Faculty of Medicine, University of Bern, Bern, Switzerland; Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland; Department of Geriatrics and Rehabilitation, Hôpital Fribourgeois Tavel, Tavel, Switzerland.
Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland.
Clin Microbiol Infect. 2020 Mar;26(3):333-339. doi: 10.1016/j.cmi.2019.06.028. Epub 2019 Jul 5.
Toxic serum cefepime trough concentrations are not well defined in the current literature. We aimed to define a more precise plasma trough concentration threshold for this antibiotic's neurological toxicity and to identify individuals at risk for developing neurotoxic side effects.
Retrospective study including all individuals who underwent cefepime therapeutic drug monitoring (TDM) between 2013 and 2017. Individuals with cefepime concentrations other than trough were excluded. The primary outcome was to assess the incidence of neurotoxicity and its relationship with cefepime plasma trough concentrations. Secondary outcomes were the relationship of renal function, cefepime daily dose, age, and cerebral and general co-morbidities with the occurrence of neurotoxicity. We also compared the mortality rate during hospitalization in individuals with and without neurotoxicity, and the possible impact of neuroprotective co-medications on outcomes.
Cefepime concentrations were determined in 584 individuals. Among 319 individuals with available trough concentrations included, the overall incidence of neurotoxicity was 23.2% (74 of 319 individuals). Higher cefepime plasma trough concentrations were significantly associated with risk of neurotoxicity (no neurotoxicity 6.3 mg/L (interquartile range (IQR) 4.1-8.6) versus with neurotoxicity 21.6 mg/L (IQR 17.0-28.6), p <0.001). Individuals with presumed cefepime neurotoxicity had a significantly lower renal function (estimated glomerular filtration rate 82.0 mL/min/1.73 m (IQR 45.0-105.0) versus 35.0 mL/min/1.73 m (IQR 23.3-53.3], p <0.001), and significantly higher in-hospital mortality (19 (7.8%) versus 26 (35.1%) individuals, p <0.001). No neurotoxic side effects were seen below a trough concentration of 7.7 mg/L. Levels ≥38.1 mg/L always led to neurological side effects.
In individuals with risk factors for cefepime neurotoxicity, such as renal insufficiency, TDM should be systematically performed, aiming at trough concentrations <7.5 mg/L.
目前文献中尚未明确毒血清头孢吡肟谷浓度的定义。我们旨在为该抗生素的神经毒性确定更精确的血浆谷浓度阈值，并确定发生神经毒性副作用的风险人群。
本回顾性研究纳入了 2013 年至 2017 年间接受头孢吡肟治疗药物监测（TDM）的所有个体。排除了头孢吡肟浓度非谷值的个体。主要结局是评估神经毒性的发生率及其与头孢吡肟血浆谷浓度的关系。次要结局是肾功能、头孢吡肟日剂量、年龄以及脑和全身合并症与神经毒性发生的关系。我们还比较了有神经毒性和无神经毒性个体住院期间的死亡率，以及神经保护合并用药对结局的可能影响。
共确定了 584 名个体的头孢吡肟浓度。在纳入的 319 名可获得谷浓度的个体中，神经毒性的总发生率为 23.2%（74/319 名个体）。较高的头孢吡肟血浆谷浓度与发生神经毒性的风险显著相关（无神经毒性者为 6.3mg/L（四分位间距（IQR）4.1-8.6），而有神经毒性者为 21.6mg/L（IQR 17.0-28.6），p<0.001）。有神经毒性的个体肾功能明显降低（估计肾小球滤过率为 82.0ml/min/1.73m（IQR 45.0-105.0），而肾功能正常的个体为 35.0ml/min/1.73m（IQR 23.3-53.3]，p<0.001），住院死亡率显著升高（19（7.8%）例与 26（35.1%）例，p<0.001）。谷浓度低于 7.7mg/L 时未见神经毒性副作用。浓度≥38.1mg/L 时总会出现神经副作用。
对于有头孢吡肟神经毒性风险因素的个体，如肾功能不全，应系统进行 TDM，目标为谷浓度<7.5mg/L。
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