Objective. To analyze application of a new combination of beta-lactam antibiotic and beta-lactamase inhibitor (cefepime/sulbactam) as a carbapenem-replacement technology for the treatment of severe in-hospital infections. Material and methods. We conducted a single-center, comparative, retrospective, non-interventional study. The trial included patients who received cefepime/sulbactam or carbapenem as a first-line treatment in an emergency hospital for the period from July to November 2019. The target number of patients who received at least one dose of the antibiotic was 50 in each group. Clinical and bacteriological effectiveness of the treatment, incidence of superinfection and selection of carbapenem-resistant bacteria after the onset of therapy were evaluated in both groups. Results. Treatment outcomes were evaluated in 45 patients treated with cefepime/sulbactam and in 47 patients treated with carbapenem (meropenem, ertapenem, imipenem or doripenem). The majority of patients in both groups had severe infection: 58.7% — sepsis, 29.3% — septic shock, over 80% of patients were at the ICU. The most common infection (43.5%) was nosocomial pneumonia including VAP. The studied antibiotics were prescribed empirically in most cases (83 patients) including monotherapy in 80.4% of patients. Positive clinical effect (71.1 and 61.7%, respectively) and eradication of the pathogen (87.5 and 73.0%) were observed in the majority of patients who received cefepime/sulbactam or carbapenem (p>0.05). There was significantly less incidence of superinfection in cefepime/sulbactam group compared to carbapenem therapy (22.2 and 53.3%, respectively, p=0.001). K. pneumoniae (44.8%) and A. baumannii (34.5%) predominated among the microorganisms that caused superinfection during treatment with carbapenems. Selection of carbapenem-resistant microorganisms after antibacterial therapy onset (in 5.3 days on the average) was more common in case of carbapenems (74.5%) compared to cefepime/sulbactam (20%) (p=0.0001). Carbapenem-resistant bacteria were represented by K. pneumoniae, P. aeruginosa and A. baumannii. Moreover, the last one was found only if carbapenems were administered (21 out of 35 patients) (p=0.0001). Administration of cefepime/sulbactam was associated with reduced ICU-stay after antibacterial therapy onset by 6 days (10.7±1.56 and 16.3±2.11 days, p=0.037). Conclusion. Cefepime/sulbactam is characterized by equal effectiveness with carbapenems as a first-line antibiotic therapy of severe infections in the ICU. Moreover, these drugs result significantly less risk of superinfection (RR=0.402, 95% CI 0.220—0.735) and selection of carbapenem-resistant bacteria (RR=0.269, 0.146—0.493) compared to carbapenems. As a result, reduced ICU-stay is observed.