Anti-inflammatory Effect of Metronidazole in Hospitalized Patients with Pneumonia due to COVID-19 Original paper

What was studied?

This randomized, single-blind clinical trial evaluated the anti-inflammatory effects of metronidazole in adult patients hospitalized with COVID-19 pneumonia. Conducted in May 2020 in Iran, the study aimed to determine whether oral metronidazole could modulate systemic inflammatory markers, particularly interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), erythrocyte sedimentation rate (ESR), ferritin, and C-reactive protein (CRP), when added to the standard COVID-19 treatment regimen. Patients received either standard care alone or standard care plus 250 mg of oral metronidazole every 6 hours for 7 days. Researchers evaluated changes in inflammation, oxygen saturation, and secondary clinical outcomes such as hospital stay and mortality.

Who was studied?

The study enrolled 44 adult patients with moderate COVID-19 pneumonia confirmed by clinical criteria and lung CT scans. Investigators randomly allocated 20 patients to the intervention group (standard therapy + metronidazole) and 24 to the control group (standard therapy alone). Exclusion criteria included severe disease requiring ICU admission, pregnancy, known allergy to metronidazole, or early discharge before the 7-day observation period. Both groups received national guideline-based antivirals (hydroxychloroquine, lopinavir/ritonavir, and ribavirin), but no glucocorticoids. Researchers ensured baseline comparability by adjusting for age, sex, and antiviral use in the statistical models.

What were the most important findings?

The results indicated that metronidazole significantly reduced ESR on day seven compared to the control group, despite no significant baseline differences. Both groups experienced significant reductions in IL-6, but the metronidazole group showed a greater mean reduction, although this difference did not reach statistical significance when adjusted for baseline covariates. TNF-α, CRP, ferritin, and D-dimer levels declined in both groups but without significant between-group differences. Oxygen saturation improved in both groups over time, again without a statistically significant difference. Mortality was zero in both arms, and metronidazole did not appear to impact length of hospital stay or need for ICU transfer.

From a microbiome standpoint, this study provides clinical evidence that metronidazole exerts anti-inflammatory effects independent of its antimicrobial action, especially by attenuating cytokines implicated in the COVID-19 cytokine storm. While the trial did not evaluate microbiome composition, the findings suggest metronidazole may influence microbiota-driven immune modulation, especially in diseases with overactive innate immune responses. This aligns with prior studies demonstrating its ability to lower IL-6, IL-8, and TNF-α in conditions like bacterial vaginosis and periodontal disease, where microbial dysbiosis contributes to systemic inflammation.

What are the implications of this study?

This study supports the use of metronidazole as a host-directed, immunomodulatory agent in patients with inflammatory complications of viral pneumonia, such as COVID-19. Its ability to reduce ESR and trend toward lowering IL-6 highlights a non-antibiotic role in cytokine modulation, which could be valuable in both infectious and inflammatory diseases where the microbiota fuels immune activation. For microbiome-sensitive clinical decision-making, this expands the therapeutic framing of metronidazole—not only as an anaerobic antimicrobial but also as a modulator of inflammation potentially linked to microbial interactions. However, given metronidazole’s known risk for microbiome disruption, neuropathy, and resistance development, clinicians should use it judiciously and preferentially in short, targeted regimens. The study also underscores the need for larger, longer-term trials to validate these early findings and explore how metronidazole shapes microbiome-host immune dynamics in hospitalized patients.