Physiological determinants of piperacillin and cefazolin clearance in septic and trauma patients

Physiological alterations in patients with sepsis and trauma can influence antibiotic clearance, yet reliable predictors remain poorly defined. We aimed to investigate the determinants of piperacillin and cefazolin clearance in these populations to identify bedside indicators of subtherapeutic exposure. Prospective physiological and pharmacokinetic study in patients receiving piperacillin/tazobactam for sepsis or prophylactic cefazolin post-trauma. Patients also received intravenous sinistrin. Intensive pharmacokinetic sampling, cardiac output (CO) monitoring and four urinary creatinine clearance ( u CL CR ) measurements were performed. Data were analysed with non-compartmental pharmacokinetic methods, and linear and logistic regression. We enrolled 49 septic and 28 trauma patients. Trauma patients were younger (33.5 vs. 46.5 years) and had higher u CL CR (155.5 vs. 107.5 mL/min). Linear regression identified that lower Sequential Organ Failure Assessment scores and an hyperdynamic state with higher CO and 2 and 8-h u CL CR were the strongest predictors of increased piperacillin total clearance; higher 2-h u CL CR and hypoalbuminemia were the main predictors for cefazolin total clearance. Sinistrin CL was a weak predictor. Logistic regression identified augmented renal clearance (8-h u CL CR > 130 mL/min) as the main risk factor for piperacillin subtherapeutic exposure (OR 10.9, p < 0.05), also when defined using the Cockcroft–Gault cut-off of 114.5 mL/min from ROC analysis. In sepsis, low sickness severity and a hyperdynamic state with high cardiac output lead to increased u CL CR and high piperacillin clearance. In trauma, high cefazolin clearance occurs in the presence of an elevated u CL CR and hypoalbuminemia. These bedside physiological indicators, along with Cockcroft–Gault CL CR , may serve as early indicators of risk for subtherapeutic exposure.