Similar to antimicrobial use in humans, there is substantial variation throughout the world in the availability, regulation
, control and administration of antimicrobials to animals. Whilst these factors themselves are not expected to alter the postulated causal mechanisms by which drug use affects drug resistance in microorganisms, they are likely to modify the extent to which these mechanisms have the opportunity to act. Simply put, it appears that greater usage of particular antimicrobial drugs, in a relevant time and place, is positively correlated with greater proportions of isolates tested for susceptibility in that time and place being designated as resistant. Thus, greater control over the quality and supply of antimicrobial drugs and greater regulation
and professionalism over their administration should correlate with reduced proportions of resistant isolates.
It is worthy of note that this general observation appears also to be true of anthelmintic drugs, although the ecology of macroparasites is of course different to microbes. However, in the developed world, the problem of anthelmintic resistance is more of an immediate issue for animals than humans, which means that it has received much less attention from a public health point of view. Nevertheless, sophisticated guidance on control of parasitic infestations, based on understanding their ecology, and seeking to preserve the efficacy of anthelmintic drugs, are seen as critical to future food security (e.g. see Sustainable Control of Parasites in Sheep (http://www.scops.org.uk/)).
A range of antimicrobial drugs is used widely to treat disease in domestic animals through a large and internationally varying number of preparations and through a number of different routes of administration. In most developed countries of the world, the classes of antimicrobial drug available for animal
administration, and the preparations and routes by which they can be administered, have to be specifically licensed for animal
use and are highly regulated, especially for animal
species likely to enter the human food chain. In these countries, there are also strictly enforced ‘withdrawal periods’ which define for how long an animal
must be ‘off’ treatment before products form that animal
can be used for human consumption. In some parts of the world, so-called ‘off-label’ use (i.e. an unlicensed product and/or an unlicensed route of administration) is sometimes permitted under derogation for the treatment of companion animals. Lists of critically important antimicrobials (CIAs) in humans and animals have been agreed, and are periodically updated, by the OIE and WHO and others, and the use of these drugs should be restricted to treating infections that have been demonstrated to be susceptible (and resistant to less important, so-called first-line, drugs) (OIE list of antimicrobials of veterinary importance 2007; WHO list of Critically Important Antimicrobials (CIA) 2017). In developing countries, due to limitations in infrastructure, such regulations, where they exist, are much more difficult to make effective. Coupled with a very high demand due to a high disease burden and often high population densities, and issues such as uncontrolled, unauthorized markets and counterfeit drugs, the conditions appear likely to favour intense selection for antimicrobial resistance and subsequent dissemination, though there are few reliable data to provide firm evidence of this.
Much of the controversy around use of antimicrobials in animals has concentrated on their use as growth promoters. It has been considered that routine addition of some antimicrobial compounds (usually antibacterial drugs and often at sub-therapeutic concentrations) to livestock feed increases food conversion efficiency by more than enough to outweigh the cost of adding the drugs, though this is disputed (Graham et al. 2007). However, other agents, such as anti-coccidials used by the poultry sector, are also included in this broad classification (Mendelson et al. 2017). Use of antibiotic
growth promoters is considered by many to be particularly undesirable due to the selection pressure being applied in an almost unrelenting way to the populations of microorganisms colonizing these animals, especially in instances in which drugs are used at sub-therapeutic concentrations, as this is thought to select more strongly for antimicrobial resistance. Much research has sought to investigate the impact of the use of antimicrobials for growth promotion and has been interpreted by most as demonstrating a positive association with increased prevalence of resistant organisms in exposed microbial populations (O’Neill (2015)). On the basis of this evidence, their use as growth promoters has been banned in many parts of the world, notably Europe, yet still persists in others.
