[*PG39]APPROPRIATE REGULATION OF ANTIBIOTICS IN LIVESTOCK FEED
Abstract: For decades, antibiotics have been widely used, saving lives and reducing suffering. Such drugs are routinely employed among both human and farm animal populations. However, scientific data now links the use of antibiotics at subtherapeutic levels in livestock feed to the spread of antibiotic resistant bacteria in the human population. After examining the current research, this Article concludes that despite short-term economic benefits associated with the widespread use of antibiotics in agriculture, the risk to human health justifies a change in policy. This Article recommends a number of steps to minimize the spread of antibiotic resistance. The primary changes would be to phase out the use of antibiotics as livestock feed additives, and to refuse to approve new drugs for this purpose. In either instance, this use would be permissible if the drug sponsor provides convincing evidence that the agricultural use of its particular antibiotic presents no appreciable risk to human health.
The headlines are sensational enough that it wouldnt be surprising to see them in the most notorious supermarket tabloids.1 The sto[*PG40]ries behind the headlines are scary enough that they might be the plot of a horror movie.2 Unfortunately, it is often the scientific press that is reporting on the spread of antibiotic-resistant bacteria,3 and the threat to human health and life is very real and growing.4
The increase in public awareness about the spread of antibiotic-resistant bacteria has been occasioned by a significant increase in the number of reported cases of human illness associated with antibiotic resistance.5 Studies show that infectious disease mortality rates have risen nearly 60%,6 with the Centers for Disease Control (CDC) estimating that more than half of the infection-related deaths involve resistant bacteria.7
Dubbed super-bugs in the popular press,8 multi-drug resistant bacteria are becoming more and more common. Newspapers and magazines carry stories of bacterial infections that do not respond to the antibiotics typically prescribed to control them.9 As one legal commentator observed, [m]any of the killer diseases of the past such as tuberculosis, typhoid fever, diphtheria, and pneumonia have re[*PG41]turned to wreak havoc as bacteria are increasingly resistant to antibiotics.10 While antibiotics were once regarded as an unending miracle of modern medicine,11 we are fast approaching a time when the miracle may come to an end.12
While there are doubtless many factors contributing to the spread of multi-resistant bacteria, one factor appears to be the widespread addition of antibiotics to livestock13 feed. A wide range of antibiotics are currently added, in subtherapeutic amounts,14 to animal feeds.15 A growing volume of research suggests that this practice is having devastating and potentially irreversible effects on the viability of antibiotics as agents to effectively treat diseases in human beings, but the legal community appears to be lagging far behind scientific experts in calling for an end to this practice in the United States.
The first section of this article will provide a brief introduction to the mechanisms of antibiotic resistance in bacteria and the risks to human health posed by this growing phenomenon. The next section will examine current agricultural practices with regard to the use of antibiotics in subtherapeutic amounts, including an analysis of the beneficial results attributed to these practices. It will then consider whether existing research on antibiotic resistance that identifies a link [*PG42]between the use of livestock feed and risks to human health is sufficiently convincing so as to justify a change in policy. The final section of this Article suggests legal steps which should be taken to ensure the appropriate use of antibiotics in the agricultural community.
Every human being plays host to millions of bacteria, of many different species.16 Many of the bacteria that live on and in the human body are beneficial to the host; some are even essential.17 Of course, pathogenic bacteria (those capable of causing disease) also exist.18 Symptoms of a harmful bacterial infection may be due to the presence of microbial products such as toxins, or the hosts immune response to the bacteria.19 The development and widespread availability of multiple classes of antibiotics in the latter half of the twentieth century meant that we could cure many potentially life-threatening infections.20
Unfortunately, the use of antibiotics, at both therapeutic and subtherapeutic levels, has led to the emergence of resistant bacteria that can survive in the presence of one or more classes of antibiotics.21 The use of antibiotics promotes resistance by killing off the bacteria that are most susceptible to the antibiotics. If the dosage is insufficient to kill off all the bacteria infecting the host, the bacteria that survive to propagate will be those that were most resistant to the effects of the antibiotics.
[*PG43] Antibiotic resistance can take a number of different routes.22 For example, penicillin and chloramphenicol resistance generally occurs because the resistant bacteria are able to inactivate the antibiotics.23 Tetracycline resistance most commonly occurs when the bacteria are able to increase antibiotic efflux, transport of the antibiotic from the interior to the exterior of the cell.24 Additionally, bacteria may mutate so that the target sites which the antibiotics effect are altered.25
Drug resistance is a particular problem in bacteria because resistance is so readily transmitted from bacteria to bacteria, even to different bacteria species.26 In fact, noted microbiologist Stuart B. Levy has suggested that it makes sense to think of the entire bacterial world . . . as one huge multicellular organism in which the cells interchange their genes with ease.27
There are a number of mechanisms by which drug resistance can spread among bacteria. While most of the essential genetic information for each bacterium is contained within a single circular deoxyribonucleic acid (DNA) strand,28 bacteria also carry extrachromosomal material in the form of plasmids and transposons.29 Plasmids can transmit the characteristic of drug resistance30 between bacteria by conjugation, transformation, or transduction.31 Conjugation involves contact between two bacterial cells during which genetic material [*PG44]passes from one cell to the other.32 Transformation consists of the transfer and incorporation of foreign DNA into a cell and subsequent recombination of part or all of that DNA into the cells genome.33 Transduction is the transfer of genetic material (which may be either chromosomal or plasmid DNA) between bacteria by bacteriophages.34 The prevalence of plasmids in bacterial cells therefore means that it is likely that acquired characteristics will be shared with other bacteria.
Transposons also facilitate the transfer of genes that enable the bacteria to become drug-resistant. When a bacterium dies, it typically releases its contents into the environment. Many intact bacteria contain specialized transposons, termed integrons, that are like flypaper in their propensity for capturing new genes.35 The presence of these transposons further facilitates the transfer of resistance genes between bacteria.
The speed with which bacteria propagate makes the problem of drug resistance particularly acute. Bacteria have a generation time that can be measured in minutes, and a single bacterium can easily produce more than a million progeny in less than a day.36 For example, one Escherichia coli (E. coli) can produce more than a million progeny (about twenty generations) in seven hours.37 Starting with a single drug-resistant bacterium, it does not take long to create millions of resistant bacteria first in the host and then in other hostsas the bacteria itself spreadsor in the environment.
