Too Much of a Good Thing

Antibiotics are often called “magic bullets,” drugs that can kill a pathogen without harming its host. But overuse has created a plethora of antibiotic-resistant bacteria that may be having the last laugh in infectious diseases in humans. Between 1980 and 1992, the number of infectious disease deaths increased by 58 percent, partly due to antibiotic-resistant bacteria, and doctors must increasingly rely on antibiotics earmarked as drugs of last resort, to be used only when all others have failed.

Conventional wisdom blames the docs for decades of prescribing antibiotics too often and too quickly. But it turns out that excessive reliance on the prescription pad may not be not the only culprit behind the rise in antibiotic resistance. Some scientists believe that resistant bacteria arise when livestock are treated with antibiotics and that this resistance can be transferred to bacteria that cause human illness.

How can this happen? Consider the following chain of events: an E. coli bacteria is living in the gut of a cow. This cow is regularly given antibiotics, and so to survive, the E. coli contains a gene to help it resist the antibiotic. When this cow is slaughtered, the E. coli, perhaps through sloppy handling, makes its way from the gut to ground meat that is sold in a supermarket. Mrs. Smith buys this meat and makes a hamburger. Smith gets a phone call midway through meal prep and doesn’t wash her hands thoroughly, and the E. coli manages to stay on her skin. Eventually it meets a staph bacteria and transfers its antibiotic resistance. Smith now has antibiotic-resistant staph bacteria. Staph are capable of causing toxic shock syndrome and various types of skin infection, and treatment usually includes antibiotics.

The Union of Concerned Scientists estimates that every year 24.6 million pounds of antibiotics are used for non-therapeutic purposes in pigs, poultry, and cattle. When humans ingest the flesh of these animals, they may also be exposing themselves to the genes of antibiotic-resistant bacteria. Only 3 million pounds of antibiotics are used in human medicine each year. Put another way, over 70 percent of antibiotics produced each year are used for animal husbandry.

Antibiotic use in livestock falls into three categories: therapy, prevention, and growth promotion. If an animal exhibits symptoms of an infection, it is given antibiotics as therapy, but it also may be dosed preventatively to ward off infection from exposure to sick animals or unhealthy housing conditions. Low, sub-therapeutic levels of antibiotics are also administered to promote growth. Why antibiotics promote growth is unclear, but some speculate that it suppresses disease, so the animal does not expend as much energy on maintaining its immune system. Low doses may also increase the efficiency of digestion and metabolism through manipulation of the microbial life found in the animal’s gut.

Resistance develops through a process of selection. Ideally, a dose kills off all target bacteria. But if the dose is not sufficiently high, some of the bacterial population remains. These survivors are more resistant to antibiotics—and it’s possible that resistance developed to one class of antibiotics may increase resistance to others. Six classes of antibiotics used in livestock are also used to treat people. Since most livestock receive sub-therapeutic doses of antibiotics as growth promoters and preventives over extended periods of time, antibiotic-resistant bacteria can easily develop in livestock—bacteria resistant to the same drugs used to control infection and disease in people.

Livestock excrete bacteria as well as antibiotics in their waste, which is stored in large lagoons. From these lagoons, antibiotics and resistant bacteria can make their way into the environment. Antibiotic-resistant bacteria have been isolated from groundwater and soil near animal waste lagoons. Often waste is used as fertilizer on crops, spreading resistance farther. Bacteria in the soil can pick up resistance from any resistant bacteria in the waste, and the presence of antibiotics in the soil continues the process of killing off less resistant bacteria while favoring the more resistant strains. In short, use of antibiotics in livestock has led to the formation of reservoirs of resistance both in the livestock themselves and in the surrounding environment.

Resistance can pass not only from mother to daughter cells but also between cells. Genes for antibiotic resistance usually reside on plasmids, small circular pieces of DNA separate from the genome, or on transposons, small DNA elements that can cut themselves out of the genome and paste themselves back in at a different location. Some transposons are also able to copy themselves to insert elsewhere in the genome. Resistance genes can be swapped between different bacteria, meaning resistance genes may eventually find their way from the reservoir in livestock to human bacteria. These may be beneficial bacteria that are part of the normal ecosystem in the gut, but they can become their own reservoir of resistance genes in people.

Eventually, a resistance gene may link up with pathogenic bacteria. Initial treatment of the sick individual is likely to be less effective because the doctor is unaware of the resistance. Higher, perhaps more toxic, dosages of antibiotics must be prescribed, with fewer antibiotics to choose from. Bacteria with resistance genes may also be more virulent.

The solution is simple—stop using antibiotics. Resistant bacteria have more genes and must spend more time and energy copying and repairing DNA before dividing. In the absence of antibiotics, the resistance gene is no longer needed, and the extra energy used to maintain the DNA that codes for resistance outweighs the benefit. Bacteria with such genes reproduce more slowly, so the number of antibiotic-resistant bacteria will eventually decline.

Simple in theory does not mean simple in practice: consider Denmark. By 1999, through a combination of voluntary and regulatory measures, Denmark’s broiler chicken and swine industries had stopped using antibiotics as growth promoters. To compensate, many Danish livestock producers improved sanitation and offered roomier housing. They also used alternative feed additives such as amino acids to mimic the growth-promoting effect of antibiotics. Despite these measures, more feed and time were required to raise animals to slaughter weight. Farmers also increased their use of therapeutic antibiotics. The number of antibiotic-resistant bacteria in the environment surrounding the farms has decreased significantly although there has been no clear impact on human health. Granted, Denmark did not have many problems with antibiotic resistance in human illnesses to begin with. Controversy continues over whether the growth promoter ban is beneficial.

