* Ph.D. (biochemistry), expected May 12, 2001, University of Arkansas. B.S. awarded May, 1996. I would like to thank the Graduate School at the University of Arkansas and Dr. Roger Koeppe II, my Ph.D. thesis advisor.
** Clayton N. Little Professor of Law, University of Arkansas School of Law; B.A. 1981, J.D. 1984, University of Arkansas. I would like to acknowledge the support given by the University of Arkansas School of Law in the form of a summer research grant for this project.
1 See, e.g., Zosi Kmietowicz, Superbugs are Beating at the Gates, New Scientist (July 17, 1999), available at http://www.newscientist.com/ns/19990717/newsstory12.html; Leading Superbugs Develop Dramatic Resistance to the Newest Antibiotics, U. of Toronto News & Events (July 21, 1999), available at http://www.newsandevents.utoronto.ca/bin/19990721.asp; Tamar Nordenberg, Miracle Drugs vs. Superbugs—Preserving the Usefulness of Antibiotics, FDA Consumer Magazine (Nov.-Dec. 1998), available at http://www.parenthoodweb.com/ articles/phw894.htm; Michael Day, Superbugs Take Hold, New Scientist (Apr. 25, 1998), availabe at http://www.newscientist.com/ns/980425/nsuperbug.html; Companies Race to Find Drugs to Kill Superbugs, Nando Times (Aug. 23, 1997), available at http://www. techserver.com.newsroom/ntn/health/082397/health34_5696_noframes. html.
2 One recent news story cites an “alarming” spread of drug-resistant bacteria that can “kill people with weak immune systems.” Day, supra note 1. Another draws parallels between the spread of antibiotic-resistant organisms and the “historical scourge known as the bubonic plague [that] killed up to one-third of Europe’s population in the 1300s.” Nordenberg, supra note 1. See generally Laurie Garrett, The Coming Plague (1994) (a recent book on the subject drawing similar parallels).
3 Antibiotic resistance refers to “a property of bacteria that confers the capacity to inactivate or exclude antibiotics, or a mechanism that blocks the inhibitory or killing effects of antibiotics, leading to survival despite exposure.” USDA, Antimicrobial Resistance Issues in Animal Agriculture 1 (Dec. 1999) [hereinafter USDA Report]. For a review of some of the scientific articles on the subject, see infra Part III of this article.
4 “The cause of bacterial reemergence as a threat to human health and life is the abuse of the ‘miracle drugs.’” John W. Harrison & Timothy A. Svec, The Beginning of the End of the Antibiotic Era? Part I. The Problem: Abuse of the “Miracle Drugs, 29(3) Quintessence Int’l 151, 151 (1998) [hereinafter Harrison, Part I].
5 Nat’l Research Council, Board on Agriculture, The Use of Drugs in Food Animals, Benefits and Risks 3 (1999).
6 Robert W. Pinner et al., Trends in Infectious Disease Mortality in the United States, 275 JAMA 189, 190 (1996).
7 Leslie Alan Horvitz, It’s a War to Restore Antibiotics, Insight on the News, Mar. 18, 1996, at 38, cited in Michael Misocky, Comment, The Epidemic of Antibiotic Resistance: A Legal Remedy to Eradicate the “Bugs” in the Treatment of Infectious Diseases, 30 Akron L. Rev. 733, 737 n.22 (1997).
8 See supra note 1.
9 Two recent student-written law review articles have also addressed the problem of antibiotic-resistant bacteria. See generally Scott B. Markow, Note, Penetrating the Walls of Drug-Resistant Bacteria: A Statutory Prescription to Combat Antibiotic Misuse, 87 Geo. L.J. 531 (1998); Misocky, supra note 7. Both of these articles, however, focus solely on the over-prescription of antibiotics.
10 Simon Midgely, Old Killers Resisting Arrest: Diseases Last Common in the 19th Century Have Returned with an Added Danger—the Prospect of an Antibiotic Resistant Super Bug, Times Higher Education Supplement, July 19, 1996, at 20, cited in Misocky, supra note 7, at 738.
11 Stuart B. Levy, a professor of molecular biology and microbiology at the Tufts University School of Medicine, has described this phenomenon as follows:
Ever since antibiotics became widely available in the 1940s, they have been hailed as miracle drugs—magic bullets able to eliminate bacteria without doing much harm to the cells of treated individuals. Yet with each passing decade, bacteria that defy not only single but multiple antibiotics—and therefore are extremely difficult to control—have become increasingly common.
Stuart B. Levy, The Challenge of Antibiotic Resistance, 278 Scientific American 46, need pinpoint cite (Mar. 1998), available at http://www.sciam.com/1998/0398issue/0398levy.html [hereinafter Levy, The Challenge].
