing schedules.

Citations: 1. Bratzler et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Surgical Infections. 2013;14(1):73-156.
2. Tan et.al (2024), LB-019, American Society for Clinical Pharmacology and Therapeutics. Clin Pharmacol Ther, 115: S5-S125.