Molecular characterization of carbapenem-resistant Enterobacterales (CRE) and <i>in vitro</i> activity of novel beta lactams against CRE isolates from Malaysia

Knowledge gap on the susceptibility of novel β-lactam agents (cefiderocol, ceftazidime-avibactam, imipenem-cilastatin-relebectam, and aztreonam) against carbapenem-resistant Enterobacterales (CRE) has been recognized. This study aimed to genotypically characterize CRE isolates and investigate the novel β-lactam activity against CRE. CRE is defined as Enterobacterales that is phenotypically non-susceptible to any carbapenems, including imipenem, meropenem, and ertapenem. A total of 154 CRE isolates were collected from two tertiary centers in Malaysia from October 2023 to May 2024. Carbapenemase-producing genes (<i>bla</i>_NDM, <i>bla</i>_OXA-48, <i>bla</i>_KPC, <i>bla</i>_VIM, and <i>bla</i>_IMP,) were detected using PCR. Susceptibility to β-lactams was determined using disc diffusion. Of 154 CRE isolates, 102 (66.2%) were carbapenemase-producing carbapenem-resistant Enterobacterales (CP-CRE). <i>bla</i>_NDM (76/102; 74.5%), <i>bla</i>_OXA-48-like (17/102; 16.7%), <i>bla</i>_NDM & <i>bla</i>_OXA-48-like (8/102; 7.8%), and <i>bla</i>_NDM & <i>bla</i>_VIM (1/102; 1.0%) were identified among the CP-CRE isolates. The proportion of CRE isolates that exhibited susceptibility towards cefiderocol, ceftazidime-avibactam, and imipenem-cilastatin-relebactam was 86.4% (133/154), 41.6% (64/154), and 26.0% (40/154), respectively. Among <i>bla</i>_NDM-harboring isolates, cefiderocol (57/76; 75.0%) demonstrated superior activity compared with ceftazidime-avibactam (3/76; 3.9%) and imipenem-cilastatin-relebectam (1/76; 1.3%). Among isolates harboring <i>bla</i>_OXA-48-like, cefiderocol, ceftazidime-avibactam, and imipenem-cilastatin-relebectam demonstrated 100% (17/17), 70.6% (12/17), and 17.6% (3/17) susceptibility, respectively. Nine isolates that harbored two genes (eight <i>bla</i>_NDM + <i>bla</i>_OXA-48-like, one <i>bla</i>_NDM + <i>bla</i>_VIM) demonstrated 100% susceptibility to cefiderocol but 100% resistance to ceftazidime-avibactam and imipenem-cilastatin-relebectam. The ceftazidime-avibactam plus aztreonam combination achieved 100% susceptibility in isolates harboring metallo-β-lactamases-producing genes; <i>bla</i>_NDM (76/76; 100%), <i>bla</i>_NDM + <i>bla</i>_OXA-48-like (8/8; 100%), and <i>bla</i>_NDM + <i>bla</i>_VIM (1/1; 100%). <i>bla</i>_NDM was the most prevalent gene causing CRE. Cefiderocol has the greatest activity compared with other investigated β-lactams.IMPORTANCECarbapenem-resistant Enterobacterales (CRE) has been recognized as a priority and public health concern requiring urgent attention for the development of effective antimicrobial resistance (AMR) prevention and control strategies. Differentiating between carbapenemase-producing CRE (CP-CRE) and non-CP-CRE, along with identifying carbapenemase-producing genes, is essential for guiding targeted antibiotic therapy. Among novel β-lactam agents, cefiderocol and the combination of ceftazidime-avibactam and aztreonam have shown promising activity against <i>bla</i>_NDM-producing CRE, supporting precision medicine approaches. Nevertheless, our study observed the emergence of cefiderocol resistance in isolates without prior drug exposure, highlighting a potential challenge in combating AMR.