12 At least 3 strains of bacteria capable of causing life-threatening illnesses in human beings have already been demonstrated to be resistant to every currently available antibiotic. Levy, The Challenge, supra note 11, at 46.
13 Although the term “livestock” may have a more limited meaning in other contexts, this article uses the term to mean any farm animal or poultry raised for food or food production (such as dairy cows or laying hens).
14 Despite the fact that differing drugs must normally be administered at differing levels in order to have demonstrable therapeutic effects, the Food and Drug Administration rather arbitrarily defined a subtherapeutic concentration of antibiotics as an amount added to feed at a concentration of <200 g/t. Nat’l Research Council, supra note 5, at 28.
15 See infra Part II of this article.
16 Bacteria are single-celled prokaryotic microorganisms. “Prokaryotic” means that the cell contains a primitive nucleus where the DNA-containing region lacks a limiting membrane. McGraw-Hill Dictionary of Scientific and Technical Terms 1588 (5th ed. 1994).
17 J. Nicklin et al., Instant Notes in Microbiology 156 (1999).
18 Id. at 156–57.
19 Id. at 157.
20 Penicillin alone saved countless lives in World War II by preventing soldiers from dying as a result of bacterial infection following wounding. Harrison, Part I, supra note 4, at 151. See also Nicklin, supra note 17, at 179. Antibiotics operate in a number of different ways. Harrison, Part I, supra note 4, at 152. Some antibiotics, such as penicillins and cephalosporins, inhibit bacterial cell wall synthesis. Other antibiotics, such as aminoglycoside antibiotics and tetracycline, interfere with protein synthesis. A third mechanism, employed by sulfonamides and quinolones, inhibit synthesis of bacterial nucleic acid. Nicklin, supra note 17, at 178.
21 Levy, The Challenge, supra note 11, at 49–50. If the bacteria is resistant to more than one class of antibiotics, it is generally referred to as having multi-drug resistance.
22 Random mutations may lead to resistance via any of a number of pathways, some of which are identified in the text of this article. Antibiotic use exerts a selective pressure so that the “mutant” strains have an evolutionary advantage, resulting in the creation of a dominant strain which exhibits the characteristic of resistance.
23 Nicklin, supra note 17, at 179.
24 Id.
25 Sulfonamide, methicillin, and trimethoprim resistance all occur because of such changes in the resistant bacteria. Id.
26 One normally thinks of inherited characteristics passing only to successive generations of that particular organism. This is not the case for bacteria.
27 Levy, The Challenge, supra note 11, at 48; see also Robert V. Miller, Bacterial Gene Swapping in Nature, 278 Scientific American 66 (1998).
28 Harrison, Part I, supra note 4, at 154.
29 In the strictest sense of the word, transposons are not extrachromosomal since they are integrated into the chromosomal DNA. Plasmids are an extrachromosomal genetic element found among various strains of Escherichia coli and other bacteria. McGraw-Hill, supra note 16, at 1522. Transposons are a kind of translocatable genetic element which comprise large discrete segments of deoxyribonucleic acid capable of moving from one chromosomal site to another in the same organism or in a different organism. Id. at 2061.
30 Plasmid-mediated resistance is of particular concern, not only because most bacterial species carry plasmids, but because resistance mediated by plasmids frequently results in multi-drug resistance. In addition, plasmids are easily transferred among bacterial strains and species. Harrison, Part I, supra note 4, at 154.
31 Nicklin, supra note 17, at 179.
32 Id. at 125–28.
33 Id. at 144–45.
34 Id. at 140–43. Bacteriophage, “normally called phage, are viruses that infect bacteria. They are obligate intracellular parasites that are capable of existence as phage particles outside the bacteria cell but can only reproduce inside the cell.” Id. at 127.
35 Levy, The Challenge, supra note 11, at 49.
36 Harrison, Part I, supra note 4, at 152.
37 John W. Harrison & Timothy A. Svec, The Beginning of the End of the Antibiotic Era? Part II. Proposed Solutions to Antibiotic Abuse, 29(4) Quintessence Int’l 223, 223 (1998) [hereinafter Harrison, Part II]; see also Wolfgang Witte, Medical Consequences of Antibiotic Use in Agriculture, 279 Science 959, 996–97 (1998).
38 L. Tollefson et al., Therapeutic Antibiotics in Animal Feeds and Antibiotic Resistance, 16(2) Rev. Sci. Tech. 709, 709–15 (1997).
39 Stuart B. Levy, Antibiotic Use for Growth Promotion in Animals: Ecologic and Public Health Consequences, 50(7) J. of Food Protection 616, 616–20 (1987) [hereinafter Levy, Antiboitoic Use]. Not incidentally, the spread of resistance in this manner demonstrates the complexity of microbial spread of resistance determinants.
