title: An exploratory analysis of the ability of a cefepime trough concentration greater than 22 mg/L to predict neurotoxicity.
abstract: BACKGROUND
  Cefepime trough concentrations >22 mg/L (T(>22)) have been associated with neurotoxicity in a single study.
  
  
  METHODS
  Neurotoxicity outcomes for 28 cefepime-treated adult patients with febrile neutropenia were abstracted from the literature. The precision of T(>22) to predict neurotoxicity was quantified using 95% confidence intervals. Thirty-two cefepime-treated patients contributed serum concentrations for a pharmacokinetic model, fit using the Nonparametric Adaptive Grid algorithm within the Pmetrics package for R. Concentration-time curves were simulated for common dosing schemes and 3 renal dispositions. Probabilities of neurotoxicity and numbers needed to harm were calculated from simulations according to the proposed pharmacokinetic/toxicodynamic threshold of T(>22). Bayesian modeling was utilized to explore other pharmacokinetic parameters relationships with neurotoxicity.
  
  
  RESULTS
  The mean probability of neurotoxicity at T(>22) was 51.4% (95% CI: 16.4-85.0%). Among the schemes and renal dispositions simulated, the combination of cefepime 2 g every 8 h and a creatinine clearance of 60 mL/min produced the greatest probability of neurotoxicity (48.3%). Estimated numbers needed to harm according to T(>22) ranged from 2.1 to 18.5 persons. Explorations of maximal serum concentration and area under the curve demonstrated high levels of collinearity, making it impossible to identify trough concentrations as the driver of neurotoxicity.
  
  
  CONCLUSIONS
  T(>22) had low precision as a predictive neurotoxic threshold. When a neurotoxic threshold of T(>22) was assumed, projected neurotoxicity rates and numbers needed to harm greatly exceeded observed neurotoxicity rates in the general population and in high risk subpopulations. Other drug exposure metrics should be explored.
authors.affiliation: Department of Pharmacy Practice, Midwestern University, Chicago College of Pharmacy, Downers Grove, IL, USA; Department of Pharmacy, Northwestern Memorial Hospital, Chicago, IL, USA.
authors.forename: Nathaniel J
authors.initials: NJ
authors.lastname: Rhodes
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Kuti
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
authors.affiliation: University of Southern California, Keck School of Medicine, Los Angeles, CA, USA; Laboratory of Applied Pharmacokinetics and Bioinformatics (LAPKB), Children's Hospital of Los Angeles, Los Angeles, CA, USA.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Neely
authors.affiliation: Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, NY, USA.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Nicasio
authors.affiliation: Department of Pharmacy Practice, Midwestern University, Chicago College of Pharmacy, Downers Grove, IL, USA; Department of Pharmacy, Northwestern Memorial Hospital, Chicago, IL, USA. Electronic address: mscheetz@nm.org.
authors.forename: Marc H
authors.initials: MH
authors.lastname: Scheetz
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D001499:Bayes Theorem; D000077723:Cefepime; D002511:Cephalosporins / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D006801:Humans; D007668:Kidney / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000209:etiology*
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D000077723:Cefepime
keywords: Adverse reactions; Modeling; Pharmacodynamics; Pharmacokinetics