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Antimicrobial resistance in food animals - national and international developments

David Jordan, Principal Research Scientist, NSW Department of Primary Industries, Wollongbar, NSW

Posted Flock & Herd March 2016

Introduction

Antimicrobial resistance (AMR) and antimicrobial usage (AU) has been a contentious issue at the nexus of animal and human health for over 50 years. The discovery of methicillin resistant Staphylococcus aureus (MRSA) in the UK hospital system in 1960 first brought AMR to prominence in the medical community.1 Early concerns involving animals focused on multi-drug resistant (MDR) non-typhoidal Salmonella derived from farm animals in the UK in the late 1960's.2 Interest has been periodically renewed and heightened, for example, by the emergence of vancomycin resistant enterococci in humans and animals in the 1990's,3 the global emergence of animal-associated forms of MRSA from about 2005,4 the proliferation of virtually untreatable MDR forms of key human pathogens such as Mycobacterium tuberculosis5 and Neisseria gonorrhea6, and confirmed transfer of Salmonella expressing severe forms of MDR (including ceftiofur resistance) from animals to humans on a large scale.7 Over the same period there has been tremendous enhancement of the technology available for detecting and characterizing resistance although the age-old issue of obtaining adequate sampling in the field remains a barrier to progress.

In both scientific and political terms AMR/AU is an exceedingly complex subject. Effectively, it is a myriad of interconnected issues each featuring a specific combination of antimicrobial drug, geographic location or jurisdiction, bacterium, disease, genotype, resistance mechanism, pathways, host species, host environment, time factors and so on. Owing to this complexity, it has been very easy for generalisations based on socially-appealing ideology to gain traction in the public arena, especially to do with the AU in food animals. Until recently, AMR in small animals and companion animals appears to have been largely neglected due to the focus on food animals. AU for growth promotion in Australian food animals is one excellent example of where misinformation has been widespread, often based on reports from abroad. In Australia, the reality is that growth-promotion from feeding medically-relevant antimicrobials has no practical or economic appeal for the majority of animal enterprises. Although some intensive production systems have practiced growth-promotion in the past, amendments to the registration of antimicrobials for use in food animals now make that practice illegal (the only exception being the ionophore group of drugs which do not have medical relevance). Representing a far greater threat to consumers, veterinarians, producers and trading interests in Australia is the escalating use of some high-importance drugs that can select for forms of AMR that pose a distinct public health risk. Nevertheless, the overall picture for AMR in the Australian food-animal sector appears very positive by comparison with the human population and by comparison with major livestock industries abroad.

International DEVELOPMENTS

AMR is one of the few issues in animal health that has received the attention of prominent world leaders. Much of the elevated political awareness can be attributed to the efforts of the World Health Organisation (WHO) over the past 15 years that culminated in a global action plan in 2014.8 One of the most important outcomes from the work by WHO has been the widespread dissemination of information about the importance of different classes of antimicrobials in human health (see below).9 The Office International des Epizootes (OIE) has also produced a similar list with respect to antimicrobials important in animal health.10 Both WHO and the Food and Agriculture Organisation (FAO) have been working in developing countries to improve capacity for managing AMR. The EU is making strident attempts to standardize all aspects of AMR and AU, and has produced for example, interesting comparisons of AU and AMR amongst member states.11 Denmark, Sweden, Norway and the Netherlands all have progressive programs involving a substantial surveillance effort. The most recently published surveillance reports from the latter countries12-15 and also from Canada16 are currently the benchmark for progress on building an objective basis for decision making.

Until recently the USA has experience substantial disharmony between public health, pharmaceutical industry, animal industry and food safety interests on the issue of AMR in food animals. In 1996 the National Antimicrobial Resistance Monitoring Scheme (“NARMS”) was established and the data provide a very telling account of the consequences of antimicrobial use over time, bearing in mind that the availability of drugs, drug registration constraints and amount of industry intensification are very different to Australia. The data for Salmonella in Figure 1 provides strong insight into how AMR has unfolded with time in beef carcass samples in the USA.17 What is now concerning is the likelihood of side resistance being responsible for worsening of the prevalence of resistance to some key “high importance” drugs such as ceftiofur.

