Summary

Antimicrobials are important tools that are integral to our complex food system. Antimicrobials (e.g., antibiotics and other substances that act against microorganisms) provide for high quality or good physical condition of crops and good health of food animals entering the food chain. Non-antibiotic antimicrobial agents enable disinfection or sanitization of animal production premises, transport equipment, carcasses, slaughter facility equipment, effective sanitation during food processing, and ensure food quality and safety.

Microorganisms have an inherent ability to mutate and adapt to environmental stressors, however. Thus, the potential exists for new pathogens to emerge and known pathogens to re-emerge, presenting an ongoing food safety challenge. Use of antimicrobials, and more specifically antibiotics, can create selective pressure leading to emergence of antimicrobial-resistant microorganisms, with the potential to undermine the effectiveness of antimicrobial and antibiotic applications. The Institute of Food Technologists (IFT) convened an expert panel to address the concern that the use of antimicrobials in food production, manufacturing, and elsewhere may compromise the ability to control them in these settings and human medicine. The outcome of the panel’s deliberations, summarized here, elucidates the state of the science on the public health impact of antimicrobial uses throughout the food system, and development and control of antimicrobial resistance.

Classification of Antimicrobials and Resistance

"Antimicrobial" is a general term referring to antibiotics, food antimicrobial agents, sanitizers, disinfectants, and other substances that act against microorganisms. For the purpose of this report, the term antibiotic specifically refers to naturally-occurring, semi-synthetic, or synthetic drugs used to:
(a) treat infectious disease in humans, animals, or plants by inhibiting the growth of or destroying microorganisms; or
(b) prevent or treat infectious disease and improve the performance of food animals. Legally, antibiotics are classified as "veterinary antimicrobial drugs" when used in animals, and as "pesticides" when used in plants; antibiotics are not allowed for use as food additives.

Antimicrobial resistance, from a functional perspective, refers to failure of a given antimicrobial treatment. The panel considers resistance, as described elsewhere, as temporary or permanent ability of a microorganism and its progeny to remain viable and/or multiply under conditions that would destroy or inhibit other members of the strain. Antimicrobial resistance may be intrinsic to a microorganism or it may develop via mutation, other genetic alteration, or temporary adaptation to stressors.

Antimicrobial Applications

A variety of antimicrobials are applied throughout a complex macrobiologic ecosystem and social system (Fig. 1), which includes food animal production, aquaculture, companion animals, vegetable and other crop production, food processing, hospitals, and households, where microorganisms are prevalent. Antibiotics have been used in food animals (primarily cattle, swine, and poultry) for more than 50 years to treat, prevent, and control disease, and in some cases (excluding aquaculture) to improve feed utilization and, thus, growth rate. Administration of antibiotics to food animals is one aspect of an overall management system that is a critical component in securing the health and welfare of the animals as well as the safety of the food products derived from them. Further, several non-antibiotic antimicrobials, including disinfectants and sanitizers, are used to clean or sanitize animal production premises, transport equipment, carcasses, and slaughter facility equipment. These substances are an important part of pathogen reduction strategies.

Antimicrobials are used in plant agriculture, primarily fruit trees, to control bacterial and fungal infection. Most antimicrobials used on plants are fungicides. Sanitizing and decontaminating agents are used to control microorganisms on fresh produce. Several different types of antimicrobial agents are used in food manufacturing to either clean food manufacturing environments or ensure food quality and safety. In food manufacturing, antimicrobials are applied as multiple, synergistic hurdles to inactivate or inhibit growth of spoilage and pathogenic microorganisms. Antimicrobials are also used to treat human disease and prevent infection, and have become commonplace in consumer products for home use (e.g., cleansers, soaps, toothbrushes, hand lotions, food contact surfaces, and food tissue sprays).

