Etiologic Patterns and Evolution of Healthcare-Associated Infections in the Pandemic and Post-Pandemic Periods: A County-Level Multicenter Study from Southeastern Romania

<b>Background/Objectives</b>: Healthcare-associated infections (HAIs) remain a major source of morbidity, mortality, and healthcare burden, and were profoundly affected by the COVID-19 pandemic through changes in case mix, care organization, and antimicrobial use. This study aimed to compare the epidemiology, etiology, ward distribution, risk factors, and outcomes of HAIs during the pandemic and post-pandemic periods in southeastern Romania, with particular emphasis on Clostridioides difficile infection (CDI), multidrug-resistant (MDR) pathogens, and in-hospital mortality. <b>Methods</b>: This retrospective observational study included 3929 patients with confirmed HAIs reported by 10 hospitals in one Romanian county between March 2020 and December 2024, divided into a pandemic period (March 2020-March 2022) and a post-pandemic period (April 2022-December 2024). Sociodemographic, clinical, ward-related, therapeutic, and microbiological variables, together with discharge status and cause of death, were analyzed using Fisher's exact test, Z-tests with Bonferroni correction, the Mann-Whitney U test, and multivariable models, applying national and ECDC-aligned surveillance definitions for HAIs. <b>Results</b>: Patients were predominantly older adults (median age 67 years), with a slight male and urban predominance. Hospital stays were longer during the pandemic. Immunosuppression, previous surgery, antisecretory therapy, and chemotherapy were more frequent post-pandemic. HAIs were mainly reported from medical wards, with a relative shift towards intensive care units during the pandemic; pediatric wards carried a smaller burden. CDI was the leading HAI (about half of all cases) with higher post-pandemic prevalence, whereas SARS-CoV-2 infections predominated in medical and surgical wards; <i>Acinetobacter baumannii</i> and <i>Klebsiella pneumoniae</i> clustered in intensive care units during the pandemic, and were more often associated with mortality. Overall, 59.7% of patients improved and 17.5% died, with higher mortality during the pandemic, while post-pandemic deaths were more frequently unrelated to HAIs. <b>Conclusions</b>: This study demonstrates a substantial and ongoing burden of healthcare-associated infections in southeastern Romania, with elderly patients with prolonged hospital stays and complex medical conditions being most affected and experiencing considerable mortality, particularly in medical and intensive care units. After the pandemic, <i>Clostridioides difficile</i> infections became more prevalent in the context of repeated antibiotic use and immunosuppression. Mortality among patients with HAIs was higher during the pandemic, whereas in the post-pandemic period deaths were more often unrelated to HAIs, underscoring the need to strengthen antimicrobial stewardship programs and infection prevention strategies.