The problem caused by the ready and rapid spread of drug-resistance mechanisms among bacteria is further compounded by the fact that bacteria do not exist in isolated populations, but instead mingle among humans, animals and the environment.38 Resistance which develops in animal populations may soon emerge in human populations. Scientists have already discovered evidence of similar re
[*PG45]sistance genes in bacteria of different genera inhabiting entirely different environments.39 Organisms originally present in an animal population have been found in humans who are in direct association with these animals or in contact with animal products.40 Once the resistant bacteria is in the human population, it can easily spread further to increasing numbers of human beings. One recent report characterizes the problem as follows:
There are opportunities in the microbial environment for interconnected ecosystems to allow exchange of DNA, promoting the spread of resistance from one genus to another. The combination of increased bacterial virulence and increased drug resistance creates a potential for increased risk of morbidity and mortality for animals and humans that some have extrapolated to a catastrophic potential.41
While it is impossible to trace specific bacterial infections among human populations back to the original source with 100% certainty, a growing body of scientific data points to the subtherapeutic dosing of livestock as a significant contributing factor in the spread of antibiotic-resistant organisms.42 Part III of this article will examine the current research, but in order to place the evidence in context, it is critical to understand the role that antibiotics have come to play in American agriculture.
At the current time, there are three primary uses of antibiotics in animal agriculture: therapeutic, prophylactic (to prevent potential infection), and growth promotion (with both of the latter two catego
[*PG46]ries being at subtherapeutic concentrations).43 The use of antibiotics to ward off infections and to promote growth in livestock is not new. For more than 40 years many farmers have fed their animals a diet laced with small, subtherapeutic doses of antibiotics.44
The discovery that antibiotics could be used for prevention of infection and growth promotion was serendipitous. Veterinarians began administering antibiotics to sick animals in an effort to determine whether the miracle drugs that were saving human lives could also help livestock.45 These experiments led to the discovery that feeding animals small doses of the drugs not only inhibited diseases but also enhanced growth.46 This discovery led in turn to an agricultural revolution, with farmersespecially those in very large operations47relying increasingly on subtherapeutic doses of antibiotics to keep their livestock healthy and to promote animal growth.48
In the past three decades, agricultural use of antibiotics has increased exponentially. One article has estimated that in the past thirty years, farmers have increased their use of penicillin-type antibiotics in [*PG47]farm animals by 600% and their use of tetracycline by 1500%.49 Recent statistical research continues to show an increasing reliance on the routine use of antibiotics for pigs and cattle.50 Larger operations also continue to be more likely to use antibiotics,51 and many rely on additives for periods of time in excess of ninety days.52
Part of the increase in antibiotic use is attributable to the declining effectiveness of the drugs as growth promoters. Over time, the amount of antibiotics needed to promote growth in farm animals has increased significantly. Some sources have suggested that [r]oughly 10 to 20 times the amount used four decades ago are required to produce the same level of growth in the 1990s.53 Moreover, even at concentrations approaching therapeutic levels, the benefits of growth promotion are less now than those reported several decades ago.54
The increasing use of antibiotics in agriculture has paralleled an astonishing growth in the use of antibiotics generally. In 1954 two million pounds of antibiotics were produced in this country; today more than fifty million pounds of antibiotics are manufactured every year.55 Only half of these antibiotics are consumed by human beings. Most of the remaining tens of millions of pounds annually are given to ani[*PG48]mals.56 While some of these antibiotics are used to treat infection, the bulk is mixed into animal feed at subtherapeutic levels.57
Although farmers, veterinarians and drug companies protest the inadequacies of antibiotics available for use in livestock,58 a relatively wide variety of antibiotics have been approved for use as subtherapeutic additives to animal feeds.59 Included in the list of antibiotics used as food additives in American agriculture are a number of drugs that are either themselves used as drug therapies for human patients or are closely related to such drugs. Amoxicillin, ampicillin, erythromycin, neomycin, penicillin, and tetracycline are all used to treat human illness as well as being used in animal agriculture.60
A 1992 study examining the top ten drug-resistant microbes suggests that a number of drugs fed to animals are now less effective in [*PG49]treating a wide variety of human ailments.61 Enterobacteriaceae, which cause bacteremia, pneumonia, and urinary tract and surgical wound infections, may be resistant to aminoglycosides (such as vancomycin), beta-lactam antibiotics (such as penicillin), chloramphenicol and trimethoprim.62 Enterococcus, which is implicated in all of the foregoing diseases except pneumonia, may be resistant to aminoglycosides, beta-lactams, and erythromycin.63 Haemophisus influenzae, which causes epiglottitis, meningitis, otitis media, pneumonia and sinusitis, may be resistant to beta-lactams, chloramphenicol, tetracycline and trimethoprim.64 Mycobacterium tuberculosis, which causes tuberculosis, may be resistant to aminoglycosides, ethambutol, isoniazid, pyrazinamide and rifampin.65 Neisseria gonorrhoeae, which causes gonorrhea, may be resistant to beta-lactams, spectinomycin, and tetracycline.66 Other microbes listed as causing serious diseases may be resistant to chloroquine, ciprofloxacin, sulfonamides, and/or clindamycin as well as the drugs listed above.67
In 1969, a report commissioned by the English Parliament on the use of antibiotics in animal husbandry and veterinary medicine recommended a ban on the subtherapeutic use of antibiotics in food producing animals.68 This report, chaired by Professor M.M. Swann, widely known as the Swann Report, concluded that the administration of antibiotics to farm livestock, particularly at sub-therapeutic levels, poses certain hazards to human and animal health.69 The final recommendation of the Swann Report was that only antibiotics that have little or no application as therapeutic agents in man or animals and will not impair the efficacy of a prescribed therapeutic drug or drugs through the development of resistant strains should be used for growth promotion.70 The report specifically identified chlortetra[*PG50]cycline, oxytetracycline, penicillin, tylosin (which is related to erythromycin) and the sulphonamides as unsuitable for use as growth promoters.71
Although the Swann Report was relatively influential in the United Kingdom, its recommendations have never been adopted in the United States.72 At one point, in the 1970s, the FDA proposed rules which would have prohibited the use of penicillin and tetracyclines as food additives for disease prevention and growth promotion.73 Because of political opposition, however, the proposed rule was never promulgated.74 Instead, the United States continues to study the issue while new drugs are added to the list of antibiotics approved for use in agriculture.