Although the total amount of antimicrobials used in agriculture and human medicine is not precisely known, both sectors use appreciable quantities. Estimates of use are influenced by data gaps and inaccuracies. Estimates of the total amount of antibiotics used in production agriculture range from 18.4 – 30 million pounds. These figures compare to estimates of 4.5 million – 32 million pounds of antibiotics used in humans. Quantity of use, however, does not necessarily correspond with efficacy. Despite the utility of antibiotics in agriculture, however, the trend is to reduce usage because use for any purpose, therapeutic or not, selects for resistance.

Fig 1. Antimicrobial Resistance

Emergence, Dissemination, and Monitoring of Resistance

Bacterial resistance mechanisms are quite diverse, as are the modes of action of antimicrobials. The existence of a variety of resistance genes also complicates the antibiotic resistance issue. It appears that antimicrobial resistance genes are widely disseminated in nature and are present in a diversity of microorganisms and niches. Two main factors contribute to the persistence of antimicrobial resistance microorganisms in the environment—survival of the microbe and maintenance of the resistance genotype. Commensals, such as nonpathogenic Escherichia coli and Enterococcus species, may serve as reservoirs of potential antimicrobial resistance genes in the environment, from which resistance may be transferred to other commensals or pathogenic bacteria. However, of singular interest are those antibiotic-resistant intestinal bacteria in food animals, such as Salmonella and Campylobacter, that can contaminate foods during slaughter or processing and result in human illness.

Several countries and communities have surveillance programs to measure resistance trends, but harmonization is needed before international comparisons can be made and resistance trends elucidated. In the United States, the National Antimicrobial Resistance Monitoring System for Enteric Bacteria (NARMS), a collaborative effort of the Centers for Disease Control and Prevention, Food and Drug Administration (FDA), and U.S. Dept. of Agriculture, monitors changes in susceptibilities of zoonotic pathogens (Salmonella, E. coli, Campylobacter, Enterococcus) in humans, animals, and animal products. NARMS and other surveillance data are beginning to reveal resistance trends. NARMS resistance trends are not consistently in one direction (increasing trends in some cases and decreasing trends in others).

Other surveillance programs have shown increasing resistance trends during the past 20 – 25 years whereas other sources reveal decreasing resistance trends, particularly in the last 6 – 7 years. The history of the epidemiology of Salmonella, for example, shows that clones, including multiple drug resistant (MDR)- clones, spread worldwide, and then lost predominance. Some clones of Salmonella Typhimurium DT104, which possess a penta-resistance gene cassette (genetically-linked resistance to ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline), have spread widely and resulted in foodborne disease outbreaks. It appears that the prevalence of Salmonella Typhimurium DT104 and/or the penta-resistant Salmonella Typhimurium may have peaked in 1996, and declined since then.

Notably, trends in the prevalence of resistance in a microorganism do not necessarily reflect trends in the incidences of either foodborne illness or resistant infections which in many cases have declined in recent years. Additionally, it is difficult to correlate antibiotic resistance among foodborne pathogens with antibiotic uses on the farm. An increased incidence of illness in any given year may or may not parallel increased use of antibiotics potentially selecting for resistant microorganisms. Therefore, it is difficult to compare year-to-year resistance trend data with disease prevalence and corresponding changes in annual use of a specific antibiotic or class of antibiotics.

Impacts of Antimicrobial Use and Resistance

Human Health

Antibiotic resistance among foodborne pathogens may create an increased burden to human health in different ways: (1) resistant pathogens contaminating food animals have the potential to reach humans; (2) human use of antibiotics may increase the risk of acquiring an infection with an antimicrobial-resistant pathogen; (3) human infection with a resistant microbe may limit illness treatment options (in the uncommon instances of foodborne illness in which antibiotic use is warranted); and (4) antibioticresistant foodborne pathogens may develop increased virulence. Of these potential impacts, prior exposure of humans to antibiotics (including for reasons other than foodborne illness) is the greatest risk factor for acquiring an infection with antibiotic-resistant bacteria. The preponderance of evidence strongly supports the suggestion that antibiotic resistance results in a larger number of human infections than would otherwise be the case by increasing the risk of infection in people who have had prior antibiotic exposure.

