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Sutton SS, Magagnoli J, Cummings TH, Hardin JW. Melatonin as an Antimicrobial Adjuvant and Anti-Inflammatory for the Management of Recurrent Clostridioides difficile Infection. Antibiotics (Basel). 2022;11(11):1472. Published 2022 Oct 25. doi:10.3390/antibiotics11111472




Due to the potent anti-inflammatory and antioxidants properties of melatonin and its reported antibacterial activity against some pathogens, this retrospective cohort study hypothesized that melatonin could be used as an antimicrobial adjuvant to decrease the reoccurrence of Clostridioides difficile infections (CDI). The authors found that patients exposed to melatonin had a 21.6% lower risk for recurrent CDI.


Our comments/takeaway from the article


Clostridioides difficile (C. difficile) pathogenesis has a strong association with inflammation. One function of melatonin is that it is a powerful anti-inflammatory and antioxidant, with existing research demonstrating the benefits for GI health, making it a reasonable choice as a potential therapy to aid in lowering inflammation.

The results are promising from this large cohort study, with a 21.6% lower risk for recurrent CDI; however, this study has several limitations, stressing the importance of further research to be conducted. The clinical utility of melatonin as an adjuvant therapy for patients with Clostridioides difficile infection is not yet established. We would like to see future studies include a controlled dosing intervention (i.e., 0.3 mg- the physiological dose of melatonin) over a defined time period. 


Article Summary


This retrospective cohort study includes patients with an inpatient diagnosis of recurrent Clostridioides difficile Infection (CDI) and a positive Clostridioides difficile test result. The cohort included 24,782 patients; 3,457 patients were exposed to melatonin, and 21,325 patients did not have melatonin exposure. Exposure to melatonin was identified as those individuals who were prescribed melatonin within 1 day +/ - of the positive Clostridioides difficile test result. 


Inclusion criteria:

  • Positive C. difficile polymerase chain reaction (PCR) or enzyme immunoassay (EIA) test

  • Diagnosed in an inpatient setting, including nursing homes

  • Treated with metronidazole, vancomycin, or fidaxomicin


Patients were followed 56 days after initial CDI diagnosis, death, or first incidence of reoccurrence, as most recurrence develops within 15-56 days.  


Overall, the rate of CDI reoccurrence was statistically significant, with a 13% recurrence rate for those who did not have melatonin exposure compared to 10% for those who did (p-value < 0.001). Further, when adjusting for variables using Cox proportional hazards models, the cohort exposed to melatonin had a 16% lower risk for recurrent CDI (HR=0.84, 95%CI=0.75-0.94). Finally, the propensity-score-weighted statistical model demonstrated a 22% lower rate of reoccurrence for those exposed to melatonin (HR=0.78, 95% CI = 0.67-0.91). Further sub-analyses were completed accounting for various confounding factors, with results consistent with the initial findings of a 22% reduced risk factor for CDI reoccurrence in those individuals who had taken melatonin.

Limitations include:

  • Undisclosed/unknown dose of melatonin that was taken

  • Undisclosed/unknown length of time melatonin was taken

  • The authors speculate that melatonin was taken for the management of sleep

  • Undisclosed/unknown if individuals were taking other supplements and/or medications other than 1 of the 3 antibiotics in the inclusion criteria

  • Melatonin can easily be obtained over the counter; therefore, those in the unexposed cohort may have taken melatonin, unbeknownst to the researchers.


The authors state, “...we are not advocating for the clinical utilization of melatonin as a pharmacotherapy option for recurrent CDI based on our findings. The intent of this study was to demonstrate the potential of affecting inflammation for the management of CDI and we utilized melatonin as the clinical example.”


Article reviewed by Kim Ross, DCN

Content reviewed by Deanna Minich, PhD

November 18, 2022

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