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Background: Bacterial resistance is a challenging public health problem. Immunocompromised patients, as those receiving therapy for hematological diseases, face increases in morbidity and mortality when an infection due to multi-drug resistant (MDR) agents occurs. Only some new antibiotics are available in a scenario where new resistance mechanisms displace usual antimicrobial classes in treating infections. Ceftazidime-avibactam (CAZ-AVI) and ceftolozane-tazobactam (C/T) are cephalosporins associated with beta-lactamase inhibitors, so new options for therapy. CAZ-AVI has activity against Enterobacterales and Pseudomonas aeruginosa, including producing Class A carbapenemases, ESBL and AmpC, representing an option when alternatives for using beta-lactams cease, mainly in cases with carbapenemases production (kpc). C/T is considered the first-choice therapy for MDR P. aeruginosa, but it is also an alternative for ESBL producers if C/T susceptibility is documented. This study aims to describe the susceptibility for CAZ-AVI and C/T in Gram-Negative bacteria isolated from patients admitted to a hematological and Stem Cell Transplant Unit and compare these rates with other units from the same hospital. Methods: All samples were obtained between August/2019 and December/2022. We included only strains from clinical specimens and excluded all MDR surveillance cultures. In this Hospital, CAZ-AVI and C/T are part of the therapeutic portfolio for MDR infections, following restrictive stewardship protocols. Microbiological data compiled 1,760 strains isolated in the period, including 74 strains from the Hematological and Transplant Unit (UTX). The strains were identified by MALDI-TOF mass spectrometry, tested for antimicrobial susceptibility by VITEK, and classified according to the susceptibility profile according to BrCAST (2019 to 2022). Results: Of the 1760 strains, 1,589 were tested for CAZ-AVI susceptibility, and 98 (6.2%) were resistant to CAZ-AVI with MIC ranging from 8 to >256 μg/mL. CAZ-AVI resistance was most frequent in Klebsiella pneumoniae (n = 40) and P. aeruginosa (n = 35), followed by Escherichia coli (n = 7). The highest number of isolations occurred in Intensive Care Units (ICU; n = 35), while UTX has the lowest number of cases (n = 4). Only one of the CAZ-AVI-resistant strains produced ESBL, whereas 51 produced carbapenemases, mainly by metallo-beta-lactamases (n = 47). Four strains produced Class A carbapenemases, three K. pneumoniae, and one C. freundii, all isolated at different times. The C/T susceptibility test was performed in 1760 strains, and 75 were from UTX (including 61 – 81% - from blood cultures). The overall susceptibility varied from 86% to 100%. Regarding resistant strains, 40% were K. pneumoniae, 18% E. coli, 15% Enterobacter cloacae complex, and 12% Pseudomonas spp. The susceptibility of C/T among Pseudomonas spp. was 85%. In UTX, the overall susceptibility was 92% (n = 69), similar to ICU (93%, n = 588). C/T susceptibility was 66% vs. 87% in ESBL producers and non-producers GN, respectively. Conclusion: CAZ-AVI and C/T have a high susceptibility in strains from onco-hematological patients, and they must be considered in treating MDR gram-negative bacterial infections. Our data also demonstrated that resistance is an important issue, reinforcing the necessity of rational use of these new drugs and permanent surveillance of resistance, especially in these high-risk patients.