The extent to which antibiotic use in food animals produces clinically important antibiotic-resistant infections in humans is unknown. There is evidence that points to but does not prove that antimicrobial use in food animals poses a human health threat. There are very few data regarding food animal-tohuman transfer of antimicrobial resistance to indicate more frequent or severe infections or increased morbidity and mortality.

Monitoring and surveillance of antibiotic resistance in plant production agriculture is not done on a regular basis. To date there is little evidence of a human health impact from use of antibiotics in plant production. Similarly, ingestion of antibiotic-resistant bacteria from aquaculture and contact with animals, including pets, appear to have no significant adverse impact on human health.

It appears that household use of antibacterial cleaning and hygiene products does not present an adverse human health impact. A year-long study of the use of triclosan in hand soap found that the use did not lead to resistant microbes on hands or in drains. Another study, which investigated use of triclosan at commercial levels in a simulated drain environment determined that emergence of antibiotic resistance through use of triclosan in kitchens is highly improbable. Further, use of triclosan or PCMX in industrial environments has not led to emergence of bacterial tolerance or resistance.

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Food Manufacturing

Food product modifications, such as changes in formulation or processing conditions, may lead to sublethal stressing of microbes. Surviving microorganisms may have increased resistance or virulence. Some antimicrobial treatments may lead to dominance of acid-resistant pathogens. For example, spraying meat carcasses with organic acids may select for survival of acid-tolerant E. coli O157:H7. It is notable that decontamination treatments are effective in reducing microbial contamination of carcasses and in helping meat processors meet performance standards.

The impact on human health of pathogen resistance to food antimicrobials is not fully understood. Although some studies have suggested that in certain situations (use at sublethal levels, overuse, presence of biofilms, and existence of cross-resistance mechanisms, for example) the potential for negative public health impact exists, resistance to food antimicrobials is not considered a major public health concern because the resistance mechanisms are often temporary adaptations. To date, the use in foods of chemical and biological antimicrobials and physical preservation systems has been remarkably successful in providing safe foods and has not been compromised by the occurrence of resistant microorganisms. Further, bacterial adaptation (resistance) to food preservatives and sanitizers is generally a transient state rather than genetically based.

The prevalence and mechanism of resistance among most food-use antimicrobial compounds is often unknown. When it occurs, resistance to food antimicrobials is of little practical relevance to the food industry because the antimicrobial concentrations used in food manufacturing are well above the low levels to which bacteria exhibit resistance. However, the ability of some sanitizers and disinfectants to induce MDR-pumps in microbes, which also confer antibiotic resistance, is of some concern. Additionally, resistance to sanitizers may confer resistance to some antibiotics.

In contrast to antibiotics, which inhibit a specific biosynthetic cellular target, most biocides used by the food industry attack multiple, concentration-dependent targets, causing major cell wall and membrane damage in a short period of time. Thus, mutations resulting in acquired resistance to biocides are much less likely to occur than mutations resulting in antibiotic resistance.

Environmental

Environmental impacts are not completely understood; very little is known about the exposure routes of antimicrobials in the environment and the fate of antimicrobials within ecosystems. Although there are concerns with antibiotics entering the animal production environment through manure or other waste streams, more information is needed to better understand the situation to implement effective control strategies. Current evidence suggests that it is not likely that antimicrobials in manure will pose any direct risk to soil microbiota. However, it is not yet possible to exclude other indirect effects on soil microbiota and ecosystems driven by changes in the microbial community from the presence of antibiotics.

Risks to human, animal, or environmental health from the direct impact of antimicrobials on bacteria in aquatic and terrestrial environments appear low. However, antimicrobial agents in ecosystems can lead to drastic alterations in biodiversity of affected ecosystems, reduction of microorganisms susceptible to agents, and development of antimicrobial resistance. Overall, there is a general lack of knowledge and agreement about the frequency and extent of occurrence, fate, and effects associated with antimicrobials entering the environment. As a result it is difficult to assess the environmental impact of the use of antimicrobials.

