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Advisory Board Assessment of Use at Sanderson Farms, Inc. November 28, 2018

Page 1. Executive summary 2 2. Introduction and definition of antibiotic stewardship 4 3. Advisory board assessment of Sanderson Farms, Inc. antibiotic use 5 Is there a legitimate need for in the SFI system as it 5 currently stands? Is there evidence that antibiotic use at SFI is effective? 6 Is there a viable alternative to antibiotic use to prevent disease in 6 poultry at SFI? Is there a viable non-antibiotic alternative to treat disease in poultry 7 at SFI? What would happen if antibiotics were removed from the SFI system 8 in terms of animal welfare, economics, preservation of antibiotics for use in animals and humans, and food safety? 4. Background information 15 Antibiotic stewardship 15 Medically important vs. non-medically important antibiotics 16 The special case of the ionophores 23 Reasons some antibiotics are not used in all or some food animals 24 Antibiotic resistance vs. residues 27 What are the highest risk uses of antibiotics in terms of perpetuating 30 resistance? What are the most serious resistant and where do they 32 come from? Are antibiotics used in human medicine to prevent and/or control 35 bacterial ? The precautionary principle 36 References 38 Appendix - Members of the advisory board 41

1 1. Executive Summary of Advisory Board Assessment

Potential human health risks related to the use of antibiotics in chicken management include the possibility of drugs persisting in chicken meat. Regular assessment of chicken meat in the U.S. indicates that violative concentrations of antibiotics are rarely found; only one positive sample was detected in the past three years.

Another risk is the possibility that bacteria resistant to antibiotics will infect people that come into contact with treated chickens or their products. This is not just a risk related to chickens raised with antibiotics, antibiotic resistant bacteria can be found even on the surface of uncooked chicken raised without antibiotics or raised with no antibiotics ever (RWA/RAE). Given currently available research data, it is not possible to estimate with a high level of confidence the true risk to human health posed by antibiotic use practices in poultry production.

Given that some producers market chicken as RWA/NAE, or raised without treatment with antibiotics classified as medically important, Sanderson Farms, Inc. (SFI) is vulnerable to criticism for their antibiotic use. The use at SFI of the antibiotics and virginiamycin is particularly likely to draw critical attention, because these antibiotics have been designated as medically important.

In spite of the RWA/NAE definition, poultry producers marketing such chicken must at times use antibiotics when flocks of chickens develop disease that can only be halted by antibiotics. This is necessary to prevent the death of large numbers of birds, in accord with attention to bird welfare and fiscal responsibility. Chickens in RWA/NAE systems that must receive antibiotics are then marketed as conventional chicken.

Research indicates that RWA/NAE management represents a trade-off. While generation of antimicrobial resistant bacteria can be decreased in such systems, chickens in these systems are more likely to shed Salmonella or Campylobacter, bacteria that can cause illness in people who consume undercooked chicken. Moreover, rates of chicken death (mortality) in RWA/NAE operations are slightly higher than in traditional systems, according to Agristats data.

Chicken mortality at SFI is below industry averages for chickens raised in traditional and RWA/NAE systems, and systems where medically important antibiotics are not used, indicating that chickens at SFI have better than average health.

In 2017 1.04% of SFI chicken were treated with antibiotics for disease. Although data for comparison are not readily available, the impression of Advisory Board members with relevant experience is that this rate of treatment is low relative to conventional operations of comparable size, also indicating that chickens at SFI have better than average health.

2 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018

Some of the antibiotics used at SFI are classified as not medically important. Ionophores are one example; these antibiotics have no applications in human medicine. Ionophores are used to decrease chicken sickness and death due to the disease coccidiosis. Currently available alternatives to ionophores for coccidiosis control are less effective. While it has been noted that 80% of all antibiotic sales in the United States are for use in animals, 40% of these sales are for antibiotics not classified as medically important, and the majority of this 40% are ionophores.

Because ionophores are classified as antibiotics in the U.S., operations marketing RWA/NAE chicken cannot use ionophores. This can lead to relatively high rates of sickness and death of chickens due to coccidiosis and related diseases on RWA/NAE operations. Notably, ionophores are not classified as antibiotics in Europe; therefore, RWA/NAE poultry management in Europe can include the use of ionophores. This discrepancy puts U.S. poultry farmers marketing RWA/NAE chicken at a disadvantage relative to European producers.

Although their use of the medically important antibiotics gentamicin and virginiamycin makes SFI vulnerable to criticism by individuals who advocate RWA/NAE management, currently available data indicate that movement to RWA/NAE management is expected to increase chicken death rates. The degree of increased mortality could be substantial in the near term, particularly if RWA/NAE management required exclusion of the use of ionophores for coccidiosis control.

A move by SFI to a system where non-medically important antibiotics (i.e. ionophores) can be used for prevention, and medically important antibiotics can be used for treatment and control of disease, could represent a responsible compromise to better preserve efficacy of antibiotics important for human health, while also avoiding the adverse impacts of a RWA/NAE system on chicken health and welfare. Such a system would reflect principles of antibiotic stewardship described in this document.

3 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018

2. Introduction

Much has been written and discussed in recent years regarding the production of meat from poultry and livestock that have not been treated with antibiotics. Some restaurant and retail grocery store chains have announced plans to move to some variation of a “no antibiotic ever” program with respect to chicken products. In light of investor questions regarding the SFI position on antibiotic use, and in order to provide additional information to outside board members to aid in the board’s oversight responsibilities, SFI management convened a group of individuals with expertise in poultry production, livestock health and management, and the use of antibiotics in veterinary and human medicine to review and comment on the use of antibiotics in SFI poultry production. The members of this Advisory Board and their affiliations are listed in the Appendix.

The Advisory Board members were provided with data describing current antibiotic use in SFI chicken production, including the antibiotics given, the reason the antibiotics are used, the amount or dose of antibiotics given, the stages of the production cycle when antibiotics are used, and the number of chickens receiving antibiotics. The Advisory Board members discussed the information and generated this document summarizing their assessment in both physical meetings and teleconferences.

This document summarizes the Advisory Board review. The document is organized into four sections:

1) executive summary; 2) introduction and definition of antibiotic stewardship; 3) Advisory Board assessment of SFI antibiotic use, in the form of responses to questions that may be posed regarding this use; and 4) background information provided for reference, to clarify or expand on information in sections 1-3.

Defining Antibiotic (Antimicrobial) Stewardship The concept of antibiotic stewardship underlies any assessment of antibiotic use, including the assessments in this document. Defining and practicing antibiotic stewardship will be critical to the ability of producers and veterinarians to ensure the health and welfare of animals in their care in the coming decades. This is because of expected constraints related to the impact of antibiotic resistance in bacteria that cause disease, and to regulatory oversight of various agencies.

Perhaps most relevant to this document is the American Association of Avian Pathologists (AAAP) statement on Antimicrobial Stewardship for Poultry.(1) The excerpts below capture the core meaning of antimicrobial stewardship as defined by the AAAP. More detail regarding the defining principles is contained in the document.

4 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018

“Antimicrobial Stewardship for Poultry Veterinarians Defined Antimicrobial stewardship refers to the actions poultry veterinarians take individually and as a profession to preserve the effectiveness and availability of antimicrobial drugs through conscientious oversight and responsible medical decision-making while safeguarding poultry, public, and environmental health.

Core Principles of Antimicrobial Stewardship in Poultry Veterinary Medicine Antimicrobial stewardship involves maintaining poultry health and welfare by implementing a variety of management strategies to prevent, control and treat common diseases; using an evidence-based approach in antimicrobial decisions; and then using judiciously, sparingly, and with continual evaluation of the outcomes of therapy; while protecting poultry health and ensuring safe, affordable food to the consumer.”

3. Assessment of SFI antibiotic use

Is there a legitimate need for antibiotics in the SFI system as it currently stands? Historically, many diseases of poultry were prevented through use of an antibiotic in the feed or water during the period when disease was most likely. The poultry industry has made significant strides toward improving the health and wellbeing of the birds being raised for human consumption. One of the major practices adopted over the past fifty years is to have veterinarians specializing in poultry medicine serving as integral company executives, working with the other company managers on day-to-day decisions regarding not just bird health but also many husbandry decisions.

SFI employees include six veterinarians who advise the company on all decisions regarding treatment and prevention of disease in birds. Antibiotics are used to prevent, treat, or control bacterial infections in birds at SFI. The major diseases that require antibiotics for prevention, treatment, or control include necrotic , gangrenous dermatitis, and infections due to the bacteria E. coli. The prominent role of staff veterinarians in poultry health management at SFI improves the likelihood that antibiotics are used only for legitimate applications to prevent, treat, or control disease.

One important disease due to E. coli is respiratory , including airsacculitis, which affects SFI broiler chicken houses following outbreaks of the viral disease infectious bronchitis. The infectious bronchitis virus is easily transmitted between chicken farms, and once it enters a farm, it spreads rapidly between birds in the same chicken house. Antibiotics are used to control secondary bacterial infections that can follow infectious bronchitis virus infection. In particular, this virus makes infected birds very susceptible to E. coli, which is found in all chicken houses.(6) infection causes the birds to have more severe respiratory disease that often progresses to and death. The treatment of E. coli infection of birds experiencing infectious bronchitis infection represents an example of an appropriate use of antibiotics in SFI management. Current position statements of the American

5 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018

Association of Avian Pathologists (AAAP) and the American Veterinary Medical Association (AVMA) support this. Other diseases commonly treated with antibiotics at SFI are necrotic enteritis, which is due to the bacteria Clostridium perfringens, and gangrenous dermatitis, due to the bacteria Clostridium perfringens, Clostridium septicum, and .

In 2017 was the antibiotic most commonly used for treating sick birds at SFI, and was the second most commonly used. and sulfonamides were also used. In 2017, 1.04% of birds received antibiotic treatment for disease. Although data for comparison are not readily available, this rate of treatment is low relative to conventional operations of comparable size.

The antibiotics methylene disalicylate (BMD) and virginiamycin are used at SFI for prevention of disease. This is an approved use of these antibiotics as determined by the FDA- CVM. Because virginiamycin is considered medically important (defined and discussed in Section 4), continued effort to use and confirm the benefit of disease-preventing strategies to minimize the need for antimicrobial prevention with virginiamycin is advised. Prevention can include means of excluding disease-causing agents, often referred to as biosecurity. In addition, vaccination is one of the major means of prevention, especially against primary viral disease agents to prevent secondary bacterial infections. SFI is currently using some non- antibiotic means to control disease. Birds are vaccinated against coccidiosis, and a probiotic- prebiotic (Poultry Star), which may help prevent birds from being infected (colonized) by disease causing bacteria, is used in breeder diets.

Data from Agristats indicate that SFI mortality (death) of chicks up to 7 days of life is better than the industry average, indicating that management is effective to preserve health of young birds. Given this, it may be reasonable for SFI to phase out the use of the antibiotic gentamicin in-ovo. Most broiler companies have ceased use of in-ovo antibiotics. However, removal of in-ovo gentamicin will take time, as an increase in 7-day bird mortality which can be substantial is likely to follow. Management practices to limit infection in the brooding and hatchery phases will need to be tested to keep mortality rates below industry averages if in- ovo gentamicin is removed.

Is there evidence that antibiotic use at SFI is effective?

Data from Agristats indicate that SFI mortality (death) of chicks up to 7 days of life, and mortality over the entire life of birds, is better than the industry average, indicating that current SFI management practices, including their use of antibiotics, is effective to preserve health and life of chicks and birds.

Is there a viable alternative to antibiotic use to prevent disease in poultry at SFI?

In response to consumer concerns, poultry companies use nonantibiotic alternative products (probiotics, intestinal acidifiers, natural antibacterials, enzymes, etc.) in an effort to reduce the growth of the unfavorable intestinal bacteria such as Clostridium perfringens. (14, 25) All of

6 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018 these methods can help reduce the incidence or the severity of the bacterial infection, although they are more likely to be reliable for prevention than for treatment. Principles of antibiotic stewardship require that non-antibiotic preventive strategies be utilized when effective.