40 See generally A. H. Linton, Animal to Man Transmission of Enterobacteriaceae, 97(3) R. Soc. Health J. 115–18 (1977).
41 Nat’l Research Council, supra note 5, at 70.
42 S.D. Holmberg et al., Drug-resistant Salmonella from Animals Fed Antimicrobials, 311 New Eng. J. Med. 617, 621 (1984). “Transfer of antimicrobial-resistant bacteria from animals to human beings under natural conditions is thought to be frequent but impossible to determine accurately.” See id.
43 Nat’l Research Council, supra note 5, at 19.
44 Stuart B. Levy, The Antibiotic Paradox: How Miracle Drugs Are Destroying The Miracle 138 (1992) [hereinafter Levy, Antibiotic Paradox].
45 Id. at 137–38.
46 Id. at 138.
47 “[F]armers with large operations were more likely than those with small farms to use antibiotics in feeds . . . .” George G. Khachatourians, Ph.D., Agricultural Use of Antibiotics and the Evolution and Transfer of Antibiotic-Resistant Bacteria, 159 Can. Med. Ass’n. J. 1129 (1988), at http://www.cma.ca/cmaj/vol-159/issue-9/1129.htm.
48 See generally, Barbara O’Brien, Comment, Animal Welfare Reform and the Magic Bullet: The Use and Abuse of Subtherapeutic Doses of Antibiotics in Livestock, 67 U. Colo. L. Rev. 407 (1996) (for a description of the conditions under which many farm animals are now raised). The author attributes the widespread use of antibiotics at subtherapeutic levels to changes in animal husbandry practices designed to maximize output.
The farmer, having no rules or guidelines but industry standards by which to abide, will often treat animals like machines in order to maximize output and profit. Such an approach, however, requires an arsenal of drugs to ward off the inevitable infections and health problems that animals suffer when reared under stressful conditions. Antibiotics prevent the spread of infectious disease among herds kept in close confinement. . . . The use of subtherapeutic doses of antibiotics makes factory farm practices feasible. In one trade journal, a hog farmer remarked: ‘One reason large confinement systems have worked so well is because of antibiotics. Without the antibiotics it would be hard to have these larger systems and crowd the pigs as we do in some cases.’
Id. at 412–13 (citations omitted).
49 Alex Kirby, Why Farm Antibiotics are a Worry, (BBC News, Oct. 8, 1999), available at http://news6.thdo.bbc.co.uk/hi/eng...biotics/newsid%5f436000/436398.stm.
50 USDA Report, supra note 3, at 21 (examining use of antibiotics in pigs between 1990 and 1995). The same report suggests there has also been a recent decrease in reliance on antibiotics in broiler operations in recent years. Id. at 27. The report attributes this decline to both the lack of new antibiotics approved for use in the poultry industry and “the implementation of multi-faceted preventative medicine programs(e.g. biosecurity), increased efforts to reduce production costs, enhanced focus on residue avoidance, and rapid production of efficacious vaccines by manufacturers.” Id. at 26–27.
51 Id. at 24. Cattle operations with more than 1000 head of cattle were almost 3 times as likely to use antibiotics in food and water. Id.
52 USDA Report, supra note 3, at 24 (42.1% of large operations that use antibiotic additives use them for periods of time in excess of 90 days, as compared with 32.2% of small operations that do so).
53 Harrison, Part I, supra note 4, at 157; accord Khachatourians, supra note 47. In the 1950s the recommended levels of antibiotics for use as growth promoters were in the 5–10 parts per million range. The 10 to 20 fold increase in recommended dosage is apparently not enough for all producers. An examination of 3,328 feeds in the U.S. National Swine Survey indicated that “up to 25% of the feeds contained antibiotics at concentrations higher than the recommended levels.” C.E. Dewey et al., Association Between Off-label Feed Additives and Farm Size, Veterinary Consultant Use, and Animal Age, 31 Prev. Vet. Med. 133 (1997).
54 See generally Levy, Antibiotic Paradox, supra note 44.
55 Levy, The Challenge, supra note 11, at 51.
56 Some sources estimate that 40% of the total U.S. production of antibiotics is given to animals. Id. Other sources place the figure at closer to one half. Nat’l Research Council, supra note 5, at 25. Most of this amount, which clearly accounts for more than 20 million pounds of antibiotics each year, is fed to animals in subtherapeutic amounts to promote growth or to prevent or limit potential infections. Id. (estimating that 90% of all antibiotics given to farm animals are used in subtherapeutic amounts). Accord Khachatourians, supra note 47.
