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Antimicrobial resistance was first described shortly before the start of use of antibiotics to treat infections in 1940. Bacteria have developed defenses against natural antibiotics, even to some synthetic compounds, long before the ”antibiotic era” and most antibiotics now in clinical use are naturally produced by soil micro-organisms. Such micro-organisms are also the source of many of the resistant genes that are found in bacteria that cause diseases.
Resistance to antibiotics can be linked to the structure of the bacteria, like in the case of Gram negative bacteria that have an outer membrane that the antibiotic penicillin G cannot penetrate. It can also be linked to a mutation in one of its metabolic genes that will change the way the cell works to develop resistance. This last type of acquired resistance can eventually be transferred to other bacteria.
In natural ecosystems, expression of resistant genes can act as a defense mechanism of bacteria against antimicrobial- or toxin-producing competitors in the same ecological niche, or as a self-preservation mechanism in antimicrobial-producing bacteria. For example, some signaling molecules produced by environmental bacteria for communication purposes have been found to have antimicrobial activity.
However, as the role of antimicrobials, both in bacterial physiology and in microbial ecology, is still mostly unknown – with theories ranging from the regulation of cell growth mobilization or inhibition of metabolic pathways, to environmental signaling – this role and the evolutionary origins of antimicrobial resistance genes remain hypothetical.
There are five broad categories of mechanisms that bacteria use to resist to antibiotics:
Further, the genes that determine resistance evolve from a variety of metabolic processes, from digestion and signaling to synthesis of resistant cell walls. Bacteria have the capacity to transfer genes between species, even taxonomically-distant ones, often in the form of gene “packages” known as plasmids. The transfer of resistance genes between humans, animals and the environment has also been reported and it is estimated to be the main type of genes transferred between farm environments, food, and human gut microbiota. The use of antimicrobials in the environment – as observed in hospitals or intensive farm settings – has been associated with the survival of bacterial strains with higher rates of mutation, which can develop resistance to antibiotics faster.
A number of genes that encode resistance to non-antimicrobial agents have been found to be associated with antimicrobial genes, thus fostering co-selection of resistance genes. For instance, mercury-resistance genes are commonly found along with antimicrobial genes in Gram-negative bacteria. Likewise, qac genes mediating resistance to quaternary-ammonium disinfectants – commonly used in hospital and agriculture settings – through active efflux, are found in the conserved region of a gene block that is transferred with antimicrobial genes.
There is a substantial body of evidence to support the view that the emergence of antimicrobial resistance in bacteria in livestock populations is connected to the emergence of resistance in bacterial populations that colonize and infect humans.
However, it seems that the majority of the emergence of resistance in bacteria in humans originate from other bacteria in humans while the resistance in animals originate from bacteria in livestock. In most cases, in both animals and humans, a positive association was found between the volume of antimicrobial consumption and the prevalence of resistance in the exposed bacterial populations.
Nevertheless, there is consensus within the scientific literature that there are routes for spillover of resistance between the bacterial populations of humans and food-producing animals in both directions.
The recent dramatic global changes in food consumption, international trade, agricultural production systems, and human travel in terms of spread of antimicrobial resistance and circulation, are among the causes of anti-microbial resistance whose consequences are yet scarcely known.
The widespread excessive use and the misuse of antimicrobials and antibiotics are widely recognized to be two of the major drivers for acquired resistance in bacterial populations. The use of antimicrobials in health care, agriculture, horticulture, aquaculture and industrial settings has an important impact on the expression, selection, persistence and transfer of resistance traits in bacterial populations due to the selection pressure imposed on the human and animal microbiota, and on environmental bacteria.
Antimicrobials are commonly used non-therapeutically in livestock production as a kind of additional “insurance” to the other animal disease risk-management measures commonly that are used in modern animal production to reduce the risk of introduction and spread of infections in herds. These measures include vaccination, limited co-mingling, adequate ventilation and temperature controls, biosecurity, appropriate nutrition and housing, and quality-assurance programs. Indeed, these risk-management practices usually require substantial financial investment, as well as training and incentivizing staff and even if these measures are implemented properly, a residual disease risk will remain. In animal production, the prolonged use of antimicrobial growth promoters at subtherapeutic levels in large groups of livestock, which is known to encourage resistance emergence, is indeed still common practice in many countries today.
Water is an important vehicle for the spread of both antimicrobial residues and resistance determinants since contaminated water can be consumed directly by humans and livestock and used to irrigate crops.
The crucial risk factor for the emergence of antimicrobial resistance is the presence of antimicrobial residues derived from these anthropogenic, industrial and agricultural usage in the aquatic and terrestrial environments. These contribute to selection pressure on environmental bacteria and commensal and pathogenic bacteria present in the gut microbiota of farmed animals. It has been estimated that 75 to 90 percent of antimicrobials used in livestock are excreted, mostly unmetabolized, and that the concentration of antimicrobial residues in farm environments is likely to be high.