SFI is currently using some non-antibiotic means to control disease. Birds are vaccinated against coccidiosis, and a probiotic-prebiotic (Poultry Star), which may help prevent birds from being infected (colonized) by disease causing bacteria, is used in breeder diets. A non-antibiotic (chemical), nicarbazin, is used along with the ionophores narasin and salinomycin, to control coccidiosis.

Is there a viable non-antibiotic alternative to treat disease in poultry at SFI?

There are currently no viable alternatives for antibiotic use when flocks of chickens become sick from a bacterial infection. Even broiler producers who are producers of RWA/NAE chickens have to use antibiotics to treat flocks that become sick due to bacterial infection, or the chickens die in numbers that can be substantial. These treated flocks are then marketed in the traditional channels that are not for RWA/NAE labels. It has been estimated that in the winter approximately 5% - 10% of the broilers placed by an RWA/NAE producer will have to be treated with antibiotics.

Relevant to this, a recent report by the Council for Agricultural Science and Technology (CAST) on the Scientific, Ethical and Economic Aspects of Farm Animal Welfare states: “Because of concerns related to , the use of antimicrobials in food-producing animals is a topic of much discussion. Strategies to address antimicrobial resistance include discontinuing production uses (e.g., for growth promotant and feed efficiency uses); enhanced use of other means of infectious disease prevention (e.g., improved biosecurity measures, increased use of vaccination to prevent viral diseases that may often be followed by secondary bacterial infections); greater attention to how antimicrobials are selected and used in prevention and treatment protocols (i.e., targeted application, increased veterinary oversight); and the identification, development, and use of nonantibiotic alternatives for prevention, control, and treatment (e.g., organic acids in feed and water, gene-encoded natural antibiotics, prebiotics and probiotics, bacteriophages). A related emergent animal welfare problem is that increased consumer demand for meat from animals that have not been treated with antimicrobials for any purpose—production or therapeutic—has caused and may continue to cause producers and veterinarians to withhold treatment for animals intended for the consumer market. The negative impacts on animals’ welfare resulting from disease that could be prevented and/or that cannot be controlled and treated are significant and unacceptable” (CAST, Task Force Report No. 143, April 2018, pages 24-25).(13)

The need to retain the possibility of using antibiotics to treat disease while limiting their use in preventive management is highlighted by a 2018 study by Karavolias et al.,(30) which showed that broilers raised without antibiotics had a 3.6 times greater risk of eye injury (corneal ), 1.3 times greater risk of foot infections leading to sore feet and reluctance to walk, and 1.6 times greater risk of respiratory infection (airsacculitis) leading to death, as compared to

7 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018 birds raised conventionally.

What would happen if antibiotics were removed from the SFI system in terms of animal welfare, economics, preservation of antibiotics for use in animals and humans, and food safety?

Effects on animal welfare and economics

In the U.S. broiler industry, many companies have eliminated the use of antibiotics in normal production, reserving antibiotics to treat and control disease in sick flocks. However, in these companies, a flock sometimes develops disease that can only be effectively treated with antibiotics. In such cases, to prevent excessive sickness and death, a flock may be treated with antibiotics. If this occurs, the birds in that flock cannot be sold with a no antibiotics ever (NAE) label and must be marketed through conventional distribution channels. This type of production is more generally referred to as “raised without antibiotics” or RWA/NAE. The birds marketed under the NAE or RWA/NAE claims do not receive antibiotics, but chickens that left the production system due to need for antibiotic treatment are typically not addressed in marketing information released by these producers.

In the U.S. removal of antibiotics includes removal of in-ovo antibiotics and the polyether ionophore antibiotics (ionophore anticoccidials). The removal of medically important antibiotics for growth promotion was effective as of January 1, 2017. The removal of antibiotics for prevention, control, and treatment of disease in poultry production without viable alternatives may result in welfare concerns due to elevated mortality and loss of production efficiency due to illness and death loss. Additionally, more resources are used to raise more birds to replace those that die, resulting in greater environmental impacts from increased manure production and more use of grain per unit of meat produced. Higher rates of intestinal disease may also result in increased numbers of foodborne illness-causing bacteria such as Salmonella sp. or Campylobacter sp. on the carcass. The disease necrotic enteritis (NE) can in particular have a negative impact.(26)

In a recent survey of consumers, 55% responded that they were extremely or very concerned about antibiotic use in chickens when they purchase chicken.(8) Unfortunately, this same survey demonstrated that the respondents generally have major misunderstandings about poultry production. For example, 60% of respondents considered themselves to be very knowledgeable or somewhat knowledgeable about the care of chickens, but 75% of respondents believed that there are added hormones or steroids in chicken meat and 71% of respondents believed that chickens raised to be eaten are raised in cages—neither of which is true.

The reality of raising broiler chickens without antibiotics is different than understood by most consumers. In general, the impact of raising broilers without antibiotics has been shown to have an overall negative effect on gut health and bird performance.(24, 35) Although these negative impacts can be minimized over time as producers adjust to this different style of

8 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018 production, data analyses still show overall negative effects on animal health, animal welfare, environmental sustainability and economic viability.

A recent study compared three different types of production systems: conventional, NAE, and non-medically important only, wherein only antibiotics that are not considered important to human health are used to maintain bird health. The study analyzed data regarding three important health conditions of the birds in these three production systems: eye ammonia burns, footpad lesions, and airsacculitis. The presence of these conditions can indicate poor animal welfare, and birds with these conditions can have reduced weight gain caused by decreased feed intake because of the associated pain.(30) This study found that NAE production increased the risk and severity of all three of these health conditions. Using the non- medically important antibiotics diminished this risk and severity somewhat, but the risk was still greater than for conventional production. Specifically, the odds of eye burns occurring in a bird given no antibiotics was found to be approximately 3.6 times higher than a bird given medically important antibiotics (conventional). Birds raised with non-medically important antibiotics had an approximate 1.3 times higher odds of eye burns than birds raised conventionally. The odds of footpad lesions were approximately 1.3 times higher for birds raised NAE compared to a bird raised conventionally, and this was the same difference between birds raised with non- medically important antibiotics and birds raised conventionally. Finally, the odds of airsacculitis were approximately 1.6 times higher for birds raised NAE compared to a bird raised conventionally. Interestingly, the odds of airsacculitis were lower in birds raised with non- medically important antibiotics compared to birds raised conventionally. All of the odds mentioned above were statistically significant.

The authors highlight important limitations of this study. First, they emphasize that the analyses do not prove a cause and effect relationship; in other words, they are not stating that raising birds NAE causes these conditions to become worse. Second, they emphasize that they did not analyze management practices and other related on-farm variables. They state “Transitioning from medically important antibiotics to no antibiotics ever generally requires changes be made to production including reduced stocking density, longer downtime between flock production cycles in a barn, providing an all-vegetarian feed, etc.”(30) This point, as mentioned above, is key. Many of the negative impacts of NAE production can be diminished over time, but data suggest these negative impacts might never be completely eliminated.

Other studies have also reported negative impacts of NAE production on animal health. In an early study by Smith (2011) (35), the author reports that “in addition to being more expensive to produce, due to stricter and more expensive diet requirements, drug-free birds had a higher incidence of necrotic enteritis. In a more recent study by Gaucher et al. (2015) (24), the authors reported that the drug-free program was associated with an overall negative effect on key performance indicators and gut health, which is indicative of the potentially negative effects on the overall animal welfare. In particular, the drug-free program was associated with both an increased incidence of necrotic enteritis, as well as a significant increase in feed conversion, and a decrease in both daily weight gain and mean live weight at slaughter.

9 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018

The paper by Karavolias et al. (30) states that “Prior literature investigating the impact of removing access to antibiotics on poultry production focuses on subtherapeutic (e.g., growth promotion) uses only and/or focuses on productivity impact related to bird performance and grower financial outcomes.” These authors conclude that “Policies aimed at eliminating or restricting the use of antibiotics in broiler production may come with potentially negative consequences with respect to good animal welfare. A more effective policy approach should consider comprehensive animal care plans that incorporate good housing, management, and responsible antibiotic use, including the use of ionophores. Policies aimed at informing the consumer on the positive role of access to antibiotics in supporting good animal welfare while limiting risk of antibiotic resistance in humans are needed to address the current information gap.”

The impacts of raising animals without antibiotics are not restricted to animal health and welfare. There are also potential effects on environmental sustainability and economic viability. In a study conducted by Salois et al.,(33) a simulation model was used to evaluate the impacts of NAE production. The authors conclude:

“Compared to broilers produced in a conventional system, birds raised in a single broiler house under ABF conditions will have an annual reduction of between 50,000– 100,000 lbs of edible meat (breast, legs, thighs, wings) equivalent to between 265,000– 530,000 individual 3 oz. single servings. This loss represents enough to feed 600–1,000 people annually, based on average annual consumption of chicken in the United States in 2012. In order to maintain the same supply of meat under ABF conditions, a typical broiler house will require between 15,000–33,000 more marketed broilers per year. Due to the additional broilers needed, eliminating antibiotic use has an environmental impact. Compared to a conventional house, chickens raised in a single broiler house under ABF conditions will require between 185,000–390,000 additional lbs. of feed per a year; between forty-two and ninety additional acres a year to produce that feed; between 33,000 and 78,000 additional gallons of water consumed; and between 157,000 and 333,000 additional tons of manure produced. In addition, the cost to produce edible prime meat in a broiler house under ABF conditions is between $52,000 and $110,000 per year.”

The authors extended these house-level estimates to the entire U.S. broiler industry. If the entire broiler industry were to go NAE, the authors estimate that we would need 680 - 880 million more birds to maintain supply, and 5.4 - 7.6 million tons of additional feed would be needed which would require between 2.5 - 3.3 million additional acres of land to grow. The additional birds also would require between 1.9 - 3 billion gallons of additional water and would produce between 4.6 - 6.1 million tons of additional manure.

The authors conclude that “eliminating the use of antibiotics in the raising of broilers may have a negative effect on the conservation of natural resources as well as a negative economic effect via increased prices to the consumer. Results suggest the need to communicate to consumers

10 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018 the supportive role that prudent, responsible use of antibiotics for animal disease treatment, control, and prevention plays in the sustainable production of broilers.”

The special case of ionophores: Ionophores are used to prevent coccidiosis, a protozoal (parasite) infection. In the U.S., the FDA defines ionophores as antibiotics, although they are not “medically important” (see Section 4). Coccidiosis is a common cause of intestinal disease in poultry. Moreover, coccidiosis increases the likelihood that birds will be infected by Clostridium perfringens, the bacteria that causes necrotic enteritis, a disease which can kill birds if they are not treated with antibiotics. If SFI stops using all antibiotics they will have to stop using the ionophore anticoccidial drugs. The ionophores have no use in humans and have no documented impact on human bacterial infections or antibiotic resistance. Exclusion of ionophore antibiotics in a RWA/NAE management system will likely result in more chickens having intestinal disease, and more chickens dying because of necrotic enteritis.

There are non-ionophore, non-antibiotic coccidiostats available as discussed in section 4. These are collectively referred to as chemical coccidiostats, and are often used in RWA/NAE programs. The protozoal parasites that cause coccidiosis have developed significant resistance to chemical coccidiostats, leading to efficacy that is inferior to ionophores. When an RWA/NAE producer makes the decision to exclude all antibiotics, not just medically-important antibiotics, they are making the decision to remove the ionophores from the production system and to rely solely on the chemical anticoccidials.

