17 Antimicrobial Resistance and Food Safety

Authors: Daley, P., MD MSc FRCPC DTM+H

Introduction
Antimicrobial Resistance (AMR) among bacteria which cause human infectious disease has emerged among the top ten leading threats to global public health as defined by the World Health Organization, associated with 4.95 million deaths in 2019,1 which is projected to increase to 10 million deaths by 2050.2 With a declining rate of new antimicrobial discovery due to low product profitability for the pharmaceutical industry,3 AMR threatens the efficacy of current antimicrobials and the current standard of medical care that relies on effective antimicrobials. AMR is caused by many factors, the leading factor being selection towards expression of antimicrobial resistance genes (ARG) within the community of microbial flora (microbiome), due to antimicrobial use (AMU). Beside implications for human health, increasing AMR may impact animal health, climate change, global trade and sustainable industries.
Antimicrobial stewardship has emerged as one solution, leading to a five percent reduction in AMU among humans in Canada between 2015-2019.4 The COVID-19 pandemic was also associated with a significant reduction in AMU among humans.5 However, global AMU rate is increasing and is highly variable between countries.6 Reduction in AMU may reverse AMR, but other strategies including reduction in transmission, sanitation, access to clean water, accurate diagnostics and migration must also be considered.7 With evidence that AMU among animals may contribute to AMR among humans, a One Health strategy has begun to define new interventions including antimicrobial stewardship. One Health considers the intersection between the health of humans, animals and environment, including social, political and economic contexts.8
AMR among food animals threatens the safety of the food production industry because AMR may be transmitted from animals to food consumers and food industry workers. Food safety is an essential fundamental to the achievement of the United Nations Sustainable Development Goals, and food safety impacts food security, animal health, the environment, climate change and socioeconomic development.9 Because AMR can be transmitted between animals, humans and the environment, AMR impacts planetary health.

Antimicrobial Use and Antimicrobial Resistance among Food Animals
Eighty percent of antimicrobials produced in the USA are given to animals.10 AMU among animals is projected to continue to increase globally.11 Antimicrobials are given to food animals for growth promotion, prophylaxis and treatment of bacterial infections.12 Because antimicrobials are intended for treatment of significant bacterial infections, use for growth promotion and prophylaxis are considered inappropriate use. Because the food industry gains profit from the use of antimicrobials through increased production, there is a disincentive to control AMU.
AMR predates AMU, since AMR has been described from ancient soil, isolated caves, permafrost and the gut of preserved human remains dating from approximately 1000 AD.13-15 Where antimicrobials are present within food animal production at a concentration between mutant selection concentration (enough antimicrobial to induce gene expression and alter population phenotype) and growth inhibition concentration, AMR is selected among the animal microbiome.16 There is also evidence of AMR selection due to the use of disinfectants, biocides, and heavy metals used in the livestock industry.17 ARG have been identified in many food products, including meat, poultry and dairy products from high income and low income countries,18 and in aquaculture.19 AMU and ARG expression among food animals is not always correlated, as on Danish pig farms, antimicrobial exposure had both positive and negative influence on corresponding ARG expression.20
It is not clear if reducing AMU in the food production industry will reduce AMR among animals or humans, as available studies are observational, not randomized trials. In a meta-analysis of 29 studies, reduction in AMU among animals was associated with both reduction in expression of ARG and stable expression of ARG among human and animal flora.21 Mathematical models have been proposed to generate estimates of the relationship between animal AMU and human AMR.22

AMR transmission from food animals to environment
ARG carried in the food animal gut is transferred to the environment through the spreading of manure in fields, and the contamination of the surface of fruits and vegetables with soil, fertilizer and irrigation water. The concentration of ARG in industrial wastewater is similar to that in the human gut, and higher than in control soil, water and sediment specimens, indicating environmental contamination due to industrial antibiotic pollution.23 Bacteriophages in soil acquire ARG and transfer them horizontally between bacteria through transduction.24 Environmental flora may therefore represent a latent “bank” of ARG with the capability to impact human or animal health in future.

AMR transmission from environment to humans
The role of transmission of AMR from the environment to humans is not known. Many environmental organisms lack the virulence to colonize humans. ARG identified in the environment could not be directly correlated with human colonization.25 Furthermore the direction of transfer between the environment and humans could be bilateral.