How frequently does this chain of events occur? Is it worth it to discontinue use of antibiotics in livestock?

Compelling evidence suggests that antibiotic resistance in people originated from livestock. The impacts of antibiotic-resistant Salmonella and Campylobacter are well documented. Salmonella and Campylobacter are food-borne pathogens with extremely low rates of person-to-person transmission, so resistance found in human infections can be attributed to the reservoir of resistance genes originating from livestock. For Salmonella, there are many cases dating back to 1984 linking resistant bacteria in human infections to farms, and there has been an increasing frequency of such reports. In addition, studies have linked antibiotic resistance to greater virulence. Infection with antibiotic-resistant Campylobacter is associated with increased length of illness and greater risk of death. A Danish study reports that antibiotic-resistant Salmonella is associated with a tripling of the risk of death. While this is worrying, Salmonella and Campylobacter are for the most part foodborne, and illness can be prevented through thorough cooking and adherence to sanitary measures.

In most cases, the effects of resistant bacteria are not so obvious. Much of the evidence for other bacteria is circumstantial. Studies have found that an increase in levels of antibiotic-resistant bacteria in livestock and people follows introduction of that antibiotic into livestock. For example, a class of antibiotics called fluoroquinolones was approved for human use in the US in 1986 and for animal use in 1995. There were no reports of fluoroquinolone-resistance in foodborne Campylobacter until 1995. As another example, only countries that use avoparcin in livestock have cases of a urinary tract infection in humans that is difficult to treat with vancomycin, an antibiotic very similar to avoparcin. Vancomycin resistance is especially disturbing because it is a drug of last resort. After the EU banned the use of avoparcin, levels of vancomycin-resistant bacteria in meat products, livestock, and people decreased.

In a 1976 study conducted by Dr. Stuart Levy, author of The Antibiotic Paradox, chickens on a farm were divided into two groups, one of which received an antibiotic in their feed. After two weeks, 90 percent of the antibiotic-receiving chickens excreted resistant bacteria. Moreover, after twelve weeks, multidrug resistance developed. Resistance transferred to the farmers. After six months, more than 30 percent of people on the farm excreted bacteria, 80 percent of which were resistant, compared to 6.8 percent resistance for people who lived in the surrounding area. Researchers speculated that farmers developed resistance through handling the feed and because the genes were in the environment. People who ate eggs from the chickens did not develop resistant bacteria.

Other studies compare DNA sequences of resistance genes from different bacteria. Results from these experiments show that often the bacteria infecting people are the same as those in livestock. For example, in 1982 a streptotricin antibiotic was introduced as a growth promoter for pigs. Streptotricin has never been used in people. Within one year of its introduction, resistant bacteria were detected in pigs. Within two years, bacteria with the same gene were also found in pig farmers, their families, urban residents, and E. coli from urinary tract infections. A few years later, the resistance gene was found in pathogenic bacteria. Strikingly, it not only found its way into bacteria that can infect both animals and humans but also to Shigella, bacteria that resides only in people. While not all people who are infected by Shigella exhibit symptoms, Shigella infection can lead to stomach cramping, diarrhea, and fever. A more recent study used two variants of a vancomycin resistance gene. These two variants differ only by one DNA base. In poultry, the resistance gene has a G where in pigs there is a T. In humans, there is an even mix of G and T variants except in Muslim countries (which don’t raise or consume pigs) where people contain only the G variant.

Based on such evidence, the EU, which follows the precautionary principle, has banned the use of antibiotic growth promoters that can select for resistance to human antibiotics. US policy is based on proof of principle, and there is not enough evidence to justify eliminating the positive effects of antibiotic growth promoters. If antibiotics were discontinued, the cost of meat would increase by $5 to $40 per person per year, and an additional 2 million acres of cropland would be needed because animals would grow more slowly and produce more waste in the bargain. Dr. Ian Phillips, from the University of London, writes, “The banning of any antibiotic usage in animals based on the ‘precautionary principle’ in the absence of a full quantitative risk assessment is likely to be wasted at best and even harmful, both to animal and to human health.”

And skeptics remain. These scientists believe that only in the cases of Salmonella and Campylobacter is there sufficient evidence to show negative impact on human health, and even then they believe it is minimal. They point out that in almost every case, interpretation of data is complicated by use of antibiotics in humans as well as animals. Antibiotic resistance could have arisen first in people and then spread to animals. It is safe to say that these theories represent a minority in the scientific community.

Says Dr. Lee Riley, professor of epidemiology and infectious disease at UC Berkeley, “To be blunt, the likelihood of anything changing in the industry is very low. This has been going for more than fifty to sixty years, and there’s really lots of good evidence that a lot of the antibiotic resistance in humans is traceable to animal feed. The industry has not reacted to the overwhelming evidence for many good reasons, both legal and economic.”

Riley believes the solution is to look at European practices and appreciate their results. “Decreasing the use of antibiotics doesn’t contribute to any bad effect on the food industry. And ultimately we have to consider the negative impact of what we’re doing. Europe and Asia might stop imports of American food products. We need to weigh the risks and benefits. But they’ll only do it if they see that it’s to their benefit to sell antibiotic-free products. They need to get pressure from American consumers.”

Government interference never works, Riley says: “The most powerful weapon is the consumer.”

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