A global collaboration—the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR)—spanning 29 countries and the European Commission, has made new inroads into understanding how extended-spectrum cephalosporin resistance (ESC-R) is transmitted. The study pinpoints differences in the contribution of plasmids and clonal expansion in different biological compartments for the spread of ESCR genes.

These findings were published in the journal Nature Communications on December 12, 2022 “Dynamics of extended-spectrum cephalosporin resistance genes in Escherichia coli from Europe and North America.”

Lead author of the study, Roxana Zamudio, PhD, said, “Antimicrobial resistance (AMR) is a global problem, and it is only by working collaboratively with partners in multiple countries that we can get a holistic understanding of where and how AMR is spreading.”

The World Health Organization (WHO) classifies extended-spectrum cephalosporins (ESCs) as critically important antimicrobials in human and veterinary healthcare, because they are a ‘last resort’ treatment for multidrug resistant bacteria. However, in an ominous global trend, their efficacy has continued to decrease as different pathogenic bacteria grow resistant against ESCs. Without a unified global effort, ESC-R will render millions vulnerable to infections that are currently treatable.

Despite the significance of ESCs in medicine, the mechanisms by which ESC-R genes spread in different ecological niches is unclear. In this study, scientists at Quadram Institute and the University of East Anglia, together with collaborators from France, Canada, Germany and the U.K., analyzed whole genome sequence (WGS) data of nearly 2000 resistant bacteria of the order Enterobacterales, that are rod-shaped, non-spore forming, facultative anaerobes.

“By assembling such a large and diverse collection of genomes, we were able to identify the key genes conferring resistance to these critically important drugs. We were also able to show that the majority of resistance to extended spectrum cephalosporins is spread by only a limited number of predominant plasmids and bacterial lineages,” said Alison Mather, PhD, group leader at the Quadram Institute and the University of East Anglia, and the senior author of the study. “Understanding the mechanisms of transmission is key to the design of interventions to reduce the spread of AMR.”

Adopting the One Health approach, the researchers collected bacteria from different geographic regions and diverse hosts including humans, animals, food (meat) and the environment (wastewater), to understand how related factors influenced the dynamics of ESC-R and the mechanisms by which resistance genes are transmitted. Focusing primarily on Escherichia coli collected from human and animal samples in Europe and North America between 2008 and 2016, the researchers found that some ESC-R genes were initially found in North America and spread to Europe, while others spread from Europe to North America.

Bacteria gain resistance against ESCs by producing two beta-lactamase enzymes that inactivate ESCs: extended-spectrum beta-lactamases (ESBLs), and AmpC beta-lactamases (AmpCs). The investigators showed AmpC β-lactamases were initially more dominant in North American humans and farm animals and later spread to Europe. On the other hand, specific ESBLs were initially common in animals in Europe and later emerged in North America. AmpCs and ESBLs are encoded either by bacterial chromosomes where they spread through clonal expansion from parent to progeny (vertical genetic transmission), or by plasmids that can move directly from one bacterium to another (horizontal genetic transmission).

To design effective interventions that will curb the spread of ESC-R globally, it is key to understand the mechanisms of transmission of ESC-R genes. The current study takes a step forward in this direction.