(2001; 76 pages)
Antimicrobials in animal feed: a threat to human use
Antimicrobials have been used in food animals in North America and Europe for nearly half a century. Among the most common are drugs that are either identical to or related to those administered to humans, including penicillins, tetracyclines, cephalosporins (including ceftiofur, a third-generation cephalosporin), fluoroquinolones, avoparcin (a glycopeptide that is related to vancomycin), and virginiamycin (a streptogramin that is related to quinupristin-dalfopristin). These antimicrobial agents are given to food animals as therapy for an infection or, in the absence of disease, for subtherapeutic purposes with the goals of growth promotion and enhanced feed efficiency and improved nutritional benefits of the animal feed (1).
There is considerable controversy about the amounts of antimicrobials that are given to food animals relative to the amounts given to humans, since manufacturers are not required to provide precise production figures. One estimate is that 50% of all antimicrobials produced in the United States are administered to animals, mostly for subtherapeutic uses. The Union of Concerned Scientists recently estimated that, each year, 24.6 million lb (11.2 million kg) of antimicrobials are given to animals for nontherapeutic purposes and 2 million lb (900,000 kg) are given for therapy; in contrast, 3 million lb (1.3 million kg) are given to humans (2). Whichever figures are accepted, it is fair to state that substantial amounts of antimicrobials are administered to food animals for growth promotion and feed efficiency in the absence of known disease.
An intense debate has raged over the past three decades on the impact on health in humans of the use of antimicrobial agents in food animals. Three reports have now been published (3-5) which add weight to the rising movement to ban subtherapeutic uses of antimicrobials in animals. In one study, 20% of samples of ground meat obtained in supermarkets were found to be contaminated with salmonella and 84 percent of the isolates were resistant to at least one antimicrobial (3). The authors of the report point out that the food supply is the chief source of human infection with antimicrobial-resistant salmonella. The transfer of resistant salmonella and Escherichia coli from food animals to humans is a common event, as has been demonstrated by several groups of researchers. Other studies have shown that Campylobacter jejuni, another important human pathogen, is frequently isolated from meat, particularly poultry, that is available in supermarkets, and the incidence of fluoroquinolone-resistant strains has increased with the introduction of the therapeutic use of these drugs in animals.
Another study, (4) found that at least 17 percent of chickens obtained in supermarkets in USA had strains of Enterococcus faecium that were resistant to quinupristin-dalfopristin, an important new antimicrobial that was approved for use in people after this survey was completed. Development of resistance in this important pathogen is ascribed to the widespread use of virginiamycin in chicken feed. The third study, (5) found that glycopeptide-resistant and streptogramin-resistant strains of E. faecium, isolated from chicken parts obtained at a grocery store and pigs after slaughter, were able to colonize transiently (up to 14 days) the intestinal tract of healthy volunteers. The emergence of glycopeptide-resistant strains is linked to the widespread use of avoparcin in animal feed in Europe. In 1997, its use was banned by countries in the European Union.
Over 80 percent of infections with salmonella and campylobacter in humans are acquired from food animals. One study published in 1999 estimated that there were 1.4 million cases of illness due to salmonella and 2.4 million cases of illness due to campylobacter infection in the United States (6). In that study, 26 percent of salmonella isolates and 54 percent of campylobacter isolates were resistant to at least one antimicrobial. There is also growing concern about the increasing rate of isolation of Salmonella enterica serotype typhimurium definitive type 104 (DT104) in the United States and throughout the world. This strain, which was one of those isolated from ground meat (3), is resistant to multiple drugs and has heightened virulence.
The use of antimicrobials in food animals selects for resistant strains and enhances their persistence in the environment. Drug resistance in salmonella and campylobacter can increase the frequency and severity of infections with such organisms, limit treatment options, and raise health care costs. These effects may be related to enhanced shedding and augmented virulence of resistant strains, increased rates of transmission of these strains, and the ineffectiveness of initial regimens of antimicrobial therapy against such strains. The risk of infection with a resistant strain of salmonella or campylobacter is increased when a person has taken an antimicrobial within a few weeks before the exposure.
