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

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.