In the EU, “the use of agents from classes which are or may be used in human or veterinary medicine (i.e. where there is a risk of selecting for cross-resistance to drugs used to treat bacterial infections)” as growth promoters has not been permitted since 2006 (Regulation
(EC) No 1831/2003/EC) and withdrawal periods for antimicrobial use prior to animal
slaughter are designed to ensure that there are no antimicrobial residues in food. In the USA, non-therapeutic use is still widespread in industrial farming. The USA FDA has historically been slow to respond to calls to reduce antimicrobial use and unwilling to exert its authority over the antimicrobial approval process (see Natural Resources Defense Council, et al. v. United States Food and Drug Administration, et al.). Until recently, the FDA implemented a voluntary approach to antimicrobial conservation that encouraged drug companies to withdraw approvals for antimicrobials for non-therapeutic use and replace them with approvals for other uses such as chemoprophylaxis (USDA 2012a, b). However, this policy has had little real effect on antimicrobial usage because, in many cases, the doses and durations of drug use for chemoprophylaxis and growth promotion are the same (Outterson 2014).
In emerging economies, such as the BRICS and MINT countries, it is anticipated that non-therapeutic use of antibiotics in animals may exponentially increase because of increasing intensification of agriculture/aquaculture, high prevalences of production and endemic diseases (which are likely to be better controlled in other countries) and lack of resources to ensure appropriate governance over antimicrobial use (Carlet et al. 2011; Van Boeckel 2015). In some of these countries, AMR
and antimicrobial conservation aren’t on the “political agenda” at all (Grace 2015 at p 11–12) because addressing other issues such as poverty, starvation, malnutrition through (un)sustainable livestock and farmed fish production are more urgent for the current population. The impact of antimicrobial use on accessibility of animal
food sources hasn’t been quantified for most countries, partly due to the variability and uncertainty regarding the quantities of antimicrobials used even in similarly intensive systems elsewhere (Rushton et al. 2014), and there is no agreement on the desired levels of antimicrobial consumption. Even if an enforced ban on the non-therapeutic use of antimicrobials were to be introduced, in some places, the absence of national R&D investment means that there are few alternative mechanisms (such as vaccines) to concurrently improve animal
husbandry and avoid production losses which could paradoxically increase AMR
prevalence through off-label or unprescribed use of poor quality or counterfeit antimicrobials. The relative costs of not using antimicrobials on the security of the global food supply and the success of the Sustainable Development Goals (in eradicating poverty and hunger in the current generation) have not been compared to AMR
treatment failure in people (in future generations). Although developed countries arguably have sufficient means to assist developing countries address some of these issues, they have so far focussed on their own national priorities in order to achieve wider international societal benefits (Clift 2013).
Distinction is made in veterinary medicine (at least in the developed world) between prophylactic (administering antimicrobial drugs to prevent anticipated infection) and metaphylactic use of antimicrobials (administering antimicrobial drugs to clinically well members of a population in contact with an index case of infectious disease to prevent anticipated infection), which is not recognized in human medicine. Prophylaxis in veterinary medicine is criticized by many as an excuse for poor infection prevention and control (often referred to as ‘biosecurity’ in animal
production) in a particular animal
husbandry system, but presents ethical dilemmas to veterinarians who struggle with the notion of withholding treatment in the face of what is considered to be almost inevitable disease and associated welfare compromise. In many instances, the clinical use of antimicrobials in animals is empirical and sensitivity testing of an isolate of the putative causative agent of infection is not carried out. The reasons for this are largely to do with cost and expediency in starting treatment to improve the clinical condition of the patient. Thus, data that characterize the resistance profiles of clinical isolates from animals represent a very small proportion of the putative infections treated by veterinarians, and their use for epidemiological purposes often appears to overlook this fact. However, this is also true of human medicine.
The notion that antimicrobial resistant organisms somehow ‘arise’ in animals, driven by selection pressures applied by veterinary use of antimicrobials, and pass to humans, principally through the food chain, has been a popular model of antimicrobial resistance ‘acquisition’ for some time. However, some recent research shows that transmission is likely to occur in both directions between animals and people directly and indirectly through the environment and various fomites (Mather et al. 2013). As discussed in the introduction, it is probably more reasonable to think of animals and people as inextricably linked ‘samplers’ of a shared environmental pool of organisms subject to different selection pressures in different compartments.