Graph of phenotypic resistance
Figure 1. Percent of non-typhoidal Salmonella from beef carcases (HACCP) expressing phenotypic resistance to various drugs, NARMS USA, 1997-201317

A notable international development has been the interest taken by large national and multi-national food corporations abroad. McDonald's Corporation has been at the forefront with a global policy statement and guidelines released in 2002 followed by an upgraded version “McDonald's Vision for Antimicrobial Stewardship for Food Animals” in 2015.18 Some other major players in the US food retail sector have also developed similar systems for encouraging suppliers of raw-product to embrace principles of antimicrobial stewardship. This “movement” is having a strong impact even in Australia owing to the presence of some food multi-nationals here and the export market for animal products. However, Australian consumers are not yet as sophisticated and demanding when it comes to the integrity of animal foods, particularly compared to their counterparts in Europe, Japan, North America and the emerging middle class of Asia. Nevertheless, the Australian livestock sector is only now realizing the advantage they have as a result of geographic isolation, a conservative approach to registration of antimicrobials for use in food animals, and a large proportion of animal production that has very little need for antimicrobial treatments.

The Australian Scene

The JETACAR report of 199919 looked to establish Australia amongst the leading reforming nations along with Denmark, Sweden and Norway. However, the environment for AU reforms in Australia post-2000 was not as conducive for change and although most of the recommendations from JETACAR were accepted by the Commonwealth Government at the time, progress was limited. The key areas for concern are improving the standards of antimicrobial stewardship in both the medical and veterinary communities and establishing a system of surveillance whereby all stakeholders can see the AU and AMR occurring in all sectors. One useful outcome of this era was the delivery of a pilot surveillance study for antimicrobial resistance in livestock.20 This report was well received internationally, being widely cited by other governments, and was the first real evidence that showed Australian livestock probably represent amongst the lowest AMR risk of food-animals anywhere. Unfortunately, the real value of the latter information in underlining the integrity of AU in Australian livestock was not recognized, although in 2015, with better understanding of the issues, industries now see a strategic advantage in these outcomes.

In 2013 the Commonwealth embarked on a new era of reform based on broad-based consultations. The approach has featured far more cohesion amongst interest groups to achieve a degree of mutual-understanding that was not prominent in the previous decade. Under a “one health” banner, with all prescribers treated equally, there is much greater potential for genuine, broad-based adoption of antimicrobial stewardship. In 2014 the Commonwealth released its National Antimicrobial Resistance Strategy21which it is now building on with an implementation policy that will likely include a suite of initiatives, for example, in the fields of surveillance, education, awareness and infection control. Throughout this process the consultations have captured the advice and recommendations of the animal industries, Australian Veterinary Association, pharmaceutical industry, veterinary academia and state agriculture/DPI interests as well as a plethora of interests from the human-health sector.

A sample of some of the key research and surveillance findings for AMR and AU in Australia and NSW that are of interest to veterinarians in the field are listed in Table 1. Importantly, and not shown in Table 1, the Commonwealth has just initiated a new round of surveys of AMR in major food animals species to be performed in 2015-2017. This is designed as a prelude to an ongoing surveillance program.

Table 1. Some recent relevant studies of antimicrobial use in animals and antimicrobial resistance detection/prevalence in animals and humans in Australia.
Topic Animal species/type Activity/year Comment
DAFF pilot survey20 Cattle, pigs, chicken Isolates collected 2003-2004 First major national survey of AMR in food animals
MRSA in veterinarians.22 Human 2009 Revealed a high prevalence of MRSA in equine vets
AMR in Salmonella from animals in NSW23 Cattle, pigs, avian Isolates obtained from samples submitted to EMAI 2007-2011 No resistance detected to high importance drugs at that time
AMR in pathogenic E. coli from food animals in Australia24 Cattle, pigs, chicken, sheep Isolates collected 2011-2012 from Australian veterinary labs Detection of ESBL and fluoroquinolone resistant E. coli in food animals
AMR in E. coli and Salmonella from Australian cattle25 Dairy, beef and vealer cattle Isolates collected in 2012 Large survey, low prevalence of resistance to most drugs
Use of antimicrobials in the Australian pig industry26 Pig 2007 survey of veterinarians on amount and type of antimicrobials used Emerging use of ceftiofur. Common reasons for use described.

Antimicrobial Importance Ratings

One of the most important concepts for medical and veterinary practitioners to understand are the ratings given to families of antimicrobials based on their importance in human medicine.9 There is an Australian27 and WHO based system,28 each comprising a three-point scale but using different terminology. For example, the tetracyclines family is widely used in farm animals but less so in humans and so they are given a “low” importance rating in the Australian system (the lowest rating) while in the WHO system they are given the “highly important” (middle rating). These are ratings derived from judgements of national or international committees of experts and so are affected by the variability in opinions that often prevail in such forums. Some commonly used drugs in animals and their importance rating according to Australian and WHO standards is given in Table 2.

Table 2. Some major antimicrobial drug families, their registration status for food animals in Australia and their importance ratings.