Most recently, in 1995, the FDA approved the use of fluoroquinolones in farm animals.75 The FDA approved this use despite vigorous opposition by the CDC and the Infectious Disease Society of America (IDSA).76 To address some of their concerns, the FDA restricted the use of this class of antibiotics to short-term use in limited situations, but the permitted uses still include the dosing of entire poultry flocks through their drinking water.77 The potential problems posed by fluoroquinolone resistance are significant because [*PG51]fluoroquinolones are the primary treatment for resistant stains of Salmonella typhimurium in human beings.78 Fluoroquinolones are critically important in treating several other bacteria as well.79
Members of the scientific community and the general public share a growing concern about the decrease in effectiveness and/or usefulness of antibiotics. The question remains, however, whether the use of antibiotics at subtherapeutic levels in farm animals has contributed to the spread of antibiotic-resistant bacteria in a manner which poses a significant risk to human health.80 Many health organizations, including the World Health Organization and the Institute of Medicine, regard antibiotic resistance as a documented major health threat around the world.81 Despite protests from the agricultural community and drug companies, there is a general consensus among scientists that subtherapeutic doses of antibiotics used in animal feed favors the selection of antibiotic-resistant bacteria.82
Despite the growing concern in the scientific community, very little has been written about this subject in legal literature. One recent law review article complaining about the use and abuse of subtherapeutic doses of antibiotics in livestock feed focused primarily on the ethics of animal husbandry in the United States.83 Two other student articles which purport to address the epidemic of antibiotic resistance target only physician-prescribing practices, completely ignor[*PG52]ing the role of antibiotics in agriculture as a contributing factor in the spread of antibiotic resistance in humans.84
Even in the scientific community, there is disagreement as to whether there is sufficient documentation linking subtherapeutic dosing of livestock with the spread of antibiotic-resistant bacteria in human populations. A recent multi-disciplinary report concluded that the basic answer to the question of human health consequences of antibiotic drug use in food animals is still not known for certain.85 Despite agreement that antibiotic use increases the risk of emergence of microorganisms that are resistant to specific, and perhaps other, antibiotics, and acknowledgement that [a] link can be demonstrated between the use of antibiotics in food animals, the development of resistant microorganisms in those animals, and the zoonotic86 spread of pathogens to humans, this recent multi-disciplinary report ultimately concluded that the use of drugs in the food-animal production industry is not without some problems and concerns, but . . . does not appear to constitute an immediate public health concern . . . .87
Given this background, it seems essential to consider the currently available scientific data examining whether and how the practice of feeding farm animals subtherapeutic doses of antibiotics contributes to the spread of antibiotic-resistant bacteria in human beings. A wide variety of studies have been performed which shed light on the link between antibiotic use in animal agriculture and drug-resistant bacterial infections in the human population. Most of the data comes not from controlled, laboratory experiments, but from the collection and analysis of data from animal and human case studies. These studies provide substantial evidence that the subtherapeutic use of antibiotics in livestock promotes the subsequent spread of drug-resistant bacteria which poses a risk to human health.
Some of these studies have focused on the question of how the subtherapeutic use of a particular antibiotic as a food additive for live[*PG53]stock affects drug resistance in bacteria in the animals and those who come into contact with those animals. One of the most convincing reports involved an analysis of the effects of the growth promoter nourseothricin in the former East Germany.88 Farmers used this antibiotic in pig feed from 1983 to 1990, replacing the similar use of oxytetracycline.89 Enterobacteriaceae isolated from both humans and animals in 1983 showed little resistance to nourseothricin, but by 1985 transposon-encoded resistant E. coli were isolated from pigs and meat products.90 By 1990, the resistant bacteria had also spread to the farmers, their families, and people living in surrounding areas.91 The same study also noted that the resistant transposon had further spread among several other species of bacteria including Shigella, a human pathogen.92 Other researchers have reported similar results.93
This research is particularly significant because the same drugs are often used in both farm animals and humans, making it difficult to accurately trace the spread of resistance determinants in bacteria found in animals to those found in humans. Nourseothricin, however, was used for growth promotion in pigs but was not given directly to humans. Nonetheless, within a few years after its introduction into pig feed, plasmid-borne resistance to nourseothricin was observed not only in E. coli from pigs fed subtherapeutic doses of nourseothricin, but also in similar bacteria from employees at the pig farms, their family members, and members of the surrounding community.94 In this instance, the presence of resistant bacteria in the human subjects was not attributable to the direct use or misuse of the antibiotic in the human population since the drug in question was fed only to the pigs.
A variety of case studies have also been performed in connection with salmonella outbreaks.95 In each of the following instances, the researchers attempted to trace human infections back to their original source. One such study investigated the origin of drug-resistant salmonella infections in fifty-two outbreaks originally examined by the [*PG54]CDC.96 Of the fifty-two incidents investigated, thirty-eight outbreaks were associated with identifiable sources. Food animals were found to be the source of eleven of the sixteen resistant outbreak strains and six of the thirteen sensitive strains.97 This research is particularly alarming because the case fatality rate was significantly higher for patients infected with antimicrobial-resistant salmonella (4.2%) than for those with antimicrobial-sensitive infections (0.2%).98
Another report examined case histories of eighteen people infected with resistant Salmonella newport in 1983.99 The researchers in this case ascertained that this particular strain of bacteria, characterized by a 38-kilobase plasmid, was resistant to ampicillin, carbenicillin, and tetracycline.100 The researchers compared the plasmids isolated from human and animal sources over a period of eighteen months. 101 Examination of meat distribution records indicated that the humans had been infected by eating hamburger originating from South Dakota beef cattle which had been fed subtherapeutic doses of chlortetracycline, a growth promoter.102 The researchers acknowledged difficulties in studying the complex sequence of events that begin with the selection of drug-resistant organisms in animals fed subtherapeutic quantities of antimicrobials and end with clinically significant infections in human beings; still, they concluded that antimicrobial-resistant organisms of animal origin cause serious human illness, and [their study] emphasizes the need for more prudent use of antimicrobials in both human beings and animals.103
Another case study involved a 1983 outbreak of salmonella poisoning that resulted from ingestion of raw milk contaminated with multi-resistant Salmonella typhimurium.104 In the study, a seventy-two year-old woman did not respond to treatment and died from salmonella enteridis and sepsis.105 Experimental results showed that isolates of Salmonella typhimurium from this patient, from other ill persons, and [*PG55]from raw milk from a particular dairy were resistant to several antibiotics including streptomycin, sulfonamide, chloramphenicol, kanamycin sulfate, and tetracycline.106 The multi-drug resistance in these isolates was traced back to the raw milk that the affected individuals had consumed.107 The authors of the study concluded that [t]his outbreak demonstrates the ability of drug-resistant salmonella to spread from the animal to the human reservoir and, in a suitable host, produce a fatal infection.108
Researchers also investigated a five-fold increase in Salmonella newport cases in California in 1985.109 Results of genetic analysis showed that nearly 90% of the Salmonella newport isolates in the survey population had an unusual pattern of drug-resistance, including resistance to chloramphenicol.110 This resistance was traced to a single plasmid isolated from hamburger products, slaughterhouses which were the source of the infected meat, a limited number of dairies that sent cows for slaughter, and sick dairy cows.111 Isolation of salmonella with the unusual resistance to chloramphenicol correlated to the use of chloramphenicol at the dairies where cows had tested positive for Salmonella newport.112 The authors concluded that food animals are a major source of antimicrobial-resistant salmonella infections in humans and that these infections are associated with antimicrobial use on farms.113
Researchers also traced an epidemic outbreak of Salmonella heidelberg in a hospital nursery to calves on a dairy farm where the mother of the primary infant patient lived.114 Salmonella isolates from all identified cases were resistant to several antimicrobials, including chloramphenicol and tetracycline,115 suggesting that the infections developed from a common source.
