An international research team has created a global map of antimicrobial resistance (AMR) by analyzing samples of untreated domestic sewage to identify AMR genes. Headed by a team at the National Food Institute, Technical University of Denmark, the scientists carried out a metagenomic analysis of sewage samples across 60 different countries, to characterize the abundance and diversity of antimicrobial resistance.

Their results highlighted systematic differences in the abundance and diversity of AMR genes between Europe, North America, and Australia/New Zealand, which collectively had the lowest levels of antimicrobial resistance, and Africa, Asia, and South America, where antimicrobial resistance was highest. The findings also suggested that the greatest diversity of resistance genes was found in Brazil, India, and Vietnam, while Australia and New Zealand had the lowest AMR gene diversity.

“In the fight against antimicrobial resistance, our findings suggest that it would be a very effective strategy if concerted efforts were made to improve sanitary conditions in countries with high levels of antimicrobial resistance,” commented Frank Aarestrup, PhD, a professor at the National Food Institute and head of the study, which is reported today in Nature Communications, in a paper titled, “Global monitoring of antimicrobial resistance based on metagenomics analysis of urban sewage.”

Antimicrobial resistance is an increasing global threat to public health, but is also highly complex, with “multiple and interconnected drivers, which may include changing dynamics in travel, trade, climate change, and populations,” the authors explained. Current methods for AMR surveillance are generally focused on a few pathogens, and may be based on laboratory data from patients’ specimens. The resulting data are not necessarily comparable, and also encompass only a narrow pathogen spectrum, rather than capturing all relevant AMR genes.

Urban sewage is an attractive sample option from the perspective of AMR surveillance, because it effectively samples material from large, mostly healthy populations, the authors suggested. “Analyzing sewage can quickly and relatively cheaply show exactly which bacteria abound in an area—and collecting and analyzing sewage doesn’t require ethical approval, as the material cannot be traced back to individuals,” Aarestrup commented. “Both parameters help to make a surveillance system via sewage a viable option—also in developing countries.” In fact, sewage has already been used for surveillance in the global program to eradicate polio.

For their reported metagenomics study the team analysed domestic sewage from

Sewage sample being collected in Sakasaka, Tamale, Northern Region, Ghana. [Courage Kosi Setsoafia Saba, University for Development Studies, Ghana.]
79 sampling locations in 7 geographic regions of 74 cities in 60 countries. The overall results identified 1546 different bacterial genera, although a much smaller number of organisms dominated.

In terms of geographical abundance of AMR genes, the highest levels were observed in African countries, although Brazil had the highest AMR gene abundance of all the countries. At the lower end of the spectrum were New Zealand and Australia, the team reported. “To the best of our knowledge, comparable data on the global occurrence of AMR genes of predominantly healthy people do not exist,” they noted.

In total, 1625 different AMR genes from 408 gene groups were identified. “AMR genes encoding resistance toward macrolides, tetracyclines, aminoglycosides, beta-lactams, and sulfonamides were the most abundant.” Geographically, most samples from Europe and North America had a high relative proportion of macrolide resistance genes, while Asian and African samples exhibited a high proportion of genes conferring resistance to sulphonamides and phenicols. Just 15 AMR genes contributed to 50% of the total AMR abundance. Interestingly, none of the dominant AMR genes were known to specific to particular bacterial genera.

The researchers used population health and regional development data from the World Bank to investigate factors other than antimicrobial drug use that might impact on the development of antimicrobial resistance in different countries. They found that most of the relevant variables related to sanitary conditions and the population’s general state of health. “ … we found that, irrespective of the diversity of AMR genes, the total AMR abundance was highly correlated with a limited number of World Bank variables, mainly concerning sanitation and health,” the researchers wrote. “Our findings suggest that global AMR gene diversity and abundance vary by region, and that improving sanitation and health could potentially limit the global burden of AMR.”

In contrast, the results from two different computational models applied to the data indicated that while the abundance of AMR genes belonging to specific antimicrobial class increased with increasing levels of residues of that drug class, there was no relationship between total drug residue levels and AMR genes. “While our model showed a significant increase in the abundance of AMR genes belonging to a specific antimicrobial class with increasing usage of that antimicrobial class, we found no significant effect of total usage of all antimicrobials on the abundance of the different classes,” they stated. “This suggests that, while AMU [antimicrobial use] of a specific class is an important driver of AMR genes encoding resistance to that class, the effects of cross- and/or co-resistance appear to have a relatively minor contribution to AMR abundances.”

Interestingly, human air travel also had little influence on AMR abundance. “Importantly, this suggests that the total AMR abundance is mainly influenced by local/national parameters, and even though all AMR genes might rapidly disseminate and be found in all corners of the world, local selection is required for them to reach appreciable frequencies.”

Using the World Bank data the researchers then predicted the levels of antimicrobial resistance in 259 countries/territories, and have drafted a world map of resistance in healthy populations. Their estimates suggest that the Netherlands, New Zealand, and Sweden have the lowest levels of resistance, whereas Tanzania, Vietnam, and Nigeria have the highest levels.

“Our study represents, to the best of our knowledge, the first attempt to monitor and predict the occurrence of AMR in the global predominately healthy human population, the researchers concluded. “ … while current efforts to improve surveillance of AMR in human clinical pathogens should be continued, we do suggest that our study provides the foundation for a flexible, simple, affordable, and ethically acceptable global real-time surveillance of AMR that could be immediately implemented globally also in low- and middle-income countries.” The same study design could also be used to monitor other infectious disease agents,” they suggested.

While their approach harnessed metagenomics, which can quantify thousands of genes simultaneously and generates data that can be re-examined and reanalyzed, other test methods, such as culturing or PCR, could also be used and may have better sensitivity, the scientists acknowledged. “Comparative studies evaluating the usefulness of various technologies, including evaluation of sensitivity, specificity, and number of targets detected, are warranted,” they noted. Their ultimate goal would be to develop a system that makes it possible for global researchers to exchange and interpret information in real time, and use global surveillance data to help manage diseases that threaten to spread across borders.

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