IntroductionClostridioides difficile (C. difficile)colonizes the large intestine, rendering healthy individuals asymptomatic carriers of the disease. In certain instances,C. difficileinfection (CDI) occurs. Antibiotic use remains the leading risk factor for CDI. During the coronavirus disease 2019 (COVID-19) pandemic, multiple risk and protective factors for and against CDI were identified, and as such multiple studies tried to analyze the pandemic’s overall effect on CDI incidence rates, with contradictory results. Our study’s aim is to further characterize the CDI incidence rates trends, but for a longer period of 22 months in the pandemic.MethodsWe included only adult (>18 years) patients, diagnosed with CDI during their hospitalization for the following period: January 1, 2018, to December 31, 2021. Incidence was calculated as cases per 10,000 patient days. The period identified as the COVID-19 pandemic period was the following: March 1, 2020, to December 31, 2021. All analyses were performed by an expert statistician using Minitab software (Minitab Inc., State College, Pennsylvania, United States).ResultsThe mean CDI incidence rate per 10,000 patient-days was 6.86 +/-2.1. The 95% confidence interval for the CDI incidence rate prior to the pandemic was found at 5.67 +/-0.35 while the interval during the pandemic was calculated at 8.06 +/- 0.41 per 10,000 patient days. Those results reveal a statistically significant increase in CDI incidence rates during the COVID-19 era.ConclusionMultiple risk and protective factors for and against hospital-acquired infections (including CDI) have been identified during the unprecedented COVID-19 healthcare crisis. In the literature, there is high controversy regarding the trends of CDI incidence during the pandemic. The current study analyzed an almost two-year period into the pandemic, identifying an increase in CDI rates when compared to the pre-pandemic era.