Trade

As noted in a 2004 report of the Government Accountability Office (GAO), there are differences among key U.S. trading partners (e.g., Canada and South Korea and its competitors, e.g., European Union) in acceptable uses of antibiotics, such as those permissible for growth promotion. The United States, Australia, Canada, Japan, and South Korea allow the use in animals of some antibiotics from classes important in human medicine; the EU prohibits such use, however. The GAO also reported that to date antimicrobial resistance associated with use of antibiotics in animals has not significantly affected U.S. trade in meat products. GAO indicates this issue may be a factor in the future, given the phasing out by 2006 in the EU use of all antibiotics for growth promotion.

Economic

There are two perspectives to economic assessment of antibiotic resistance in food production—costs for patients with antibiotic-resistant pathogens and economics of antibiotic use or non-use in food animal production. The GAO determined in 2004 that a ban or partial ban on antibiotics in food animal production would increase costs to producers, who would bear the greatest financial burden, decrease production, and increase retail prices to consumers. For example, eliminating antibiotic use in pork production would increase producer costs from $2.76 to an estimated $6.05 per animal, which translates to increased consumer costs for pork from $180 million to $700 million per year. Economic assessment of the consequences of use of antibiotics in human medicine is essentially nonexistent, owing to the diversity and breadth of the issues.

Risk Analysis

Risk Assessment

Qualitative and quantitative risk assessments are now being applied to address the complexity of resistance selection, transfer through the food chain, and human health consequences. For many antibiotics, such as tylosin, tilmicosin, and virginiamycin used in food animals, and for which a risk assessment has been conducted, the estimated risk to human health is small. Fluoroquinolone use in water to treat poultry disease, however, was deemed by the FDA as an unacceptable risk to humans and its approval was withdrawn. The FDA now requires new animal drug sponsors to satisfy microbial food safety criteria for antibiotic products by submitting evidence outlined in regulatory guidance that appropriate use conditions are ensured.

Managing Antimicrobial Resistance

Antibiotic-resistant foodborne pathogens are a subset of foodborne pathogens, any of which may cause illness. Antibiotic-resistant intestinal bacteria may be present in food animals, irregardless of exposure of the animals to an antibiotic. The types of bacteria, their resistance profiles, and prevalence vary from animal to animal and species to species. Given the different resistance mechanisms, conditions selecting for resistance, and dissemination patterns of resistant microorganisms, a single approach to solving the resistance issue is not possible. In spite of the best efforts to prevent or eliminate them, some antibioticresistant bacteria contaminate carcasses, as do antibiotic susceptible bacteria. Interventions that effectively reduce the prevalence of foodborne pathogens also reduce the prevalence of those that are resistant to antibiotics.

Risk management strategies to minimize and contain antibiotic-resistant foodborne bacteria are in place all along the food chain, but can be improved. The strategies that have been implemented include use of various antibiotic alternatives, implementation of judicious or prudent antibiotic use guidelines, and implementation of national resistance monitoring programs. Guidelines exist for responsible use of antibiotics in veterinary and human medicine. Responsible use, however, is not necessarily reduced use, because antimicrobials offer valuable benefits when used appropriately. Responsible use involves prescribing antimicrobial therapy only when it is beneficial to the patient, targets therapy to desired pathogens and use of appropriate drug, and confines treatment duration. The intent is to promote appropriate use of antimicrobials, maximizing efficiency and minimizing resistance development.

The key points of influence that food scientists have in preventing the spread of antibiotic-resistant and antibiotic sensitive pathogenic microorganisms in foods are preventing them from entering the food supply, and if present, inactivating them or preventing their growth. The use of multiple hurdles in food manufacturing is likely to combat resistance to singular food safety interventions.