[*PG56] Similar investigations have also focused on other kinds of bacteria.116 In one case, researchers investigated the presence of Enterococcus faecium strains resistant to glycopeptides (such as vancomycin) in a hospital setting.117 The resistant bacteria in this study were identified in chicken carcasses from a hospitals kitchen.118 Bacteria with the same resistance patterns were also identified in animals from both a pig farm and a poultry farm where avoparcin (another glycopeptide) was used as a food additive.119 The researchers concluded that it was probable that the bacteria from the farm animals had been transmitted to the hospital.120 Obviously as shown here animal farms with ergotropic use of avoparcin are an important reservoir for vanA-carrying enterococci. Via food contamination, these bacteria can also be disseminated to humans.121
Not all research on antibiotic resistance has involved the study of actual case histories. For example, other research has focused on the mechanisms by which resistance might be transferred between animals and humans. Researchers involved in these efforts have attempted to identify evidence which would make the transfer of resistant bacteria between animal species and human beings plausible.
Regardless of a studys focus, salmonella remains a favorite subject of investigators, possibly because of its serious potential impact on human health. One study concluded that plasmids found in outbreaks of Salmonella typhimurium were similar in both animals and humans.122 Researchers tested isolates of salmonella from reference laboratories in the United States to determine their susceptibility to antibiotics, and also extracted plasmids from isolates resistant to dif[*PG57]ferent combinations of antibiotics.123 These researchers used restriction endonuclease digestion to demonstrate that plasmid molecules from animal and human isolates were frequently identical or extremely similar.124 These findings suggest that resistance plasmids may be widely shared between animal and human bacteria.125
Another research team recently demonstrated that the molecular characteristics, as determined by pulsed-field gel electrophoresis (PFGE),126 of a ceftriaxone-resistant strain of Salmonella enterica serotype typhimirium isolated from a child were indistinguishable from one isolated from cattle.127 The isolates were both resistant to thirteen antimicrobial drugs.128 This study provides additional evidence that antibiotic-resistant strains of salmonella in the United States evolve primarily in livestock.129
Another favorite research subject130 is vancomycin-resistant bacteria, particularly Enterococcus faecalis (E. faecalis). The spread of vancomycin-resistant bacteria is significant for human health officials and other observers because vancomycin is the antibiotic of last resort for many human infections.131 For example, Staphylococcus aureus (S. [*PG58]aureus) (a major cause of hospital-acquired infections) can be fatal, and [w]orldwide, many strains of S. aureus are already resistant to all antibiotics except vancomycin.132 Health officials have expressed concern that the spread of vancomycin-resistant E. faecalis will soon deliver strong vancomycin resistance to those S. aureus strains, making them incurable.133
Vancomycin is a glycopeptide used to treat human infections; avoparcin, a glycopeptide which shows cross-resistance to vancomycin, is or was fed to livestock as a growth promoter worldwide, with the notable exceptions of Canada and the U.S.134 The use of avoparcin as a growth promoter added to animal feeds was particularly extensive in countries in the European Community.135 Thus, studies of vancomycin-resistant bacteria provide a basis for concern about the spread of cross-resistance of at least some antibiotics used as additives in livestock feeds.136
One study of vancomycin-resistant enterococci (VRE) examined samples of vancomycin-resistant Enterococcus faecium (E. faecium) from clinical sources, including sixty-two isolates from non-human sources, thirty-five isolates from raw sewage, twenty-two from farm animals, and five from uncooked chickens.137 All strains possessed the vanA gene which confers a high level of resistance to vancomycin.138 Further characterization of forty-two of these isolates resulted in fourteen clearly distinguishable types, two of which were ribotyping patterns [*PG59]found in both animal and human sources.139 These results indicate that animals may likely serve as a source of VRE which may allow the bacteria to enter humans through the food chain.140
Another researcher investigated the occurrence and spread of non-nosocomial highlevel glycopeptide-resistant, vanA-positive E. faecium strains.141 Highly resistant E. faecium were isolated from commercially available frozen poultry.142 In addition, glycopeptide-resistant E. faecium (vanA type) were detected in five of thirteen samples of raw meat from pigs originating from thirteen different butchers shops.143 In addition to the animal sources, twelve of 100 non-hospitalized humans from nearby rural areas demonstrated detectable quantities of vanA type E. faecium strains.144 This research suggests a wide dissemination of vancomycin resistance, primarily in animal populations but also at significant levels in human populations.
Experiments from Germany using PFGE showed that a strain of VRE from a human and an isolate from minced pork were indistinguishable.145 Short reports from the Netherlands found indistinguishable isolates (again using PFGE) from a turkey and a turkey farmer.146 These studies provide substantial evidence that resistant bacteria are present in both animal and human populations, and that the mechanisms for resistance are often indistinguishable.
