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Ecology, not antibiotic consumption, the main driver of resistance – French study

The spread of antibiotic resistance may not be primarily driven by antibiotic consumption, according to scientists, who suggest instead that its spread across Europe between 1997 and 2018 is mostly explained by exchanges between ecosystems, and human exchanges like merchandise imports or travel.

The results of the research by the French team, published in eLife, support the idea that interventional strategies based on reducing antibiotic use should be complemented by a stronger control of exchanges, especially between ecosystems.

Antibiotic resistance represents one of the largest threats to global public health, food security and global development faced today.

Due to its spread, a growing number of infections, like pneumonia and tuberculosis, are becoming harder to treat, leading to longer hospital stays, greater costs and increased mortality.

“Many public health agencies have recommended reducing antibiotic use in response to the challenges caused by resistance,” said co-author Léa Pradier, a former PhD student at University of Montpellier, France, who conducted the study with Stéphanie Bedhomme, a researcher at CNRS (the French National Centre for Scientific Research).

“However, there are cases where developed countries have reduced their antibiotic consumption and not halted the spread of antibiotic resistance genes across bacterial populations, implying other factors are at play.”

To explain this, Pradier and Bedhomme set out to describe the genetic, geographical and ecological distribution of resistances to a class of antibiotics called aminoglycosides, and from this information, quantify the relative contribution of different factors driving the spread of antibiotic resistance.

Aminoglycosides have limited clinical use in humans, but are often a last resort for treating multi-resistant infections. They are also commonly used in the treatment of farmyard animals, meaning resistance to them poses a significant threat to global food security.

They utilised a computational approach to screen the genetic information of more than 160 000 bacteria genomes, looking for genes encoding aminoglycoside-modifying enzymes (AMEs) – the most common mechanism of aminoglycoside resistance. They detected AME genes in around a quarter of genomes screened, and in samples from all continents (excluding Antarctica) and all biomes investigated.

The majority of AME-gene-carrying bacteria were found in clinical samples (55.3%), human samples (22.1%) and farm samples (12.3%).

The duo then focused on the distribution of AME genes across Europe, from 1997-2018, when the most detailed data were available. During this period, aminoglycoside usage remained relatively constant, but was highly variable between countries.

Comparing the prevalence of AME genes between countries with different aminoglycoside usage over time, the team determined that aminoglycoside consumption was only a minor explanatory factor, with few positive or directional effects on AME gene prevalence.

Instead, the dataset implies that human exchanges through trade and migration, and exchanges between biomes, explain most of the spread and maintenance of antibiotic resistance when modelled over time, space and ecology.

AME genes can be carried over continents by plant and animal products, and international trade and travellers, and may then spread to local strains of bacteria through a process called horizontal gene transfer – the movement of genetic information between organisms.

The pool of AME genes sampled from plants, wild animals and soil had the strongest overlap with other communities, suggesting these biomes are major hubs for AME gene propagation, either by horizontal resistance gene transfer or by resistant bacteria movement.

The findings suggest the largest cause of AME gene spread is through the movement of antibiotic-resistant bacteria between ecosystems and biomes – aided by mobile genetic elements, increasing the likelihood for a genome to carry several copies of the same AME gene. This increases the expression of transferred AME genes and allows bacteria to evolve new antibiotic resistance functions through the duplicated sequences.

These findings are preliminary, as limited by the use of publicly available data, rather than deploying a dedicated sampling method.

In addition, the genetic data sourced from multiple different research projects caused a sampling bias towards industrialised countries and biomes with clinical interest, leading to some locations and biomes being over-represented.

“Our study provides a broad overview of the spatial, temporal and ecological distributions of AME genes, and establishes that the recent variations of AME bacteria in Europe are first explained by ecology, then human exchanges and lastly, by antibiotic consumption,” said Bedhomme.

“Although the conclusions of this study should not be extended to antibiotic genes other than AMEs, the methods used could easily be applied to further studies on other antibiotic resistance gene families.”

Study details

Ecology, more than antibiotics consumption, is the major predictor for the global distribution of aminoglycoside-modifying enzymes

Léa Pradier and Stéphanie Bedhomme.

Published in eLife on 14 February 2023

Abstract

Antibiotic consumption and its abuses have been historically and repeatedly pointed out as the major driver of antibiotic resistance emergence and propagation. However, several examples show that resistance may persist despite substantial reductions in antibiotic use, and that other factors are at stake. Here, we study the temporal, spatial, and ecological distribution patterns of aminoglycoside resistance, by screening more than 160,000 publicly available genomes for 27 clusters of genes encoding aminoglycoside-modifying enzymes (AME genes). We find that AME genes display a very ubiquitous pattern: about 25% of sequenced bacteria carry AME genes. These bacteria were sequenced from all the continents (except Antarctica) and terrestrial biomes, and belong to a wide number of phyla. By focusing on European countries between 1997 and 2018, we show that aminoglycoside consumption has little impact on the prevalence of AME-gene-carrying bacteria, whereas most variation in prevalence is observed among biomes. We further analyse the resemblance of resistome compositions across biomes: soil, wildlife, and human samples appear to be central to understand the exchanges of AME genes between different ecological contexts.
Together, these results support the idea that interventional strategies based on reducing antibiotic use should be complemented by a stronger control of exchanges, especially between ecosystems.

 

eLife article – Ecology, more than antibiotics consumption, is the major predictor for the global distribution of aminoglycoside-modifying enzymes (Creative Commons Licence)

 

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