By Susan T. Marcolina, MD, FACP
As multiple drug resistance patterns have emerged in bacteria, closer surveillance of medical antibiotic prescribing practices has been undertaken.1 Another area that requires further evaluation, however, is the use of antibiotics in animal husbandry, because this constitutes the largest use of antimicrobial agents outside human medicine.2
This article tracks the link between agricultural antibiotic use and the emergence of drug-resistant bacteria in foodborne illnesses that have become increasingly difficult to treat.
Agricultural Antibiotic Use
The practice of using antibiotics in the raising of food animals on farms originated in Europe and North America in the 1950s and was lauded as a mechanism to promote growth and increase feed efficiency. Animals that receive small but regular amounts of antibiotics in their feed gain 4-5% more weight than animals eating conventional feed.3 In addition to growth promotion, healthy animals also are given low-dose antibiotics for disease prevention purposes. Veterinarians also prescribe antimicrobials therapeutically to sick animals.4
According to statistics provided by the Animal Health Institute (AHI), an organization representing manufacturers of drugs for animal use, 22 million pounds of antibiotics were used on farms in 2001. The pharmaceutical industry, however, is not required to reveal sales statistics on antibiotics for agricultural use. Table 1 summarizes estimates compiled by the Institute of Medicine5 and the Union of Concerned Scientists.6
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Classes of Antibiotics Used in Food Animals
The FDA has specified three categories of antimicrobial drugs used in agriculture. These categories are based on the drug’s relative importance to human medicine. Category I antimicrobials have unique and important uses for serious human diseases for which there are few or no therapeutic alternatives. Category II antimicrobials are important in the therapy of serious infectious diseases, foodborne or otherwise, but for which there are satisfactory alternate therapies. Category III antimicrobials have little or no use in human medicine and are not drugs of choice or significant alternatives for treating human infections. Table 2 lists antimicrobials approved by the Food and Drug Administration (FDA) for growth promotion.4,7
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Meat Production Practices
Industrialized animal agriculture, which predominates in the United States and other developed countries, relies upon crowded, often unsanitary, stressful growing conditions in order to meet the market demands to provide large amounts of inexpensive meat. Proponents of the use of antibiotics for growth promotion and disease prevention in livestock and poultry farming consider them to be an integral part of these intensive livestock operations.7 Sweeping changes in the use of these agents has raised concerns about a loss of income to farmers. In Sweden, where the use of antimicrobials for growth promotions was prohibited in 1986, improved animal hygiene and altered farming practices have restored the initial productivity losses.8
Ramifications of Agricultural Nontherapeutic Antimicrobial Use
The nontherapeutic use of antimicrobials in animals has created selection pressures that favor the survival and spread of a pool of resistant organisms in the intestines of the animals and, hence, in animal wastes spread throughout the environment, in surface water, ground water, and soils.4 Nearly 2 trillion pounds of manure is generated on U.S. farms annually. The resistance genes in the fecal bacteria can transfer to unrelated bacteria, including types that cause human disease.9
Levy et al examined the effect of feed containing chlortetracycline on the intestinal flora of chickens and human farm dwellers. Following a controlled experimental design, the chickens were divided into two groups; one group received feed containing subtherapeutic doses of oxytetracycline and the control group received antibiotic-free feed. After a two-week interval, 90% of the experimental chickens excreted tetracycline-resistant organisms. Multidrug resistance (to sulfonamides, streptomycin, ampicillin, and carbenecillin) also developed. This resistance was transferred to humans. Within a six-month interval, more than 30% of fecal samples from farm dwellers contained greater than 80% tetracycline-resistant bacteria, compared with 6.8% in neighborhood control subjects (P < 0.001).10
Holmberg et al examined a six-state outbreak of illness caused by a plasmid-mediated, multidrug resistant strain of Salmonella newport. This human illness was attributed to ingested beef that was traced back to a feedlot that used subtherapeutic doses of chlortetracycline as a growth promoter. Study investigators documented the presence of the outbreak organism in isolates from animals and humans on an adjacent dairy farm. Additionally, this study identified an increased risk of illness with a resistant S. newport strain in patients who recently had taken antibiotics for other infections (odds ratio: 51.3; P = 0.001). This study enhances our understanding of how resistant enteric pathogens can be transmitted through the food chain.11
Such drug resistances acquired by Salmonella and Campylobacter pathogens increase the frequency and severity of disease, limit treatment options, and increase health care expenses.4
Regulation
The National Antimicrobial Resistance Monitoring System (NARMS) is a joint surveillance system for monitoring antimicrobial resistance in foodborne pathogens. It is a cooperative effort of the Center for Disease Control and Prevention (CDC), the U.S. Department of Agriculture, the FDA’s Center for Veterinary Medicine (CVM), and 17 participating state and community health departments that was established in 1996.