Other studies have focused on the related question of whether the resulting antibiotic resistance is associated with subtherapeutic dosing of farm animals with antibiotics. For example, in 1995, the Danish Veterinary Laboratory completed a detailed comparison of farms using and not using avoparcin, and concluded that VRE is fifty-five times more likely to be detected if the farm animals in question [*PG60]were fed avoparcin.147 In five out of eight chicken farms using avoparcin, resistant bacteria were isolated.148 At the same time, of the six conventional farms where avoparcin was not used, none tested positive for the resistant strains.149
Another laboratory experiment examined the plasmid contents and antibiotic susceptibilities of streptococci isolated from pigs fed tylosin.150 This research showed an increased risk for the spread of resistance as a consequence of tylosin feeding.151 Data showed the addition of tylosin to the feed selected for multiple antibiotic resistance.152 More importantly, a strong sequence homology was established between resistance genes in isolates from humans and those from farm animals.153
Yet another survey looked at the question of whether food products could act as the vector through which antibiotic-resistant bacteria might travel. An investigation of vancomycin-resistant bacteria in a vegetarian and a non-vegetarian nursing home in the Netherlands revealed that of the forty-two persons in the vegetarian nursing home, although twenty-three tested positive for the bacteria Enterococcus faecium, none tested positive for the resistant variety.154 In comparison, of the sixty-two patients in the non-vegetarian nursing home thirty-two patients tested positive for Enterococcus faecium and six residents tested positive for strains resistant to vancomycin.155
In addition to the more limited data suggested by these kinds of experiments or case studies, some researchers have attempted to demonstrate the entire process by which subtherapeutic dosing of animals promotes the growth of drug-resistant bacteria and the spread of such microorganisms from animal to man. One such study [*PG61]was conducted by Stuart B. Levy and associates in the late 1980s.156 His experiments started with a group of young chickens, all of which were progeny of hens that had not been exposed to any antibiotic for more than a decade.157 The chickens were divided into two groups; one group was fed subtherapeutic doses of oxytetracycline while the other groups feed was free of antibiotics. Inspection of the fecal material from the two groups revealed dramatic changes and differences over time. Chickens fed subtherapeutic doses of tetracycline began excreting increasing numbers of tetracycline-resistant organisms in under two days, and in short order more than 90% of the excreted coliforms from this group were resistant.158 The bacteria isolated from the control group remained mainly sensitive to tetracycline.159 In addition, the tetracycline-fed chickens were excreting multi-drug-resistant organisms within three months while the control groups excrement did not contain multiply-resistant flora.160
Perhaps the most worrisome data reported by Levy was that not only the chickens were affected. Humans living on the farm where the chickens were being given subtherapeutic doses of the antibiotics were also affected.161 Within six months of the introduction of the tetracycline-supplemented feed, individuals on the farm began to excrete tetracycline-resistant and multiply-resistant organisms. Samples from a group of neighbors showed no corresponding changes.162
Further experiments to determine the effects of the removal of tetracycline from the chicken feed showed that removal, even with multiple cleaning of the cages, did not significantly reduce the levels of tetracycline-resistant organisms, even though no tetracycline was detected in the samples.163 The chickens had to be removed to a new environment before non-resistant bacteria began to reappear in the chickens.164
Levy and his co-workers also studied the spread of this resistance. They introduced a marked plasmid (bearing a temperature sensitive chloramphenicol acetyltransferase gene) into Escherichia coli (E. [*PG62]coli).165 Chickens were then inoculated with this bacteria and fed tetracycline to establish the marked strains. The chickens were then divided into two groups, (each group housed separately), with one group being fed tetracycline-supplemented feed and the other fed normal feed.166 The researchers found that the marked plasmid spread quickly among chicken that were fed subtherapeutic levels of tetracycline. Even more remarkable was the discovery of the marked plasmid in E. coli isolated from chickens being fed tetracycline-feed in a second cage fifty feet away.167 These chickens had never been directly exposed to the E. coli containing the marked plasmid. The organisms with the marked plasmid were never found in the control group even though they had also been inoculated.168 The conclusion of the author of these studies was that long-term subtherapeutic antibiotic use leads to selection and spread of transferable multiple-resistance plasmids among chickens and man.169
Respected members of the scientific community have reviewed this data, and when their opinions are not constrained by the political process or economic pressures, their conclusions are not reassuring. The consensus appears to be that infections with resistant strains of bacteria could pose significant health risks. For both nosocomial and community-acquired infections, the mortality, the likelihood of hospitalization, and the length of hospital stay were usually at least twice as great for patients infected with drug-resistant strains as for those infected with drug-susceptible strains of the same bacteria.170 In addition, these researchers conclude that [a]lthough the adverse economic and health effects of drug-resistant bacterial infections can only be roughly quantified, . . . antimicrobial resistance is an important health problem and an economic burden to society.171
The import of these observations is debated. Some respected researchers continue to plead the case for a ban on the use of subtherapeutic doses of antibiotics if the antibiotic in question is or has analogues which are of potential value in treating infections in human [*PG63]beings or if the antibiotic selects for multi-drug resistance.172 Consider the following, written in the summer of 1999 by Danish experts:
Accumulating evidence now indicates that the use of glycopeptide avoparcin as a growth promoter has created in food animals a major reservoir of Enterococcus faecium, which contains the high level glycopeptide resistance determinant vanA . . . . Furthermore, glycopeptide-resistant strains, as well as resistance determinants, can be transmitted from animals to humans. Two antimicrobial classes expected to provide the future therapeutic options for treatment of infections with vancomycin-resistant enterococci have analogues among the growth promoters, and a huge animal reservoir of resistant E. faecium has already been created, posing a new public health problem.173
The conclusion reached by these scientists was that antimicrobial agents should not be used for growth promotion if they are used in human therapeutics or are known to select for cross-resistance to antimicrobial drugs used in human medicine.174
The Center for Science in the Public Interest has emphasized that any ban should include not only antibiotics which are themselves used in human treatment, but also drugs which select for cross-resistance. They included the following warning in a 1998 report:
For instance, the new antibiotic Synercid is one of the last hopes against deadly antibiotic-resistant bloodstream infections. Although it has not yet been approved for use in humans, Synercids value already has been compromised because resistance to one antibiotic can cause resistance to others. Thus, researchers at Wayne State University have found Synercid-resistant bacteria in turkeys that had been fed another antibiotic, virginiamycin, to promote growth.175
[*PG64] On the other hand, there are other experts who acknowledge the concerns of public health authorities, infectious disease specialists and plasmid biologists,176 but still conclude that it is not clear whether the banning of these drugs as feed additives while allowing their use for therapeutic applications through prescription would represent any advantage.177 The debate between these two camps leads squarely to the issue of what should be done in response to the mounting scientific data which suggests a link between the subtherapeutic dosing of farm animals with antibiotics and the spread of antibiotic-resistant bacteria in human populations.