Other substances have been associated with the rise of antimicrobial resistance, among them are non-specific biocides like ammonia, preservatives used in feed, and heavy metals.
It is also been observed that enteric bacterial isolates detected in food-producing animals and in meat are now commonly resistant to ampicillin, tetracycline, co-trimoxazole and streptomycin. The range of types of resistance observed was broader among poultry and chicken meat isolates, with notable additional resistance to quinolones and third-generation cephalosporins, which are critically important in human medicine.
Antimicrobial usage is particularly high in monogastric species compared to other food-producing animals (poultry and pigs have only one stomach compared to cattle and sheep who have a more complex system of interconnected stomachs). These are typically kept in intensive, indoor production systems at high densities, and are therefore vulnerable to infectious disease challenges. In such monogastric production systems, the dosage, frequency and duration of antimicrobial therapy is likely to be high.
It must be noted that antimicrobials differ in how efficiently they are processed in animal guts, and in how long the residues remain bioavailable in the environment. Therefore, different antimicrobials pose different levels of public health risk.
Antibiotics in a farm setting can thus be used in a number of ways, all of which can give rise to resistance if used improperly:
In practice, the intensive conditions under which pigs and chickens are often housed may be associated with greater disease potential and greater use of antimicrobials in order to control sub-clinical infections. In some non-European countries, antimicrobials are widely used by farmers without veterinary supervision due to their relatively low cost and ready availability for sale over the counter. By consequence, among chicken and swine bacterial isolates, resistance to tetracycline, penicillins and sulphonamides has been commonly observed and multi-drug resistance has been reported as significantly higher in these isolates than those from cattle.
In this context, acquisition of resistance by enterococci bacteria isolated from livestock and poultry associated with persistence of resistant bacteria and resistance genes in the farm environment and in medicated feed, is currently a major public health issue.
Presence of antimicrobial residues derived from anthropogenic, industrial and agricultural usage in the aquatic and terrestrial environments also contribute to selection pressure on environmental bacteria and commensal and pathogenic bacteria present in the gut microbiota of farmed animals. It must be noted that antimicrobials differ in how efficiently they are processed in animal guts, and in how long the residues remain bioavailable in the environment. Therefore, different antimicrobials will pose different levels of public health risk.
The substances widely used in aquaculture are the same as those licensed for therapy and prophylaxis of infectious diseases in humans and livestock. No antimicrobial agents have ever been developed solely for fish or shellfish therapy, in part due to the difficult and expensive registration process for anti-microbial drugs.
Classical antimicrobials are thus widely used in aquaculture for therapeutic, metaphylactic and prophylactic purposes, and antimicrobial resistance can occur through direct exposure to antimicrobials delivered as group therapy to fish, or through livestock and human effluents containing resistant bacteria, resistance genes and antimicrobial residues. Furthermore, no international guidelines currently exist for maximum antimicrobial residue limits in water.
Therefore, water can spread antimicrobial residues, resistant bacteria and resistance genes far and wide through the flow of natural water bodies and anthropogenic influences such as irrigation.
Land-based extensive systems
Extensive livestock farming systems, typically characterized by low inputs generating low outputs (the converse of intensive systems) may potentially require lower inputs of anti-microbials, and thus, by default, result in lower rates of resistance emergence.
However, by comparison with intensive systems, extensive systems require higher animal numbers for the same output. Extensive systems involving free-roaming animals in large numbers may exhibit high commensal and pathogenic bacterial transmission rates and exposure to multiple bacterial species, which may not be as prevalent in intensive systems. These factors may result in promoting the generation and transmission of anti-microbial resistant genetic material and bacterial populations.
Food chain
Food is likely to be quantitatively the most important potential transmission pathway from livestock to humans, although direct evidence linking anti-microbial resistance emergence in humans to food consumption is lacking.
Organic systems
Organic production systems in different countries can vary in the level of anti-microbial therapies allowed. In Europe, restrictions exist in the number of therapeutic courses allowed and the duration of withdrawal periods and pro- and metaphylactic use of antimicrobials is prohibited. Alternative therapeutic plans are encouraged and use of antimicrobials is only permitted when necessary. By contrast, use of vaccines for disease prevention is permitted and encouraged. Recent studies comparing resistance levels in livestock reared in organic versus conventional production systems showed higher concentrations in the latter.
There is however a risk that in a poorly managed organic system the drive to reduce antimicrobial use may lead to the administration of doses of antimicrobials below the minimum inhibitory concentration, leading to an increased selection pressure for resistant bacteria and/or recurrent infections or extensive onward transmission. Then, this requires repeat treatment of single or multiple animals and instigating selection pressure for antibiotic resistance.
