Use of Therapeutic Drug Monitoring to Characterize Cefepime-Induced Neurotoxicity

Abstract

Background: The incidence of cefepime-induced neurotoxicity (CIN) in hospitalized patients is highly variable. Although greater cefepime exposures incite neurotoxicity, data evaluating trough thresholds associated with CIN remains limited. The objectives of this study were to evaluate the incidence of CIN, assess the relationship between cefepime trough concentrations and CIN, investigate clinical factors associated with CIN, and describe electroencephalogram (EEG) abnormalities in CIN. Methods: This was a retrospective study of adult patients who had received ≥ 5 days of cefepime with ≥ 1 trough concentration > 25 mg/L. Potential CIN cases were identified utilizing neurological symptoms, neurologist assessments, EEG findings and improvement of neurotoxicity after cefepime discontinuation. Results: One-hundred and forty-two patients were included. The incidence of CIN was 13% (18/142). The mean cefepime trough concentration in CIN patients was significantly greater than the non-neurotoxicity group (74.2 mg/L ± 41.1 vs. 46.6 mg/L {plus minus} 23, p=0.015). Lower renal function (creatinine clearance < 30 ml/min), greater time to therapeutic drug monitoring (TDM) (≥72 hours), and each 1 mg/mL rise in cefepime trough were independently associated with increased risk of CIN. Moderate generalized slowing of the background rhythm was the most common EEG pattern associated with CIN.Conclusion: Cefepime should be used cautiously in hospitalized patients due to the risk of neurotoxicity. Patients with greater renal function and those who had early cefepime TDM (≤ 72 hours) had lower risk of CIN.

Cefepime-Induced Neurotoxicity in the Setting of Acute Kidney Injury: A Case Series and Discussion of Preventive Measures

“…Steady-state is usually achieved after 3 to 4 half-lives, which justifies trough sampling before the 4th or 5th dose [16]. Indeed, a greater time to TDM was associated with an increased risk for CIN [5].…”

“…High plasma concentrations of cefepime, which is primarily cleared by the kidneys, are associated with neurotoxicity in neutropenic patients with renal dysfunction [3]. In fact, impaired kidney function is considered the most important risk factor for CIN [3][4][5]. Risk factors for acute kidney injury (AKI) include critical illness or concomitant nephrotoxic drug treatment, female sex, and several chronic diseases among others [6].…”