Aim: <i>Escherichia coli</i> is one of the Gram-negative bacteria, known to cause many nosocomial infections. Multi-drug (MDR) and extensively-drug resistant (XDR). <i>E. coli</i> are of particular note, due to significant limitations in antibiotic therapy. Ceftolozane-tazobactam and ceftazidime-avibactam are novel therapeutic options against Gram-negative bacteria; hence the aim of this study was to evaluate and compare the <i> in vitro </i> activity of ceftolozane-tazobactam and ceftazidime-avibactam against MDR and XDR clinical <i>E. coli</i> isolates. Material/Methods: The study included 100 non-replicate <i>E. coli</i> isolates derived from clinical samples of patients hospitalized in teaching hospitals. Bacteria were identified by applying mass spectrometry in the MALDI Biotyper system (Bruker). ESBL (bla<sub>CTX-M-1group</sub>, bla<sub>CTX-M-9group</sub>) and carbapenemase (bla<sub>KPC</sub>, bla<sub>VIM</sub>, bla<sub>NDM</sub>, bla<sub>OXA-48</sub>, bla<sub>OXA-181</sub>) genes were detected using the eazyplex® SuperBug CRE test, based on a loop-mediated isothermal amplification (LAMP). The in vitro susceptibility to ceftolozane-tazobactam and ceftazidime-avibactam was tested using validated MIC Test strips (Liofilchem). Results: All 84 extended-spectrum β-lactamase-producing (ESBL) <i>E. coli</i> isolates were susceptible to ceftazidime-avibactam and 83 to ceftolozane-tazobactam. Among 17 <i>E. coli</i> isolates with resistance to at least one of the carbapenems, three (17.6%) were susceptible to ceftolozane-tazobactam and ceftazidime-avibactam. All 14 blaVIM gene-positive <i>E. coli</i> isolates were resistant to both ceftolozane-tazobactam and ceftazidime-avibactam. Both antibiotics were active against bla<sub>CTX-M-9group</sub> and bla<sub>OXA-48</sub> gene-positive <i>E. coli</i> isolates, but they were not active against bla<sub>CTX-M-1group</sub> and bla<sub>VIM</sub> gene-positive isolates. Conclusions: Ceftolozane-tazobactam and ceftazidime-avibactam are alternative, non-carbapenem therapeutic options for ESBL-positive <i>E. coli</i> strains, and they are promising in the treatment of carbapenem-resistant <i>E. coli</i> strains, but not for those carrying the metallo-β-lactamase enzymes. Both drug combinations have comparable activity against ESBL, however, lower MIC values were found for ceftazidime-avibactam.