In summary, if SFI were to move to RWA/NAE production, this could improve opportunities to market certain products through certain channels. However, current assessments indicate that the percent of their chickens that get sick and that die will increase. This increase in the number of chickens expected to die means that more chickens will have to be hatched and raised in order to produce the same number of pounds of chicken as a traditional system. Hatching and raising more birds will require increased resources such as feed and energy, and will result in some increase in waste production, over that of the current traditional system.

Effects on preservation of antibiotics for animals and people

Effective, relatively non-toxic antibiotics have been available since 1935, with the introduction of sulfonamides. Following the first large scale availability of penicillin in 1942, there was an approximately 40-year flurry of new antibiotic class discovery, ending in the mid 1980’s.

The last new antibiotic group for which a member of that group was eventually available for use in food animals was the 1978 release of (a fluoroquinolone) for human use. The history of this group in chickens and turkeys is discussed in Section 4; fluoroquinolone antibiotics are no longer legal for use in chicken production. While some new molecules in existing antibiotic groups have been made available for use in some food animal species since 1978, no new antibiotic groups have become available for use in food animals, and the probability that more will become available is extremely low.

11 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018

While preserving antibiotics for use in humans should be at the forefront of antimicrobial stewardship efforts, preserving the ability to treat the animals under our care is also necessary. If resistance builds to the remaining effective antibiotics we are left with little for intervention in disease outbreaks when preventive practices are overwhelmed. The cost of using antibiotics as routine preventive practices is that they may not be effective in the future when they are needed for therapeutic interventions. Specifically, in relation to the antibiotic use practices of SFI, the question is whether the use of the following antibiotics in preventive programs have the potential to introduce resistant pathogens into the food chain or environment where there is a detrimental effect on human health, or to contribute to the erosion of antibiotics as therapeutic interventions in chicken disease outbreaks in the future.

• Medically important o Gentamicin in-ovo o Virginiamycin in feed • Non-medically important o Ionophores o Bacitracin Methylene Disalicylate (BMD) in feed (while classified as non- medically important in the U.S., the cyclic polypeptides [the group which includes bacitracin] are classified as medically important by the World Health Organization)

Although used on a much smaller scale, the same questions could be asked for the antibiotics used only for treatment of disease at SFI; the FDA considers all of these medically important in human medicine. They are used only in response to disease outbreaks and are administered through the water. • Lincomycin • Penicillin • •

The definite establishment of links between poultry antibiotic use and human health, and the magnitude of such links, are beyond the scope of this document. However, it is clear that bacterial populations in chickens, humans, and the environment can overlap. Moreover, the potential for erosion of therapeutic efficacy of our few remaining effective antibiotics because of the development of antibiotic resistance is an issue that is quite real. Therefore producers and veterinarians should focus on the preventive use of antibiotics as an interim practice while management practices that allow continued reduction of such antibiotic use are pursued.

Separating the precautionary principle (as discussed in Section 4) from legitimate, science- driven concerns is a challenge in both this report, and in addressing consumer concerns about poultry production practices.

12 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018

Effects on food safety

Human health risks related to the use of antibiotics in chicken management include the possibility of antimicrobial drugs persisting in chicken meat, and the possibility that bacteria resistant to antibiotics will infect people that come into contact with treated chickens or their products. Regular assessment of chicken meat in the United States indicates that violative concentrations of antibiotics are rarely found (discussed below). In the last three years of testing, only one violative level of antibiotic residue was found in chicken meat, and it was an antibiotic, nitrofurazone, which is not approved for use in animals raised for food. The two most common bacterial foodborne illnesses in the U.S. are non-typhoidal Salmonella and Campylobacter, accounting for a Centers for Disease Control and Prevention (CDC) estimated 1.0 million and 0.8 million cases per year respectively.(9) The most common source of these infections is contamination of meat by material from the intestines of animals raised for food; these bacteria are found in other food-producing animals and are not restricted to poultry. It is possible that exposure of animals to antibiotics in food or water may contribute to antibiotic resistance in these two bacterial pathogens. The latest National Antibiotic Resistance Monitoring System (NARMS) report states that no antibiotic resistance was found in 76% of non-typhoidal Salmonella isolates. Multidrug antibiotic resistant bacteria were found but the majority of the antibiotics to which Campylobacter and Salmonella were resistant were , , , sulfonamides and tetracyclines, all antibiotics that would not be used to treat human illness due to Salmonella or Campylobacter. Overall there was a decline in multi-antibiotic resistant Salmonella from 17% to 12% over ten years. Ciprofloxacin is a critical antibiotic to treat Salmonella in adults and was banned from use in poultry by the FDA in 2005. Only 0.7% of Salmonella isolates from chicken meat samples showed resistance to ciprofloxacin, whereas 6% of human isolates were resistant. Another consideration regarding a move to an NAE system is that, as discussed above, more birds are expected to become sick. When chickens are sick, they eat more bedding material (litter), which can result in higher numbers of Salmonella sp. and Campylobacter sp. in their intestinal tract.(12) Also, it has been shown that birds from flocks having higher rates of carcass condemnation due to airsacculitis had higher levels of E. coli and Campylobacter on their carcasses.(32)

There are food safety implications specifically related to any decision to remove ionophore antibiotics, which would be required in a RWA/NAE system as currently practiced in the United States. Baba, et al.,(5) found that coccidiosis resulted in more Salmonella typhimurium in the livers and spleens of chickens, and Volkova, et al.,(36) noted that the method of coccidiosis control may influence the prevalence of Salmonella at the processing plant. The disease necrotic enteritis, which is exacerbated by coccidiosis, may not directly result in an increased colonization by Salmonella, but it can result in greater variation in bird size due to the

13 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018 subclinical form of the disease.(27) As Russell found, poorer body weight uniformity can result in greater intestinal tract tears and greater risk of Campylobacter contamination on chicken carcasses.(32) Thus, reducing animal illness likely plays a critical role in reducing the chances of contamination during processing.

When assessing the potential risks of antibiotic use in poultry, we must begin to take a more holistic view of health into consideration. Specifically, we should be assessing the potential risks and the potential benefits associated with antibiotic use. Phrased another way, are there potential unintended consequences of removing antibiotics from use in food animals? Recent models have predicted that there might be significant negative human health consequences associated with the removal of certain antibiotics from animal production. This is an instance in which the precautionary principle would lead to an action of banning antibiotics in animal agriculture, but that action could have even worse unintended consequences. It might not be intuitive, however, how an antibiotic that is used in animal agriculture can actually benefit human health.

Mathematical models have been developed to relate animal illness to human illness.(34) These models demonstrate that there can be large increases in human illness associated with small increases in animal illness, suggesting that agricultural management strategies may have significant impacts on human health. Antibiotics that are administered to poultry via the feed for disease prevention raise concern about their potential to increase rates of antibiotic resistance, posing a risk to human health. However, these applications also improve animal health and can promote size uniformity among animals in the flock. Antibiotic uses in animals can therefore have potential human health risks, but also benefits. Models such as the one cited previously, are able to evaluate simultaneously the human health risks and benefits associated with antibiotic use in animal agriculture. The cited model addressed the relationship between the negative human health impact of increased antibiotic resistance and the positive human health impact of fewer foodborne infections, both of which are due to the use of the antibiotic in animal agriculture. The model showed that the potential benefits to human health associated with the use of antibiotics in animal agriculture can far outweigh the potential risks. This finding has been validated by additional studies.(7, 28)

In summary, if SFI moves to a RWA/NAE system of chicken production, they will have more opportunity to market certain chicken through certain channels. Moreover, rates of identification of antibiotic resistant bacteria are expected to be lower in a RWA/NAE system. However, it is important to remember that even in a RWA/NAE system, flocks of chickens will occasionally need antibiotic treatment for bacterial disease, or chickens will die in numbers that would be considered unacceptable in terms of animal welfare and fiscal responsibility. Also, removal of ionophores antibiotics, which would be required in a RWA/NAE system as currently practiced in the United States, would increase sickness and death due to coccidiosis and to necrotic enteritis, which is exacerbated by coccidiosis. Increased numbers of Salmonella and Campylobacter would be expected to be identified in and on chickens in a RWA/NAE system; this represents a food safety concern because these bacteria can cause disease in people who consume undercooked chicken or who come into contact with chickens carrying these bacteria.

14 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018

A move by SFI to a system where non-medically important antibiotics can be used for prevention, and medically important antibiotics can be used for treatment and control of disease, could represent a responsible compromise to better preserve efficacy of antibiotics important for human health, while also avoiding the adverse impacts of a RWA/NAE system on chicken health and welfare. Such a system would reflect principles of antibiotic stewardship described in this document.

Section 4: Background Information

Antibiotic stewardship Stewardship has been defined differently by physicians and veterinarians. The Infectious Disease Society of America has a stewardship definition applied to human medicine which does not include infection prevention.(29) In human medicine, infection prevention and antibiotic stewardship are considered two separate but overlapping processes. However, in veterinary medicine, these two aspects of stewardship are addressed together. Therefore, the concept of antibiotic stewardship in veterinary medicine is all encompassing, including disease prevention and the judicious use of antibiotics when they are needed (Figure 1).

Figure 1: Components of an Antibiotic Stewardship Program

Within this stewardship cycle, there are aspects of antibiotic use which may be benchmarked to make the veterinarian and their clients aware of the primary disease challenges being experienced by others, and how they are being addressed. The nature of different production

15 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018 systems creates a situation in which the optimal antibiotic stewardship benchmarking metrics are often specific to the species, and even the production system type within species.

The American Veterinary Medical Association (AVMA) recently defined antimicrobial stewardship and core principles.(4) “Antimicrobial stewardship refers to the actions veterinarians take individually and as a profession to preserve the effectiveness and availability of antimicrobial drugs through conscientious oversight and responsible medical decision- making while safeguarding animal, public, and environmental health.” Core principles as defined by the AVMA are… “Antimicrobial stewardship involves maintaining animal health and welfare by implementing a variety of preventive and management strategies to prevent common diseases; using an evidence-based approach in making decisions to use antimicrobial drugs; and then using antimicrobials judiciously, sparingly, and with continual evaluation of the outcomes of therapy, respecting the client’s available resources.” More details on the principles are provided on the AVMA website.

Medically important vs. non-medically important antibiotics Medically important antibiotics are those antibiotics which are deemed important for treating diseases in humans. This classification has no bearing on the likelihood or magnitude of resistance development due to use in food animals. In the United States the regulatory status of antibiotics as medically important, as listed below, is defined in Appendix A of Guidance for Industry (GFI) 152.(16) The FDA Center for Veterinary Medicine (CVM) is currently in the process of working with the FDA Center for Drug Evaluation and Research (CDER) to revise this document. The groups with superscript1 are those that the World Health Organization cites as being the Highest Priority of the Critically Important classification.(37) The groups with superscript2 have at least one member of the group with a food animal label.

• Beta-lactams a. Penicillins2 – natural, penase resistant, antipseudomonal and amino- b. Cephalosporins1,2 – 1st through 4th generation in the document, a revision would most likely also include 5th and subsequent generations. The example with a poultry label is ceftiofur sodium (Naxcel®) c. d. • Quinolones and fluoroquinolones1,2 (no products in the U.S. for poultry) • Aminoglycosides2 • Macrolides1,2 (includes , triamalides, and azolides) • Lincosamides2 ( is the class representative) • Tetracyclines2 • Glycopeptides1,2 • Streptogramins2 (Virginiamycin in food animals, Synercid in humans) • Oxazolidinones

16 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018

• • • • Chloramphenicol2 ( in food animals) • • /sulfa2 (food animal labels in the U.S. are not potentiated with trimethoprim or other potentiators) • Polymyxin B1 Of these drugs, the medically important antibiotics used in preventive programs at SFI, Inc., include virginiamycin (Stafac®, a ). Antibiotics used in preventive programs at SFI, Inc., which are not medically important antibiotics are Bacitracin methylene disalicylate (BMD®), and the narasin component of the combination drug Maxiban®. It should be noted that the cyclic glycopeptides, which include bacitracin, are not classified as medically important in the U.S., but they are included as a medically important antibiotic in the WHO list of medically important antibiotics. While not used systemically in humans, it is a component of topical products in which bacitracin serves as a component aimed at Gram + bacteria. Other non-medically important antibiotics which are available for use in poultry feed that are not used at SFI, Inc., are Avilamycin (Inteprity®), and Bambermycins (Flavomycin®).

