Metronidazole-associated Neurologic Events Original paper

What was studied?

This study investigated the association between metronidazole exposure and the occurrence of central and peripheral nervous system adverse events. Specifically, the study focused on older adults in Ontario, Canada, to determine if there was an increased risk of neurologic toxicity, including cerebellar dysfunction, encephalopathy, and peripheral neuropathy, in those who had recently received metronidazole, compared to those treated with clindamycin.

Who was studied?

The study analyzed a cohort of older adults residing in Ontario, Canada, between 2003 and 2017. It included 1212 patients who were hospitalized or visited the emergency department due to new neurologic events (e.g., cerebellar dysfunction, encephalopathy, or peripheral neuropathy) within 100 days of exposure to metronidazole or clindamycin. These patients were matched with control subjects who had also received either metronidazole or clindamycin but did not experience any neurologic events. The study matched cases and controls based on age, sex, and prior hospital encounters.

What were the most important findings?

The study found a significant association between metronidazole exposure and neurologic events compared to clindamycin. This association remained robust after adjusting for patient demographics, comorbidities, and other medications. Specifically, central nervous system events, including encephalopathy and cerebellar dysfunction, were more strongly associated with metronidazole use than peripheral neuropathy.

The incidence of neurologic events was relatively low, with 0.25% of metronidazole users experiencing a neurologic event within 100 days of exposure. The study did not observe a clear dose-response relationship, although even low doses of metronidazole were linked to an increased risk of neurologic toxicity. These findings suggest that metronidazole’s neurotoxic effects are not strictly dose-dependent, but the drug’s neurologic toxicity still poses a notable risk, particularly for older patients with pre-existing health conditions such as liver disease, alcohol use disorder, and renal dysfunction.

What are the implications of this study?

This study underscores the neurologic risks associated with metronidazole, particularly for older adults, who may be more susceptible to its neurotoxic effects. The findings highlight the importance of monitoring for central and peripheral nervous system adverse events during metronidazole treatment, especially in patients with underlying health conditions. Clinicians should be aware that even low doses of metronidazole may increase the risk of encephalopathy and cerebellar dysfunction, and these risks may not correlate directly with cumulative dose, as traditionally expected.

The study also draws attention to the potential for microbiome-related mechanisms in metronidazole-induced neurotoxicity, as metronidazole’s action on gut microbes and its ability to cross the blood-brain barrier may interact in complex ways that exacerbate neurologic damage. These findings are critical in microbiome-sensitive prescribing, where clinicians must weigh the benefits of metronidazole in treating anaerobic infections like C. difficile and H. pylori against the risks of neurologic toxicity, especially in vulnerable populations.

Overall, this study calls for enhanced awareness and risk stratification when prescribing metronidazole to elderly or comorbid patients and highlights the need for alternative therapies or adjunctive treatments that mitigate the risk of neurologic damage.