Frequency and Risk Factor Analysis for Metronidazole-Associated Neurologic Adverse Events

Background: Little is known about the risk factors and frequency of metronidazole-associated neurological adverse events.

Objective: To investigate the risk factors and frequency of metronidazole-associated neurological adverse events.

Design: This retrospective study contained two parts. First, we investigated metronidazole treatment-associated neurologic adverse events by performing a population-based cohort study using the Korea Adverse Event Reporting System (KAERS) database from January 2011 to December 2020. Second, we conducted a matched case-control study based on a retrospective cohort of patients treated with metronidazole between January 2006 and July 2021 at a tertiary hospital in South Korea. The data analysis was performed from August 2021 to April 2022.

Participants: In the case-control study, case patients were defined as those diagnosed with metronidazole-associated encephalopathy or peripheral neuropathy during the study period with causal assessment based on the clinical diagnoses and findings from associated tests. In a ratio of 1:3, case patients were compared to a control group of patients prescribed metronidazole without neurologic adverse events matched for age and cumulative dose of metronidazole.

Main measures: Frequency and risk factors for metronidazole-associated neurological adverse events.

Key results: Overall, 2,309 cases of neurologic adverse events were reported to the KAERS from 2011 to 2020, and the number of reported neurological adverse events showed an increasing trend. Further, 92,838 patients were prescribed metronidazole during the study period at the Severance Hospital; 54 patients were diagnosed with metronidazole-associated encephalopathy or peripheral neuropathy, 40 with central and 28 with peripheral nervous system adverse events. Liver cirrhosis, chronic kidney disease, intravenous administration, and lower body weight were identified as risk factors for these adverse events.

Conclusions: The number of reported metronidazole-associated neurological adverse events are increasing. Prolonged metronidazole treatment in patients with the aforementioned factors requires careful examination for neurological adverse events.