The Resistance Paradox in COVID-19 Ventilator-Associated Pneumonia: A Retrospective Study on Rapid Molecular Stewardship

<b>Background/Objectives:</b> The COVID-19 pandemic complicated the diagnosis of Ventilator-Associated Pneumonia (VAP), leading to empiric antibiotic overuse due to the difficulty in distinguishing viral progression from bacterial superinfection. However, it remains unclear whether COVID-19-associated VAP displays a distinct antimicrobial resistance profile compared to classical VAP. <b>Methods:</b> This monocentric, retrospective cohort study primarily investigated differences in clinical phenotypes and antibiotic resistance profiles between patients with VAP-COVID (n = 26) and non-COVID-VAP (n = 26). Logistic regression was used to identify factors associated with the COVID-19 phenotype and predictors of antimicrobial resistance. As a secondary objective, we evaluated the diagnostic efficacy of a multiplex Point-of-Care PCR (POC-PCR) system (n = 22) compared to standard culture (n = 26) regarding turnaround time and resistance detection. <b>Results:</b> Patients with VAP-COVID exhibited significantly higher resistance rates to carbapenems (76.9% vs. 50%, <i>p</i> = 0.04) and fluoroquinolones (88.5% vs. 61.5%, <i>p</i> = 0.02) despite fewer traditional risk factors at admission. The clinical profile of the VAP-COVID group was distinguished by a significantly lower incidence of parapneumonic pleural effusion (19.2% vs. 84.6%, <i>p</i> < 0.001) and a higher median Neutrophil-to-Lymphocyte Ratio (41.36 vs. 9.63, <i>p</i> < 0.001). Regarding diagnostic speed, POC-PCR significantly reduced the time to result validation compared to standard culture (~1 h vs. ~62.5 h, <i>p</i> < 0.001). <b>Conclusions:</b> VAP in COVID-19 patients presents a distinct microbiological profile characterized by higher antimicrobial resistance. In this context, the integration of rapid molecular diagnostics may support earlier microbiological guidance compared to standard methods.