Continuous infusion of cefepime and neurotoxicity: a retrospective cohort study

Abstract

Objectives: Neurotoxicity related to cefepime is increasingly reported in the literature but specific data concerning continuous infusion (CI) of the drug are still lacking. Our primary objective was to evaluate the incidence of neurotoxicity related to CI of cefepime and the associated risk factors. Our secondary objectives were to analyse the plasma cefepime concentrations and to define the threshold above which neurotoxicity occurs. Methods: In this single-centre retrospective cohort study, all adult patients who underwent at least one cefepime therapeutic drug monitoring (TDM) and were treated with CI of 4 g/day between January 2017 and June 2019 were included. Neurotoxicity was evaluated according to a strict definition and was correlated with steady-state concentration at the time of toxicity presentation. Results: Ninety-eight patients with 201 cefepime TDM studies were included, with an incidence of neurotoxicity of 14.3% (14/98). Patients with neurotoxicity had more often underlying brain disease (35.7% (5/14) vs 11.9% (10/84), p ¼ 0.030)) and higher steady-state concentrations (mean ± standard deviation 71.8 ± 32.9 mg/L vs 49.6 ± 30.6, p ¼ 0.036) than the others. A receiver operating characteristic curve analysis yielded a cefepime steady-state concentration of 63.2 mg/L as the best cut-off point between patients with or without neurotoxicity. A mean steady-state concentration of 46.4 mg/L was achieved if the dosages of cefepime were adapted to renal function which was under our threshold concentration but above our highest pharmacokinetic/pharmacodynamic target of 32e40 mg/L. Conclusions: Our results suggest that 4 g/day of cefepime adapted to renal function and infused over 24 h is a trade-off for the risk/benefit ratio, when used empirically.

Too Much of a Good Thing: Defining Antimicrobial Therapeutic Targets to Minimize Toxicity

“…In studies of patients receiving β‐lactams as intermittent infusions, significantly higher C min concentrations have been reported among subjects experiencing neurotoxicity 65,68,69 . Meanwhile, higher C SS have been reported among patients with neurotoxicity during receipt of continuous infusions 67 . Overall, these studies demonstrate a clear exposure‐toxicity relationship for β‐lactams and neurotoxicity.…”

“…65,68,69 Meanwhile, higher C SS have been reported among patients with neurotoxicity during receipt of continuous infusions. 67 Overall, these studies demonstrate a clear exposure-toxicity relationship for βlactams and neurotoxicity. However, the neurotoxic potential of these agents may differ by drug and class (i.e., penicillins, cephalosporins, and carbapenems), although no comparative safety studies have been conducted.…”

“…Unfortunately, several βlactam agents have become increasingly recognized as potential causes of neurotoxicity. 65 Reports of βlactam-associated neurotoxicity have implicated cefepime, [66][67][68][69] carbapenems, 65,68 piperacillin, 65,68 flucoxacillin, 65 and other agents in this class 70,71 as potential causes. Although the mechanism underlying this adverse drug effect is not firmly established, a myriad of presenting signs and symptoms have been reported, including encephalopathy, cognitive impairment, seizures, and coma.…”

β-Lactam Therapeutic Drug Monitoring in Critically Ill Patients: Weighing the Challenges and Opportunities to Assess Clinical Value

“…Finally, β-lactam TDM is founded from serum concentrations, which may be a poor surrogate in an individual patient for either infected tissue concentrations of interest (e.g., lung) or, in the case of toxicity, the CNS. In a pertinent example, observational studies examining the relationship between cefepime exposure and neurotoxicity cite a wide range of serum concentrations associated with neurotoxicity (87)(88)(89). The lack of agreement between these datasets suggests a current inability to draw universal conclusions between β-lactam exposure and toxicity in the serum, an observation recently highlighted by Barreto et al (90).…”

Setting the Beta-Lactam Therapeutic Range for Critically Ill Patients: Is There a Floor or Even a Ceiling?

“…A systematic review of cefepime neurotoxicity cases reported the median time to symptom onset was 4 days (interquartile range, 2–6 d) ( 56 ). Days on therapy, a surrogate for total exposure, has predicted neurotoxicity in certain analyses ( 75 , 76 ), but results have been mixed ( 71 , 72 ). Considering one of the largest risk factors for developing neurotoxicity is kidney dysfunction, progressive accumulation of medication over time may lead to sustained toxic exposure, although this remains speculative.…”