University of New England College of Pharmacy, 716 Stevens Ave, Portland, ME, 04102, USA.
Department of Pharmacy, Maine Medical Center, 22 Bramhall St, Portland, ME, 04102, USA.
Crit Care. 2017 Nov 14;21(1):276. doi: 10.1186/s13054-017-1856-1.
Cefepime is a widely used antibiotic with neurotoxicity attributed to its ability to cross the blood-brain barrier and exhibit concentration-dependent ϒ-aminobutyric acid (GABA) antagonism. Neurotoxic symptoms include depressed consciousness, encephalopathy, aphasia, myoclonus, seizures, and coma. Data suggest that up to 15% of ICU patients treated with cefepime may experience these adverse effects. Risk factors include renal dysfunction, excessive dosing, preexisting brain injury, and elevated serum cefepime concentrations. We aimed to characterize the clinical course of cefepime neurotoxicity and response to interventions.
A librarian-assisted search identified publications describing cefepime-associated neurotoxicity from January 1980 to February 2016 using the CINAHL and MEDLINE databases. Search terms included cefepime, neurotoxicity, encephalopathy, seizures, delirium, coma, non-convulsive status epilepticus, myoclonus, confusion, aphasia, agitation, and death. Two reviewers independently assessed identified articles for eligibility and used the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) for data reporting.
Of the 123 citations identified, 37 (representing 135 patient cases) were included. Patients had a median age of 69 years, commonly had renal dysfunction (80%) and required intensive care (81% of patients with a reported location). All patients exhibited altered mental status, with reduced consciousness (47%), myoclonus (42%), and confusion (42%) being the most common symptoms. All 98 patients (73% of cohort) with electroencephalography had abnormalities, including non-convulsive status epilepticus (25%), myoclonic status epilepticus (7%), triphasic waves (40%), and focal sharp waves (39%). As per Food and Drug Administration (FDA)-approved dosing guidance, 48% of patients were overdosed; however, 26% experienced neurotoxicity despite appropriate dosing. Median cefepime serum and cerebrospinal fluid (CSF) concentrations were 45 mg/L (n = 21) and 13 mg/L (n = 4), respectively. Symptom improvement occurred in 89% of patients, and 87% survived to hospital discharge. The median delay from starting the drug to symptom onset was 4 days, and resolution occurred a median of 2 days after the intervention, which included cefepime discontinuation, antiepileptic administration, or hemodialysis.
Cefepime-induced neurotoxicity is challenging to recognize in the critically ill due to widely varying symptoms that are common in ICU patients. This adverse reaction can occur despite appropriate dosing, usually resolves with drug interruption, but may require additional interventions such as antiepileptic drug administration or dialysis.
头孢吡肟是一种广泛应用的抗生素，具有神经毒性，这与其能够穿过血脑屏障并表现出浓度依赖性γ-氨基丁酸（GABA）拮抗作用有关。神经毒性症状包括意识降低、脑病、失语症、肌阵挛、癫痫发作和昏迷。有数据表明，多达 15%的接受头孢吡肟治疗的 ICU 患者可能会出现这些不良反应。风险因素包括肾功能不全、过量用药、预先存在的脑损伤和血清头孢吡肟浓度升高。我们旨在描述头孢吡肟神经毒性的临床过程和对干预措施的反应。
通过 CINAHL 和 MEDLINE 数据库，在 1980 年 1 月至 2016 年 2 月期间，使用图书馆员辅助搜索，检索了描述头孢吡肟相关性神经毒性的出版物。搜索词包括头孢吡肟、神经毒性、脑病、癫痫发作、谵妄、昏迷、非惊厥性癫痫持续状态、肌阵挛、意识混乱、失语症、激越和死亡。两名审查员独立评估了入选文章的资格，并使用系统评价和荟萃分析报告的首选报告项目（PRISMA-P）进行数据报告。
在 123 条引用中，有 37 条（代表 135 例患者）符合入选标准。患者的中位年龄为 69 岁，常见的肾功能不全（80%）和需要重症监护（81%的患者报告了地点）。所有患者均表现出精神状态改变，意识降低（47%）、肌阵挛（42%）和意识混乱（42%）是最常见的症状。所有 98 例（队列的 73%）进行了脑电图检查的患者均存在异常，包括非惊厥性癫痫持续状态（25%）、肌阵挛性癫痫持续状态（7%）、三相波（40%）和局灶性尖波（39%）。根据食品和药物管理局（FDA）批准的剂量指南，48%的患者用药过量；然而，尽管剂量合适，仍有 26%的患者出现神经毒性。头孢吡肟血清和脑脊液（CSF）的中位数浓度分别为 45mg/L（n=21）和 13mg/L（n=4）。89%的患者症状改善，87%的患者存活至出院。从开始用药到症状出现的中位时间为 4 天，干预后中位缓解时间为 2 天，干预措施包括停止使用头孢吡肟、使用抗癫痫药物或血液透析。
由于 ICU 患者中常见的症状变化广泛，因此在重症患者中很难识别头孢吡肟引起的神经毒性。尽管剂量合适，但仍可能发生这种不良反应，通常停药后可缓解，但可能需要其他干预措施，如使用抗癫痫药物或透析。
