Using a ceftriaxone plasma concentration cut-off value to identify ceftriaxone-related neurotoxicity in ICU patients: mission impossible?

Abstract

Abstract Background: Ceftriaxone is a 3rd generation cephalosporin commonly used in the Intensive Care Unit (ICU). Little is known about the occurrence of ceftriaxone-related neurotoxicity (CRN) in this group of patients and its relation with the (free) ceftriaxone plasma trough concentration (Ctrough). The free fraction, which is able to distribute to cerebrospinal fluid (CSF), may be increased in ICU patients due to highly variable pharmacokinetics. Patients and method: ICU patients, who received ceftriaxone and were at high risk of toxicity based on their plasma concentrations (total Ctrough > 100 mg/L and/or a free Ctrough > 10 mg/L), were identified from the DOLPHIN-database. Medical records were screened for symptoms of neurotoxicity and assessed for ceftriaxone causality. Potential cases were independently reassessed by a second reviewer prior to case inclusion. Results: From the 108 patients receiving ceftriaxone, 31 patients were at high risk of toxicity. We identified 2 cases of CRN presenting with myoclonus and non-convulsive status epilepticus (NCSE), respectively. High total and free Ctrough were observed in the first case, whereas the second case only showed high free Ctrough. Conclusion: Identifying CRN in the ICU population is extremely challenging due to a multitude of confounding factors. Our findings suggest that Therapeutic Drug Monitoring (TDM) of the free ceftriaxone Ctrough may aid in the diagnosis of CRN in ICU patients. Early recognition of CRN, in particular of ceftriaxone-induced NCSE, is of great importance as timely discontinuation may impact clinical outcomes.