Regulatory Environment

The regulatory environment is geared toward protecting the public from additional risk without consideration of benefits, hence the emphasis on risk assessment. Within the current U.S. regulatory framework, it is not possible for regulatory agencies to judge between the benefits of antibiotic use to livestock producers and risks to the public. Therefore, regulators must reject any practice that appears to produce an apparent risk unless a demonstrated higher risk would occur upon rejection of the practice. For example, there is evidence that there are significant human health benefits from subtherapeutic antibiotic use to prevent subclinical disease in food animals and reduce levels of Salmonella and Campylobacter contamination of poultry carcasses. In such situations the risk of antibiotic use to control subclinical disease is more than compensated for with a human health benefit. It has been estimated that at least 40,000 illness-days per year are prevented by continued use of virginiamycin to reduce bacterial illness in poultry. Similar results have been reported for enrofloxacin and macrolide use in poultry.

In Europe the elimination of the use of antibiotics for feed efficiency and growth promotion, which was done on the basis of the precautionary principle, resulted in increased intestinal disease in animals, concomitant use of more therapeutic antibiotics, and an increase in resistance. For example, while the total use of antibiotics in animals in Denmark decreased 30% between 1997 (before the ban) and 2004, there was a 41% increase in therapeutic uses between 1999 (after ban) and 2004. Although the prevalence of resistant strains decreased for some antibiotics in some animals, prevalence increased for other antibiotics, bacteria, and animals.

Regulatory targeting of specific antibiotic-resistant foodborne pathogens may not be the most successful or cost effective means to reduce overall foodborne illness. A Hazard Analysis Critical Control Point approach applied throughout the food system is the most effective measure to control pathogens and reduce foodborne illness. Most of the interventions applied at critical control points are equally effective in controlling microbes regardless of their resistance to antibiotics. Thus, applying interventions to control foodborne pathogens in general, rather than focusing specifically on antibiotic-resistant strains would have the greatest impact in reducing overall foodborne illness.

Specific Recommendations

IFT’s Expert Panel identified specific areas warranting attention or investigation. These are:

• Increase attention to the public health benefits, as well as risks, of losing the efficacy of existing and future antimicrobials.

• Determine the public health impact of antimicrobial resistance on the basis of risk assessment, and consider resistance on the basis of an individual microorganism exposed to a specific agent under a specific condition of use.

• Guide risk management strategies by the results of risk assessments.

• Always practice prudent use of antimicrobials to limit resistance selection and to maintain maximal benefit of antimicrobials in the future.

• Expand development of prudent use guidelines to include all antibiotic uses. Prudent use does not necessarily correlate with reduced use; an unknown risk of maintaining use may be less than an equally unknown risk of reducing use.

• Modify prudent use guidelines as new scientific evidence on antimicrobial resistance becomes available.

• Develop, validate, and implement prudent use guidelines for bactericidal food antimicrobial agents and sanitizers.

• Conduct more research to identify effective alternatives to antibiotics.

• Implement surveillance programs and food attribution models as means for measuring the effectiveness of the food industry’s microbiological interventions.

• Determine and evaluate the relationship between use of specific antibiotics in food animal husbandry to resistance selection rates among major foodborne bacteria at slaughter on farms where antibiotics are used and farms where antibiotics are not used.

• Initiate characterization of resistance to food antimicrobial agents and sanitizers.

• Advance understanding of the mechanisms of resistance to food antimicrobial agents and sanitizers.

• Improve the ability of scientists to predict the potential for cross-resistance with antibiotics through increased focus on determining and understanding mechanisms of resistance.

• Aid in elucidating reasons that some combinations and sequences of antimicrobial interventions result in synergistic “multiple hurdle” effects while others cause stress-hardening or adaptation through increased knowledge of mechanisms of resistance.

• Implement further study to confirm that current data indicate that microbial interventions are equally effective for antimicrobial susceptible and resistant microorganisms.