Although therapeutic dosing of farm animals (and human beings) can also lead to the proliferation of resistant bacteria, subtherapeutic dosing regimens are particularly problematic, for a number of reasons. Not only is the sheer volume of antibiotics administered as prophylactics and growth promoters troubling, but this type of dosing creates an ideal situation for the selection and propagation of resistant bacteria.178 In addition, an objective cost-benefit analysis calls into question the decision to use antibiotics in livestock feed.
On the benefit side of the equation, farmers have attributed lower costs of meat, eggs, and milk to subtherapeutic doses of antimicrobials in animal feed.179 In 1999, the National Research Councils Committee on Drug Use in Food Animals180 issued a report which included a detailed economic analysis of the benefits of subtherapeutic dosing of livestock. The report concluded that the total cost of banning subtherapeutic use of antibiotics in agriculture would be between $1.2 billion to $2.5 billion per year.181 While this number seems high, the number can be put in perspective by examining the approximate cost on a per capita basis. The National Research Council calculated that the average annual per capita cost to consumers of a [*PG65]ban on subtherapeutic drug use in animal agriculture would be in the range of $4.84 to $9.72 per year, with the effect being lowest for poultry ($1.09 to $2.20 for chickens, $0.27 to $0.56 for turkeys) and highest for cattle ($2.01 to $4.02).182 In terms of the price per pound increase, the report estimated that the cost of chicken would increase somewhere in the range of $0.0130.026 per pound; the cost of turkey would increase between $0.0150.031 per pound; beef would cost between $0.030.06 more per pound; and pork would increase $0.030.06 per pound.183
In each case, the high end of the price range is based on the assumption that there is no substitute for the subtherapeutic use of antibiotics. However, there are several possible alternatives, including increased reliance on vaccinations (both those currently approved, and those that have yet to be developed/approved) and numerous changes to animal management practices that should reduce the economic impact of banning the subtherapeutic use of antibiotics.184 Notably, improvements in animal hygiene and changes in animal confinement practices have the potential for significant improvements in productivity which would help minimize the negative consequences of reducing reliance on subtherapeutic doses of antibiotics.185
The National Resource Council has identified other potential economic benefits of allowing the subtherapeutic dosing of farm animals.186 These include: a slight advantage in export competitiveness,187 avoiding the personal and financial cost of producers who [*PG66]might be forced out of business if subtherapeutic use of antibiotics is prohibited,188 higher profits for pharmaceutical companies,189 and reduced costs for eggs, dairy and pet-food.190
An additional potential benefit of allowing the subtherapeutic dosing of farm animals is the development of new animal drugs by the animal health industry. The 1999 National Research Council report identifies this as potentially one of the most important consequences of such a ban.191 According to this source, approximately $355 million was spent for internal research on animals drugs, and approximately $26 million was spent externally (principally in Universities).192 On the other hand, of these amounts, only 17% was allocated to food additives,193 so the significance of a ban on the use of antibiotics as additives at subtherapeutic levels is uncertain. Moreover, the potential benefits of such targeted research for human patients are uncertain, both because the outcome of research is always uncertain and because the very nature of this research is that it is directed towards use in the agricultural sector.
On the cost side is the economic impact of increased antibiotic resistance. These numbers are also difficult to quantify. Researchers generally agree that the long-term, subtherapeutic dosing regimens contribute to the development of drug resistance in bacteria.194 The very nature of subtherapeutic antibiotic use makes the proliferation of antibiotic-resistant bacteria likely. Unlike therapeutic doses used by veterinarians to treat infectious diseases in livestock, the small subtherapeutic doses used for growth promotion are administered for many months, sometimes years. This is a particularly dangerous com[*PG67]bination of antibiotic use that promotes antibiotic resistance.195 As described in the preceding section of this Article, the extended use of subtherapeutic concentration of antibiotics can lead to the selection of multi-drug-resistant bacteria which then enter a common environmental pool. From there, resistance determinants from various sources disseminate widely.196 The transfer occurs not only from one bacterium to another, but also from one animal host to another, and from one geographic location to others. The same resistance determinants have been traced to many different genera of bacteria associated with animals, foods, and humans where they pose a threat to public health.197
The costs associated with this phenomenon are staggering. The U.S. Office of Technology Assessment has estimated that the minimal hospital costs of five types of infections (e.g., surgical wound infection and pneumonia) due to antibiotic resistance were $4.5 billion per year.198 On a per person basis, the cost of antibiotic-resistance can be overwhelming. One source has reported that [t]he cost of treating a patient with tuberculosis increases from $12,000 for a patient with a drug-susceptible strain to $180,000 for a patient with a multi-drug-resistant strain.199 Moreover, the economic cost may not be the most significant factor. The increase in drug-resistance also translates to an increase in human suffering, as death rates increase once resistant bacteria begin to infect the human population.200
Ironically, these costs have long been known or anticipated by various authorities. In 1969, a report commissioned by the English Parliament on the use of antibiotics in animal husbandry and veterinary medicine recommended a ban on the subtherapeutic use of an[*PG68]tibiotics in food producing animals.201 The call for a ban has been picked up by a growing number of scientists and medical experts in this country, and indeed, throughout the world. The Environmental Defense Fund, the Center for Science in the Public Interest, the Union of Concerned Scientists, the Public Citizens Health Research Group and the Food Animal Concerns Trust have all asked the FDA to end the use in livestock and poultry feeds of antibiotics that are used in . . . [or] closely related to those used in human medicine.202 This position is supported by the World Health Organization, the CDC, the American Public Health Association, the Association of State and Territorial Health Officials, the Natural Resources Defense Council, the American Medical Womens Association, and other organizations.203 This Article seeks to join this call to action by bringing the debate into focus in the legal literature.
The specific steps which seem justified at this time include limiting the approval of new antibiotics for agricultural use, phasing out the subtherapeutic use of antibiotics in farm animals, regulating the therapeutic use of antibiotics in farm animals, and developing and disseminating information about alternatives to the use of antibiotics in livestock. Each of these suggestions deserves a more detailed consideration.
