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

## TL;DR

This study analyzed CRE isolates from Malaysia and found that cefiderocol is the most effective new antibiotic against these drug-resistant bacteria.

## Contribution

The study provides new insights into the effectiveness of novel β-lactam antibiotics against CRE in Malaysia.

## Key findings

- Cefiderocol showed 86.4% susceptibility among CRE isolates, outperforming other β-lactams.
- Ceftazidime-avibactam plus aztreonam was 100% effective against isolates with metallo-β-lactamase genes.
- Cefiderocol resistance emerged in some isolates without prior exposure, signaling a potential AMR challenge.

## Abstract

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 (blaNDM, blaOXA-48, blaKPC, blaVIM, and blaIMP,) 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). blaNDM (76/102; 74.5%), blaOXA-48-like (17/102; 16.7%), blaNDM & blaOXA-48-like (8/102; 7.8%), and blaNDM & blaVIM (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 blaNDM-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 blaOXA-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 blaNDM + blaOXA-48-like, one blaNDM + blaVIM) 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; blaNDM (76/76; 100%), blaNDM + blaOXA-48-like (8/8; 100%), and blaNDM + blaVIM (1/1; 100%). blaNDM was the most prevalent gene causing CRE. Cefiderocol has the greatest activity compared with other investigated β-lactams.

Carbapenem-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 blaNDM-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.