# Safety concerns associated with high-dose continuous infusion of cefepime among critically ill patients with mild renal impairment to augmented renal clearance at a level 1 trauma center: CEFTOX study

## TL;DR

This study found that high-dose cefepime can cause toxicity in ICU patients, especially those with mild kidney issues, highlighting the need for careful drug monitoring.

## Contribution

The study identifies risk factors for cefepime overexposure and neurotoxicity in critically ill patients with varying kidney function.

## Key findings

- Cefepime overexposure occurred in 44.4% of patients, highest in those with mild renal impairment (87.5%).
- Cefepime-induced neurotoxicity was more common when drug monitoring was delayed beyond 48 hours.
- Age over 33 years increased overexposure risk in patients with augmented renal clearance.

## Abstract

High-dose continuous infusion of cefepime is frequently employed in ICU patients with a creatinine clearance above 60 mL/min. The CEFTOX study aimed to investigate whether this regimen could lead to cefepime overexposure and cefepime-induced neurotoxicity (CIN) in a cohort of severe trauma and brain-injured patients. This retrospective cohort study included patients from a Level 1 Trauma Center who received a continuous infusion of 6 g/day of cefepime and had a therapeutic drug monitoring (TDM) within 24–48 h of treatment initiation. They were divided into three groups based on creatinine clearance: mild renal impairment (60–90 mL/min), normal clearance (90–150 mL/min), and augmented renal clearance (ARC) (>150 mL/min). The primary outcome was cefepime overexposure. A key secondary outcome was CIN. One hundred and sixty-two critically ill patients were included: 84 with ARC, 62 with normal renal clearance, and 16 with mild renal impairment. Cefepime overexposure occurred in 72 (44.4%) patients. While 50% of patients with normal renal clearance experienced overexposure, the rate was higher in those with mild renal impairment (87.5%) and lower in those with ARC (32.1%; P < 0.0001). In the ARC group, age > 33 years was a risk factor for overexposure (odds ratio [OR] 3.76; 95% CI [1.30–10.95]; P = 0.01), while sepsis was a protective factor (OR 0.30; 95% CI [0.11–0.83]; P = 0.02). CIN was observed in 24% of overexposed patients when TDM results were obtained ≤48 h compared to 57.4% when results were delayed >48 h (P = 0.006). These results highlight the need for early TDM and individualized dose adjustment to avoid CIN.