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

Natalie A. Haddad, Diana J. Schreier, Jennifer E. Fugate, Ognjen Gajic, Sara E. Hocker, Calvin J. Ice, Sarah B. Leung, Kristin C. Mara, Alejandro A. Rabinstein, Andrew D. Rule, Erin F. Barreto

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)73-80
Number of pages8
JournalNeurocritical care
Issue number1
StatePublished - Aug 2022


  • Antibiotic
  • Cefepime
  • Encephalopathy
  • Piperacillin/tazobactam

ASJC Scopus subject areas

  • Clinical Neurology
  • Critical Care and Intensive Care Medicine


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