In-feed medically important antibiotics available for treatment of E. coli infection include sulfadimethoxine/ormetoprim (RofenAid®) and /oxytetracycline (Neo-Terramycin®). In 2017 at SFI, Inc., 90,500 broilers received Neo-Terramycin in a broiler study, and 90,300 broilers received RofenAid in the feed. RofenAid has been unavailable for approximately a year and a half at the time of this writing.

The other uses of medically important antibiotics at SFI, Inc. in 2017 included the following.

• In-ovo o Gentamicin (an ) to all eggs at 18 days of incubation at a dose of 0.05 to 0.1 mg/embryo for the control of post-hatch mortality related to E. coli. • Broilers administered medically-important antibiotics through the water o Lincomycin (a lincosamide) in the water if water acidification is unsuccessful for control of necrotic enteritis or gangrenous dermatitis. The threshold for moving to lincomycin is more than 50 dead birds/house per day. Records indicate administration to 4,217,720 birds in 2017 (0.75% of birds) o Penicillin (a natural penicillin of the beta-lactam group) in the water as a rescue drug if lincomycin was ineffective. Records indicate administration to 1,016,000 birds in 2017 (0.18% of birds) o Sulfadimethoxine (a sulfa) in the water to 16,500 birds (0.003% of birds in 2017) o Oxytetracycline (a ) to 446,100 birds (0.08%)

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The use of in-ovo gentamicin may contribute to the relatively high rates of gentamicin resistance found in the bacteria E. coli isolated from U.S. poultry products or poultry processing environments, as compared to samples from U.S. beef or pork (Figure 2).

Figure 2: Gentamicin resistance in E. coli isolated from various commodities. These data were retrieved from the National Antibiotic Resistance Monitoring System (NARMS) Now: Integrated Data Website hosted by the Food and Drug Administration Center for Veterinary Medicine. These data are available at https://www.fda.gov/animalveterinary/safetyhealth/ antimicrobialresistance/nationalantimicrobialresistancemonitoringsystem/ucm416741.htm

Table 1 illustrates antibiotics approved in the U.S. with food animal labels by species, indication, and route.(3) Classes of antibiotics sold for use in food animals are reported in Table 2 from the FDA Center for Veterinary Medicine report on 2016 sales of antibiotics with a food animal label (excerpted as Table 3b in the FDA/CVM report).(23) Species values are based on estimates by drug sponsors as to species distributions of their product sales.

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Table 1: Antibiotics labeled for food animal use in the United States classified by medical importance status with reported sales proportion in 2013, by species and labeled routes of administration. These routes may be as part of a combination product, are approved specific to disease indications, and may also include only specific use classes and age restrictions within the species. This table contains label approvals as represented at "Animal Drugs@FDA", the electronic version of the "Green Book" containing FDA CVM approvals.

Medically important antimicrobials as defined in Guidance 152 Appendix A Beef % of antibiotic Cattle, sales for food Non- animals in U.S. Lactating Lactating for this category Dairy Dairy in 2013 Class Drug Swine Cattle Cattle Goats Sheep Chickens Turkeys IMM Streptomycin O O IMM O 2.9% Gentamicin W, I, O T I I Neomycin W,M,F,O W,M,F,O W,M,F,O W,M,F,O W,F W,F O W, I I Ceftiofur I I I, IMM I I I I 0.3% Cephapirin IMM Enrofloxacin I I I 0.2% Fluoroquinolones Danofloxacin I Lincomycin I,F,W W,F 2.6% IMM Tulathromycin I I F,I IMM W,F F Gamithromycin I 6.1% Tildipirosin I Tilmicosin O O,I F,I,W F,I F,W W Tylvalosin W

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Amoxicillin IMM Ampicillin O,W,I O,I I 9.0% Penicillins Cloxacillin IMM Hetacillin IMM Penicillin G I I IMM W Sulfadimethoxine O,W,I I W W Sulfadimethoxine/ F F Ormetoprim Sulfamethazine W,F W,F,O W W 4.2% Sulfonamides Sulfachlorpyridazine W,O W,O,I Sulfaethoxypyridazine W W,O,I W W Sulfaquinoxaline W F,W F,W W,F,O W,F,O F W,F W,F 70.8% Tetracyclines Oxytetracycline W,I,F W,I,F,O I W,F W,F W,F Tetracycline W W W W Not Individually Florfenicol W,F I Reported = 3.9% Virginiamycin F F F F

Antimicrobials not categorized as medically important as defined in Guidance 152 Appendix A Beef % of antibiotic Cattle, sales for food Non- animals in U.S. Lactating Lactating for this category Dairy Dairy in 2013 Class Drug Swine Cattle Cattle Goats Sheep Chickens Turkeys Monensin F F F Lasalocid F F F F 79.3% Polyether Ionophores Laidlomycin F Salinomycin F Narasin F F F Aminocoumarins Novobiocin IMM 20.7% Glycolipids Bambermycins F F F

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Bacitracin zinc F F F F Polypeptides Bacitracin Methylene F F F F Disalicylate W,F Quinoxaline derivatives Carbadox F

F Feed IMM Intramammary I Injectable IU Intrauterine M Milk O Oral S Solid dose implant T Topical V Intravaginal W Water

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Table 3 from the same report illustrates the high proportion of medically important antibiotics administered to food animals through the feed (72% of medically important antibiotics administered to food animals) and water (23%) (excerpted as Table 4 from the FDA/CVM report.(23) These values are based on reported percent of total weight of active ingredient and do not reflect potency of the products. At the writing of this report the 2017 sales data have not yet been released; it is expected that feed antibiotic administration in food animals will decrease in the 2017 data due to the new product labels with Veterinary Feed Directive (VFD) requirements for use which became effective January 1, 2018.

Table 2: Table 3b from FDA/CVM report on 2016 sales of antibiotics labeled for food animals.

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Table 3: Table 4 from FDA/CVM report on 2016 sales of antibiotics labeled for food animals.

The special case of the ionophores In the United States, the ionophores are considered to be antibiotics. This is because they meet the definition of an antibiotic, which is a substance produced by one organism which impedes the growth of, or kills another organism. In Europe, the ionophores are classified as “anticoccidials” rather than antibiotics, allowing their use in antibiotic-free systems. Because coccidiosis is one of the most common diseases of poultry, this difference in classification of ionophores makes it more difficult for U.S. RWA/NAE poultry systems to keep birds healthy, as compared to European RWA/NAE systems. It is important to recognize that ionophores are considered to be non-medically important because they are not used in human medicine. There is no credible evidence that use of ionophores in any food animal species is selecting for resistance to medically-important antibiotics for human or animal therapy. There are multiple ionophores available for use in poultry feed in the United States. Rotation of ionophores in an attempt to minimize selection for resistant coccidia is a common practice in the industry, and is practiced at SFI. This list includes commentary on use in SFI production,

23 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018 demonstrating the clinical reasoning that goes into positioning these products for maximum effect.

• Salinomycin (Sacox) • Narasin (Monteban) – Trials have demonstrated narasin is more effective in control than salinomycin. Narasin also has an effect on clostridial bacterial species. It has less impact on feed intake compared to others, so works well in the summer when feed intakes are depressed due to heat. • Monensin (Coban) – Monensin is used more in the winter due to an observed decrease in feed intake. It can also decrease production in breeding flocks. • Narasin (an ionophore) + Nicarbazin (a chemical anticoccidial, see below) (Maxiban) • Lasalocid (Avatec) – low efficacy and detrimental effect on feed conversion, so is not used. There are also multiple non-ionophore anticoccidial compounds available. These are synthetic compounds, not produced by the fermentation process of a biological organism. They are therefore often referred to as “chemical’ anticoccidials. Since they are not an antibiotic by definition, they are often used in antibiotic-free production systems. Of these, Nicarb and Maxiban are the most useful to SFI.

• Nicarbazin (Nicarb) – resistance development is viewed as less than others, but tolerance to heat can suffer • Zoalene (Zoamix) – This compound allows some coccidia to reproduce without causing disease, allowing development of immunity while controlling disease. • Decoquinate (Decox) – Resistance can be an issue • Diclazuril (Clinacox) • Narasin and Nicarbazin (Maxiban) – as above, an ionophore/chemical combination • Clopidol (Coyden) – Some trade restrictions associated with use of this product • Amprolium (Amprol) – Typically used in the water The anticoccidials may be used in different types of strategies, some of them using both an ionophore and a chemical product in different stages of production. Coccidial live vaccines also require careful consideration of health status and time of the year. The vaccines are viewed as marginally effective for vaccine control.

Reasons some antibiotics are not used in all or some food animals

The FDA Center for Veterinary Medicine maintains a list of antibiotics prohibited from extralabel use in food animals. If there is not a label for a food animal species, this prohibits any and all uses of a drug in that species. The list includes these antibiotics, as well as other drugs.(22) • Chloramphenicol • Dimetridazole, ipronidazole, and other nitroimidazoles

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• and nitrofurazone • drugs in lactating dairy cattle, except for the approved use of sulfadimethoxine, sulfabromomethazine, and sulfaethoxypyridazine • Fluoroquinolones • Glycopeptides • Cephalosporins (not including cephapirin) in cattle, swine, chickens, or turkeys o For disease prevention purposes o At unapproved doses, frequencies, durations, or routes of administration, or o If the drug is not approved for that species and production class. • The following drugs, or classes of drugs, that are approved for treating or preventing influenza A are prohibited from extra-label uses in chickens, turkeys, and ducks. o Adamantane o Neuraminidase inhibitors

Placement on this list may be due to concern about potential human health adverse effects if residues were to be present in the food chain due to use of a product without appropriate food safety evaluation which occurs during the approval process. Other reasons include specific cases such as chloramphenicol can cause aplastic anemia in humans, although the authors are not aware of any cases where this condition has occurred through food exposure. Both the nitroimidazoles and are considered to be carcinogenic or pre-carcinogenic. Glycopeptides are included due to their importance for therapy of Gram positive pathogens in humans (e.g., Enterococcus faecium) and a concern that use in food animals could select for resistant pathogens, or nonpathogens carrying transferable resistance genes, which could then spread to humans through the environment or food supply.

The fluoroquinolone class previously had two approvals in poultry, including sarafloxacin (SaraFlox, Abbott laboratories) and enrofloxacin (Baytril, Bayer Animal Health). Sarafloxacin had been approved for water soluble and injectable use in chickens and turkeys in 1995. Enrofloxacin was approved in 1996. In 2000, the FDA Center for Veterinary Medicine published a Notice of Opportunity for Hearing (NOOH) related to these approvals in the Federal Register. (15) The notice stated that the FDA CVM had determined that…

• The use of fluoroquinolones in poultry causes the development of fluoroquinolone- resistant Campylobacter, a pathogen to humans, in poultry; • This fluoroquinolone-resistant Campylobacter is transferred to humans and is a significant cause of the development of fluoroquinolone-resistant Campylobacter infections in humans; and • Fluoroquinolone-resistant Campylobacter infections are a hazard to human health.

The label for Sarafloxacin was immediately withdrawn by the sponsor. Bayer Animal Health completed the administrative hearing process, with the result being removal of the

25 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018 enrofloxacin poultry label in 2005.(17) As of the writing of this report, label indications for enrofloxacin in cattle and swine, and danofloxacin in cattle, remain. Any extralabel use of fluoroquinolones in the approved food animal species (cattle and swine), or any use in any other food animal species without a label, is prohibited.

