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IPVS 2022
The following technical article is related to the event::
IPVS 2022

Antimicrobial resistance, a one welfare challenge for pig farming

Published on: 12/20/2021
Author/s : Mark A. Holmes / University of Cambridge, Department of Veterinary Medicine, Madingley Road, Cambridge CB3 0ES, UK.
One of the most pressing problems that has attracted considerable publicity in the last few years is the prospect of widespread multidrug resistance leading to a breakdown in human healthcare systems throughout the world. The O’Neil report (O’Neil et al 2016), estimates “that by 2050, 10 million lives a year and a cumulative 100 trillion USD of economic output are at risk due to the rise of drug- resistant infections”. The O’Neil report recommends a reduction in the unnecessary use of antimicrobials in agriculture and their dissemination into the environment. 
There is no doubt that the use of antimicrobials is a driver for antimicrobial resistance (AMR). When a mixed population of susceptible and resistant bacteria are exposed to antimicrobials the resistant organisms will survive and the susceptible ones die – this is simple natural selection. Consequently, the use of antimicrobials in agriculture will lead to increased AMR. One of the key questions is the degree to which agricultural use of antimicrobials contributes to the human burden of AMR. 
The recent WHO guidelines on use of medically important antimicrobials in food-producing animals (Anon, 2017) and the systematic reviews (Tang et al, 2017) that informed these guidelines highlighted the dearth of good quality evidence on the impact of agriculture on human AMR. Only 13 studies were found to be of sufficient quality to be used to make meaningful conclusions and almost all these studies were performed in Western Europe and North America. There is a pressing need to address this knowledge gap, particularly in a wider context that should include low and middle income countries where high antibiotic use and limited regulation place them in the front-line in the global fight against drug-resistant infections. Research is currently underway in my own and other labs across the world to address knowledge gaps highlighted in the OIE Strategy on Antimicrobial Resistance and the Prudent Use of Antimicrobials (Anon, 2016). 
There are two good examples which highlight the potential threat of agricultural sources of resistant bacteria to human health. These are livestock-associated methicillin resistant S. aureus (LA-MRSA) and colistin resistance in enterobacteriaciae. 
Staphylococcus aureus is an opportunistic pathogen that normally colonizes the host asymptomatically, but can cause a variety of pathogenic infections. Some S. aureus clones are more successful human pathogens than others, and some show a high degree of host specificity for different animal species (Sung et al, 2008). Recently, a specific lineage belonging to multi-locus sequence type (ST)398, most likely of human origin, has spread among livestock globally, acquired methicillin resistance and is now transferring back to humans leading to both colonization and disease (Price et al, 2012). Pigs constitute a large reservoir for LA-MRSA ST398 and contribute to an ongoing spread and genetic adaptation in Europe and North America. Although the ST398 lineage of S. aureus was the first designated to be ‘livestock-associated’ in Europe and the US, broader investigations have confirmed that MRSA of other MLSTs (e.g., ST9, ST5) also occur in swine populations (Sun et al, 2015). Furthermore, the relative prevalence of these lineages, and subtypes within lineages, appears to vary geographically (Battisti, 2010; Sun et al, 2015). While ST398 variants have been predominant in studies of pigs in Europe, ST9 has been identified as the predominant LA-MRSA lineage in most Asian countries (Chuang, 2015). Both ST9 and ST398 LA-MRSA have been reported in both China and the UK suggesting that both lineages may be established in both countries (Hadjirin et al, 2015; Yan et al, 2014). Of considerable concern is the report of reduced vancomycin susceptibility in porcine ST9 MRSA isolates from pigs in China (Kwok, 2013). The identification of LA-MRSA ST9 isolates (in China; Yu et al 2014) and ST398 isolates (in the Europe; Ward et al 2014) from human infections and carriage clearly indicating the threat to human health of these lineages. 
The molecular epidemiology of LA-MRSA is required in order to confirm transmission pathways and identify significant virulence factors. Comparative genomic studies of LA-MRSA have identified some phage associated genes that appear to be correlated with virulence in humans, but no genes of importance for successful colonization or infection in livestock or other animals have been identified (Uhlemann et al, 2012). A greater understanding of the pathogenicity and transmission of LA-MRSA requires further investigations into the survival mechanisms utilized by these lineages. This understanding will inform the development of strategies to reduce the impact of LA-MRSA on the colonization of livestock and human health. However, there is no doubt that LA-MRSA from pig farms leads to human carriage and disease. 
Carbapenem-resistant bacteria are a big problem in human medicine. Colistin (polymyxin E) is a polycationic peptide antimicrobial that was isolated and characterized in 1949. For many years it was largely abandoned in human medicine due to toxicity issues, but widely used in veterinary medicine. In recent years it has become a “last-line” therapeutic drug, for the treatment of infections in hospitalized patients caused by carbapenem-resistant Gram-negative bacteria (Nation et al, 2017). The discovery of plasmid-mediated mobilized colistin resistance (mcr) genes originating from pigs in China has become a major issue (Liu et al, 2016). At the time of writing there have been relatively few reports of multi-drug resistant bacteria with colistin resistance that are causing widespread problems, but the gene is now widely distributed and the potential for such infections is growing. It is highly likely that the use of colistin as a growth promotant contributed to the selection pressure that led to the emergence of the mcr gene.
In both of these examples, there appears to be little effect on animal health. S. aureus is not a primary pig pathogen and has little opportunity to be a secondary pathogen compared to human medicine. It appears that livestock act as a reservoir of MRSA that add to human MRSA carriage rates, which then may lead to disease as carriage is the biggest risk factor for MRSA infection. Similarly, there have been no reports of treatment failures due to colistin resistance in pig farms but bacteria harbouring the mcr gene do escape from farms into the environment and into the human population. 
Colistin resistance is an example of a low probability event (considered as likelihood at a single point of time) with the potential of a high cost to public health. LA-MRSA is an example of a high probability event with a relatively low cost to public health (again looking at single point events). There are concerns that either of these scenarios could be repeated with the acquisition of new AMR resistance genes in bacteria which are pathogenic to people originating on farms. 
It is important to appreciate that it is likely that in comparison to the contribution that the misuse of antimicrobials by the medical profession when treating people has made to AMR, the contribution from agriculture probably represents a very small proportion. A mathematical modelling study from van Bunnik and Woolhouse (2017) concludes that “Our results suggest that, for a wide range of scenarios, curtailing the volume of antibiotics consumed by food animals has, as a stand- alone measure, little impact on the level of resistance in humans.” This may reflect the current situation, but this does not excuse the historic overuse or misuse of antibiotics in some agricultural sectors, on the other hand it does provide some context. 
Excessive and injudicious use of antimicrobials in farming is unsustainable. It has long been argued that overmedication of livestock has been used to compensate for poor welfare and bad husbandry. The overarching aim of good antibiotic stewardship is to use as little as possible, but as much as necessary. Preventive medicine approaches include the use of vaccines and making husbandry changes that reduce incidence of disease. Clearly, reducing incidence of disease leads to a reduction in the need to medicate with antimicrobials. While the pig industry has been historically good in areas such as biosecurity it has striven to increase productivity levels with little regard to other effects. Freedom from disease is one of the tenets of good animal welfare, and agricultural sustainability is essential to support rural economies and feed our growing population. A coordinated and proportionate response to the AMR crisis from the industry and government is required to this one-welfare issue.
Published in the proceedings of the International Pig Veterinary Society Congress – IPVS2020. For information on the event, past and future editions, check out https://ipvs2022.com/en.

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