Great differences in the use and licensing of antibiotics for use in food animals exist worldwide. The European Union banned the use of all antibiotic growth promoters in 1999. Tylosin and virginiamycin are still used in the United States as growth promoters and cause cross resistance to similar classes of antibiotics, the macrolides and streptogramins, respectively, that are utilized in human medicine. Chloramphenicol is still used for veterinary purposes in Russia. Because meat products are traded globally, evolving bacterial populations with multiple antibiotic resistances also transcend geographic boundaries to cause human disease.3
Antimicrobial Resistance in Foodborne Pathogens
Antibiotic resistance that arises from animal husbandry practices affects zoonotic pathogens (those transmissible from animals to humans) such as Salmonella and Campylobacter sp., both of which are responsible for diarrheal diseases.12 A retrospective study of infections with Salmonella enterica serotype typhimurium DT 104 by the CDC revealed that the percentage of isolates with multiple antibiotic resistances (ampicillin, chloramphenicol, streptomycin, sulfonamide, and tetracycline) increased from 0.6% in 1979-1980 to 34% in 1996.13 This Salmonella strain also has been identified in several countries in Europe. The recent development of fluoroquinolone and ceftriaxone resistance is of specific concern because the fluoroquinolones are the drugs of choice in adults and ceftriaxone is the drug of choice in children for the treatment of disseminated salmonellosis. This form of Salmonella occurs in 3-10% of cases, primarily affecting patients at the extremes of age.14,15
In August 1995, the FDA approved fluoroquinolones to treat Escherichia coli and Pasturella sp. infections in poultry. Between 1997 and 1999, NARMS noted an increase in fluoroquinolone resistance from 12.9% in Campylobacter sp. to 17.6% in C. jejuni (human pathogen) and 30% in C. coli (a commensal in chicken intestinal flora). Similar increases in resistant isolates were obtained from chicken in slaughterhouses and retail stores. As a result, the CVM has begun to withdraw approvals for therapeutic use of fluoroquinolones in poultry.16
In many European and Asian countries where fluoroquinolones were approved in the mid-1980s for use in food animals, resistance in humans is now firmly established.17 Of additional concern is the fact that the minimal inhibitory concentrations for fluoroquinolones in U.S. Salmonella isolates are increasing, which threatens the efficacy of these drugs for more serious infections.18
Consumer Guidelines
An on-line guide "Eat Well, Eat Antibiotic Free," produced by the Institute for Agriculture and Trade Policy, helps consumers identify and understand the labels for meat and poultry raised without antibiotics. The guide provides listings by state of the supermarkets, cooperatives, restaurants, and community-supported agriculture networks that sell and serve antibiotic-free meats.19
Conclusion
Intensive farming practices that produce meat products raised with antibiotic supplementation select for resistant intestinal and pathogenic bacteria in the animals, which can be transferred to humans via resistance genes, resulting in difficult-to-treat foodborne illnesses.
Recommendation
When possible, patients should purchase meat products from smaller-scale farming practices that favor organic standards for food animals without the nontherapeutic use of antibiotics for growth promotion. Such changes would decrease the burden of antimicrobial resistance in the environment and provide health-related benefits in terms of decreased bacterial resistance patterns for both humans and animals.
Many patients cannot afford to exclusively purchase organic meat and poultry. If conventionally raised meats are purchased, careful attention must be paid to ensuring adequate cooking and refrigeration temperatures according to FDA Food Information Guidelines. It is important to avoid contamination of table-ready food with raw meat juices since bacteriologic surveys have shown that retail purchases of beef, poultry, and pork frequently are contaminated with resistant strains of bacteria.