57 Id.
58 “As therapeutic options become less effective, drug companies and veterinarians have urged the approval of additional human-use antibiotics, such as fluoroquinolones, to treat animal diseases . . . .” Patricia B. Lieberman, Ph.D., & Margo G. Wootan, D.Sc., Protecting the Crown Jewels of Medicine—A Strategic Plan to Preserve the Effectiveness of Antibiotics, Center for Science in the Public Interest (1998), available at http:/www.espinet.org/re-ports/abiotic.htm.
59 A December 1999 report of the United State Department of Agriculture lists the following antibiotics and sulfonamides for growth promotion and feed efficiency, therapeutic purposes or both in dairy and beef cattle: amoxicillin, ampicillin, bacitracin, ceftiofur, chlortetracycline, dihydrostreptomycin, erythromycin, furamazone, gentramycin, lacalocid, monensin, neomycin, oxytetracycline, penicillin, streptomycin, tetracycline, tilmicosin, tylosin, sulfabromomethazine, sulfachloropyridazine, sulfaethoxypyridazine, sulfaethazine, and sulfamethoxine. USDA Report, supra note 3, at 19. The following antibiotics are approved for use in hogs: amoxicillin, ampicillin, apramycin, bacitracin, chlortetracycline, efrotomycin, lincomycin, neomycin, oleandomycin, oxytetracycline, penicillin, spectinomycin, streptomycin, tetracycline, tiamulin, tylosin, and virginiamycin. Id. Various sulfonamides have also been approved for use in hogs. Id. Fewer antibiotics have been approved for use in sheep. They include chlortetracycline, erythromycin, neomycin, oxytetracycline, penicillin, and penicillin/streptomycin. Id. The following antibiotics have been approved by the Food and Drug Administration (FDA) for use in chickens and turkeys: bambermycin, bacitracin, chlortetracycline, erythromycin, gentramycin, neomycin, novobiocin, oleandomycin, oxytetracycline, penicillin, roxarsone, spectinomycin, streptomycin, tetracycline, tylosin, virginiamycin and fluoroquinolones. Id. Various sulfonamides have also been approved for use in poultry. USDA Report, supra note 3, at 19–20.
60 Lieberman, supra note 58. Another antibiotic approved for use with livestock, tylosin, is closely related to the family of drugs that includes erythromycin. Id.
61 Exploring New Strategies to Fight Drug-Resistant Microbes, 257 Science 1036, 1036 (Aug. 1992) [hereinafter Exploring New Strategies].
62 Id.
63 Id.
64 Id.
65 Id.
66 Exploring New Strategies, supra note 61, at 1036.
67 Id.
68 See House of Lords, Science and Technology—Seventh Report (Mar. 17, 1998), available at http://www.parliament.the-stationery-office . . . 199798/Idselect/ Idsctech/ 081vii/st0701.htm [hereinafter House of Lords]; Report of the Comptroller General of The United States, Need to Establish Safety and Effectiveness of Antibiotics Used in Animal Feeds 10 (1977) [hereinafter Comptroller’s Report].
69 House of Lords, supra note 68.
70 Id.
71 Id.
72 For comparison purposes, England implemented the Swann Report recommendations in March 1971 by issuing the Therapeutic Substances Regulation of 1971 which, among other things, restricted the availability of penicillin, chlortetracycline, oxytetracycline, tylosin, nitrofurans and most sulfonamides. Comptroller’s Report, supra note 68, at 10.
73 See generally Comptroller’s Report, supra note 68, and Lieberman, supra note 58. The FDA published rules in the April 20, 1973 Federal Register which stated the agency’s intention to withdraw approval for the subtherapeutic use of antibiotics in animal feeds within two years “unless data were submitted by drug sponsors to establish conclusively . . . their safety to humans and animals and effectiveness for their intended purposes.” Comptroller’s Report, supra note 68, at 10–11.
74 The Comptroller’s Report noted that despite the original promulgation of rules which would have withdrawn approval for the subtherapeutic use of antibiotics in 1975, the FDA “permitted the continued use of the products” despite the fact that “a number of the antibiotics currently marketed for subtherapeutic use in animals feeds, including penicillin, tetracyclines, and sulfaquinoxaline, have been shown to either create a hazard to human or animal health or have not been shown to be effective for some of their disease prevention uses.” Id. at 34.
75 Lieberman, supra note 58.
76 Id.
77 Id. Two years after this approval, the Minnesota State Department of Health reported a significant increase in fluoroquinolone resistance in bacteria isolated from poultry and human beings. The CDC also reported that 13% of human Campylobacter isolates have become fluoroquinolone resistant. Id.
78 Id. (noting that 32% of Salmonella typhimurium cases in the U.S. (approximately 3,000 cases confirmed with cultures) are resistant to ampicillin, chloramphenicol, streptomycin, sulphonamides and tetracyclines (all antibiotics that are or were commonly used in animals)). In addition, fluoroquinolones are important in treating humans for urinary tract infections, sexually transmitted diseases, invasive Campylobacter infections, respiratory infections, infections in patients with cystic fibrosis, and many other antibiotic-resistant diseases. Lieberman, supra note 58.
