Healthcare-Associated Infections in Critically Ill COVID-19 Patients Across Evolving Pandemic Waves: A Retrospective ICU Study

<i>Background and Objectives</i>: Healthcare-associated infections (HAIs) significantly increase morbidity and mortality in critically ill patients, and their burden became more pronounced during the COVID-19 pandemic. However, data describing the temporal evolution of HAIs, pathogen distribution, and associated risk factors across consecutive pandemic waves remain limited. This study aimed to characterize the epidemiology, microbiology, and outcomes of HAIs in COVID-19 intensive care units (ICU) patients and to identify clinical and laboratory predictors of mortality. <i>Materials and Methods</i>: This retrospective observational study included adult patients with RT-PCR-confirmed COVID-19 who developed at least one HAI ≥ 48 h after ICU admission between March 2020 and December 2020, encompassing the first three pandemic waves in Türkiye, in a tertiary-care ICU. Demographic, clinical, laboratory, and microbiological data were collected. Inflammatory markers and severity scores (SAPS-II, MCCI, and NLR) were analyzed. Receiver operating characteristic (ROC) curve analysis was used to determine optimal cut-off values for mortality prediction. <i>Results</i>: Among the 1656 ICU admissions, 145 patients (8.7%) developed HAIs; after exclusions, 136 patients were included in the final analysis. Bloodstream infections were the most frequent HAI (57%), followed by urinary tract infections (31%), ventilator-associated pneumonia (9%), and surgical site infections (1%). <i>Klebsiella pneumoniae</i> was the predominant pathogen, followed by <i>Candida albicans</i> and <i>Acinetobacter baumannii</i>. Multidrug-resistant organisms, including MRSA and VRE, showed variable distribution across pandemic periods. Overall in-hospital mortality was 74.3%. Non-survivors had significantly higher SAPS-II, MCCI, and NLR values. ROC analysis identified NLR > 38.8 and SAPS-II > 35.5 as mortality-predictive thresholds. Dynamic inflammatory marker patterns correlated with infection timing, and early peaks of CRP, WBC, and IL-6 were associated with worse outcomes. <i>Conclusions</i>: HAIs imposed a substantial clinical burden on critically ill COVID-19 patients, with high mortality driven predominantly by multidrug-resistant bloodstream infections. Severity indices and inflammation-based biomarkers demonstrated strong prognostic value. Temporal shifts in pathogen ecology across pandemic waves underscore the need for adaptive infection-prevention strategies, continuous microbiological surveillance, and strengthened antimicrobial stewardship in critical care settings.