More generally, we need to know much more about the impact, in different types of agricultural production systems, of the use of antimicrobials on the spread of resistance into the environment, and in particular we lack data from low- and middle-income countries.
Any mechanism that helps spread bacteria has the potential to transfer resistant bacteria. Both pathogenic and non-pathogenic resistant bacteria can be transmitted from livestock to humans via food consumption, or via direct contact with animals or their waste in the environment. Resistance may also be conferred by the exchange of genetic elements between bacteria of the same or different strains or species, and such transfer can occur in any environment where resistant bacteria have the opportunity to mix with a susceptible bacterial population, such as in the human or animal gut, in slurry spread on agricultural soil, or in aquatic environments.
If resistance develops in bacteria present in the natural environment, this can also create animal or human health problems when such bacteria contaminate water, food crops or animal feed, introducing the opportunity for bacterial mixing with commensal or pathogenic species in the animal or human gut.
There are considerable gaps in current knowledge in this area, in part because environmental sites such as flowing watercourses are difficult to study due to their dynamic nature and of water’s diluting effect. While several studies from various regions have linked the presence of resistance in the environment with contamination by waste from livestock or aquaculture, human sources of contamination in the environment make it difficult to ascertain the contribution of livestock production to the environmental spread of anti-microbial resistance.
As a consequence of the challenges associated with data collection on environmental spread, food-borne transmission often becomes the primary focus for studies of livestock-to-human spread of resistance. Meat contamination is undoubtedly easier to study, so there is some bias in favour of exploring this transmission route. As a result, there is a considerable body of evidence describing the food distribution network as a risk pathway for transmission and spread from animals to humans. In a globalized world, people and products are transported around the earth in a matter of days, and resistant bacteria and resistance genes are disseminated with them.
Despite convincing evidence for the existence of potentially important risk pathways for food-borne transmission of antibiotic resistance, direct evidence for resistance in humans resulting from consumption of food products is very limited. This may be in part because hygiene procedures during meat processing can be very effective at removing bacteria.
The application of manure to crops intended for human consumption is a possible pathway for the spread of resistance from animals to humans. However, it has been found that resistant bacteria on vegetables grown for human consumption were ubiquitous regardless of farming system or geographical location, thought to be due to the naturally-occurring and ancient presence of resistance in soil bacteria. Furthermore, manuring the soil did not increase the prevalence of resistant bacteria on vegetables sold for consumption.
Reduction of numbers of resistant bacteria may only be possible if these are outnumbered by susceptible bacteria in an antimicrobial-free environment in which only a small number of individuals have been exposed to antimicrobials, or in the presence of a limited “selection density”.
The growing prevalence of multi-drug resistant organisms enables co-selection, hence requiring the removal of all antimicrobials in order to achieve a useful reduction in the prevalence of resistance. However, this will usually not be the case in high-selection-density environments such as hospitals and conventional intensive farms.
If the selection pressure imposed by the use of antimicrobials was completely removed this would not necessarily stop the circulation of resistance. This is an “easy to get and hard to lose” problem because resistance is very difficult to reverse due to the ability of genetic transfer elements to adapt to new hosts and new environments.
It would be advantageous to reduce or cease completely the transportation of live animals for breeding purposes, as it is possible instead to trade in embryos or semen, thereby avoiding the transportation of large numbers of bacteria in animal guts.
Another problem is that antimicrobial residues in the environment are not monitored in the same way as are other hazadous substances, thus their concentration in the environment is likely to be underestimated or unrecognized.
In low- and middle-income countries, the present situation of high antimicrobial use along with inadequate resources and infrastructure to ensure rigorous hygiene during slaughter and meat processing do present significant challenges.
A considerable amount of research has been conducted into the improvement of waste water treatment due to concerns over pharmaceuticals with undesirable effects on wildlife, such as contraceptives or painkillers. Improving the ability of waste water treatment plants to remove these pollutants would also help to lower environmental concentrations of antimicrobials with similar molecular size, particularly in aquatic environments.
Improved hygiene and biosecurity should be a major focus for all types of animal production systems so that the risks of introducing pathogens and resistance genes – and the spread of these within animal populations – can be reduced. Applying hazard Analysis and Critical Control Point (HACCP) protocols would help to improve the situation. Because some antimicrobials are not readily biodegradable and may persist at high concentrations for long periods, future development of quickly biodegradable antimicrobials could help reduce environmental contamination.
Mitigation strategies are thus possible and require a joint approach based on agricultural, medical and environmental interests. Because livestock, humans and the environment are intimately connected, it is important to consider the emergence and spread of resistance from a “One Health” perspective, which provides a framework for an interdisciplinary approach to dealing with this enormous challenge.
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