Incidence and Predictive Factors Associated with Beta-Lactam Neurotoxicity in the Critically Ill: A Retrospective Cohort Study

Background: Beta-lactam neurotoxicity is a relatively uncommon yet clinically significant adverse effect in critically ill patients. This study sought to define the incidence of neurotoxicity, derive a prediction model for beta-lactam neurotoxicity, and then validate the model in an independent cohort of critically ill adults. Methods: This retrospective cohort study evaluated critically ill patients treated with ≥ 48 h of cefepime, piperacillin/tazobactam, or meropenem. Two separate cohorts were created: a derivation cohort and a validation cohort. Patients were screened for beta-lactam neurotoxicity by using search terms and diagnosis codes, followed by clinical adjudication using a standardized adverse event scoring tool. Multivariable regression models and least absolute shrinkage and selection operator were used to identify surrogates for neurotoxicity and develop a multivariable prediction model. Results: The overall incidence of beta-lactam neurotoxicity was 2.6% (n/N = 34/1323) in the derivation cohort and 2.1% in the validation cohort (n/N = 16/767). The final multivariable neurotoxicity assessment tool included weight, Charlson comorbidity score, age, and estimated creatinine clearance as predictors of neurotoxicity. Incidence of neurotoxicity reached 4% in those with a body mass index more than 30 kg/m². Use of the candidate variables in the neurotoxicity assessment tool suggested that a score more than 35 would identify a patient at high risk for neurotoxicity with 75% sensitivity and 54% specificity. Conclusions: In this single center cohort of critically ill patients, beta-lactam neurotoxicity was demonstrated less frequently than previously reported. We identified obesity as a novel risk factor for the development of neurotoxicity. The prediction model needs to be further refined before it can be used in clinical practice as a tool to avoid drug-related harm.