In 2008, the FDA/CVM released a final rule to prohibit all extralabel uses of cephalosporins in food animals. After considering a large number of substantive comments, the original rule was rescinded and the final form of the rule was published in 2012.(19) In a press release, the FDA/CVM indicated that the reason for the prohibition was the substantial use of cephalosporins in human medicine and the desire to maintain the effectiveness of this use.(20) “FDA is taking this action to preserve the effectiveness of drugs for treating disease in humans. Prohibiting these uses is intended to reduce the risk of cephalosporin resistance in certain bacterial pathogens.

Cephalosporins are commonly used in humans to treat pneumonia as well as to treat skin and soft tissue infections. In addition, they are used in the treatment of pelvic inflammatory disease, diabetic foot infections, and urinary tract infections. If cephalosporins are not effective in treating these diseases, doctors may have to use drugs that are not as effective or that have greater side effects.

In its order, FDA is prohibiting what are called “extralabel” or unapproved uses of cephalosporins in cattle, swine, chickens and turkeys, the so-called major species of food-producing animals. Specifically, the prohibited uses include: • using cephalosporin drugs at unapproved dose levels, frequencies, durations, or routes of administration; • using cephalosporin drugs in cattle, swine, chickens or turkeys that are not approved for use in that species (e.g., cephalosporin drugs intended for humans or companion animals); • using cephalosporin drugs for disease prevention.

In 2008, FDA issued and then revoked an order that prohibited extralabel uses of cephalosporins in food-producing animals with no exceptions. Today’s announcement responds to public comment and includes the following exceptions, which protect public health while considering animal health needs: • The order does not limit the use of cephapirin, an older cephalosporin drug that is not believed by FDA to contribute significantly to antimicrobial resistance. • Veterinarians will still be able to use or prescribe cephalosporins for limited extra-label use in cattle, swine, chickens or turkeys as long as they follow the dose, frequency, duration, and route of administration that is on the label. • Veterinarians may also use or prescribe cephalosporins for extralabel uses in minor species of food-producing animals such as ducks or rabbits.

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‘We believe this is an imperative step in preserving the effectiveness of this class of important antimicrobials that takes into account the need to protect the health of both humans and animals," said Michael R. Taylor, Deputy Commissioner for Foods.’”

The third generation cephalosporin labeled for chickens is ceftiofur sodium, for which the label indicates control of early mortality, associated with E. coli organisms susceptible to ceftiofur, in day old chicks and turkey poults. It is to be administered by subcutaneous use only. The cephalosporin extralabel use prohibition made the extralabel injection of eggs with ceftiofur illegal.

The actions related to fluoroquinolones in poultry and the extralabel use of cephalosporins were both associated with controversy related to strength and interpretation of evidence. Nevertheless, these prohibitions are now in effect.

In addition to regulatory actions, some antibiotics are not used today because of supply chain concerns about using these medically important antibiotics in food animals. Examples are the macrolides (e.g., tylosin) which have been withdrawn from use in some poultry systems due to their classification as one of the most critically important antibiotic classes in humans, and also possibly due to an observed lack of effect against the label pathogens. When the macrolides are not used, and injection of day-old chicks with ceftiofur is not practiced, a poultry system uses none of the most critically important antimicrobial classes as defined by the world health organization. This does not mean that resistance to these most critically important antimicrobials cannot be selected for through co-selection of multidrug resistant organisms, but it does mean that primary selection is not present.

Antibiotic resistance vs. residues Confusion sometimes occurs regarding the concepts of “antibiotic resistance” and “antibiotic residues”. Antibiotic resistance is discussed elsewhere in this document, but in short, antibiotic resistance (related to clinical use) means that the antibiotic is unable to have the clinical effect which is desired. Residues, in contrast, are about detectable parent drug or metabolites being present in the edible tissues of the food animal. Not all residues present a food safety issue, and during the approval process an acceptable concentration of residues is determined. In the United States, this is referred to as a tolerance, and represents a concentration of the marker residue which indicates that the sum of all residues in the edible tissue is at or below a concentration which may be consumed every day by the average person for their lifetime with no toxic effects. What is the incidence of violative antibiotic residues in poultry? According to the FSIS FY 2017 Redbook, there was one violative residue (nitrofurazone, a prohibited drug in food animals) out of 738 young chickens tested.(10) In the FSIS FY 2016

27 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018

Redbook, 742 young chickens were tested with no violative residues. In FY 2015, 701 young chickens were sampled with no violative samples.(10) Over the last three reported fiscal years, 2181 young chickens were tested in FSIS laboratories with 1 violative residue, which was not due to legal use of a drug. Determination of withdrawal times to prevent unacceptable antibiotic residues The development of a tolerance, and a withdrawal time, involves the following steps during the drug approval process as described in Guidance for Industry (GFI) #3.(18) Multiple toxicology studies in different mammalian species to determine the No Observable Adverse Effect Level (NOEL). The NOEL is expressed in mg of total residues per kg of body weight of the consumer.

• The FDA Center for Veterinary Medicine will determine a safety factor based on their interpretation of the studies. The NOEL is divided by this safety factor (up to 1000) to arrive at the Acceptable Daily Intake (ADI) which is in mg/kg. • The Safe Concentration of the total residues in the 4 main edible tissues (muscle, kidney, liver, and fat) are determined by using standard consumption values for each of the tissues, the ADI, and the average weight of a human (60 kg is the regulatory average weight). o Safe concentration = 60 kg* ADI / weight of tissue consumed o When the animal in question also produces milk or eggs, the safe concentration is split between one of the 4 primary edible tissues and either milk (a dairy cow) or eggs (a layer). This has the effect of cutting the safe concentration in muscle, kidney, liver, and fat approximately in half. • The Tolerance is determined by selecting one of the residue products (it may be the parent compound or a metabolite) to be the marker residue. This is done by doing a study to determine what percentage of the total residues is made up of the marker residue, and then taking this percentage times the safe concentration. The process to this point was NOEL, ADI, Safe Concentration, and finally a Tolerance. The next step is to determine the slaughter withdrawal time (WT). The WT is determined by conducting a study where 5 animals are slaughtered at each of 4 timepoints after administration of the drug at the label regimen. At the timepoint where all 5 animals have all of the 4 primary edible tissues (muscle, liver, kidney, and fat) below the tolerance, the variation in the concentration of the target residue tissue (the tissue which held the residue the longest) is used to conduct a statistical test to determine the WT. Because the target tissue holds the residue the longest, if it is below the tolerance the entire carcass is considered below the tolerance. If milk or eggs are involved, there is a withdrawal time also determined for them. In the case of a laying hen, there is a slaughter withdrawal time for the hen and also for consumption of eggs. In the case of FDA approved drugs for laying hens, all egg withdrawal times are zero. Dairy cows have both a slaughter and milk withdrawal time for approved drugs.

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Evaluation of microbiological safety in more recent approvals of antibiotics for food animals. In 2003, a new process was added to the approval of an antibiotic for use in food animals. Guidance for Industry (GFI #152) added the requirement of a quantitative risk assessment that estimated the probability (low, medium, or high) of 3 linked occurrences.(16) 1. Release – the probability that resistant bacteria are present in the target animal as a consequence of drug use 2. Exposure – the probability for humans to ingest bacteria in question from the relevant food commodity 3. Consequence – the probability that human exposure to resistant bacteria results in an adverse health consequence These estimations are then used to determine a risk management approach consisting of the allowable duration of administration and the number of animals to which the drug may be administered at one time. The next major change in approval of medically important antibiotics for food animals came in 2012, when Guidance for Industry (GFI) 159 (21) was published. Until GFI #159 all withdrawal times were based solely on the toxicology method as described above. Guidance for Industry #159 requires evaluation of the potential for tissues consumed with the maximum allowable residue concentration (as determined by the tolerance) to have an effect on the intestinal bacterial populations (the microbiota) of humans. It is possible for the tolerance required to minimize this effect to be lower than the tolerance derived from toxicology studies, and therefore the microbiological tolerance would result in a longer withdrawal time. How this applies to the antibiotics currently used at SFI. All of the medically important antibiotics used at SFI were approved before the enactment of GFI documents #152 and #159, so they have not undergone either type of evaluation in the approval process. This does not mean that these drugs lead to a microbial safety risk for humans, but does point out that their withdrawal times are based on toxicology data only. How does meeting the withdrawal time relate to being antibiotic free? The withdrawal time is statistically estimated to assure that at the withdrawal time, no more than 1 in 1,000 animals would have a marker residue concentration in the target tissue which exceeds the tolerance as measured by the approved regulatory method. Adhering to the withdrawal time does not assure that there are no detectable residues still present in the carcass, nor that the carcass or characteristics of the carcass represent an antibiotic free production system. The American Association of Avian Pathologists (AAAP) in their statement on judicious use of antibiotics in poultry stated the following in response to the expressed question: (2) “Is the meat from animals treated with antibiotics safe to eat? “

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Yes, all animals treated with antibiotics have to be held for a specified number of days after treatment to ensure that the antibiotic is out of their system. This time period is determined by the FDA and is regularly monitored to ensure no harmful residues are in our food supply.” The second sentence is correct, addressing the issue of harmful residues rather than no residues. The first sentence correctly refers to a specified number of days, but the time period assures that the drug residues are below the tolerance, not completely out of the system. With the continued evolution of mass spectrometry technology, the claim of “no residues” is becoming more and more difficult to obtain. Many drugs have a long, low tissue concentration curve tail when measured at very low concentrations. For example, the tetracyclines have been shown to maintain substantial concentrations in bone due to calcium binding, which then slowly release into systemic circulation and maintain a very low but detectable presence for a substantial period of time. In one example of this, very substantial residues in bones of chickens were detected at slaughter 10 days after administration of oxytetracycline in the water.(31) The concentrations suggest persistence for a much longer period of time. Another study showed detectable concentrations of oxytetracycline and residues in muscle and feathers for 12 and 46 days, respectively, after administration of oxytetracycline in the water for 10 days.(11) The withdrawal time for the U.S. formulations of water soluble oxytetracycline are zero days. Oxytetracycline, a member of the tetracycline class, was used in 0.08% of the birds in SFI in 2017.

What are the highest risk uses of antibiotics, in terms of perpetuating resistance? A recurrent question in the discussion regarding the responsible use of antibiotics is: is administration of a non-medically important antibiotic, or less critically important antibiotic, for a short period of time less likely to perpetuate resistance than a longer course of a more medically important antibiotic? We simply do not know. Little research has addressed this subject, and the existing data lead to different interpretations. Short term antibiotic use is usually designed to kill or stop the growth of a few bacteria that an animal or human may be exposed to from a sick individual in close proximity, or during a time of stress. This is generally an approach intended to prevent or control disease. Longer term, and sometimes higher dose antibiotic therapy is used to treat individuals who are sick because of bacterial infection. This treatment is designed to kill or stop the growth of many bacteria making an animal or person sick, and to provide time for the patient’s immune system to develop a response to help kill or stop the growth of the bacteria. In this example, it is not necessary to kill all the bacteria, just enough to allow the patient to recover. Therefore, some bacteria may survive and may have become resistant, though not in numbers high enough to sicken the host.