Drug family Example Registered in Australia for Food Animals Australian importance rating27 WHO importance rating28
Tetracyclines Oxytetracycline Yes Low Highly
Penicillins (narrow spect) Benzyl penicillin Yes Low Critically
Aminoglycosides Gentamicin No Medium Critically
Aminoglycosides Neomycin Yes Low Critically
Third generation cephalosporins Ceftiofur Yes High Critically
Sulphonamides Sulfadimidine Yes Low Highly
Quinolones and fluoroquinolones Ciprofloxacin No High Critically
Macrolides Tylosin Yes Low Critically
Imapenems Carbapenem No High Critically
Amphenicols Florfenicol Yes Low Highly
Cyclic polypeptides Bacetracin Yes Low Important
Streptogramins Virginiamycin Yes High Highly

With the demise in the use of antimicrobials as growth promoters in Australia, the focus of attention has shifted to improving the stewardship of those drugs used in animals that are also of “high importance” in human medicine. Of greatest concern are third generation cephalosporins (specifically ceftiofur in food animals, and cefovecin in cats), fluoroquinolones and gentamicin (in companion animals). Historically there have been major controversies involving streptogramins (virginiamycin) and glycopeptides (vancomycin for humans, avoparcin for animals). Avoparcin has been unavailable in Australia since 2000 and gentamicin and fluoroquinolone drugs have never been registered in this country for use in food animals. However, the use of ceftiofur in pigs and cattle in Australia is contentious because the analogous drugs in human medicine are highly valued as reserve agents (last line of defense) and their use in the health care system is tightly controlled. In contrast, veterinarians are able to readily prescribe ceftiofur for use in food animals where it is typically targeted against infections having a substantial economic impact. Reasonable fears do exist that the use of ceftiofur in Australian livestock will continue to escalate and promote the emergence of extended spectrum beta lactam-resistance in human pathogens in this country. In North America, epidemiological data for AMR in Salmonella enterica shows that that this has already occurred for some zoonotic strains, most notably serovars Typhimurium, Newport and Heidelberg that typically already have resistance to five other antimicrobials. The implications for human health where these organisms emerge in livestock are substantial because non-typhoidal Salmonella are one of the most common causes of food-borne infections. A small proportion of these cases, develop an invasive form of disease where the pathogen escapes the gut to colonise blood and tissues. Resistance of these pathogens to third generation cephalosporins makes effective therapy highly problematic and serious complications and mortality more likely.

Challenges for Australian veterinarians

Improving the education and experience of veterinarians on the issues of stewardship, AMR, infection control and diagnostics is a priority. The Australian Veterinary Association has sponsored research and activities to address some of these issues. Moreover, there are political and economic hurdles to overcome in Australia. For example, private veterinarians are both prescribers and dispensers of antimicrobials thus creating a conflict of interest that is rightfully of concern to public-health interests. Nevertheless, it is difficult to imagine an alternative system of prescription and supply of antimicrobials that is affordable under Australian conditions. To counter this, veterinarians may need to be more pro-active in allowing scrutiny of prescribing practices by supplying information (type of drug, volume used, species and indication) as part of surveillance of AU, and clinical specimens as part of AMR surveillance. In the long term, the challenge is to have clients coming to food-animal veterinarians not to obtain a supply of antimicrobials but motivated to access the best-available expertise on the subject of prevention and control of disease.

Animal managers and veterinarians, particularly in companion and performance animal practice face special challenges. One major issue is that of infection control. For example, there is growing evidence of bi-directional transfer of MRSA involving humans and small animals29, humans and horses30 and humans and pigs.31 It appears possible that human strains of MRSA can enter animal populations and acquire new resistance genes. Another major barrier is the adoption of antimicrobial susceptibility testing: both the willingness of clients and veterinarians to submit and pay for a service; and secondly, the establishment of a uniformly high standard of organism identification and susceptibility testing with a rapid turn-around.

Summary

Overall, Australian animal production is in an enviable position. Restrictions on some of the highest importance drugs, comparatively low drug use by many industries (although more data here is needed), and some outstanding AMR survey findings to date are all reasons for an optimistic outlook for food animals. Nevertheless, the lesson from abroad are that it will not stay that way if standards of stewardship are not lifted and failure to do so will threaten both public health and long-term economic outlook for the food-animal sector. Veterinarians and industries have to work hard on the “hot spots” where high importance drugs are used too often, for the wrong reason, or when another approach to disease control could be used or developed. Australian industries and jurisdictions that successfully embrace reforms such as education, surveillance, improved diagnostics and alternative control measures will be promoting their food-animal industries in the domestic and international arenas.

References

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