79 Id.
80 Nat’l Research Council, supra note 5, at 70.
81 World Health Org., The Medical Impact of Antimicrobial Use in Food Animals, Report of a WHO meeting. Berlin, Germany (WHO Doc. WHO/EMC/ZOO/97.4 (1997).
82 Nat’l Research Council, supra note 5, at 150. This source also notes a number of other factors, including: crowded confinement of numerous animals with similar disease susceptibilities, poor animal hygiene, and other practices which also contribute to the selection of antibiotic-resistant bacteria. Id.
83 See generally O’Brien, supra note 48. While this article does address the issue of antibiotic resistance, the author mainly addresses the conditions in which animals in the United States are currently raised.
84 Markow, supra note 9; Misocky, supra note 7.
85 Nat’l Research Council, supra note 5, at 15. This report was put together by the National Research Council’s Committee on Drug Use in Food Animals. Id. at 2. This committee consisted of a number of academicians and health care professionals, two consumer group representatives, a farmer and a director of a corporate poultry business unit. Id. at 235–38.
86 A “zoonotic” disease is one that is “biologically adapted to and normally found in lower animals but which under some conditions also infects humans.” McGraw-Hill, supra note 16, at 2193 (defining zoonoses).
87 Nat’l Research Council, supra note 5, at 7–9.
88 Witte, supra note 37, at 996-97.
89 Id. at 996.
90 Id.
91 Id.
92 H. Tschäpe, 15 FEMS Microbiology Letters 23 (1994), cited in Witte, supra note 37, at 996.
93 See Ruth Hummel et al., Spread of Plasmid-mediated Nourseothricin Resistance Due to Antibiotic Use in Animal Husbandry, 26 J. Basic Microbiology 461–66 (1986).
94 Id.
95 E.g., Scott D. Holmberg et al., Animal-to-Man Transmission of Antimicrobial-Resistant Salmonella: Investigations of U.S. Outbreaks, 1971–1983, at 225 Science 833, 833–35 (1984).
96 Id. at 833.
97 Id. Antibiotic susceptibility was not determined in the remaining instances. Id. at 833–34.
98 Id. at 834.
99 Holmberg et al., supra note 43, at 617.
100 Id.
101 Id.
102 Id. at 619–20.
103 Id. at 617.
104 Carol O. Tacket et al., An Outbreak of Multiple-Drug-Resistant Salmonella Enteritis from Raw Milk, 253 JAMA 2058, 2058–60 (1985).
105 Id. at 2058.
106 Id. at 2058–59.
107 Id. at 2058.
108 Id. “This outbreak demonstrates the importance of animals as a source of antimicrobial-resistant Salmonella. . . . [O]ther outbreaks have clearly demonstrated the spread of resistant organisms from an animal reservoir to humans.” Id. at 2060.
109 John S. Spika et al., Chloramphenicol-Resistant Salmonella Newport Traced Through Hamburger to Dairy Farms: A Major Persisting Source of Human Salmonellosis in California, 316 New Eng. J. Med. 565, 565 (1987).
110 Id. at 565.
111 Id. at 566–68.
112 Id. at 568.
113 Id. at 565.
114 Robert W. Lyons et al., An Epidemic of Resistant Salmonella in a Nursery--Animal-to-Human Spread, 243 JAMA 546, 546 (1980).
115 Id. at 546.
116 E.g., Janice Bates et al., Farm Animals as a Putative Reservoir for Vancomycin-Resistant Enterococcal Infection in Man, 34 J. Antimicrobial Chemotherapy 507, 507–14 (1994) (demonstrating farm animals are a source of vancomycin-resistant enterococci).
117 I. Klare et al., vanA-Mediated High-Level Glycopeptide Resistance in Enterococcus faecium from Animal Husbandry, 125 FEMS Microbiology Letters 165, 165 (1995) (published erratum appears in 127 FEMS Microbiology Letters 273 (1995)). This is particularly worrisome because the vanA gene confers a high level of resistance to vancomycin, often the antibiotic of last resort in human beings. See Bates, supra note 116, at 507–14. For a further discussion of the importance of vancomycin resistance, see infra notes 125–128 and accompanying text.
118 Id. at 165.
119 Klare, supra note 117, at 165. When researchers tested chickens from a farm where avoparcin was not used, no glycopeptide-resistant enterococci were isolated. Id.
120 Id. at 165–66.
121 Id. at 170.
122 T.F. O’Brien et al., Molecular Epidemiology of Antibiotic Resistance in Salmonella from Animals and Human Beings in the United States, 307 New Eng. J. Med. 1, 1 (1982).
