Background In the era of the increase in carbapenem resistance, searching for alternative drugs becomes mandatory. In this study, an in vitro activity of β-lactam/β-lactamase inhibitors against extended-spectrum β-lactamase–producing Enterobacteriaceae (ESBL-PE) isolated from bloodstream infections was investigated. Methods Blood samples were collected from patients with bloodstream infections in both pediatric and internal medicine intensive care units of Tanta University Hospitals, Egypt. BacT/ALERT was used, and positive blood cultures were subcultured on MacConkey, blood, chocolate agar and then incubated at 5% to 10% CO2, 37°C for 24 hours. Identification of the bacterial isolates was performed by VITEK 2TM Compact 15. Susceptibility testing was performed for isolated Escherichia coli and Klebsiella species using Kirby-Bauer disk diffusion and minimum inhibitory concentration. E test strips were used for cefoperazone/sulbactam, ceftazidime/avibactam, and ceftolozane/tazobactam. All isolates that were resistant to third-generation cephalosporins as per Clinical and Laboratory Standards Institute recommendations were confirmed for ESBL detection by modified double-disk synergy test, VITEK2 system, and multiplex polymerase chain reaction. Results One hundred twenty-five Enterobacteriaceae were isolated; 100 of them (80%) were ESBL positive. The best used β-lactam/β-lactamase inhibitors were ceftazidime/avibactam and ceftolozane/tazobactam with lower minimum inhibitory concentration at which 50% of isolates are inhibited (≤0.016, 0.094 μg/mL, respectively) than that of meropenem (0.125 μg/mL), so they can be used as carbapenem sparers in the treatment of ESBL-PE to decrease the incidence of carbapenem resistance. Conclusions Ceftazidime/avibactam and ceftolozane/tazobactam can be used as carbapenem sparers in the treatment of ESBL-PE to decrease the incidence of carbapenem resistance.