title: Cefepime plasma concentrations and clinical toxicity: a retrospective cohort study.
abstract: OBJECTIVE
  Cefepime remains an important antibiotic for severe bacterial infections, yet some meta-analyses have shown elevated mortality among patients randomized to it. Therapeutic drug monitoring (TDM) of β-lactam antibiotics is increasing, but optimal plasma concentrations remain unknown. We examined clinical outcomes of patients undergoing cefepime TDM in an initial effort to define the drug's toxicity threshold.
  
  
  METHODS
  In this single-centre retrospective cohort study, we enrolled all adult hospitalized patients receiving cefepime and undergoing TDM from January 2013 through July 2016. The primary outcome was the incidence of clinical toxicity; a secondary outcome was clinical failure. Plasma samples were analysed via high-performance liquid chromatography with ultraviolet detection.
  
  
  RESULTS
  A total of 161 cefepime concentrations were drawn from 93 patients. Roughly half (82/161, 51%) and one-third (49/161, 30%) were trough and steady-state levels from patients receiving intermittent and continuous infusions, respectively; median concentrations were 17.6 mg/L (IQR 9.7-35.2) and 29.2 mg/L (IQR 18.9-45.9). Ten patients (11%) experienced a neurologic event considered at least possibly related to cefepime; neurotoxicity was associated with poorer renal function (median creatinine clearance 54 (IQR 39-97) vs. 75 mL/min/1.732(IQR 44-104)) and longer cefepime durations (mean 8.3 (SD±6.7) vs. 13.3 days (± 14.2), p = 0.071). Patients with trough levels >20 mg/L had a fivefold higher risk for neurologic events (OR 5.05, 95% CI 1.3-19.8).
  
  
  CONCLUSIONS
  Neurotoxicity potentially related to cefepime occurred at plasma concentrations >35 mg/L. For those receiving intermittent infusions, trough concentrations >20 mg/L should be avoided until further information is available from prospective studies.
authors.affiliation: University of Geneva School of Medicine, Geneva, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Huwyler
authors.affiliation: University of Geneva School of Medicine, Geneva, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Lenggenhager
authors.affiliation: Infection Control Programme, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Abbas
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors.forename: K
authors.initials: K
authors.lastname: Ing Lorenzini
authors.affiliation: Toxicology Laboratory, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Hughes
authors.affiliation: Infection Control Programme, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland; Division of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Huttner
authors.affiliation: Toxicology Laboratory, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Karmime
authors.affiliation: Division of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors.forename: I
authors.initials: I
authors.lastname: Uçkay
authors.affiliation: Infection Control Programme, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: von Dach
authors.affiliation: Toxicology Laboratory, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Lescuyer
authors.affiliation: Infection Control Programme, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland; Division of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Harbarth
authors.affiliation: Infection Control Programme, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland; Division of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Huttner
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D000077723:Cefepime; D002511:Cephalosporins / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000453:epidemiology; D010949:Plasma / Q000737:chemistry*; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D000077723:Cefepime
keywords: Cefepime; Plasma concentration; Toxicity; Toxicity threshold; β-Lactam therapeutic drug monitoring