From the Duke Clinical Research Institute, Durham, North Carolina.
Department of Surgery, Duke University Medical Center, Durham, North Carolina.
Pediatr Infect Dis J. 2023 Jan 1;42(1):27-31. doi: 10.1097/INF.0000000000003726. Epub 2022 Oct 3.
Infants frequently receive metronidazole at variable doses and duration for surgical site infection prophylaxis and treatment of intra-abdominal infections. Seizures are a rare (but potentially devastating) side effect of metronidazole, yet the prevalence of seizures in infants, as well as the relationship with metronidazole dose and exposure, are unknown.
We examined the Pediatrix Clinical Data Warehouse for infants in neonatal intensive care units from 1997 to 2018 who received at least 1 dose of metronidazole during their first 120 days of life. We used an existing population pharmacokinetic model to simulate exposure parameters, estimating multivariable associations between metronidazole dosing and exposure parameters, and the occurrence of seizure.
There were 19,367 intravenous doses of metronidazole given to 1546 infants, and 31 experienced a seizure. Infants with a seizure had a longer median (interquartile values) duration of metronidazole exposure than those without (11 days [6, 15] vs. 7 [4, 11], P = 0.01). Each added day of metronidazole (OR = 1.06, 95% CI: 1.02-1.10), and each standard deviation increase in cumulative area under the plasma concentration-time curve (OR = 1.27, 95% CI: 1.11-1.45) were associated with increased odds of seizure. Higher simulated maximum plasma concentration was associated with lower odds of seizure (OR = 0.88, 95% CI: 0.81-0.96).
Longer metronidazole exposure and higher cumulative exposure could be associated with increased odds of infant seizures. Using a large observational dataset allowed us to identify a rare adverse event, but prospective studies are needed to validate this finding and further characterize metronidazole dose- and exposure-safety relationships.
婴儿经常接受不同剂量和时长的甲硝唑用于手术部位感染预防和治疗腹腔内感染。癫痫发作是甲硝唑的一种罕见（但潜在破坏性）的副作用，但目前尚不清楚婴儿癫痫发作的发生率，以及与甲硝唑剂量和暴露的关系。
我们在 1997 年至 2018 年期间检查了新生儿重症监护病房的佩特里克斯临床数据仓库中至少接受过 1 剂甲硝唑治疗的婴儿，他们在生命的前 120 天内接受了至少 1 剂甲硝唑治疗。我们使用现有的群体药代动力学模型来模拟暴露参数，估计甲硝唑剂量与暴露参数和癫痫发作之间的多变量关系。
共给予 1546 例婴儿 19367 剂静脉甲硝唑，其中 31 例发生癫痫发作。有癫痫发作的婴儿的甲硝唑暴露中位数（四分位间距）比无癫痫发作的婴儿长（11 天[6，15] vs. 7 [4，11]，P = 0.01）。甲硝唑暴露天数增加（OR = 1.06，95%CI：1.02-1.10），累积血浆浓度-时间曲线下面积增加一个标准差（OR = 1.27，95%CI：1.11-1.45）与癫痫发作的可能性增加相关。较高的模拟最大血浆浓度与较低的癫痫发作可能性相关（OR = 0.88，95%CI：0.81-0.96）。
较长的甲硝唑暴露和较高的累积暴露可能与婴儿癫痫发作的可能性增加有关。使用大型观察性数据集可以识别罕见的不良事件，但需要前瞻性研究来验证这一发现，并进一步描述甲硝唑剂量-和暴露安全性关系。