30 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018

The relative impact of each scenario described above on antimicrobial resistance is not clear. An additional relevant factor is that short term therapy to prevent or control disease may be given to more individuals than long term therapy to treat disease. While it seems intuitive that long term antibiotic therapy is more likely to induce antibiotic resistance than short term therapy, if more individuals receive short term therapy, it may be that antibiotic resistance is disseminated more widely by that practice. In food animal medicine, a therapeutic regimen would involve a higher dose for a shorter period when administered to the individual animal or through the water. Doses administered through the feed to food animals for which there is a therapeutic claim include durations as short as “up to 5 days” for chlortetracycline labeled for treatment of bovine respiratory disease in cattle as compared to a duration of 7-14 days for chlortetracycline labeled for the treatment of enteric and respiratory disease in swine. In-feed control and prevention claims for food animals may include regimens with defined durations of administration or regimens with no defined duration with indications to “feed continuously”. Labels with no defined durations of administration are currently under scrutiny by the FDA Center for Veterinary Medicine. Therefore, the comparative question in food animals is the “short and high” treatment regimens compared to the “lower and longer” regimens for prevention and control. When characterizing one of these as having more or less impact on resistance selection, the conversation is incomplete when focusing only on the antibiotic regimen; the remaining consideration is that of the exposed bacterial population. Regardless of the consideration of the relative resistance selection pressure for these two approaches, the best way to avoid resistance selection is to avoid the use of the antibiotic in the first place. An example as it relates to human medicine: If an adult contracts meningococcal , he or she will be given IV , a third generation cephalosporin for one week if all goes well. Before the spinal fluid cultures returned the identity of the bacteria, the patient may have also received rifampin and, if it is tick season, . All people living in the same household as this patient would be given a single dose of 500 mg of ciprofloxacin by mouth. It may be assumed that treatment of the patient with a one week course of ceftriaxone, and possibly rifampin and doxycycline, would be more likely to generate harmful antibiotic resistance. However, depending on multiple factors, treatment of the entire household with a single dose of ciprofloxacin may in fact lead to more antibiotic resistance. This is an area where more research is needed to provide accurate answers to guide the most responsible use of antibiotics. What are most serious resistant bacteria and where do they come from?

31 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018

In 2013 the Centers for Disease Control released a report that included 18 of the most serious antibiotic resistant bacteria in the U.S. They categorized them into three categories of Urgent, Serious and Concerning. Of these resistant bacteria, there are 2 which are of primary concern to this report due to their association with chickens; these are Campylobacter and Salmonella. The report is summarized here; the full report can be seen at http://www.cdc.gov/drugresistance/biggest_threats.html.

URGENT:

Carbapenem-Resistant Enterococcus (CRE): Almost always hospital acquired after an invasive procedure, these bacteria are usually resistant all antibiotics and half of infected hospitalized patients die.

Clostridium difficile (C Diff): This is an intestinal infection brought about by an overgrowth of the bacteria Clostridium difficile (C. diff), which is most commonly induced in people given high- dose, broad spectrum antibiotics in a hospital setting to treat another serious infection. Antibiotics are of little use to treat C. diff.

Neisseria : This is an infection of the reproductive system brought about most commonly by sexual intercourse. It used to be highly susceptible to penicillin but is becoming more difficult to treat due to antibiotic resistance.

SERIOUS:

Fluconazole-Resistant Candida: This is a yeast infection, usually seen in hospitalized patients on high dose, broad spectrum antibiotics. We all harbor asymptomatic Candida on our skin, but when the normal bacterial flora are killed by antibiotic therapy, a Candida infection may follow. This is the fourth most common hospital acquired infection.

Multidrug-Resistant Acinetobacter: This is perhaps the most rapidly increasing nosocomial (hospital acquired) infection in the U.S. It is found naturally in soil, but it has now worked its way into health care facilities and can cause pneumonia, meningitis, urinary tract infections and sepsis.

Vancomycin-Resistant Enterococcus (VRE): This is almost always a health care facility acquired infection after an invasive procedure. can only be administered intravenously, and usually under the direction of an infectious disease specialist, so the usual mantra of inappropriate use, and stopping antibiotics too early does not apply. In Europe, the use of another glycopeptide (avoparcin) as a growth promoter in food animals was linked to an increase in glycopeptide resistant enterococci in the feces of food animals (VRE). While there was also a significant component of VRE in humans in the E.U., the removal of avoparcin as a growth promotant did not reduce the VRE incidence in people. There is also a significant presence of VRE in people in the U.S.; however, no glycopeptide has ever been used in food animals in the U.S.

32 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018

Multidrug-Resistant aeruginosa: Another of the bacteria most commonly associated with invasive procedures in a health care facility. Pseudomonas is not considered a foodborne pathogen.

Methicillin-Resistant Staphylococcus aureus (MRSA): Bacteria in the genus Staphylococcus (“Staph”) were found to be resistant to just one year after this antibiotic was introduced to human medicine in the 1950s. These bacteria are resistant to many other antibiotics that also fall into the beta-lactam class. MRSA infection used to be limited almost entirely to hospital settings, but as sicker patients are now being treated as outpatients there is a growing community-acquired MRSA presence. The CDC, along with the nation’s hospitals, is leading a successful effort in decreasing the rate of MRSA infections. MRSA have been isolated from swine in the United States and veterinarians and workers associated with the swine industry have been associated with nasal carriage of MRSA. However, the predominant type associated with swine (ST398) is only very rarely associated with human disease and is not the strain causing human disease in hospitals or the community.

Drug-Resistant pneumoniae: Sometimes referred to as Pneumococcus, these bacteria are the number one cause of pneumonia and meningitis in the U.S. Penicillin used to bring almost immediate relief to the accompanying fever and pleurisy, but this treatment is no longer reliably effective. This is generally a community-acquired infection, meaning that people are usually infected in their home or community, and not because they have visited a health care facility.

Extended Spectrum B-Lactamase Producing Enterobacteriaceae (ESBLE): Extended-Spectrum Beta-Lactamase (ESBL) is an enzyme that allows bacteria to develop resistance to many broad- spectrum penicillins and cephalosporins. These ESBL containing Enterobacteriaceae are resistant to many strong antibiotics and are becoming more difficult to treat. Again, the great majority of infections with ESBLE are health care facility acquired.

Drug-Resistant : Worldwide, tuberculosis is one of the most common infections and is spread through the air. Antibiotic resistant bacteria that cause tuberculosis have developed mostly because of incomplete or wrong treatment, cost, lack of available drugs and lack of development of new treatment modalities. Most drug-resistant tuberculosis patients in the U.S. were born in other countries and migrated here.

Drug-Resistant Salmonella Serotype Typhi: These bacteria can cause typhoid fever, an often fatal infection. It is most common in developing countries with unsanitary drinking water conditions.

Drug-Resistant non-Typhoidal Salmonella: The most common source of this infection is food contaminated by fecal material, including but not limited to, green leafy vegetables, meat and poultry. It causes , sometimes bloody, and can get into the blood stream and cause long term arthritis, among other illnesses.

33 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018

The risk of multi-drug resistant Salmonella (MDR Salmonella) is sometimes exaggerated. The National Antibiotic Resistance Monitoring System (NARMS) run by the FDA, USDA and CDC have noted an increase in MDR Salmonella in human samples (from 9% to 12% in their latest report), but that report also clearly states that the MDR Salmonella remain overwhelmingly sensitive to the antibiotics most commonly used as front-line drugs to treat Salmonellosis. The report says the four antibiotics to which Salmonella is most commonly resistant are tetracycline, streptomycin, sulfisoxazole and ampicillin; these four antibiotics are not used to treat Salmonella infections in people. Multi-drug resistance does not necessarily mean that bacteria will cause more serious disease than non-resistant bacteria. The most recent NARMS report showed that 76% of human isolates of Salmonella showed no resistance to any antibiotics. The report can be seen in its entirety at: http://www.fda.gov.AnimalVeterinary/NewsEvents/CVMUpdates/ucm58143.htm

Drug-Resistant Shigella: This is another infection that causes diarrhea and can cause reactive arthritis. It is most commonly found in the very young and elderly, and in men who have sex with other men.

Drug-Resistant Campylobacter: Campylobacter is the number one cause of foodborne illnesses in the U.S. manifested by diarrhea, sometimes bloody, and occasionally temporary paralysis. This pathogen is associated with chickens and their food products.

CONCERNING:

Vancomycin Resistant Staphylococcus aureus (VRSA): Staphylococcal aureus resides on our skin and in our noses. When a patient has an invasive surgical procedure, or requires a ventilator or urinary catheter, the Staph on their skin or in their noses can spread to other body systems and cause disease. If Staph infecting a patient become resistant to vancomycin there are few other treatment options available, as the Staph will most likely also be resistant to methicillin and other broad-spectrum antibiotics.

Erythromycin-Resistant Group A Streptococci: Group A Streptococcus sp. (“Strep”) cause strep throat, rheumatic fever, toxic shock syndrome and necrotizing fasciitis (sometimes referred to as “flesh eating bacteria”). Group A Strep remain fairly sensitive to penicillin in most cases, but for those allergic to penicillin, erythromycin would likely be the antibiotic of choice for strep throat. Increasing resistance to erythromycin means there are fewer safe options for treating strep throat in people who are allergic to penicillin.

Clindamycin-Resistant Group B Streptococci: Group B Strep can cause serious infections in all age groups. Again, if one is allergic to penicillin, clindamycin may be the drug of choice for treating illnesses such as meningitis, sepsis and pneumonia.

Are Antibiotics used in Human Medicine to Prevent and/or Control Bacterial Infections?

34 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018

The simple answer is yes. The use of antibiotics to prevent and/or control bacterial infections in herds and flocks of livestock is sometimes cited as a leading cause of dissemination of antibiotic resistance. However, it is important to remember that antibiotics are also used to prevent and/or control infection in people, and this use also contributes to the dissemination of antibiotic resistance. Therefore, attention to antibiotic stewardship is necessary in both animals and humans at risk of bacterial infection.

A few examples of the common use of antibiotics to prevent and/or control bacterial infection in humans follow:

1. If a resident in a college dormitory is diagnosed with meningococcal meningitis, all residents of that dorm will be offered a short, low dose course of antibiotic therapy to control the disease, as would individuals living in the same house as a patient not living in a dormitory. 2. If a person is exposed to someone just diagnosed with active tuberculosis, that person will be offered a low dose, short term of therapy to control the disease. 3. If a pregnant woman in labor suffers from prolonged ruptured membranes and subsequently develops a fever, she will likely, depending on stage of labor, undergo a Caesarian section for emergent delivery. Before the skin incision is made, she will likely have an IV, broad spectrum, antibiotic given in case the fetus has been exposed to a bacterial infection from the vagina of the mother. 4. Some surgeons always administer an IV antibiotic one hour prior to making a skin incision to prevent infection; almost all orthopedic surgeons do this if they are replacing a joint. 5. If a dental patient has an artificial heart valve or a valve defect, they will be asked to take oral antibiotics for 24 hours prior to a dental visit that involves teeth cleaning, and to continue for up to 3 days afterwards, to prevent bacteria released from the gums into the blood stream from lodging on the valve and creating long term problems. 6. Some women prone to repeat bladder infections will be offered a once a day, low dose and low spectrum, antibiotic long term to prevent these infections. 7. If a traveler is going to a country where is an ongoing problem, they will be offered therapeutic doses of doxycycline to prevent infection. 8. If a child is bitten by an animal, such as a dog, antibiotic treatment will be recommended to prevent infection. 9. If an older person with chronic obstructive pulmonary disease (COPD), or emphysema, develops symptoms of a viral respiratory infection (i.e. a cold), they may be offered an antibiotic to prevent an infection from overgrowth of bacteria during the viral infection.

The precautionary principle

Multiple definitions have been published for a concept referred to as the precautionary principle (PP). Originally the PP was discussed in terms of environmental issues but is more recently being applied to concerns of public health. Combining points from three published international declarations or communications on PP results in a definition of “when human

35 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018 activities may lead to unacceptable harm* that is scientifically plausible but uncertain, actions shall be taken to avoid or diminish that harm.” However, in the case of antibiotic use in food producing animals, the PP is often simplified to justify the elimination of entire categories of use such as growth promotion, control and/or prevention.

SFI is reviewing antimicrobial use in light of a shareholder proposal to adopt a policy to phase out the use of medically important antibiotics for disease prevention. When applying the PP, as opposed to using evidence based medicine or risk-analysis, one of the pivotal elements becomes the phrase “scientifically plausible but uncertain”. It is reasonable to consider the application of the PP under various circumstances. One extreme would be the situation where there is, in fact, little or no scientific research or information. A very different circumstance occurs when the scientific information amassed by completed and ongoing research renders that which has been considered scientifically plausible less likely.

