Background/Objectives: Ventilator-associated pneumonia (VAP) is the main nosocomial infection in intensive care units (ICUs) that causes the highest morbidity and mortality. The aim of our study is to investigate variations in crude ICU mortality among patients with VAP over the past decade. We also wish to identify associated risk factors, evaluate changes in the etiology, and assess the incidence and impact of inappropriate empirical antibiotic treatment (IEAT). Methods: We conducted a retrospective, observational, single-center study over a 10-year period (2014–2024), including critically ill patients who developed VAP. The population was divided into three periods: (P1) from 2014 to 2018 (pre-COVID-19); (P2) from 2019 to 2021 (COVID-19); and (P3) from 2022 to 2024 (post-COVID-19). Binary logistic regression was used to identify which variables were independently associated with ICU mortality. Results: A total of 220 patients were included in the study (P1 = 47, P2 = 96, and P3 = 77 patients). The most prevalent microorganisms identified were P. aeruginosa, Klebsiella spp., and S. aureus. Significant variations in etiology were not observed over the years. The incidence of IEAT was 4.5%, with no observed differences between the study periods. Crude ICU mortality was 33.6%, with higher rates observed in IEAT (40% vs. 33.3%, p = 0.73). In patients with appropriate empiric antibiotic treatment (AEAT), there was a significant decrease in crude mortality over the years from 42.2% in P1 to 22.2% in P3 (p < 0.001). Age (OR = 1.04; 95% CI = 1.01–1.08) and P2 (OR = 2.8; 95% CI = 1.1–7.4) were found to be independently associated with an increased risk of mortality. Conversely, a lower risk of death was associated with mean arterial pressure (OR = 0.94; 95% CI = 0.69–0.99) and the use of syndromic respiratory panel (OR = 0.23; 95% CI = 0.07–0.68). Conclusions: A reduction in crude VAP mortality over the years was observed, with no change in the etiology or rate of IEAT. The implementation of protocols using respiratory syndromic panels could be a measure to implement to reduce VAP mortality.
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