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Background: Carbapenem-Resistant Gram-Negative Bacteria, including Carbapenem-Resistant Enterobacterales (CRE) and Carbapenem-Resistant Pseudomonas aeruginosa (CRPA), are common causes of infections in intensive care units (ICUs) in Italy., Objective: This prospective observational study evaluated the epidemiology, management, microbiological characterization, and outcomes of hospital-acquired CRE or CRPA infections treated in selected ICUs in Italy., Methods: The study included patients with hospital-acquired infections due to CRE and CRPA treated in 20 ICUs from June 2021 to February 2023. The primary endpoint was the 1-year incidence of CRE/CRPA infections. Secondary endpoints included the rate of CRE/CRPA infections, mortality in ICU, infection outcome, and microbiological characterization., Results: Among 13,088 patients admitted over the 12-month study period across each of the 20 ICUs, 283 had CRE infections, and 138 had CRPA infections. The incidence of CRE and CRPA infections was 3.57 per 1000 patient days and 1.74 per 1000 patient days, respectively. The proportion of CRE and CRPA infections over the total number of infections due to Enterobacterales and Pseudomonas aeruginosa was 19.2% and 26.8%, respectively. Among 158 patients included in the full analysis, 98 (62%) had CRE infections and 60 (38%) had CRPA infections. Ventilator-associated pneumonia and bloodstream infections were the most common infections, occurring in 53.8 and 34.2% of cases. Empirical therapy targeting gram-negative pathogens resulted inappropriate in 59.2% of analysed patients (77/130). The overall crude mortality in ICU rate was 30.4%, with a higher rate in CRE patients (36.7%) than in CRPA patients (20.0%). Clinical success, including microbiological eradication, was achieved in 50.6% of cases. Klebsiella pneumoniae was observed as the predominant CRE species, and all CRE isolates, including metallo-β-lactamases-producing CRE (MBL-CRE), were susceptible to Aztreonam-Avibactam., Conclusions: These results highlight the high prevalence of CRE/CRPA infections in Italian ICUs and emphasize the need for enhanced prevention and surveillance strategies., Competing Interests: Declarations. Consent for publication: Not applicable. Competing interests: F.R.F and M.A.V.P. are Pfizer employees. G.D.P. received research grants from Pfizer and Gilead. A.C. received fees for lectures or advisory board membership from Gilead, MSD, Mundipharma, Pfizer. M.A. received fees for board participation from Shionogi, Menarini and Pfizer, and research grant from GE and Fisher & Paykel. A.D. received fees from Aspen, BIOVIIIx, Edwards, Grifols, Viatris. A.F. received fees for scientific communication from Shionogi and Grifols. M.G. received fees for advisory board and speaking service at congresses from Pfizer, Gilead, MSD, Thermofisher. G.M. received fee for board participation form Gilead, 3 M, Thermofisher and was a lecturer for Pfizer. F.P was Co-Principal investigator for the profit study “Clinical and economic evaluation of faster versus conventional AST in Covid-19 and non Covid-19 ICU patients with bloodstream infections (LIFETIMES study)”, sponsored by HEOR-Qlinea. P.V. was a consultant/speaker for Shionogi, an advisor/speaker for Gilead, Pfizer, Merck, Biomerieux, Advan, an advisor for Menarini, and received research grant from Advanz and Gilead. The other authors declare no conflict of interest., (© 2025. The Author(s).)