The long-standing problem of antibiotic resistance suddenly is getting fresh attention. A blistering report from a project chartered by the British government predicts it will kill one person every three seconds by the year 2050. The World Health Organization made it a priority at this year’s World Health Assembly. In agriculture, the Food and Drug Administration is asking the livestock industry for the first time to account for how drugs are used in different meat animal species.
And that all seems to be happening just in time, given the discovery in the United States last week of E. coli bearing the gene for colistin resistance, which takes away the effectiveness of the last available last-resort antibiotic.
To root out the sources of resistance, researchers are looking in every possible reservoir, including not just animals, but the dirt they are raised on. In the past two months, two research teams working in the United States, South America and Asia have reported that the soil around farms—large conventional properties, and also small subsistence farms—serves as a mixing bowl in which bacteria can swap antibiotic resistance genes. What emerges from the soil—when it is excavated or disturbed or when stormwater washes it away—are bacteria that have become resistant even to drugs that they were not exposed to, and that could cause illnesses far from the farms where they originated.
In one study, published in April in the journal mBio, Timothy Johnson and James Tiedje of Michigan State University, along with collaborators at the Chinese Academy of Sciences and in the U.S. Department of Agriculture, analyzed soil from very large modern hog farms in three regions of China. They found identical clusters of genes that confer resistance, and mobile genetic elements—short strings of genetic material containing multiple genes—even in widely spread out farm properties.
In the other study, published this month in Nature, Gautam Dantas of Washington University School of Medicine in St. Louis, along with colleagues there, and in Baltimore, La Jolla, Calif., El Salvador and Peru, studied the resistance genes being carried by people in their intestines, and also found in the environment, in a subsistence-farming village in El Salvador and an urban shantytown in Lima. They found hot spots that seemed to encourage the swapping and piling-up of resistance genes outside chicken coops in the village and, in the city, near a modern wastewater treatment plant.
Both sets of results reveal that the undermining of antibiotics can happen far outside healthcare, which usually gets most of the blame for the occurrence of resistance. They also emphasize that potentially harmful bacteria are emerging and evolving in locations where we don’t look for them. Many countries including the United States have some kind of surveillance system that watches for resistance bacteria in animals given antibiotics, but they focus on the animals themselves or the meat they become, not the manure they excrete or the environments they live in.
“We are interested in antibiotic resistance genes in the environment—what are their sources and their potential impacts, and how can we minimize undesired outcomes from them,” Tiedje tells The Plate. “I view this as equally concerning as medical use of antibiotics. Probably three-fourths of the antibiotics used globally are used in animal agriculture, so that is a large dose for the environment. And there are other sources: antibiotics coming through water-treatment plants from personal use and hospital use, and waste from (drug) production and formulation facilities. All of those select for antibiotic resistance.”
How animal manure spreads pathogens into the environment—both foodborne organisms and resistant bugs—is a live policy issue. In March, the Food and Drug Administration announced that it is launching a scientific assessment of the risks. And a long series of lawsuits and legislation has attempted to pin down the role of chicken litter—the mix of manure and wood shavings that lines the floors of broiler barns—in polluting the Chesapeake Bay.
In an earlier paper, Tiedje’s group analyzed farm soil and pig manure from Chinese farms and identified an unexpectedly high number of unique resistance genes. In this work, they sequenced the genes and gene fragments, which allowed them to draw relationships between them.
The sequences “are the same in north, central and south China, and some of them are identical to sequences of genes in known potential human pathogens,” Tiedje says. “It would suggest that it is all from an original single source, that these genes and mobile genetic elements originated somewhere in the country and now are widespread.”
Dantas and colleagues, though also interested in resistance genes’ behavior in the environment, steered away from large farms. They chose their study sites, with the help of their South American collaborators, because both were in disadvantaged areas; they wanted to assess, “where access to sanitation and hygiene is low, what kind of microbial exchanges can you predict,” says Dantas, an assistant professor of pathology and immunology.
Their study is the first to compare the genetics of bacterial resistance across many sources in a single area: soil and water, animals and people. In both the village and the slum sites, he said, they found “a vast repertoire of novel resistance genes” that had not previously been identified. When their relationships were drawn, most of the genes tended to be most like other genes found in similar environments, such as human feces and animal feces.
But there were outlier genes, and the team found those worrisome, because they signaled gene jumping or swapping among bacteria from different environments. When the genes were picked up by new hosts, they joined with existing resistance genes already in bacteria to create multi-drug resistance. There were certain locations in the study sites where this was most likely to happen: at the outflow of the municipal sewage plant, and under the village chicken coops.
“Something in the mix of the soil in the chicken coop and the chickens themselves is enabling a potential hotspot for exchanging resistance genes,” Dantas says. “This is important because this is a village of subsistence farmers; the chickens roam around freely, often coming into the houses. But from a public health perspective we have got genetic evidence that these chickens are viable vectors of moving resistance genes back and forth.”
The chickens in rural El Salvador, of course, don’t receive antibiotics. The resistance genes the team found in them already exist in nature; if antibiotics were present, they would create conditions that would allow those genes to multiply.
“This has lots of implications for industrial poultry farming in the U.S., where large amount of antibiotics are pumped into broiler chickens,” Dantas says. “It doesn’t take too much to imagine that if you dump antibiotics onto this system, you will only enrich for these [gene] exchanges.”