The Danish Integrated Antimicrobial Resistance Monitoring and Research Programme, DANMAP was initiated more than 20 years ago to monitor the use of antimicrobial agents in humans and animals. This resulted in discontinued use of several antibiotics used for growth promotion from 1994-1999 and, more recently, voluntary bans of the use of cephalosporins in swine and cattle, and regulatory legislation regarding therapeutic use. The lack of scientific data on the effects of antibiotic use in animals on antibiotic resistance and public health suggests that the implementation of DANMAP is an example of the application of the PP. Antibiotic use data from Denmark during a period from 1994 to 2016 demonstrates a reduction to zero by 1999 of antibiotic growth promoters and a near doubling of prescribed veterinary antibiotics. The list of antibiotics which are considered important or critically important for use in human medicine is very extensive. As reviewed in this document, these antibiotics are used with varying frequency in human medicine. One possible unintended consequence of the implementation of a program like DANMAP is a change is use patterns which reflects an increase in use of medically important antibiotics which are used more frequently in human medicine

Antibiotic usage in the operations of SFI is reviewed elsewhere in this document but the implementation of the FDA Guidance Document 209 and 213 and the Veterinary Feed Directive on January 1, 2017, affected some of the antibiotic uses in SFI operations. Research on the effects of antibiotic use on antibiotic resistance in humans and animals, both internal and external to SFI, are ongoing.

*Unacceptable harm is considered to include threats to human life or health, effects which are serious and effectively irreversible, effects which are inequitable to current and future generations, or results which are imposed without adequate consideration for the human rights of those affected.

36 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018

References

1. AAAP. American Association of Avian Pathologists (AAAP) Antimicrobial Stewardship for Poultry. https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&ved=2ahUKEwjEuqjjuYDdAhU B54MKHXf6BZ8QFjAAegQIAhAC&url=https%3A%2F%2Fwww.aaap.info%2Fassets%2FPositions%2FAAAP %2520Antimicrobial%2520Stewardship.pdf&usg=AOvVaw32GiXKroW4q1dpTq9e2iZ9, 2018.

2. AAAP. Judicious Use of Antibiotics in Poultry Production. https://www.aaap.info/assets/Positions/AAAP%20antibiotics_2018.pdf, 2018.

3. Apley MD. Unique Considerations Pertaining to the Use of Drugs in Food Animals In: Riviere JE,Papich MG, eds. Veterinary Pharmacology & Therapeutics. 10th ed. Ames, IA: Iowa State Univesity Press, 2017;1358-1372.

4. AVMA. Antimicrobial Stewardship Definition and Core Principles. https://www.avma.org/KB/Policies/Pages/Antimicrobial-Stewardship-Definition-and-Core- Principles.aspx, 2018.

5. Baba, E., K. Sawano, T. Fukata, and A. Arakawa. Paratyphoid infection induced by Eimeria tenella in the broiler-type chickens. Avian Pathol. 16(1):31-42. 1987.

th 6. Barnes, H. J., J.-P. Valliancourt and W. B. Gross. Colibacillosis. Diseases of Poultry, 11 ed. Y. M. Saif, editor. Iowa State Press. 631-652. 2003.

7. Berrang, M.E., Ladely, S.R., Meinersmann, R.J., Fedorka-Cray, P.J., 2007. Subtherapeutic tylosin phosphate in broiler feed affects Campylobacter on carcasses during processing. Poultry Science 86, 1229-1233.

8. Boyer, A., Neth, J., Nunlist, M., 2017. Consumer chicken consumption survey results. Chicken Marketing Summit. Asheville, NC. 9. Centers for Disease Control and Prevention. https://www.cdc.gov/foodborneburden/2011- foodborne-estimates.html Accessed October 17, 2018.

10. United States Department of Agriculture/Data Collection and Reports/Residue Chemistry/Red Books. Accessed October, 2017 at https://www.fsis.usda.gov/wps/portal/fsis/topics/data-collection- and-reports/chemistry/red-books/red-book

11. Cornejo J, Pokrant E, Krogh M, et al. Determination of Oxytetracycline and 4-Epi-Oxytetracycline Residues in Feathers and Edible Tissues of Broiler Chickens Using Liquid Chromatography Coupled with Tandem Mass Spectrometry. J Food Prot 2017;80:619-625.

12. Corrier, D. E., J. A. Byrd, B. M. Hargis, M. E. Hume, R. H. Bailey and L. H. Stanker. Presence of Salmonella in the crop and ceca of broiler chickens before and after preslaughter feed withdrawal. Poult. Sci. 78:45-49. 1999.

13. Council for Agricultural Science and Technology (CAST). Task Force Report on Scientific, Ethical, and

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Economic Aspects of Farm Animal Welfare. Ames, Iowa. No. 143, April 2018.

14. Elwinger, K. C. C. Schnitez, F. Berndtson, O. Fossum, B. Teglof and B. Bagstrom. Factors affecting the incidence of necrotic enteritis, cecal carrage of Clostridium perfringens and bird performance in broiler chickens. Acta. Vet. Scand. 33:369-378. 1992.

15. FDA/CVM. Enrofloxacin for Poultry; Opportunity for Hearing. Federal Register, 2000;64954 - 64965.

16. FDA/CVM. Food and Drug Administration Center for Veterinary Medicine Guidance for Industry #152 Evaluating the Safety of Antimicrobial New Animal Drugs with Regard to Their Microbiological Effects on Bacteria of Human Health Concern. http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndus try/UCM052519.pdf, 2003.

17. FDA/CVM. Enrofloxacin for Poultry; Final Decision on Withdrawal of New Animal Drug Application Following Formal Evidentiary Public hearing: Availability. Federal Register, 2005;44105.

18. FDA/CVM. Food and Drug Administration Guidance for Industry #3: General Principles for Evaluating the Safety of Compounds Used in Food-Producing Animals. GFI #3. http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndus try/UCM052180.pdf, 2006.

19. FDA/CVM. New Animal Drugs; Cephalosporin Drugs; Extralabel Animal Drug Use; Order of Prohibition. Federal Register, 2012;735-745.

20. FDA/CVM. FDA to Protect important Class of Antimicrobial Drugs for Treating Human Illness, 2012.

21. FDA/CVM. Food and Drug Administration Center for Veterinary Medicine Guidance for Industry # 159 Studies to Evaluate the Safety of Residues of Veterinary Drugs in Human Food: General Approach to Establish a Microbiological ADI. https://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndu stry/UCM124674.pdf, 2012.

22. FDA/CVM. The ins and outs of extra-label drug use in animals: a resource for veterinarians. http://www.fda.gov/AnimalVeterinary/ResourcesforYou/ucm380135.htm#Drugs_Prohibited_from_Extr a-Label_Uses_in_Animals: Food and Drug Administration Center for Veterinary Medicine, 2015.

23. FDA/CVM. FDA Annual Summary Report on Antimicrobials Sold or Distributed in 2016 for Use in Food-Producing Animals https://www.fda.gov/downloads/ForIndustry/UserFees/AnimalDrugUserFeeActADUFA/UCM588085.pdf : Food and Drug Administration Center for Veterinary Medicine, 2017.

24. Gaucher ML, Quessy S, Letellier A, Arsenault J, Boulianne M. Impact of a drug free program on broiler chicken growth, performances, gut health, Clostridium perfringens, and Campylobacter jejuni occurrences at the farm level. Poultr Sci 94:1791-1801. 2015

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25. Hofacre, C. L., R. Froyman, B. George, M. A. Goodwin and J. Brown. Use of Aviguard, virginiamycin or bacitracin MD against Clostridium perfringens-associated necrotizing enteritidis. J. Appl. Poult. Sci. 7:412-418. 1998.

26. Hofacre, Charles L., John A. Smith, and Greg F. Mathis. An optimist’s view on limiting necrotic enteritis and maintaining broiler gut health and performance in today’s marketing, food safety, and regulatory climate. Poultry Sci. 97:1929-1933. 2018.

27. Hofacre, C.L., G.F. Mathis, S. H. Miller, and M.W. LaVorgna. Use of Bactracin and Roxarsone to reduce Salmonella Heidelberg shedding following a necrotic enteritis challenge model. J. Appl. Poult. Res. 16:275-279. 2007.

28. Hurd, H.S., Malladi, S., 2008. A stochastic assessment of the public health risks of the use of antibiotics in food animals. Risk Anal. 28, 695-710.

29. IDSA. Promoting Antimicrobial Stewardship in Human Medicine. http://www.idsociety.org/Stewardship_Policy/: Infectious Disease Society of America, 2017.

30. Karavolias J, Salois MJ, Baker KT, Watkins K. Raised without antibiotics: impact on animal welfare and implications for food policy. Transl Anim Sci. DOI 10.1093/tas/txy/016. 2018.

31. Odore R, De Marco M, Gasco L, et al. Cytotoxic effects of oxytetracycline residues in the bones of broiler chickens following therapeutic oral administration of a water formulation. Poult Sci 2015;94:1979-1985.

32. Russell, S. M. The effect of airsacculitis on bird weights, uniformity, fecal contamination, processing errors, and population of Campylobacter spp. and Escherichia coli. Poult. Sci.82:1326-1331. 2003.

33. Salois, M.J., Cady, R.A., Hesket, E.A., 2016. The Environmental and Economic Impact of Withdrawing Antibiotics from US Broiler Production. Journal of Food Distribution Research 47, 79-80. 34. Singer, R.S., Cox, L.A., Dickson, J.S., Hurd, H.S., Phillips, I., Miller, G.Y., 2007. Modeling the relationship between food animal health and human foodborne illness. Prev. Vet. Med. 79, 186-203.

35. Smith JA. Experiences with drug-free broiler production. Poultr Sci. 90:2670-2678. 2011

36. Volkova, V.V., R.W. Wills, S.A. Hubbard, D. Magee, J.A. Byrd, and R.H. Bailey. Associations between vaccinations against protozoal and viral infections and Salmonella in broiler flocks. Epidemiol. Infect. 139:206-216. 2011.

37. WHO. World Health Association List of Critically Iimportant Antimicrobials (WHO CIA List). Accessed 8-9-2018 at http://www.who.int/foodsafety/publications/antimicrobials-fifth/en/, 2017

39 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018

Appendix

Members of the Advisory Board

John R Glisson, DVM, MAM, PhD Advisory Board Chair Vice President of Research U.S. Poultry & Egg Association

Michael D. Apley, DVM, PhD, DACVCP Professor Kansas State University

Charles Hofacre, DVM, MAM, PhD President Southern Poultry Research Group

Richard Raymond, MD Food Safety/Public Health Consulting

M. Gatz Riddell Jr., DVM, MS Professor Emeritus Auburn University

Randall Singer, DVM, MPVM, PhD Professor University of Minnesota

Amelia R. Woolums, DVM, MVSc, PhD Professor Mississippi State University

40 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018

Randall Singer, DVM, PhD Professor of Epidemiology College of Veterinary Medicine University of Minnesota

Affiliations: Recipient of Global Engagement Award by the Global Programs and Strategy (GPS) Alliance

Education: PhD, University of California, Davis DVM, University of California, Davis MPVM, University of California, Davis BA, University of California, San Diego

“Research in my lab seeks to understand the factors that influence the emergence, evolution, spread and persistence of microbes within different ecosystems. We use this information to design strategies for reducing the negative impacts that these pathogens have on human and animal health. These studies emphasize epidemiologic methods, specifically the development and validation include...