Another concern is the horizontal spread of the resistance genes from bacteria in food animals to commensal strains in the intestinal microflora of humans. Extensive transfer of antimicrobial-resistance genes has been demonstrated among enteric bacteria, bacteroides, and Gram-positive bacteria in the human colon (7). These organisms serve as a reservoir of resistance genes that can be transferred to other members of the microflora or to pathogenic bacteria. Not all antimicrobial resistance in human pathogens can be ascribed to the use of these drugs in food animals, however. The use of antimicrobials in humans, much of which is inappropriate, is responsible for rising levels of resistance in organisms such as Streptococcus pneumoniae, Staphylococcus aureus, and Neisseria gonorrhoeae, as well as in many bacteria acquired in hospitals.
The same may apply to vancomycin-resistant enterococci, which currently account for 25 percent of nosocomial enterococcal infections in the United States. In some European countries, the rates of carriage of vancomycin-resistant enterococci in the general population range from 12 to 28 percent; yet in most European hospitals the incidence of infection with these organisms remains very low. The opposite situation prevails in the United States. As reported (4), the rate of carriage of vancomycin-resistant enterococci in the general population is one percent, whereas nosocomial infections with vancomycin-resistant enterococci are widespread in many hospitals in the United States. The epidemiologic characteristics of vancomycin-resistant enterococci in the United States indicate that acquisition within a hospital, particularly in an intensive care unit, and prior use of certain antimicrobial drugs are risk factors for infection (8). Although the transmission of vancomycin-resistant enterococci in the United States has not been related to the use of antibiotics in food animals, the increasing burden of resistant E. faecium in the food chain (4) and the ability of these strains to colonize the human intestine (5) represent a potential threat.
The most widely proposed argument in favor of the use of antimicrobials for growth promotion and feed efficiency in animals is economic savings. However, there are alternatives, as shown in Europe after the use of these drugs was abandoned. The economic losses could be minimized and even neutralized by improvements in animal husbandry, the quality of feed, and hygiene. On the basis of discussions by an expert committee of the Alliance for the Prudent Use of Antibiotics, several recommendations can be made.
• Antimicrobials should be used only when indicated in individual infected animals for a targeted pathogen and prescribed by a veterinarian.
• The use of certain drugs that have important uses in humans, such as fluoroquinolones and third-generation cephalosporins, should be prohibited in animals.
• Finally, the subtherapeutic use of these agents to promote growth and feeding efficiency should be banned - a move that would decrease the burden of antimicrobial resistance in the environment and provide health-related benefits to both humans and animals.
1. Gorbach, S.L. Antimicrobiao use in animal feed - Time to stop. New England Journal of Medicine, 345: 1202-1203 (2001).
2. Mellon. M., Benbrook, C., Benbrook, K.L. Hogging it: estimates of antimicrobial abuse in livestock. Cambridge, Mass., Union of Concerned Scientists, 2001.
3. White, D.G., Zhao, S., Sudler, R. et al. The isolation of antibiotic-resistant salmonella from retail ground meats. New England Journal of Medicine, 345: 1147-1154 (2001).
4. McDonald, L.C., Rossiter, S., Mackinson, C. et al. Quinupristin-dalfopristin-resistant Enterococcus faecium on chicken and in human stool specimens. New England Journal of Medicine, 345: 1155-1160 (2001).
5. Sorensen, T.L, Blom, M., Monnet, D.L. et al. Transient intestinal carriage after ingestion of antibiotic-resistant Enterococcus faecium from chicken and pork. New England Journal of Medicine, 345: 1161-1166 (2001).
6. Mead, P.S., Slutsker, L., Dietz, V. et al. Food-related illness and death in the United States. Emerging Infectious Diseases, 5: 607-625 (1999).
7. Shoemaker, N.B., Vlamakis, H., Hayes, K., Salyers, A.A. Evidence for extensive resistance gene transfer among Bacteroides spp. and among Bacteroides and other genera in the human colon. Applications of Environmental Microbiology, 67: 561-568 (2001).
8. Gold, H.S. Vancomycin-resistant enterococci: mechanisms and clinical observations. Clinical Infectious Disease, 33: 210-219 (2001).