123 Id.
124 Id.
125 Id.
126 Pulsed-field gel electrophoresis is considered to be the most sophisticated method of showing that isolates from animals and humans are equivalent. See J. Bates, Epidemiology of Vancomycin-Resistant Enterocci in the Community and the Relevance of Farm Animals to Human Infection, 37 J. Hospital Infection 89, 96 (1997).
127 Paul D. Fey et al., Ceftriaxone-Resistant Salmonella Infection Acquired by a Child from Cattle, 342 New Eng. J. Med. 1242, 1242 (2000).
128 Id.
129 Id.
130 Salmonella and Enterococcus faecalis are not the only strains of bacteria which have been studied or identified in both animal and human populations. See, e.g., Lawrence J. Abraham et al., Worldwide Distribution of the Conjugative Clostridium perfringens Tetracycline Resistance Plasmid, pCW3, 14 Plasmid 37 (1985) (identifying identical conjugative R-plasmids from C. perfringens strains from human, animal, and environmental sources in five countries and concluding that C. perfringens strains in humans and animals throughout the world have overlapping gene pools).
131 This topic is addressed thoroughly in a recent biomedical essay by C.P. Hunt of the British Department of Clinical Microbiology. See C.P. Hunt, The Emergence of Enterococci as a Cause of Nosocomial Infection, 55 British J. Biomedical Sci. 149–56 (1998). Hunt contends that “[t]he possibility that vancomycin-resistant strains of enterococci are entering the community via the food chain indicates the need for greater control of the use of glycopeptide antibiotics in animal feed.” Id. at 149. Enterococci readily transfer antibiotic resistance between strains and, in addition, enterococcal plasmids frequently encode multiple-resistance determinants which simultaneously allows the transfer of multiple antibiotic resistance. Id. at 151. Of particular concern is the potential for the spread of vancomycin resistance. Experiments have demonstrated that the vanA gene can be found in corynebacterium, arcanobacterium, and lactobacillus emphasizing the potential for spread of vancomycin resistance. Id. Vancomycin-resistant strains of E. Faecium have been found both in healthy animals and in animal products. These findings suggest that vancomycin-resistant bacteria may be entering the community via the food chain. Id. at 153. The author concludes that it is quite possible that avoparcin, a glycopeptide with cross-resistance to vancomycin which has been used as a growth promoter in animal feeds since the mid 1970s, contributes to the seriousness of the problem. Id.
132 Levy, The Challenge, supra note 11, at 46.
133 Id. Laboratory experiments have demonstrated that, under conditions similar to those found in the environment, high levels of vancomycin resistance can be transferred via conjugation from E. faecalis to S. aureus. E.g., W.C. Noble et al., Co-Transfer of Vancomycin and Other Resistance Genes from Enterococcus faecalis NCTC 12201 to Staphylococcus aureus, 72(2) FEMS Microbiology Letters 195, 197 (1992).
134 Bates, supra note 126, at 93.
135 Id.
136 Id. at 99. Bates also cites a study which suggests that the emergence of quinolone-resistance infections in humans is linked to the use of enrofloxacin (a fluroquinolone) as a growth promoter in poultry. H.P. Endtz et al., Fluroquinolone Resistance in Campylobacter spp. Isolated from Human Stools and Poultry Products, 335 Lancet 787 (1990), cited in Bates, supra note 126, at 93.
137 Bates, supra note 116, at 507.
138 Id.
139 Id. at 511.
140 Id. at 507.
141 I. Klare et al., Enterococcus faecium Strains with vanA-Mediated High-Level Glycopeptide Resistance Isolated from Animal Foodstuffs and Fecal Samples of Humans in the Community, 1 Microbial Drug Resistance 265, 265 (1995).
142 Id. No glycopeptide-resistant enterococci could be detected in samples of chickens where the feed history did not include avoparcin. Id.
143 Id.
144 Id.
145Bates, supra note 126, at 96.
146A. Van den Bogaard et al., Prevalence of Resistance of Fecal Bacteria in Turkeys, Turkey Farmers and Turkey Slaughterers (Abstract) E27 36th Interscience Conference on Antimicrobial Agents and Chemotherapy 86 (1996), cited in Bates, supra note 126, at 96.
147 F.M. Aarestrup, Occurrence of Glycopeptide Resistance Among Enterococcus faecium Isolates from Conventional and Ecological Poultry Farms, 1 Microbial Drug Resistance 255, 255–57 (1995).
148 Id.
149 Id. at 255–56.
150 P.J. Christie & G.M. Dunny, Antibiotic Selection Pressure Resulting in Multiple Antibiotic Resistance and Localization of Resistance Determinants to Conjugative Plasmids in Streptococci, 149 J. Infectious Diseases 74, 74 (1984).
