Association between Beta-Lactam concentration and Liver Injury in Critically Ill Patients.

Abstract

Introduction: Therapeutic drug monitoring (TDM) may help optimize antibiotic dosing while minimizing toxicity in critically ill patients. This study investigated whether elevated plasma concentrations of beta-lactam antibiotics assessed by TDM were associated with an increased risk of liver injury in the intensive care unit (ICU) setting.

Methods: We conducted a single center retrospective cohort study of ICU patients admitted to the Hôpital Universitaire de Bruxelles (2009-2014) who underwent TDM for beta-lactam antibiotics. Total plasma trough concentrations (C₀) were measured for piperacillin-tazobactam, meropenem and ceftazidime/cefepime. Liver injury was identified via liver function tests on the day of TDM and classified into hepatocellular, cholestatic, or mixed patterns.

Results: Among 425 ICU patients with β-lactam TDM, 154 (36.2%) developed liver injury, including hepatocellular (8.7%), cholestatic (22.1%), and mixed (5.4%) patterns. TDM was performed a median of 5 days after ICU admission and 2 days after antibiotic initiation. The overall C₀ for PIP, MER and CEF were 37.8 (12.0-69.5), 4.5 (2.5-9.0) and 29.8 (18.7-47) mg/L, respectively. Patients with DILI had numerically higher beta-lactam C₀ than patients without DILI; however, this difference was only statistically significant in patients treated with PIP (44.7 [23.4-76.7] vs. 30.6 [6.4-59.5]; p=0.03). In a logistic regression analysis, C₀ was not independently associated with liver injury. Considering only patients that received piperacillin/tazobactam (n = 164), a piperacillin C₀ >20.95 mg/L had a sensitivity of 78% and specificity of 43% to identify patients with liver injury. In a multivariate analysis, piperacillin C₀ >20.95 mg was independently associated with the development of liver injury.

Conclusions: In this cohort of patients, no clear association was found between trough concentration of beta-lactams and the development of liver injury. The potential hepatoxicity of piperacillin warrants further investigation.