Rapid spread of antibiotic-resistant E. coli across Europe raises concerns

In a recent study published in the journal Eurosurveillance, researchers performed whole genome sequencing (WGS) on 874 Escherichia coli (E. coli) isolates carrying the bla _NDM-5 gene, which encodes New Delhi metallo-β-lactamase (NDM)-5. They retrieved the study sample set from 13 European Union (EU)/European Economic Area (EEA) countries between 2012 and June 2022.

Rapid communication: Rapid cross-border emergence of NDM-5-producing Escherichia coli in the European Union/European Economic Area, 2012 to June 2022. Image Credit: Kateryna Kon / Shutterstock

Background

In a survey of carbapenem- and/or colistin-resistant Enterobacterales (CCRE survey) performed across 36 European countries in 2019, researchers detected 62 of 201 carbapenemase-producing E. coli isolates carrying NDM-5 encoding gene ‘bla_NDM-5’ in 15 countries.

Additionally, they observed that some of these 62 E. coli isolates belonged to high-risk sequence types (STs), which increased the risk of extraintestinal infections. Since these findings were concerning, the European Centre for Disease Prevention and Control (ECDC) requested further investigation into the matter.

About the study

In the present study, researchers initiated the collection of WGS and epidemiological data on bla _NDM-5-carrying E. coli isolates from all countries in the EU and EEA via their EpiPulse platform. In response, they received data for 905 E. coli isolates from 13 countries.

They discarded 29 isolates that did not fulfill the quality criteria or did not carry the bla NDM-5 gene. The final analysis set encompassed data on 874 E.coli isolates collected between 2012 and 2022 and referred to as ‘national collections.’ Notably, the ECD1C also deposited this data in the European Nucleotide Archive. Using the same quality criteria, the ECDC retrieved WGS data from the National Center for Biotechnology Information (NCBI) Pathogen Detection system in 2022, which added 2,561 additional E. coli isolates to the study analysis dataset.

The researchers used version 2.0.9 of the multilocus sequence typing (MLST) tool from the Danish Technical University (DTU) to determine the STs of the isolates from national collections, categorizing them into major and minor STs. The former and the latter represented >10% and between 5-10% STs, respectively. In addition, they used DTU’s PointFinder tool to detect fluoroquinolone resistance point mutations and the EnteroBase cgMLST scheme with a threshold of 10 allelic differences to find clusters of linked E. coli isolates.

Likewise, they used the E. coli analysis plugin of BioNumerics version 7.6.3 with thresholds of ≥60% sequence length and ≥90% sequence identity for gene coverage to determine resistance genes. Furthermore, the team collected epidemiological variables for isolates from national collections, including sampling site, year, month, sample type, clinical relevance, collection location, patient characteristics, such as in- or outpatient, age, gender, past six-month travel and hospitalization history, and their epidemiological link with other patients.

Results

The study dataset encompassed 3,435 E. coli isolates with bla_NDM-5 derived from 267 STs, of which 83 were present in the 874 isolates. The five predominant STs were ST167, ST405, ST410, ST361, and ST648; the first three were major STs, and the remaining two were minor. The researchers detected these five in six countries Finland, Denmark, France, the Netherlands, Ireland, and Sweden, all of which submitted more than 20 isolates.

The authors noted a temporal increase in E. coli isolates carrying bla _NDM-5. Strikingly, 500 of 874 isolates from national collections were involved in 114 multi-country clusters. Of 3435 E. coli isolates carrying bla _NDM-5, 180 harbored additional carbapenemase genes, and bla_OXA-181 was the most frequently co-carried carbapenemase gene as it was present in 110/180 E. coli isolates.

Of five dominant STs, 69 ST410 isolates carried two carbapenemase genes, i.e., the highest proportion compared to other major STs. Of 3435 E. coli isolates carrying bla _NDM-5, 2129, i.e., 62% harbored a  minimum of one extended-spectrum β-lactamase (ESBL) gene and bla_CTX-M family genes were the most frequently identified ESBL genes with 62.3% of E. coli isolates being of the dominant STs.

Two genes, bla CMY-42 and bla CMY-2, encoded for acquired AmpC β-lactamases, of which the second one belonged to ST410, one of the five high-risk clones. A staggeringly high proportion of E. coli isolates carrying bla _NDM-5 (94.2%) were also highly resistant to aminoglycosides. Likewise, due to type II topoisomerase gene mutations, these E. coli isolates were frequently resistant to fluoroquinolones.

Based on combined findings of these resistance markers, 58.2% of these bla _NDM-5-carrying E. coli isolates in the study dataset emerged as multidrug-resistant, including all β-lactams, aminoglycosides, and fluoroquinolones. At present, clinicians use these antibiotics to treat severe E. coli infections.

Furthermore, the researchers made several important epidemiological findings for all 874 E.coli isolates from national collections. For instance, they had information on the infection status of 618/874 isolates and knew the sample type of 766/874 isolates. Urine was the most common specimen type (178/874), while blood (23/874) and the respiratory tract (6/874) were the most uncommon sample types.

Conclusions

This study presented a more comprehensive analysis of the spread of five high-risk E. coli STs carrying bla_NDM-5 in Europe. It confirmed the CCRE survey findings that these high-risk clones have emerged in the EU/EEA, and 84.2% (287/341) had a link with a country on the African (36.7%) and Asian (46.3%) continents. The authors had past six-month travel and hospitalization information for only 341 E. coli isolates carrying the bla _NDM-5 gene.

Since 30% of the E. coli isolates carrying the bla_NDM-5 gene are linked to multidrug resistance and severe extraintestinal infections, it raises the urgent need to detect and control them early. Even after detection, they could pose serious health risks because 62% had ESBL genes that made them resistant to aztreonam, a β-lactamase antibiotic.

In addition, if they become resistant to aminoglycosides and fluoroquinolones, which is highly possible, clinicians will have even fewer options to treat severe E. coli infections, e.g., cefiderocol. Therefore, immediate action is needed to detect and control carbapenem resistance in E. coli to prevent patients and healthcare systems from the adverse consequences of severe E. coli infections.