No new antibiotics should be approved for agricultural use unless the drug sponsor can provide convincing evidence that the use of the drug in this manner presents no appreciable risk to human health. At a minimum, compliance with this standard would require proof that the antibiotic in question is not itself approved for use in human therapies, is not related to any such antibiotics or antibiotics that are under development for such purposes in such a manner that cross-resistance is possible, and that use of the antibiotic does not select for multi-drug resistance. The burden of proof would be on the drugs sponsor, typically the manufacturer, to establish that these criteria have been met. In addition, it might be desirable to include a specific [*PG69]requirement that the sponsor prove that the drug is effective for its intended purpose as a feed additive, but consideration of any such requirement is beyond the scope of this Article.
This should be the first step in any appropriate response to the problem of drug resistance among bacteria because of evidence suggesting that the problem is somewhat akin to Pandoras box. Once antibiotic resistance has emerged and becomes prevalent, it may not be easy to address the problem by retroactively revoking approval to use the drug at subtherapeutic levels. The National Research Council, for example, opined that [o]nce an antibiotic has been introduced into animal management practice, either as a subtherapeutic feed application or as a specific therapeutic drug, the emergence of some microbial resistance is highly probable, and cessation of antibiotic use does not significantly alter the pattern of resistance.204 The primary evidence for this assertion appears to have come from the European Union, where a ban on many antibiotics has not been immediately effective in redressing the problem of drug resistance.
The accuracy of the conclusion that a ban on the subtherapeutic use of antibiotics already approved for this purpose would be ineffective in addressing the problem is, however, open to debate. Other experts have concluded that it is possible to have an appreciable effect on the spread of antibiotic resistance by rescinding approvals for use of antibiotics in animals.
Consider, for example, the evidence from Europe resulting from the relatively recent decision to ban the use of avoparcin as a food additive for livestock.205 Prior to 1995, Denmark (and many other European Union countries) widely used avoparcin, a glycopeptide closely related to vancomycin, as a growth promoter. This use was accompanied by a significant increase in the incidence of vancomycin-resistance.206 Denmark, responding to public health concerns, banned the use of avoparcin as a food additive in 1995; Germany did the same in 1996, and the entire European Union banned its use in 1997.207 This change resulted in a marked reduction in vancomycin-[*PG70]resistant bacteria in poultry in Denmark,208 and significant decreases in resistant bacteria in poultry and human beings in Germany.209
This is the type of evidence which both suggests the wisdom of requiring convincing evidence before any decision to approve additional classes of antibiotics for use in livestock is made and supports the second part of the response suggested in this articlethe systematic cessation of subtherapeutic dosing of animals with antibiotics.
Subtherapeutic use of antibiotics in farm animals should be phased out as rapidly as possible, unless the drug sponsor can provide convincing evidence that the use of the antibiotic in question presents no appreciable risk to human health. Ideally, this suggestion would be accomplished by the voluntary cessation of subtherapeutic dosing of livestock with antibiotics, but the use of antibiotics is so ingrained in this country that it will almost certainly be necessary to implement regulations phasing out the subtherapeutic use of antibiotics in agriculture.210 An exception to this requirement could be made, however, if the drugs sponsor proves that this type of use presents no risk to human health.
If the antibiotic is not itself approved for use in human therapies, is not related to any such antibiotic or antibiotics that are under development for such purposes in such a manner that cross-resistance is possible, and use of the antibiotic does not select for multi-drug resistance, the health risks and associated costs described in this article would seem to be irrelevant to the question of whether subtherapeutic doses should be permitted.211 However, even where the risks to human health are not appreciable, regulators might want to consider whether antibiotics approved for use in animals should also be reserved for therapeutic treatment of livestock. Again, however, this suggestion is beyond the scope of this Article.
The justification for prohibiting the subtherapeutic dosing of livestock is principally that the risk to human health is too great to permit the practice to continue. A senior researcher for the Environ[*PG71]mental Defense Fund, Rebecca Goldburg, phrased the problem this way: Few Americans would deliberately choose to jeopardize the health of people for the sake of small economic advantages to the meat industry, yet, current FDA policies do just that.212 The potential cost to consumers of a ban on this use of antibiotics, on a per capita basis, seems reasonable even if one assumes that there is no way to promote animal growth except through the subtherapeutic use of antibiotics.213
This approach is made even more reasonable when one looks at the range of available alternatives to the use of antibiotics at subtherapeutic levels:214
Antibiotics as promoters of animal growth can be phased out gradually. Similar benefits can be generated by improving other aspects of animal care, such as hygiene. In the long run, an industrial investment in alternatives to antimicrobials for animal growth promotion should pay off in more efficient production of food animals as well as protection of the fragile resources that are critical to successful management of human infectious disease.215
This conclusion seems supported by evidence from Sweden, where improvements in animal care and hygiene have largely offset any declines in growth rates caused by that countrys decision to ban the use of antimicrobials as growth promoters.216
Agricultural use of antibiotics should be limited to short-term use under the care of a licensed veterinarian unless the drug sponsor can show that the antibiotic in question is not used in human population, is not medically related to such drugs, and does not select for multi-drug resistance in bacteria. Another aspect of the appropriate use of antibiotics in connection with the raising of livestock is to ensure that all antibiotics are administered under the supervision of a licensed veterinarian, in accordance with policies which require such use to be [*PG72]short-term.217 The routine use of antibiotics should not be permitted even if it means that animal husbandry practices have to adapt.
The justification for requiring antibiotics to be administered under the supervision of a veterinarian is to insure compliance with appropriate treatment regimens. If a farmer is permitted to dose his animals with antibiotics without any requirement that the decision to use such medicines be determined by a professional to be medically warranted, the problem of inappropriate use cannot be avoided. Thus, the veterinarian should act as a gatekeeper, in much the same way that a physician controls access of antibiotics to his or her human patients.
Information about alternatives to the use of antibiotics to maintain livestock health and growth rates should be developed and disseminated among the agricultural and veterinary community. This suggestion is a matter of common sense. Alternatives to antibiotic use for maintaining animal health and productivitysuch as new vaccination techniques, improved animal nutrition, and genetic strategiesmust be sought. Existing alternatives should be implemented in a practical manner so that the appropriate uses of antibiotics and their effectiveness are maintained.218 Once developed, every effort should be made to see that information about these alternatives is widely disseminated. This will help reduce the potentially negative consequences of limiting the subtherapeutic use of antibiotics.
