While there is a general consensus that antibiotics are critical tools in human medicine, you don’t have to take the discussion much further before encountering disagreements. Questions regarding antibiotic use in animals, the ways they are used in humans and the causative factors in the emergence of antibiotic resistance in pathogens quickly find disagreement among various stakeholder groups.
However, a movement toward dialogue and cooperation could replace the “fortress” mentality and potentially lead to science-based policies that protect human health and animal health in the long term.
In November 2013, the National Institute for Animal Agriculture (NIAA) hosted a conference in Kansas City titled “Bridging the Gap between Animal Health and Human Health,” involving representatives from the human medical community, veterinary medicine, industry and consumer-advocacy groups.
Richard Raymond, MD, former undersecretary for food safety with the USDA’s Food Safety and Inspection Service, moderated the discussions. He led off by noting common but misleading statements from each side of the issue. Critics of agriculture regularly state that livestock account for 80 percent of all antibiotic use in the United States, a figure Raymond said is misleading and untrue. Supporters of animal agriculture, on the other hand, use the argument that all use of antibiotics in livestock is under the control and direction of veterinarians, which also is misleading and untrue. Raymond said we need to move the discussion away from polarized positions and misinformation, toward more honest, open dialogue.
The human-medicine perspective
The conference kicked off from the perspective of the human medical community, with presentations on antimicrobial resistance from physicians and scientists from the U.S. Centers for Disease Control and Prevention (CDC), state health departments and academia. These helped set the stage for the rest of the conference by providing background on the history and current state of antimicrobial resistance.
Steven Solomon, MD, director of the office of antibiotic resistance at the CDC, said the centers recently released the first scientific report of the incidence of antibiotic-resistant diseases in the United States, estimating a minimum of more than 2 million illnesses and 23,000 deaths annually due to resistant pathogens. Solomon said antibiotic resistance could be the most complex problem in public health, due to the interactions between pathogens, humans, animals and drugs.
Development of antibiotic resistance is a naturally occurring phenomenon, he said, even in the absence of human use of antibiotics. However, all use of antibiotics contributes to the emergence of resistance in some way. Humans can slow the process by preventing infection, tracking resistance, improving antibiotic stewardship and developing new drugs, Solomon said. The development pipeline for new antibiotics has slowed though, increasing the importance of the first three strategies.
Solomon noted that up to 50 percent of antibiotic use in hospitals is unnecessary or inappropriate. The CDC and other agencies are working to educate physicians and patients, develop benchmarking systems for hospitals and improve prescription policies for better antibiotic stewardship.
Another CDC physician, Dr. Robert Tauxe, who serves as deputy director for the Division of Foodborne, Waterborne and Environmental Infections, encouraged a one-health approach toward the issue of antibiotic resistance, involving human, animal and environmental health. He said antibiotic treatments have been critical in human and veterinary medicine since the 1940s, and resistance has been a challenge nearly as long. The CDC has tracked antibiotic resistance since the 1970s and in 1996 initiated the National Antimicrobial Resistance Monitoring System, tracking resistant pathogens in humans, animals and food in cooperation with the USDA and FDA.
Since the 1980s, Tauxe said, outbreaks of resistant pathogens have been linked to livestock. In some cases, resistant bacteria transmitted through the food chain or from contact with animals cause an increase in disease and mortality among humans. Other “silent infections” occur when a patient taking an antibiotic for one reason is exposed to other pathogens resistant to that antibiotic.
Tauxe offered several examples of resistance linked to antibiotic use in livestock, such as resistant strains of Campylobacter jejuni appearing soon after poultry producers began using the antibiotic ciprofloxacin.
In another example, poultry producers in Quebec voluntarily stopped injecting eggs with ceftiofur when resistant strains of Salmonella Heidelberg became prevalent on poultry meat. After they stopped using the product, the incidence of resistant pathogens dropped significantly.
In human medicine, Tauxe said, it has been routine to treat all cases of shigella with ciprofloxacin and to use the drug in prophylaxis to prevent the disease among family membersor classmates of infected children. Recently, physicians emphasized sanitation instead of antibiotic use for prevention of shigella infections and limited prescriptions to severe cases, and the incidence of resistantpathogens has declined. Antibiotic resistance presents a substantial challenge, Tauxe said, but it is possible to reverse the trend in many cases if physicians and veterinarians engage in efforts to assure judicious use.
Terry Dwelle, MD, state health officer of North Dakota, acknowledged that using antibiotics in livestock production can add to the risk of the emergence of resistantpathogens but also said society must balance the risk of using antibiotics in animal agriculture with the need for food. Dwelle voluntarily practices medicine in Sub-Saharan Africa and has seen first-hand the effects of malnutrition. Malnutrition magnifies the effects of infectious diseases, particularly in children, and plays a role in half of the 10.9 million childhood deaths from infectious disease each year. Production of animal protein is important in battling global malnutrition, he said.
