Author: Williams Shawna
Institution: Biochemistry
Date: September 2002
Hospitals kill. According to the educational news source Health Sentinel, every year 88,000 people in the United States die from infections acquired in hospitals -- more than the number that die from breast and prostate cancers combined. One reason why this number is so high is that many infections are antibiotic-resistant, meaning they do not respond to one or more of the drugs commonly used to treat them.
Many reasons exist for the prevalence of these impervious germs in hospitals. Hospitals concentrate very sick people into a small area, people whose weakened immune systems leave them highly vulnerable not only to their own illnesses, but also to germs from other patients. Even normally harmless intestinal bacteria can turn deadly in someone with a compromised immune system. Because they treat illness, hospitals dole out large quantities of antibiotics, which encourage resistance not only in their target bacteria, but in other strains as well. These factors contribute to making hospitals what the National Institutes of Health terms "a fertile environment for drug-resistant pathogens."
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Other elements also contribute to the development of drug-resistant pathogens in hospitals and elsewhere. Scientists and policymakers are giving increased attention to the large quantities of antibiotics given to farm animals, and their possible contribution to antibiotic resistance in human pathogens. A growing body of circumstantial -- and some direct -- evidence indicates that the two may indeed be linked, and that antibiotics are losing effectiveness as a result.
By definition, antibiotics target bacteria (they have no effect on viruses). Antibiotic resistance occurs naturally in a small percentage of bacteria, which are either able to expel the antibiotic or to find ways around using whatever part of their system the drug targets. Once exposed to an antibiotic, non-resistant bacteria die and resistant ones fill in the population gap, becoming much more prevalent. In evolutionary terms, the antibiotic exerts "selective pressure," giving a competitive edge to resistant bacteria.
Antibiotics are used on farms to treat illnesses in animals, to prevent the spread of disease through herds and to make animals grow more while consuming less food. No one is quite sure why low doses of antibiotics mixed in with food promote growth, but according to a 2001 analysis by the Union of Concerned Scientists, a non-profit environmental group, 25 million pounds of antibiotics are used each year in the United States for growth promotion (the industry group Animal Health Institute puts the number lower, at 3.1 million pounds annually for growth promotion). This compares to 3 million pounds used in human medicine.
In 1998, a 62-year-old Danish woman died when the food poisoning she contracted from eating Salmonella-infected pork failed to respond to the antibiotic ciprofloxacin. Researchers led by Henrik Wegener of the Danish Veterinary Laboratory were able to genetically match the drug-resistant Salmonella strain to one in a specific herd of pigs. Though the pigs had not been treated with ciprofloxacin, nearby herds were treated with a similar drug, and resistant bacteria had moved between farms.
Demonstrating a direct link between antibiotic use on the farm and resistant, disease-causing bacteria was an important step for the researchers. "It's the closest that anyone has come to a smoking gun," says Abigail Salyers, a microbiologist at the University of Illinois, Urbana-Champaign.
One striking aspect of this story is the belief Wegener has that his country has the most aggressive surveillance system for resistant Salmonella in the world, meaning that if it had happened somewhere else, the source of the ciprofloxacin-resistant germs might never have been identified.
Another case, reported in 2000 by Paul Fey of the University of Nebraska medical center, was that of a Nebraskan boy who contracted the same strain of Salmonella that infected some cows on the ranch where he lived. The cows had been infected by cattle on a nearby ranch that had been treated with the antibiotic ceftiofur. When the boy's doctors treated his infection with a similar drug, ceftriaxone, the Salmonella turned out to be resistant. Fortunately, the boy recovered anyway.
Although cases in which such a direct link has been identified are rare, disturbing trends can be seen in larger-scale studies. For example, in 1994 the Food and Drug Administration (FDA) approved the use of a class of antibiotics known as quinolines, which are also used in medicine, for prevention of infection in chickens. In the next seven years the percentage of people with quinoline-resistant Campylobacter, an intestinal bacteria, rose from 1% to 17%, according to the Minnesota Department of Health.
Until 1997, the glycopeptide avaroparcin was used as a growth promoter in European livestock. Even in parts of Germany where another glycopeptide, vancomycin, is rarely prescribed, vancomycin-resistant Enterococci (VRE) - another intestinal bacteria - was fairly common in people. In 1997 the European Union banned the use of avaroparcin as a growth promoter, and between 1996 and 2001 researchers at the University of Antwerp saw VRE in Belgian hospitals drop from a prevalence of 5.7% to just 0.6%.
In these cases the mechanism of transfer between animals and humans is straightforward: Resistant bacteria survive the slaughterhouse and meat is not cooked thoroughly enough to kill it before it reaches the table, so it survives to infect the person eating it. Since only food-borne bacteria can be contracted in this way, it might then seem that we need not worry about antibiotic use in animals fomenting resistance in pathogens that are passed between people, such as tuberculosis or pneumonia. But this assumption overlooks a feature of bacterial physiology with potentially serious implications. As Salyers warns, "The spread of genes is the problem, not just the spread of bacteria."