It is clear that there is no easy solution to the problem of antibiotic resistance. The complexity of the problem is such that it will always be possible to question the data and raise doubts about the appropriate response. For example, it can be argued that other practices (such as the misuse of prescription drugs among the human population or the therapeutic use of antibiotics generally) are more important in promoting the spread of antibiotic-resistant bacteria. In addition, the adequacy of the existing scientific data can be attacked on the basis that there are too few studies which look at dosing levels, or [*PG73]which examine the question of how varying treatment regimes are related to the development of antibiotic resistance. It is also true that many antibiotics have not been studied extensively, and so we do not know for sure if their use promotes antibiotic resistance. It can even be argued that the evidence about whether use of antibiotics in animals causes significant increases in human morbidity or mortality is inconclusive. Finally, it can be asserted that banning the subtherapeutic dosing of animals has not been proven as an appropriate or effective response to the problem.
All of these objections have some merit, but none of them come close to providing convincing evidence that the subtherapeutic use of antibiotics in livestock feeds is prudent or wise. They do, however, tend to make one focus on the larger picture. Realistically speaking, it is clear that the use of subtherapeutic levels of antibiotics for farm animals is only part of the picture. Complicating things significantly is the use and abuse of prescription antibiotics by physicians who over-prescribe and patients who fail to complete their prescribed treatment regimens. These patterns of behavior in the human population undoubtedly are a significant factor in the spread of antibiotic resistance. Sources estimate that as many as one third of all prescriptions in this county are unnecessary or inappropriate,219 and there are no reliable statistics on how many patients fail to take all of a prescribed course of antibiotics or dose themselves or others with the left-over of a prior course of treatment. Thus, a comprehensive solution to the problem of antibiotic resistance necessarily includes steps to address this problem. Public and physician education and increased reliance on diagnostic tests such as culturing of infections to determine which, if any, antibiotics are appropriate220 would be desirable components of a response to the over-prescription of antibiotics in the human population. Other steps might also be appropriate.221
[*PG74] The recent advent of increasingly popular antibiotic household and personal cleansers has also been identified by some as another threat to the continued viability of antibiotics.222 Certainly, to the extent that such products cross-select for resistant bacteria, they also contribute to the problem. Again, public education might suffice, but it might also be desirable or necessary to regulate the use of antimicrobial products that have the potential to select for cross-resistant strains of bacteria.
There are also additional problems with the agricultural use of antibiotics beyond those identified in this Article. First, there is the questionable practice of allowing antibiotics to be used as pesticides. Between 40,000 and 50,000 pounds of antibiotics are sprayed on fruit trees each year.223 While this amount may seem trivial in comparison with the millions of pounds of antibiotics used as animal food additives, it has also been identified as a potential factor in the spread of resistance among bacteria.224 Again, it seems prudent to ban this use of antibiotics unless the proponent can provide convincing evidence that there is no risk to human health from this application.
Similarly, the practice of allowing farmers to choose therapeutic dosing levels of antibiotics for their livestock is also questionable.225 While existing data may fall short of what would be sufficient to justify a ban on the therapeutic use of antibiotics among livestock, there certainly seems to be enough data to support a requirement that such use be supervised by a licensed veterinarian. When antibiotics were first made available to the human population, there was no requirement that the patient obtain a physicians prescription.226 The practice of self-dosing quickly promoted the spread of resistant bacteria, as people used antibiotics inappropriately.227 Similar patterns might be expected for farmers. The risk that farmers will medicate livestock when there is no medical justification for antibiotic use should be lim[*PG75]ited if antibiotics are available only when supervised by licensed professionals.228
In addition, it should be made clear through the regulatory process that the only antibiotics available for mass-dosing (i.e., of the entire herd or flock) will be those which are not used by human beings, are not medically related to drugs used by human beings, and do not select for multi-resistance. Otherwise, animal antibiotic use should be limited to the treatment of individual animals. This would effectively prevent the dosing of large numbers of healthy animals, which significantly increases the likelihood that resistant strains of bacteria will spread among animal populations.
It should also be acknowledged that the failure of the government (which provides funding for a great deal of research, especially at the University level) and pharmaceutical companies to anticipate the speed with which bacteria would become resistance to new treatments is a contributing factor in the seriousness of the problem of antibiotic resistance.229 Various surveys have noted that there are essentially no new antibiotics on the immediate horizon.230 Because of the time and expense associated with the development of new treatments,231 this means that the rapid proliferation of resistant bacteria is of considerable concern because there is no quick fix for this problem. Moreover, if new drugs are found and developed, the potential for cross-resistance may mean that they will be of limited usefulness, as well.232 Even with these limitations, however, pharmaceutical companies should be encouraged to increase their efforts to develop new [*PG76]classes of antibiotics and new approaches to the problem of antibiotic resistance.
Finally, the failure of the agricultural community to develop or accept alternatives to subtherapeutic dosing of animals makes the problem which this Article addresses politically sensitive. Consider the efforts of the FDA in the 1970s to ban certain agricultural uses of antibiotics.233 Following a task forces recommendations, the FDA promulgated proposed rules which would remove penicillin and tetracyclines from the list of antibiotics approved for use as food additives for disease prevention and growth promotion. The proposed rules would also have restricted the use of antibiotics in animals to short-term therapeutic use prescribed by a veterinarian, unless the drugs sponsor submitted data establishing that the use for agricultural purposes would pose no risk to human health. The proposed rules prompted vigorous opposition from agri-business and farm-state legislators in Congress, and the proposed limits on the agricultural use of antibiotics were not implemented.234
The problem posed by the politics of the situation probably also requires a multifaceted response. It would be foolish not to recognize that the political acceptability of the response suggested here depends on a number of factors. The first step is education of the public about the dangers of antibiotic resistance. Realistically, a political solution will only emerge if it is politically acceptable. This requires an educated and concerned population.
In addition, education of the agricultural community about the risks associated with the routine use of subtherapeutic doses of antibiotics would certainly help, as would education about alternatives to this practice, such as increased reliance on vaccinations and changes in animal hygiene and confinement practices. The U.S. Department of Agriculture can play a significant role in the education process and in seeing that sufficient resources are applied to developing alternatives to the routine use of antibiotics in farm animals.
Taken as a whole, the factors discussed briefly here make it obvious that the problem of antibiotic resistance is incredibly complex. The complexity of the situation does not, however, diminish the dimensions of the problems posed by antibiotic resistance. Whether or not subtherapeutic dosing of animals is the major cause of the prob[*PG77]lem, it is clearly a cause. Whether or not banning such use will solve the problem by itself is not the real question. The question is whether the existing evidence suggests that this is an appropriate and reasonable part of the solution.
Our reading of the evidence suggests that it is.