Dwelle said from 30 to 60 percent of antibiotic prescriptions in human medicine are inappropriate, including improper dosing and use of broad-spectrum antibioticsas first-line treatments. Studies also have shown a high rate of antibiotics prescribed for colds and other viral sicknesses, largely due to patients pressuring their physicians to prescribe something when they feel sick. Studies have shown 32 percent of patients believe taking an antibiotic during a cold prevents more serious illness and 48 percent expect to take antibiotics for a cold.
Animal applications also play a role, Dwelle said, and where a direct link is found, discontinuing specific animal applications for specific antibiotics can reverse the trend toward resistant pathogens.
Dwelle offered the following suggestions for minimizing the risk of antibiotic-resistant pathogens in livestock production:
• Use antibiotics only when indicated.
• Use the least broad-spectrum products first.
• Use them for the least time possible.
• Use adequate therapeutic doses.
• Use antibiotics not important to human medicine whenever possible.
• When using “crossover drugs,” manage them for the least impact on human health.
• Appropriately monitor cultures and sensitivities to detect signs of resistance.
Dwelle finished by saying he is personally interested in participating in a collaborative effort involving physicians, veterinarians and public-health experts to address the issue.
The veterinary perspective
Later in the conference, Mike Apley, DVM, PhD, a professor at Kansas State University, discussed the current state of antibiotic use and resistance in animal agriculture, and the importance of a true commitment to judicious use.
Apley acknowledged that antibiotic use in food animals can change bacteria susceptibility profiles, leading to resistant pathogens that can be transferred through the food chain or through contact with animals. Documented cases of antibiotic resistance in pathogens affecting humans, linked to animal agriculture, and cases of reduced effectiveness of antibiotics for treatment of animal disease, such as bovine respiratory disease from Manheimia haemolytica, necessitate a close look at current practices.
Ionophores, which have no application in human medicine, account for about 29 percent of the total volume of antimicrobials used in animal agriculture, Apley said. Tetracyclines account for about 42 percent of the total and about 64 percent of the medically important antibiotics used in animal agriculture. Most of that use in livestock is for treatment of disease, with smaller percentages for disease prevention or for production purposes. Apley said veterinarians and the industry need to continuously evaluate whether particular uses of specific products are effective and necessary, and if not, reconsider those uses.
Apley outlined guidelines for judicious use, including:
• Use an antimicrobial product when there is not an effective alternative for the treatment or prevention of disease.
• Choose the antibiotic based on evidence it will be safe and effective for that use.
• Maintain a commitment to administer antibiotics according to a regimen demonstrated to be safe and effective. Apley noted, however, that researchbased evidence for optimum dosing and duration of treatment, with regard to development of antibiotic resistance, is lacking.
• Continuously search for alternative management practices that reduce the need for antibiotics.
Control of antibiotic use in food animals should be in the hands of veterinarians, within the context of a valid veterinarian-clientpatient relationship, Apley said.nEducation on judicious use and antibiotic resistance should begin in veterinary schools and continue through post-graduate training. The veterinary community and producer organizations should not tolerate inappropriate activities that place public health at risk, he said, adding that responsible involvement of veterinarians can help them retain access to the tools they need while protecting their role in the animalhealth decision process.
FDA guidance on the issue
FDA initiated its judicious-use effort in 2010, by issuing Draft Guidance 209, which was finalized in 2012. In December 2013, the agency finalized Guidance 213, which provides details on the implementation of Guidance 209. During the conference, FDA veterinarian Craig Lewis, DVM, MPH, DAVCPM, described some of the changes veterinarians can expect to see.
Under the Guidance 213, companies will voluntarily remove production claims such as for growth promotion or feed efficiency. Companies will have the option to pursue therapeutic “prevention” label claims for products currently fed for performance purposes. Under another proposed rule, a range of drugs currently available over the counter would fall under the veterinary feed directive (VFD) if used in feed or water. These include aminoglycosides, lincosamides, macrolides, penicillins, streptogramins, sulfonamides and tetracyclines.
Lewis explained that in drafting Guidance 213, FDA determined antibiotics delivered in feed and water offered the greatest potential for an overall reduction in antibiotic use. Also, while “production” applications impact producer returns, they do not affect animal health and well-being to the extent of products used for control and treatment of disease.
Lewis said within three years of finalizing Guidance 213, FDA expects drug manufacturers to specify their intended changes to labels of affected drugs. Also, FDA has issued its proposal for streamlining the VFD process and bringing affected drugs under the VFD. That proposal will be subject to a public comment period, but FDA hopes to move toward finalization and implementation within thesame three-year timeframe as for implementation of Guidance 213.