Bacterial genes coding for antibiotic resistance are typically found on plasmids, small rings of DNA separate from the main genome. Plasmids are regularly passed between bacteria -- even between different strains -- in a process called conjugative transfer. When an animal or human takes antibiotics it is not only pathogens that are affected, but also what are called "commensal" bacteria, which have no adverse effect on the host. The commensal bacteria must develop resistance to survive, and thus become what microbiologist Anne Summers of the University of Georgia-Athens calls "a resistance reservoir" within the host. This is dangerous because, as she explains, "an entering pathogen might obtain resistance genes from the commensal bacteria" and become resistant itself.
Summers goes on to cite studies showing that resistance genes for various drugs are frequently linked, residing close together on the same plasmid. What this means in practice is that exposure to one antibiotic can breed resistance not only to that drug, but to others as well.
So when it comes to antibiotic resistance, clear causes and effects are hard to identify. Indeed, the effects of any antibiotic use are far-reaching, ecological.
"There is growing evidence . that antimicrobial-resistance genes and their genetic vectors, once evolved in bacteria of any kind anywhere, can spread indirectly through the world's interconnecting commensal, environmental, and pathogenic bacterial populations to other kinds of bacteria anywhere else," says Thomas O'Brien of Harvard Medical School's Brigham and Women's Hospital.
One such piece of evidence comes from researchers at the University of Illinois Urbana-Champaign, who found antibiotic-resistant bacteria as far as 250 meters downstream from lagoons where waste from swine farms was dumped. In accordance with Summer's and O'Brien's warnings, they found antibiotic genes not only in intestinal bacteria from pigs that had survived in the groundwater, but also in "typical soil inhabitants," microorganisms that originated in the soil itself.
The researchers mention the possibility that groundwater contaminated with such resistant bacteria might flow, untreated, to a well, so that "the occurrence of antibiotic resistance genes in drinking water provides a possible way for antibiotic resistance to enter the animal and human food chain."
Because of the risks associated with routine antibiotic use on farms, the Swedish government banned the use of antibiotics as growth promoters in 1986. With some improvements in hygiene and changes in diet, however, Swedish farmers were able to continue raising pigs almost as cheaply as before the ban. Other practices that reduce the need for antibiotics are vaccination and probiotics, the practice of using certain commensal bacteria to crowd out potential pathogens in an animal's digestive system.
In 1998 the FDA proposed stricter regulations on agricultural antibiotic use in the United States. The proposal includes thresholds of antibiotic resistance, one for people and one for animals, which, if exceeded, would indicate that a ban was needed on administration of a drug to a particular species.
"[The] FDA has shifted the discussion away from We will do something when we see a problem in humans' to saying We will potentially do something when we see development of resistance in animals.' says J. Glenn Morris Jr. of the University of Maryland School of Medicine. "To my mind, that is a major positive step."
Many scientists, though, would go further. The Facts about Antibiotics in Animals and their Impact on Resistance (FAAIR) Scientific Advisory Panel, a collaboration of researchers who studied the impact of agricultural antibiotic use for two years, concluded that antibiotics should not be given to healthy animals at all (with the exception of ionophores and coccidiostats, two classes of antibiotics that have no analogues in human medicine).
Antibiotic resistance is a complex problem, involving myriad interactions between humans, animals, drugs, and the environment. Yet out of this complexity a simple truth emerges: Antibiotics breed resistance, no matter where they are taken or by whom. As Fred Angulo of the Centers for Disease Control and Prevention says, "It's nonsensical to cut the problem into pieces."
Salyers characterizes antibiotic resistance as "a slowly spreading stain," a cumulative effect of many years of medicinal and agricultural use. Preserving the potency of antibiotics against disease necessitates using them responsibly. And responsible use entails learning all that we can about the various factors that promote resistance, and using this knowledge to make reasoned decisions about how and where antibiotics should be used.
References
"Adverse Drug Events and Hospital Acquired Infections." Health Sentinel. Jan 14, 2001. http://www.healthsentinel.com/Briefs/ADEs.htm
"Antimicrobial Resistance." National Institutes of Health. http://www.niaid.nih.gov/factsheets/antimicro.htm
Ferber, Dan. "Livestock Feed Ban Preserves Drugs' Power." Science 295 (2002): 27-8.
Ferber, Dan. "Superbugs on the Hoof?" Science 288 (2000): 792-4.
Hileman, Bette. "Furor Over Animal Antibiotic Use." Chemical and Engineering News Feb 19, 2001: 47-52.
Mathew, A.G.; Upchurch, W.G.; Chattin, S.E. "Incidence of antibiotic resistance in fecal Escherichia coli isolated from commercial swine farms." Journal of Animal Science 76 (1998): 429-434.
Mlot, Christine. "Antidotes for antibiotic use on the farm." Bioscience 50 (2000): 955-60.
O'Brien, Thomas F. "Emergence, Spread, and Environmental Effect of Antimicrobial Resistance: How Use of an Antimicrobial Anywhere Can Increase Resistance to Any Antimicrobial Anywhere Else." Clinical Infectious Diseases 34 (2002): S78-S84. http://www.journals.uchicago.edu/CID/journal/issues/v34nS3/020123/020123.html
Summers, Anne O. "Generally Overlooked Fundamentals of Bacterial Genetics and Ecology." Clinical Infectious Diseases 34 (2002): S85-S92. http://www.journals.uchicago.edu/CID/journal/issues/v34nS3/020124/020124.html