In this time-series study, we found a significant association between oral vancomycin use and the incidence of hospital-acquired VRE. This association remained robust even after adjusting for the usage of different types of antibiotics and the baseline VRE carriage rate in the model, as well as in sensitivity analyses assuming various time lags. These results suggest that increased use of oral vancomycin may be a contributing factor to the rise in VRE colonisation and infection within hospitals.

The acquisition of VRE is attributed to transmission from external sources or other patients, rather than de novo emergence [12]. Therefore, not only individual antibiotic use but also antibiotic use at the surrounding or institutional level contributes to the risk of VRE spread. Indeed, admission to a bed previously occupied by patients with VRE colonisation has been identified as a risk factor for VRE acquisition [13]. Additionally, the presence of neighbouring patients receiving vancomycin was associated with VRE colonisation, and the duration of VRE colonisation was significantly longer in ICUs with high vancomycin use [14, 15]. This necessitates an analysis of the risk of VRE colonisation based on antibiotic usage, including oral vancomycin, at the institutional level.

In this study, using a dynamic regression time-series model, a significant association between oral vancomycin and the acquisition of VRE was observed. In contrast, the use of IV vancomycin showed no significant association with VRE acquisition. This significant association of oral vancomycin, but not IV vancomycin, with VRE acquisition can be attributed to the fact that the oral form achieves significantly higher concentrations in the gut, the primary milieu for VRE colonisation [16, 17]. Additionally, oral vancomycin interacts with gastrointestinal mucin to form aggregates, which prevents its rapid removal from the gastrointestinal tract [18]. This also leads to prolonged exposure to the antibiotic, thereby contributing more significantly to VRE selection and persistence in the gastrointestinal tract. Indeed, oral vancomycin, compared to metronidazole used in the treatment of CDI, causes greater disruption of normal flora and contributes to VRE persistence in a mouse model [19].

On the other hand, in addition to oral vancomycin, cefuroxime showed a negative association with VRE acquisition, whereas ampicillin-sulbactam showed a significant positive association. Notably, linezolid, an antibiotic used to treat VRE, also showed a positive correlation with VRE acquisition. This counterfactual result may stem from a spurious relationship where increased VRE leads to more linezolid use and decreased VRE leads to less linezolid use [20, 21]. The possibility of spurious relationships between linezolid and VRE is supported by the sensitivity analysis results in this study, that the significant association between linezolid and VRE colonisation at time lag 0 months disappeared at the time lags of 1, 2, and 3 months. In contrast, oral vancomycin was the only antibiotic that consistently showed a robust association with VRE colonisation across all time lags (0, 1, 2, and 3 months), suggesting a true association.

This study has several limitations. First, it was a single-institution observational study. Therefore, further ecological studies from different countries and institutions are needed to confirm the association between oral vancomycin and VRE colonisation. Second, because of the retrospective design of the study, there may have been undetected VRE cases during the study period. Additionally, unmeasured confounders such as changes in infection control policies for patients with VRE or the degree of environmental contamination by VRE, which can be measured through environmental cultures, were not accounted for in this study. Third, as this analysis employed models incorporating differencing, there is a potential risk that valuable information regarding cointegration among the variables may have been lost. Fourth, the inclusion of higher-order ARIMA models and additional variables may have reduced the degrees of freedom and increased model complexity. This complexity could compromise the parsimony and interpretability of the results, which should be considered when drawing conclusions. Lastly, although visual inspection of the residuals from the final ARIMA model suggested approximate normality, statistical tests indicated deviations from a normal distribution, which may affect the reliability and robustness of the results.

In conclusion, we found that the institutional level of monthly oral vancomycin use was significantly associated with hospital-acquired VRE incidence. These results emphasise the need for meticulous attention and antibiotic stewardship regarding the use of oral vancomycin.