Detection of High-Risk blaNDM-5-Positive Escherichia coli ST167 Clones in Singapore

To the Editor—We read with great interest the discussion by Aitken et al [1] and Fabrizio and Tascini [2] on the potential roles of durlobactam and imipenem-cilastatin-relebactam in treating New Delhi metallo-β-lactamase (NDM)–producing Escherichia coli with penicillin-binding protein 3 (PBP3) mutations. Their findings underscore the urgency of developing effective strategies, validated drug susceptibility tests, or genomic markers that can predict resistance profiles and combat these resistant strains. Cefiderocol has shown potent in vitro activity against carbapenemase-producing Enterobacterales [3]. However, the E. coli sequence type (ST) 167 strain expressing NDM-5 has been found to be resistant to most β-lactam antibiotics, including cefiderocol [4–6]. This is highly concerning as avibactam-aztreonam, another frontline option for NDM-producing carbapenem-resistant Enterobacterales has also reported diminishing susceptibility in these resistant pathogens [4, 5, 7]. Resistance to cefiderocol was shown to be driven by mutations in PBP3 (YRIN insertion at amino acid position 334, E349K, I532L) and iron-catecholate transporter cirA (truncated at amino acid position 105) [4–6]. Resistance to cefiderocol has been reported prior to clinical use, highlighting that baseline resistance to this last-resort antibiotic could be present locally prior to its introduction [6]. Cefiderocol is not yet a registered therapeutic product in Singapore. We investigated if this high-risk strain was circulating in Singapore by determining phylogenetic relationships between the reported genomes and carbapenem-resistant isolates collected from a single public hospital in Singapore between 2019 and 2022 (Figure 1). Phylogenetic tree based on core genomes of blaNDM-5-positive Escherichia coli sequence type 167 isolates from Singapore (n = 19), the United States (n = 1), Canada (n = 1), and China (n = 20). The colored circles represent the presence of blaCMY variants, PBP3, cirA, and their corresponding mutations. All of the truncated cirA sequences with stop codon at amino acid position 105 are the same and 315 base pairs long, with the stop-codon at position 105 and producing a protein 104 amino acids long. Abbreviations: CRE, carbapenem-resistant enterobacterales; PBP3, penicillin-binding protein 3; USA, United States. Alt text: Phylogenetic tree based on core genomes depicts relationship of isolates from different regions of the world. The panels show expression of blaCMY variants and mutation profiles of PBP3 (blue) and cirA (green). One hundred forty-nine NDM-producing E. coli were collected from a single hospital between 2019 and 2022. Whole-genome data identified 20 (13.4%) ST167 isolates, of which 19 were blaNDM-5 positive. Sixteen harbored mutations and YRIN insertions associated with cefiderocol resistance, similar to the isolates from the United States, Canada, and China (Figure 1) [4–6]. Seven isolates found to express truncated cirA (truncated at amino acid position 105) also carried PBP3 mutations and belonged to a phylogenetic clade with cefiderocol-resistant, blaNDM-5-positive E. coli ST167 isolates from other regions. Although susceptibility testing of cefiderocol was not performed, the genomic results suggest that these 7 local isolates likely exhibit resistance to the drug. Nine isolates within the phylogenetic clade and isolates reported by Aiken et al [1] and Fabrizio and Tascini [2] also harbored blaCMY variants, which likely contributed to cefiderocol resistance (Figure 1) [1, 2, 4]. Truncation of cirA at amino acid position 56 was also detected in 3 local isolates, but these isolates did not appear to carry additional mutations in PBP3 closely associated with cefiderocol resistance. As this truncation has not been reported, additional work to assess the susceptibility of these isolates to cefiderocol would provide insights into the involvement of PBP3 and cirA mutations in cefiderocol resistance among the high-risk blaNDM-5-positive E. coli ST167 clones. Of the 5 strains reported by Aitken et al, 1 strain was ST167 and resistant to cefiderocol. The NDM-5–producing E. coli strain described by Fabrizio and Tascini also harbored mutations in both PBP3 and cirA. It is plausible that 1 or both studies encountered isolates from this blaNDM-5 ST167 clade. In conclusion, cefiderocol-resistant blaNDM-5-positive E. coli ST167 is more widely distributed than previously recognized. Establishing phylogenetic relationships between PBP3 mutant isolates is crucial for understanding the role of the NDM-5–expressing E. coli ST167 clone in extensively drug-resistant infections. Ethics statement. This study was reviewed and approved by the ethics institutional review boards of National Healthcare Group Singapore (DSRB reference 2014/00617), which did not require that patients provide written informed consent. Disclaimer. Any opinions, findings, conclusions, or recommendations expressed in this material are those of the authors and do not reflect the views of the Singapore Ministry of Health and/or the National Medical Research Council. Financial support. This research was supported by the Singapore Ministry of Health's National Medical Research Council (NMRC) under its NMRC Clinician Scientist Award (MOH-000276), NMRC Clinician Scientist Individual Research Grant (MOH-001706-01), NMRC Collaborative Grant: Collaborative Solutions Targeting Antimicrobial Resistance Threats in Health Systems (CoSTAR-HS; CG21APR2005), and NMRC Open Fund–Large Collaborative Grant: AntiMicrobial resistance Research and Intervention Alliance Singapore (AMRITAS; MOH-001326-01).