151 Id. at 74.
152 Id. at 77. “These analyses strongly suggest that the introduction of a macrolide antibiotic into the feed of livestock creates a pressure for the selection of a multiple drug-resistant bacteria.” Id.
153 Id. at 74.
154 Henrik C. Wegener et al., Use of Antimicrobial Growth Promoters in Food Animals and Enterococcus faecium Resistance to Therapeutic Antimicrobial Drugs in Europe, 5(3) Emerging Infectious Diseases 329, 331 (1999).
155 Id.
156 Levy, Antibiotic Use, supra note 39, at 616–17.
157 Id. at 617.
158 Id.
159 Id.
160 Id.
161 Levy, Antibiotic Use, supra note 40, at 617.
162 Id.
163 Id.
164 Id.
165 Id.
166 Levy, Antibiotic Use, supra note 39, at 617.
167 Id.
168 Id.
169 Id.
170 Scott D. Holmberg et al., Health and Economic Impacts of Antimicrobial Resistance, 9 Rev. of Infectious Diseases 1065, 1065 (1987).
171 Id.
172 Stuart B. Levy is one of the cadre of American experts leading this call. See generally, Levy, The Challenge, supra note 11; Levy, Antibiotic Paradox, supra note 44.
173 Wegener, supra note 155, at 329.
174 Id. at 333.
175 Lieberman, supra note 58.
176 See, e.g., Herbert L. DuPont & James H. Steele, The Human Health Implication of the Use of Antimicrobial Agents in Animal Feeds, 9(4) Veterinary Q. 309 (1987).
177 Id. at 320.
178 See generally Levy, The Challenge, supra note 11.
179 DuPont, supra note 177, at 309.
180 See Nat’l Research Council, supra note 5; see also supra text accompanying note 85.
181 Nat’l Research Council, supra note 5, at 184.
182 Id. at 184–85. These numbers are based on per capita costs, calculated by multiplying the projected percentage increase in annual production costs by the retail price and the annual retail quantity sold per capita. Id. at 184.
183 Id. at 185–86. The data is consistent with prior literature on the subject, notably 1992 and 1994 studies that estimated a retail price increase for pork of $0.04 per pound. Id. at 186.
184 See World Health Org., supra note 81, at 15.
185 Research from some European countries suggests that a shift to less intensive farming methods and improved animal hygiene can resolve many situations that create the need for antibiotic dosing. See, e.g., Witte, supra note 37, at 997; World Health Org., supra note 81, at 15.
186 This list was composed by the National Research Council. Nat’l Research Council, supra note 5, at 185–86.
187 The extent to which American farmers need this edge is debatable, given that, effective July 1, 1999, the European Union banned four antimicrobials (bacitracin zinc, spiramycin, virginiamycin and tylosin phosphate) considered to be important for treating infections in human beings. USDA Report, supra note 3, at 1. In addition, the European Union, Japan, Australia, and New Zealand have banned subtherapeutic use of penicillin and tetracyclines. Lieberman, supra note 58.
188 Note, however, that this does not necessarily mean that the small farmer will face an increasing risk of failure. Rather, the larger operations are more likely to use antibiotics to allow the use of more intensive confinement systems. See O’Brien, supra note 48, at 412–13. To some extent, limiting the use of subtherapeutic doses of antibiotics may help make smaller operations more competitive.
189 The British experience, however, suggests that decreased profits due to diminished sales of restricted antibiotics can be at least partially offset by increased sales of antibiotics which are still available for feed use. See Comptroller’s Report, supra note 68, at 22. Thus, if the ban on the subtherapeutic use of antibiotics in animals feed does not extend to all antibiotics, there is at least some possibility that this loss will be minimized.
190 Presumably, these would be of the same general magnitude as the economic benefits associated with chicken, turkey, beef, and pork production. See supra text accompanying notes 180–184.
191 Nat’l Research Council, supra note 5, at 186.
192 Id.
193 Id.
194 See discussion supra Part III of this Article. Accord Inst. of Medicine, Antimicrobial Resistance: Issues and Options (1998).
195 Harrison, Part I, supra note 4, at 157.
196 See discussion supra Part I of this Article.
197 Levy, Antibiotic Use, supra note 39, at 616, 618.
198 Khachatourians, supra note 47; Levy, Antibiotic Paradox, supra note 44. Accord Alexander Tomasz, Multiple-Antibiotic-Resistant Pathogenic Bacteria—A Report on the Rockefeller University Workshop, 330 New Eng. J. Med. 1247, 1248 (1994) (“Antibiotic-resistant pathogens contribute to the skyrocketing costs of inpatient care.” Also citing the increase in cost to be “an estimated minimum of $4.5 billion” each year.) Other estimates of the cost of antibiotic resistance vary greatly. The National Foundation for Infectious Diseases estimates an annual cost “as high as four billion dollars annually.” USDA Report, supra note 3, at 3.