Antibiotic Use and Resistance: For almost 20 years I have been studying antimicrobial resistance in bacteria. These studies have included analyses of spatial distributions of resistant microbes and resistance genes, mathematical models of resistance development and spread, quantitative risk assessments related to the use of specific antibiotics and the subsequent augmentation of resistance, molecular analyses of resistance genes and their spread, and public health analyses estimating the excess burden of illness caused by these resistant microbes.

Food Safety: I actively investigate the ecology of foodborne pathogens such as Salmonella and Campylobacter in agricultural environments. The goal of these projects is to develop interventions on the farm and in the processing plant that reduce the risk to humans of being exposed to these pathogens.

Ecology of Infectious Disease: In addition to studying the ecological factors affecting antimicrobial resistant pathogens and foodborne pathogens, I have studied other bacterial and viral pathogens. These studies have focused on the spread of these pathogens at the interface of humans, animals and the environment and on the assessment of interventions for minimizing the risk of transmission among these populations.”

Select references: “Urinary tract infections attributed to diverse ExPEC strains in food animals: evidence and data gaps.” Singer RS. Front Microbiol. 2015 Feb 4;6:28. doi: 10.3389/fmicb.2015.00028. eCollection 2015.

“Human health impacts of antibiotic use in agriculture: A push for improved causal inference.” Singer RS, Williams-Nguyen J. Curr Opin Microbiol. 2014 Jun;19:1-8. doi: 10.1016/j.mib.2014.05.014. Epub 2014 Jun 17.

41 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018

“Confusion over antibiotic resistance: ecological correlation is not evidence of causation.” Cox LA Jr, Singer RS. Foodborne Pathog Dis. 2012 Aug;9(8):776. doi: 10.1089/fpd.2012.1160. Epub 2012 May 21.

42 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018

Michael D. Apley, DVM, PhD, DACVCP Professor, Production Medicine / Clinical Pharmacology Frick Professorship College of Veterinary Medicine, Kansas State University

Education: DVM: Kansas State University PhD: Kansas State University Diplomate: American College of Veterinary Pharmacology

Teaching: Beef Production Medicine (4th year) Pharmacology (2nd year) Clinical Pharmacology (3rd year) Food Animal Medicine (3rd year)

Research: Food animal therapeutics Antimicrobial resistance Pharmacokinetics and pharmacodynamics of veterinary drugs

Clinical: Beef production medicine with an emphasis on feedlot production.

Selected references: “A literature review of antimicrobial resistance in Pathogens associated with bovine respiratory disease.” DeDonder KD, Apley MD. Anim Health Res Rev. 2015 Dec;16(2):125-34. doi: 10.1017/S146625231500016X. Epub 2015 Sep 16. Review.

“Use estimates of in-feed antimicrobials in swine production in the United States.” Apley MD, Bush EJ, Morrison RB, Singer RS, Snelson H. Foodborne Pathog Dis. 2012 Mar;9(3):272-9. doi: 10.1089/fpd.2011.0983. Epub 2012 Feb 10.

“Antimicrobial drug use in veterinary medicine.” Morley PS, Apley MD, Besser TE, Burney DP, Fedorka-Cray PJ, Papich MG, Traub-Dargatz JL, Weese JS; American College of Veterinary Internal Medicine. J Vet Intern Med. 2005 Jul-Aug;19(4):617-29. Review.

43 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018

Amelia Woolums

Amelia R. Woolums, DVM, MVSc, PhD, DACVIM, DACVM Department of Pathobiology and Population Medicine

College of Veterinary Medicine Mississippi State University Mississippi State, MS 39762 [email protected]

Education: DVM Purdue University, 1988 Internship: Agricultural Practices, Kansas State University, 1989 Residency: Large Animal Internal Medicine, Western College of Veterinary Medicine, University of Saskatchewan, 1991 MVSc: University of Saskatchewan, 1991 PhD: Comparative Pathology, UC Davis, 1998

Certifications: Diplomate, American College of Veterinary Internal Medicine, Specialty of Large Animal Internal Medicine Diplomate, American College of Veterinary Microbiologists

Clinical Interests: Infectious diseases of large animals, immunity and vaccination in large animals, respiratory diseases in large animals

Research Focus:

Bovine respiratory disease (BRD), viral respiratory pathogens of cattle, vaccination and immunity to prevent BRD

44 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018

Charles L. Hofacre, BS, MS, DVM, MAM, PhD

Affiliations: Professor Emeritus University of Georgia, College of Veterinary Medicine, Poultry Disease Research Center

Education: BS (cum laude), The Ohio State University, College of Agriculture, Department of Animal Science MS, The Ohio State University, College of Agriculture, Department of Poultry Science DVM, The Ohio State University, College of Veterinary Medicine MAM, The University of Georgia, College of Veterinary Medicine, Department of Avian Medicine PhD, The University of Georgia, College of Veterinary Medicine, Department of Medical Microbiology

Research Interests My area of interest is in clinical avian medicine. I primarily work with the avian medicine students and the poultry industry in Georgia and throughout the Southeastern United States.

I will do collaborative research with other researchers in our department or other institutions. Presently my area of research interest is in organisms that can cause food borne illness in people (salmonella, E.coli, Campylobacter). I want to help the poultry industry find practical ways to reduce these bugs on the final product.

Selected References: Hofacre, C.L., R.S. Singer and T.J. Johnson. Antimicrobial Therapy (Including Resistance). In: Diseases of Poultry, 13th Edition. John Wiley & Sons, Inc., Ames, IA. 2013.

Hofacre, Charles L., Jenny A. Fricke and Tom Inglis. Antimicrobial Drug Use in Poultry. In: Antimicrobial Therapy in Veterinary Medicine, Fifth Edition. John Wiley & Sons, Inc., Ames, IA. 2013.

Lu, Jingrang, Charles Hofacre, Fred Smith, Margie D. Lee. Effects of feed additives on the development on the ileal bacterial community of the broiler chicken. Animal: The International Journal of Animal Bioscience 2(5):669-676. 2008.

Vieira, Antonio R., Chuck L. Hofacre, John Smith, and Dana Cole. Human contacts and potential pathways of disease introduction on Georgia Poultry Farms. Avian Dis. 53:55-62. 2009.

Alali, Walid, Hofacre, Charles, Mathis, Greg, Faltys, Gary, Ricke, Steven, and Doyle, Michael. Effect of Non-pharmaceutical Compounds on Shedding and Colonization of Salmonella Heidelberg in Broilers. J. Appl. Poultry Research. Submitted March, 2012.

45 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018

Gatz Riddell, DVM, MS, DACT

Affiliations: Past President of the North American Veterinary Conference (NAVC) Executive Vice President of American Association of Bovine Practitioners (AABP) Past-President of the AABP (1995-1996) Parliamentarian of the AABP from 1999 to 2005 Past Chair of CPAC, AVMA’s Clinical Practitioner Advisory Committee, AVMA’s Council on Biologic and Therapeutic Agents (COBTA) (2005) FDA’s Veterinary Medical Advisory Committee (VMAC) – committee dissolved 9/24/2013

Education: Professor Emeritus – retired from teaching Large Animal Medicine and Surgery at Auburn University in 2005 DVM- Kansas State MS, Diplomate of American College of Theriogenologists- Auburn Univerisity

Dr. Riddell represented the American Association of Bovine Practitioners (AABP) on the AVMA Drug Advisory Committee and later served on and chaired AVMA’s Council on Biologic and Therapeutic Agents. He received the AABP Award of Excellence in 1999.

Gatz Riddell was raised on a homesteaded farm near Conway, KS. He received his D.V.M. degree from Kansas State University in 1977. Following an internship and residency at Auburn University from 1977 to 1981, he practiced in Tennessee until returning to Auburn University in 1984. He became a Diplomat of the American College of Theriogenologists in 1982 and received his MS from Auburn in 1984. Dr. Riddell represented the American Association of Bovine Practitioners (AABP) on the AVMA Drug Advisory Committee and later served on and chaired AVMA’s Council on Biologic and Therapeutic Agents. He received the AABP Award of Excellence in 1999. He retired from Auburn University in 2005 as Professor Emeritus and is currently the Executive Vice President of the American Association of Bovine Practitioners. He is immediate Past President of the North American Veterinary Conference (NAVC). He lives in Auburn, Alabama and is married to Kay Pelly Riddell and they have three children, Molly, Wes and Jonathan. Current hobbies since both travel baseball and club soccer have officially ended, are biking, reading and grilling.

46 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018

John R. Glisson Director for Research of the U.S. Poultry and Egg Association Harold E.Ford Foundation

Affiliations: Professor Emeritus University of Georgia, College of Veterinary Medicine, Poultry Disease Research Center

Education: DVM (1980), The University of Georgia MAM (1983), The University of Georgia PhD (1985), The University of Georgia

Dr Glisson will administer the Association's comprehensive research programme that encompasses all components of poultry and egg production and processing. He will work with the Foundation's Research Advisory Committee, receiving and evaluating research proposals and making recommendations to the board of directors for funding approval. Over $22 million has been invested in research funding over the last 20 years.

Among Dr Glisson's extensive experience, he recently retired as Head of the Department of Population Health at the University of Georgia, was Head of the Department of Avian Medicine, and was Associate Dean of Public Service and Outreach at the University of Georgia's College of Veterinary Medicine. He is a past president of the American Association of Avian Pathologists and has received numerous honors for his work. He received his BS in Biology from Valdosta State and his DVM, Master of Avian Medicine, and PhD in Medical Microbiology from the University of Georgia.

Selected References: Antibiotic Stewardship Updates by Species: Poultry - Dr. John Glisson, Vice President, Research Programs, U.S. Poultry & Egg Association, from the 2016 NIAA Antibiotic Symposium - Working Together For Better Solutions, November 1 - 3, 2016, Herndon, Virginia, USA. https://www.youtube.com/watch?v=gG2HZ0dATbA

Glisson, John R. and Charles L. Hofacre. The future of veterinary medicine in poultry production. JVME. 33(4):492-495. 2006.

47 Advisory Board Assessment of Antibiotic Use at Sanderson Farms, Inc. November 2018

Richard Raymond

Affiliations: Dr. Richard Raymond is the former undersecretary of agriculture for food safety.

Education: Dr. Raymond received his Doctor of Medicine from the University of Nebraska College of Medicine in 1972.

Dr. Richard Raymond is the former undersecretary of agriculture for food safety. In that role at USDA from 2005 to 2008, he was responsible for setting food safety policy related to the meat industry. At a time of climbing rates of E coli 0157:H7 in ground beef testing and Salmonella in poultry testing, coinciding with increased numbers of beef recalls associated with human illnesses, Dr. Raymond worked to focus USDA inspection activities on vulnerable points in the food safety system and to implement a more risk-based inspection system.

Dr. Raymond is currently an affiliate professor at Colorado State University and an industry consultant and public speaker on food safety and public health issues. He is a member of the Board of Trustees of the International Life Sciences Institute NA. He is an editor for two food safety blogs, Meatingplace.com and Feedstuffs Foodlink.

Prior to joining USDA, Dr. Raymond was the chief medical officer for the state of Nebraska. Before that, he established and directed a family medical practice residency at Clarkson Hospital in Omaha, Neb. after 17 years as a rural family physician in the O’Neill, Neb. area.

He was elected by his peers to the presidency of the Nebraska Medical Association in 1988 and the presidency of the Association of State and Territorial Health Officials in 2004.

From Wikipedia: “In December 2006, he disputed a report by Consumer Reports in which 83% of chickens they tested were infected with campylobacter and/or salmonella bacteria, noting that the sample of 500 chickens tested was "very small." In February 2007, Richard Raymond ordered stepped-up inspections at some meat and poultry plants where the threat of E. coli is high or past visits found unsafe practices.”

Selected References: “Superbugs and Other Nonsense”, BY DR. RICHARD RAYMOND | DECEMBER 23, 2013 Food Safety News

“Advances in Animal Agriculture Help to Feed the World”, BY DR. RICHARD RAYMOND | OCTOBER 28, 2013 Food Safety News

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