For some stakeholders, the FDA efforts do not go far enough. Susan Vaughn Grooters, a foodsafety research and policy associate at the Center for Science in the Public Interest (CSPI), represented consumer interests at the conference. CSPI, she said, aims to focus on prevention rather than reacting to outbreaks CSPI believes FDA Guidance 209 and Guidance 213 represent a first step but fall somewhat short. FDA is asking drug manufacturers to voluntarily remove growth-promotion claims from their labels and does not outline how the agency will monitor effectiveness of the changes. Vaughn Grooters also expressed concern that companies could pursue prevention claims to replace growth promotion, and she said the FDA does not sufficiently define prevention uses.
CSPI has collected data on foodborne illness and currently has information on over 7,000 outbreaks that occurred between 1990 and 2011, Vaughn Grooters said. She cited a CSPI review of studies on 55 outbreaks from 1973 through 2011 that found increasing frequency of outbreaks associated with antibiotic-resistant pathogens over time. CSPI published a white paper on the review, which is available on the group’s website at cspinet.org. Food items most likely associated with antibiotic-resistant pathogens included dairy products, ground beef and poultry. These three food categories were implicated in more than half of reported outbreaks. Salmonella was the most common cause of antibiotic-resistant outbreaks identified, accounting for 48 of the 55 outbreaks. Pathogens exhibiting multi-drug resistance to five or more antibiotics were identified in 56 percent of the outbreaks. CSPI petitioned USDA in 2011 to declare four serotypes of Salmonella as adulterants in food.
Consumers do not understand why animals can receive antibiotics without a prescription or for prevention of disease, in contrast with human medicine, Vaughn Grooters said. Others in the conference pointed out that antibiotics are used for prevention in human medicine, such as when a highly virulent bacterial disease appears in a daycare facility or school classroom.
Vaughn Grooters said antibiotic-resistant illnesses account for $16 billion to $26 billion in U.S. annual healthcare costs, and consumers are increasingly concerned about the declining efficacy of antibiotics. They attribute some of that loss to over-use of the products in livestock production and want alternatives. CSPI, she said, favors adoption of policy similar to that in the European Union, discontinuing the sub-therapeutic use of antibiotics for production purposes and removing important human drugs from veterinary medicine altogether. She acknowledged, though, that veterinarians and producers should have access to antibiotics for treatment of disease, and thus, for animal welfare.
Ease of misunderstanding
Several presenters noted that, for consumers, emotions rather than science shape attitudes on food safety and antibiotic resistance. Science alone will not “bridge the gap” on this issue. But even scientists with the technical background to conduct and evaluate research into the causes of antibiotic resistance struggle with inconsistent methods and measurements and conflicting results.
Discussions throughout the conference illustrated the complexity of the issue. Guy Loneragan, DVM, a veterinary epidemiologist and professor of food safety and public health from Texas Tech University, and Morgan Scott, DVM, PhD, a Kansas State University E.J. Frick professor of epidemiology, provided an interesting point-counterpoint discussion focusing on several key scientific papers regarding cause and effect in antibiotic resistance. For each case, one of the scientists argued in favor of the research methodology and conclusions while the other played “devil’s advocate,” pointing out flaws or weaknesses in the research.
Loneragan and Scott addressed several reports that have influenced scientific discussions of antibiotic resistance and the role of animal agriculture in recent years. One was the Quebec case mentioned earlier, where poultry producers were using in ovo injections of ceftiofur for disease prevention in chicks. Another example examined the Belgian experience, where a ban on all antibiotic use for growth promotion resulted in an increase in use for treating sick cattle, at least in the short term. Other examples focused on a series of papers on genomic and phenotypic modeling for interspecies transmission of resistant pathogens, third-generation cephalosporin-resistant E. coli and livestock-associated methicillin-resistant Staphylococcus aureus.
The two scientists traded off, either arguing in support of the research conclusions or against. Both provided convincing and well-reasoned arguments to support their “positions,” illustrating how people with different opinions or perspectives, even those with the background to understand the research, can interpret reports differently. If scientists can misinterpret the data, so can the consumer media, activist groups and politicians.
Loneragan and Scott summarized that antibiotic resistance should be taken seriously and approached with rigorous scientific discipline. Most antibiotics are derived from existing micro-organisms such as soil bacteria, and resistance has been occurring as long as there have been bacteria on the earth. Any antibiotic use selects for less-susceptible and sometimes resistant bacteria, but the selection process for resistance is highly complex, as is determining cause and effect based on observational data. Over-simplification in interpreting data can lead to unintended consequences.
Recordings of the conference presentations and a white paper are available on the NIAA website at animalagriculture.org.