In health care today, public concern is mounting regarding the threat of microbial resistance to antibiotics. These antibiotics destroy or disable disease-causing bacteria in our bodies, and have been considered instrumental to the treatment of infectious human and animal diseases since the 1940's. As time has passed, however, it has become clear that the increased use of antibiotics - currently 50 million pounds per year, up from 2 million pounds in 1954 - creates some problems. In response to increased use, an increasing number of microorganisms are becoming resistant to antibiotics' once-lethal effect.

Such resistance has the potential to create profound impacts on health care. The World Health Organization, the American Medical Association, and the Food and Drug Administration have all released statements on what the AMA terms a problem of "potentially crisis proportions." If a bacterium that causes infection in humans is resistant to a popular antibiotic, the antibiotic simply doesn't work against the infection. Finding a new antibiotic is then necessary for treatment. Already, antibiotic resistance is limiting treatment options; raising health care costs; and increasing the number, severity, and duration of infections. For example, one strain of tuberculosis is resistant to nine antibiotics. A recent study found that antibiotic resistance in just six strains of bacteria has increased hospital costs by $1.3 billion in 1992 dollars. Due to their weaker immune systems, the young, old, and HIV/AIDS and cancer patients are particularly susceptible to these problems.

Is agriculture implicated?

Recently, groups such as the Alliance for the Prudent Use of Antibiotics (APUA) have argued that antibiotic use in animal production is a leading cause of increased antibiotic-resistant microbes in the environment. Groups such as the APUA seek to limit the presence of antibiotics in agriculture, or to ban their use altogether.

Dr. Satish Gupta, a researcher at the University of Minnesota, cautions that limited research has been done on the presence of pharmaceuticals in the environment. He is among another large group of individuals that does not believe that sufficient evidence exists to attribute microbial resistance to agricultural causes, and is leading a team of researchers to address this question. The other team members are Dr. Sagar Goyal and Dr. Ashok Singh of the Veterinary Diagnostic Laboratory; Dr. Kuldip Kumar and Dr. Anita Thompson, of the Department of Soil, Water, and Climate; and Dr. Helene Murray of the Minnesota Institute for Sustainable Agriculture. Their two-year study aims to determine the extent that the use of antibiotics in agriculture might be leading to microbial resistance to antibiotics in the environment.

According to Gupta, many farmers currently give antibiotics to livestock regardless of whether or not any illness is present, applying between 1 and 100 grams per ton of feed. These antibiotics change the microbiology of the animal's gut, promoting certain kinds of nutrients, thereby changing the absorption processes of the gut. These changes ultimately prove beneficial for the farmer: "The use of antibiotics in animal feed helps increase the animal's ability to absorb feed and thus reach market weight quicker," explains Gupta. "In addition, supplementing antibiotics in animal feed may be helpful to counteract the effects of crowded living conditions and poor hygiene in intensive animal agriculture." But according to Gupta, significant amounts of these antibiotics get excreted in urine and manure, which allows more bacteria in the environment to come into contact with them. It is this increased exposure which has caused concern. In a recent report, the APUA wrote that "the risk of developing resistance rises each time bacteria are exposed to [antibiotics]." Gupta says there is general consensus on this point, but emphasizes that he is concerned with the long-term consequences. "People want to ban antibiotic use," he says. "But we are trying to see if resistant microbes are or are not spreading between animals and people."

Tracing bacteria from the farm outward

Gupta's team is focusing on the practice of applying manure on land, a common agricultural practice that is receiving increasing public attention. "Manure is land applied mainly because of its value in supplying nutrients to crops, but in some cases it is also a means of disposing unwanted waste," Thompson explains. Once manure is applied on land, the presence of antibiotics and antibiotic-resistant microbes in the manure can potentially spread into the environment as a form of non-point source pollution. Thompson suspects this may have been the case in February 2000, when antibiotics were found in a lake in Ohio. It's most likely that surface runoff from nearby manure-applied fields were the cause, Thompson says.

Many bacteria, such as Acinetobacter spp., are naturally present in the soil, and are a key part of Gupta's research. By comparing the level of resistance in the soil's bacteria between two farms, one that applies manure from antibiotic-treated animals and one that does not, the researchers will be able to see whether or not resistance is spreading from farm animals into the soil environment. In addition to testing soil bacteria, the research team will look at the fecal matter from farm dogs for the presence of antibiotic-resistant bacteria. "That's what's really going to tell us whether there's any spreading of the antibiotic resistance," says Dr. Kumar. "If it's going to spread from livestock to dogs, it's going to reach humans as well." Gupta's team will also study whether events such as high rainfall can carry these antibiotics, as well as resistant microbes, out of the soil and into neighboring environments.

At first glance, it may seem odd to be concerned that antibiotics used to select for beneficial bacteria in the livestock gut could wind up being a human health risk. How exactly might this happen? Some worry that the actual process might be remarkably easy. Interestingly, the trait of antibiotic resistance in bacteria is not necessarily the product of genetic mutation, nor is it only passed down through offspring. Bacteria's most effective bag of tricks is its plasmid, a small circle of DNA that exists outside the chromosome and can pass between different types of bacteria, allowing the trait of resistance to literally be handed over from one bacterium to the next. Imagine ingesting harmless bacteria from your drinking water that has nevertheless acquired the trait of antibiotic resistance from a nearby farm. That trait of resistance may be then passed on to another bacteria that occurs naturally in your stomach. Then, at some time in the future, when a harmful infection arrives in your gut, it too could acquire that genetic trait of resistance. When the doctor prescribes the standard antibiotic, it could end up useless against the infection, which has picked up the trait of resistance that originated from the farm.

Others do not believe evidence is in place to support such a chain of events. For now, Gupta's team is at the beginning of this kind of hypothetical scenario, examining farm soils and comparing those levels of resistance, then moving on to trace potential run-off. The research project should provide significant insight into identifying the potential causes of increased microbial antibiotic resistance in the environment, hopefully addressing growing public concern over the potential problem. However, at such an early stage in the project, Gupta stressed that it was still too early to draw any conclusions from the work.

Satish Gupta: gupta002@umn.edu

Sagar Goyal: goyal001@umn.edu

Ashok Singh: singh001@umn.edu

Kuldip Kumar: kumar025@umn.edu

Anita Thompson: grub0002@umn.edu

Helene Murray: murra021@umn.edu