Finally, medical professionals must work with all stakeholders to implement strategies that will slow the trajectory of antibiotic resistance. The giant fast food conglomerate McDonald’s has taken up this cause with an indictment of the use of antibiotics in livestock production that made front page headlines on June 19, 2003.20 The McDonald’s policy, which will be implemented worldwide by the end of 2004, requires direct beef and poultry suppliers to refrain from using antimicrobials as growth promoters and to keep records and submit to audits verifying adherence. This policy change came as a result of concerns raised by consumer and public health advocacy groups. Physicians need to continue to advocate for the highest standards in food safety for our patients.
Dr. Marcolina is a board-certified internist and geriatrician in Issaquah, WA.
References
1. Seppala H, et al. The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in Group A streptococci in Finland. N Engl J Med 1997; 337:441-446.
2. Swartz MN. Committee on Human Risk Assessment of Using Subtherapeutic Antibiotics in Animal Feeds, Institute of Medicine, Division of Health Promotion and Disease Prevention. Human Health Risks with the Subtherapeutic Use of Penicillins or Tetracyclines in Animal Feed. Washington DC: National Academy Press; 1989.
3. Witte W. Medical consequences of antibiotic use in agriculture. Science 1998;279:996-997.
4. Shea KM. Antibiotic resistance: What is the impact of agricultural uses of antibiotics on children’s health? Pediatrics 2003;112:253-258.
5. Harrison PF, Lederberg J, eds. Antimicrobial Resistance, Issues and Options, Forum on Emerging Infections. Washington DC: Institute of Medicine; 1998.
6. Mellon M, et al. Hogging It! Estimates of Antimicrobial Abuse in Livestock. Washington DC: Union of Concerned Scientists; 2001.
7. National Research Council, Committee on Drug Use in Food Animals, Panel on Animal Health, Board of Agriculture, Food and Drug Nutrition Board, Institute of Medicine. The Use of Drugs in Food Animals: Benefits and Risks. Washington DC: National Academic Press; 1999.
8. Antimicrobial Feed Additives Government Official Reports, No 132. Stockholm, Sweden; 1997.
9. Food and the Environment. Prescription for Trouble: Using Antibiotics to Fatten Livestock. Available at: www.keepantibioticsworking.com/News/news.cfm?Archive=Yes. Accessed Sept. 1, 2003.
10. Levy SB, et al. Changes in intestinal flora of farm personnel after introduction of a tetracycline-supplemented feed on a farm. N Engl J Med 1976:295:583-588.
11. Holmberg SD, et al. Drug-resistant Salmonella from animals fed antimicrobials. N Engl J Med 1984:311:617-622.
12. Gorbach SL. Antimicrobial use in animal feed—Time to stop. N Engl J Med 2001;345:1202-1203.
13. Glynn MK, et al. Emergence of multidrug-resistant Salmonella enterica serotype typhimurium DT104 infections in the United States. N Engl J Med 1998;338:1333-1338.
14. Mead PS, et al. Food-related illness and death in the United States. Emerg Infect Dis 1999;5:607-625.
15. White DG, et al. The isolation of antibiotic-resistant Salmonella from retail ground meats. N Engl J Med 2001; 345:1147-1154.
16. U.S. Food and Drug Administration. Enrofloxacin for poultry: Opportunity for Hearing. Fed Reg 2000;65: 64954-64965.
17. Engberg J, et al. Quinolone and macrolide resistance in Campylobacter jejuni and C. coli: Resistance mechanisms and trends in human isolates. Emerg Infect Dis 2001;7: 24-34.
18. Center for Disease Control and Prevention. Serotypes of non typhi Salmonella with reduced susceptibility or resistance to ciprofloxacin. Available at: www.cdc.gov/narms/annual/1999/html/tables/table_11.htm. Accessed Aug. 25, 2003.
19. "Eat Well, Eat Antibiotic Free." An on-line guide. Available at www.iatp.org. Accessed Sept. 11, 2003.
20. Marc Kaufman. McDonald’s Asks Meat Suppliers to Stop Using Antibiotics. Washington Post June 19, 2003. Available at: www.washingtonpost.com/ac2/wp-dyn/A12881-2003Jun19?language=printer. Accessed July 31, 2003.
Marcolina S. Antibiotic-resistant foodborne illness: More than 'meats' the eye. Altern Med Alert 2003;6(11):128-131.
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