**4. Discussion**

In this study, ICU admission for non-COVID-19 acute respiratory failure requiring invasive mechanical ventilation during the first wave of the COVID-19 pandemic was not associated with an increased risk of healthcare-associated infection. As concerns multidrug resistance, no difference was observed in the number of patients developing MDR infections, neither considering cumulative cultures, nor respectively comparing bloodstream, respiratory tract, and urinary tract infections. Finally, we observed a change into the approach to the antimicrobial therapy, with an increased attention to antibiotic de-escalation and a lower total antimicrobial use.

Several studies explored the epidemiology of ICU infections during the COVID-19 pandemic. The overall increased incidence of HAIs reported during the pandemic [11] could be related to environmental causes (new ICU beds in other spaces in the hospital or ICU, incorporation of new doctors and nurses not previously trained in critical care, changes in the standards of patient care, use of PPI during long shifts) [12] or to the immunological and/or therapeutic characteristics of the COVID-19 infection [13]. Although HAIs in COVID-19 patients are increased [14,15], the relative role of the environmental and/or disease related factors is still not clear. By analyzing non-COVID-19 patients, we found that HAI incidence did not increase during the first wave of the pandemic. Therefore, the increased risk of HAIs already previously found in COVID-19 patients, as compared to non-COVID-19 patients [11,20], may be related to the immunological dysregulation determined by the SARS-CoV-2 virus [21] and/or to use of immunomodulatory drugs [22,23], more than it is related to environmental reasons.

Baccolini et al. [11] observed a higher proportion of HAIs in COVID-19 patients, compared to non-COVID-19 patients (admitted both before and during pandemic), but did not compare HAIs between non-COVID-19 patients admitted before and during the pandemic. They hypothesized a relation between better outcomes in non-COVID-19 patients and a less severe clinical situation on admission during the pandemic, due to social lock-down measures and fear of becoming infected inside the hospitals. Shbaklo et al. [24] observed a reduction in MDR infections during the first wave of the COVID-19 pandemic (the same period as our observation) compared with an increase in the overall bacterial infections during the late period of the pandemic. They attributed this to the growing adherence to infection prevention and control (IPC) procedures [25–27], suggesting that the COVID-19 pandemic may have raised awareness of the need to prevent HAIs and increased the compliance of healthcare workers to IPC in the ICU. We can confirm these findings as we found a comparable incidence of ICU HAIs before and after the start of the COVID-19 pandemic. Moreover, we found no difference in the simplified acute physiology score II (SAPS II) and in diagnosis on admission that were therefore comparable in gravity.

We also assessed the effect of the pandemic on the approach to antimicrobial therapy in ICU patients with ARF. The antimicrobial approach is determined by antimicrobial stewardship programs, listing among the objectives the sustainability of empirical and target treatments (performed through antibiotic selection), dose adjustments, drug monitoring de-escalation and shortening duration to reduce multidrug resistance and selective pressure [28]. We found that being admitted to the ICU in the before the pandemic period was independently associated with a higher risk of antimicrobial use (Table S1). Despite this, we observed no difference in the duration of ICU stay, mortality and number of MDR infections after the shortening of both overall antimicrobial and target therapy in the IP group, as confirmed by previous evidence [29].

Our findings on the tendency to reduced antimicrobial use during the pandemic are in line with the data of the European Centre for Disease Prevention and Control (ECDC), which showed a decrease in the total antibiotic consumption in humans between 2019 and 2020 in both community [30] and hospital settings [31]. Although the report does not provide definite reasons for the reduction in antimicrobial prescription, the reasons may be found in the increase in ICU-related antimicrobial stewardship programs [32] and probably in the redistribution of resources for the ongoing pandemic, which led to a stricter tendency in antibiotic prescription. Interestingly, we also reported a decrease in the duration of steroid therapy during the first wave of the pandemic. Although the cumulative dose was not different among groups, the therapy was shorter in the IP group. This may also

be connected to a higher awareness of the side effects of prolonged steroid therapy on HAIs and therefore is strongly linked to our findings on antibiotic prescription trends. Nevertheless, although the duration of steroid therapy was different, it was not associated with changes in HAI incidence. This could also be an issue considering the possible link between corticosteroid therapy and HAIs previously reported for COVID-19 patients [33].

When analyzing the microbial species associated with HAIs, it was found that *Candida* spp. was the only microorganism whose percentage of isolation increased between PP and IP, becoming the most frequently isolated family of the IP group. Fungal deaths increased during 2020–2021 compared with previous years, primarily driven by COVID-19, particularly those involving *Aspergillus* spp. and *Candida* spp. [34]. Poor data are available on non-COVID-19 patients admitted during the pandemic. Interestingly, the increase of *Candida* spp. infections did not seem to affect the duration of ICU stay, MV and mortality.

Our study has some limitations. First, it is a retrospective single-center cohort study evaluating a limited number of patients. Secondly, the classification of antimicrobial therapy was conducted a posteriori by analyzing the medical records. Thirdly, since the number of patients enrolled in our study is limited, the results must be considered exploratory. Finally, we only evaluated a limited period during the COVID-19 pandemic. Since some recommendations regarding antibiotic prescription changed over time [35], our findings refers only to the first wave of the pandemic and cannot be applied to the other periods.

#### **5. Conclusions**

ICU admission during the first wave of the COVID-19 pandemic for non-COVID-19 acute respiratory failure was not associated with a higher risk of developing hospitalassociated infections. The first wave of the pandemic was characterized by an overall reduction in antimicrobial use in non-COVID-19 patients. Furthermore, this reduction was not related to an increase in hospital-acquired infections or to a worsening of ICU outcomes.

**Supplementary Materials:** The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/jcm11237080/s1, Figure S1: Relative percentage of isolated microorganisms' classes in the cumulative positive cultures, bloodstream cultures, respiratory tract cultures and urinary tract cultures in the two years of analysis. PP, pre-pandemic; IP, intra-pandemic.; Table S1: Multivariate Analysis on risk factors associated to total antimicrobial use; Table S2: Microbial isolations in blood, respiratory tract and urinary tract samples, divided in families in the two years.

**Author Contributions:** Conceptualization: R.C., C.A.V., S.S. and G.S.; Data curation, E.B., A.Q. and G.S.; Formal analysis, E.B. and G.S.; Investigation, A.Q.; Methodology, S.S.; Resources, E.M. and R.R.; Supervision, R.C., E.M., S.B., A.B., R.R. and G.S.; Visualization, V.C. and C.A.V.; Writing—original draft, E.B.; Writing—review and editing, R.C., V.C., R.L.R., C.A.V., S.S. and G.S. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of Area Vasta Emilia Centro (IRCCS Azienda Ospedaliera—Universitaria di Bologna, Policlinico S. Orsola-Malpighi; Protocol number 235/2022/Oss/AOUFe, date of approval 18 May 2022).

**Informed Consent Statement:** Informed consent was obtained or waived when collection was not possible due to the retrospective nature of the analysis, according to local regulations.

**Data Availability Statement:** The data presented in this study are available on request from the corresponding author.

**Acknowledgments:** We would like to thank the staff of the Azienda Ospedaliera Universitaria of Ferrara who collaborated in the clinical management of the patients, especially during the pandemic.

**Conflicts of Interest:** The authors declare no conflict of interest.