AMR transmission from food animals to humans
AMR transmission from animals to humans may be a result of direct contact with animals, including animal or fish handlers or abattoir workers, or indirectly through food consumption. Direct transmission is more common in low-income countries, where close animal exposure is common, and indirect transmission is more common among high-income countries.18 Evidence of indirect transmission includes identification of genetically identical organisms present in animals and humans without occupational exposure to animals.26 However, this evidence does not implicate food as the cause of contamination.27

Foodborne Illness in Humans
Food may become unsafe during production, distribution, sale, preparation or consumption. Safe food does not cause harm to the consumer, because the food is free of damage, deterioration or biological or chemical agents.9 However, food which contains antimicrobials or ARG may be associated with negative health outcomes in humans, primarily affecting low and middle income countries.18
Foodborne illness is disease caused by ingestion of contaminated food or water, generally associated with lack of access to clean food and water supply. Foodborne illness caused 600 million human cases and 420,000 premature human deaths globally in 2010,28 disproportionally affecting children, pregnant women and elderly, with the highest incidence observed in Africa.29 Approximately 1,000,000 children die annually of diarrheal illness in South East Asia.30 The principle bacterial causes of foodborne illness are Salmonella, Campylobacter and E.coli,31 organisms that are included in the World Health Organization list of priority pathogens identified as global AMR concerns.32 Besides gastrointestinal illness, foodborne urinary tract infection may be associated with gut colonization with resistant organisms.33
The impact of increasing AMR among food products on global human foodborne illness and death rates is unknown. If humans or animals are treated with antimicrobials for foodborne illness, but the antimicrobials are ineffective due to AMR, mortality may increase due to lack of treatment response. Many foodborne illnesses are not treated with antimicrobials, due to self-limiting disease or lack of access to treatment in low-income settings, so treatment failure due to AMR may not influence outcome among these cases.

Food Safety and Food Security
Increasing AMR among food products may impact the achievement of the World Health Organization Sustainable Development Goals focused on poverty, hunger and socioeconomic development, and may impact climate change. With global population projected to reach 11.2 billion by 2100,34 the loss of approximately one third of food production due to waste, and the high proportion of poverty and malnutrition,35 any reduction in global food production could impair food security. Food security is already poor in some low-income countries, where AMR rates are high.
If AMR reduces treatment effectiveness among animals, animal mortality due to endemic or outbreak infections could reduce food production and increase food prices. Modern industrial farming techniques may increase animal crowding and infection transmission, increasing the demand for AMU.36
The impact of AMR on global prosperity has been estimated at a loss of $100 trillion over the next thirty-five years,2 with the largest impact in low-income countries which have economies dependent on food production. Foodborne outbreaks have been associated with enormous financial impact.37 Disease outbreaks may create disruption in the trade of food between countries.38

AMR and the Environment
The use of antimicrobials in animal husbandry, agriculture and fish farming releases antimicrobials in their active form into wastewater, groundwater and soil.39 AMR associated with runoff is observed in river water downstream of cattle feedlots.40 The ocean is the largest reservoir of ARG in the environment, with higher concentrations observed in coastal runoff compared to runoff from forested areas.41 Recreational use of water during swimming, diving or watersports may expose humans to ARG. Sub-inhibitory concentrations of antimicrobials were detected on carrots and lettuce irrigated with contaminated water.42 Manure fertilization is associated with AMR in soil, even if the manure is collected from animals not treated with antimicrobials.43
Animal agriculture is the second largest contributor of greenhouse gases, next to fossil fuel harvesting.44 Greenhouse gases contribute to climate change. Cows treated with the antimicrobial tetracycline produce increased methane, which is a greenhouse gas.45 Sixty percent of global fresh water and thirty percent of available land is dedicated to animal production.46 The demand for increased food production in the near future will increase demand for antimicrobial use and greenhouse gas production.

Conclusions
The evidence connecting observed increasing AMR rates in food with reduced food safety is emerging, but not definitive. Surveillance of AMR and AMU trends is a focus of new national and international programs. Many questions regarding AMR are unanswered, such as the relationship between AMU and AMR, the role of AMR transmission between humans, animals and environment, and the impact of AMR on human, animal and environmental health.47 Furthermore strategies to reduce AMR among the food production industry and the environment are also new. Appropriate AMU restrictive measures among animal production are being explored.48