Background: This topic is aimed to review the treatment approach in adult patients diagnosed with urosespsis in order to decrease mortality and to maximize the outcome of the antibiotic stewardship efforts. Methods: We present an approach of antibiotic therapy in urosepsis from an infectious diseases physician perspective based on the recently published data integrating the epidemiology of the urinary tract infections in a multidisciplinary hospital from Romania. Results: The principles of therapy in urosepsis should have five goals but not limited to rapid diagnosis specific intensive care unit treatment obtaining urine and blood cultures anti-infective treatment and identifying and correction of underlying risk factors. Due to the higher prognostic value the antimicrobial therapy in urosepsis should consist in “two steps” regimen: initial antimicrobial therapy based on “empirical” approach for the first 48 - 72 hours and directed or “definitive” antimicrobial therapy adapted to the susceptibility profile of the isolated pathogens the penetration into the urinary tract and the patient clinical response. Clinicians should be aware of the different antibiotic susceptibility profile of the bacteria from the hospital compared to the community. Thus the initial choice of antimicrobial agents depends on several criteria like the severity of illness and the risk factors for multidrug resistant pathogens: the immune status of the patient (age debilitating chronic illnesses immunosuppressive treatment or uncontrolled malignancies) broad-spectrum antimicrobial use and health care environment exposures in the previous 3 to 6 months susceptibility of prior urinary isolates and local community resistance prevalence of bacteria. Conclusions: Our important messages highlighted the need of a holistic approach of urosepsis in a multidisciplinary team with integration of risk factors for AMR focusing on the first phase of antibiotic treatment as the main driven of the survival rate