199 Lieberman, supra note 58.
200 One website reports that “[e]ven with treatment, roughly half of all MDR-TB [multi-drug-resistant tuberculosis] patients die. This mortality rate matches that of patients with regular TB who received no medical care at all.” OnHealth: Tuberculosis—Renewed Concern, at http://onhealthnetworkcompany.com/conditions/resource/conditions/item.681. asp.
201 See Comptroller’s Report, supra note 68, at 9.
202 Agricultural Use of Antibiotics Poses Major Public Health Threat, EDF News Release (Mar. 9, 1999), available at http://www.myworld.org/pubs/NewsReleases/1999/Mar/ d_agriculture.html [hereinafter EDF News Release].
203 See Petition to the U.S. Food and Drug Administration to Ban the Use of Certain Antibiotics in Livestock Feed: Executive Summary, (Sept. 28, 2000), available at http://www.cspinet.org/ reports/petition_antibiotic.htm.
204 Nat’l Research Council, supra note 5, at 159.
205 For a discussion of glycopeptide resistance, and the problem of vancomycin-resistance caused by the use of avoparcin in agriculture, see supra text accompanying notes 130–136.
206 Wegener, supra note 155, at 332.
207 Id.
208 Id. In 1995, 82% of poultry flocks tested positive for vancomycin-resistant bacteria. This percentage dropped to 12% by 1998. Id.
209 Id. The incidence of resistance bacteria in poultry decreased from 100% in 1994 to 25% in 1997, and in fecal samples from human beings it decreased from 12% in 1994 to 3% in 1997. Id.
210 See discussion supra Part II.
211 See discussion supra Part IV.
212 EDF News Release, supra note 203.
213 For a discussion of this issue, see supra notes 182–184 and accompanying text.
214 See Witte, supra note 37, at 997.
215 Id.
216 Id.
217 Admittedly, this suggestion will probably require expenditures to ensure that veterinarians are educated about the risks of antibiotic resistance and the appropriate use of antibiotics. See discussion supra Part IV.
218 Nat’l Research Council, supra note 5, at 9.
219 The Centers for Disease Control and Prevention estimate that of the approximately 150 million antibiotic prescriptions written by physicians on an outpatient basis each year, as many as 50 million may be unnecessary. Levy, The Challenge, supra note 11, at 51.
220 In today’s economic climate, this would also necessarily require that health maintenance organizations and private insurance companies cover the cost of diagnostic tests to assure appropriate use of antibiotics. This might also require steps to encourage physicians to perform strep tests in their offices, such as exempting rapid strep tests from requirements imposed by the Clinical Laboratory Improvement Amendments of 1988 (Pub. L. No. 100–578, 102 Stat. 2903 (1988), relevant provisions codified at 42 U.S.C.A. § 263a (1998).
221 For possible regulatory responses to this problem, see Misocky, supra note 7, at 737, and Markow, supra note 9, at 545–49.
222 Levy, The Challenge, supra note 11, at 48.
223 Lieberman, supra note 58.
224 Id.; accord Khachatourians, supra note 47; Levy, Antibiotic Paradox, supra note 44.
225 Lieberman, supra note 58. “Currently, many antibiotics, such as tylosin, penicillin, tetracycline, and gentamicin, are available over the counter to farmers to administer at their discretion to livestock by injection, orally, and as feed additives.” Id.
226 Harrison, Part 1, supra note 4, at 151.
227 Id. at 152.
228 To encourage the appropriate treatment of sick animals, the FDA or USDA should develop and promulgate a symptom-based formulary describing appropriate treatment regimens for common infections. See discussion supra Part IV.
229 Levy, The Challenge, supra note 11, at 52. Apparently, most pharmaceutical companies focused on the development of treatments for chronic ailments rather than on developing new antibiotics. Whatever the cause, however, the current situation (where we have no new general antibiotics in the pipeline) is not healthy.
230 Harrison, Part I, supra note 4, at 155.
[T]he pipeline of new antibacterial drugs is essentially empty, the result of a prolonged lack of research interest and funding. A survey of large US and Japanese pharmaceutical companies . . . found that half of the companies either reduced or phased out their antibacterial programs in the last decade . . . .
231 The cost of development of a new antibiotic has been estimated to approach $300 million and twelve years of time. Id. at 156.
232 Id.
233 For a general discussion of this issue, see Lieberman, supra note 58; see also supra notes 73–74 and accompanying text.
234 Lieberman, supra note 59.