Antimicrobial resistance in production animals

Background

The history of agricultural usage of antimicrobials began in the mid-1930s with the use of synthetic sulfonamides to treat mastitis in dairy cattle.¹ Since, then, antibiotics have been used in agriculture to prevent and treat disease, increase feed conversion efficiency, average weight gain and contribute to food preservation. Little more than 30 years later, a multidrug-resistant Salmonella Typhimurium phage type 29 caused a spike in infection in calves in the United Kingdom² that was also linked with many human cases of salmonellosis. Multidrug-resistant bacterial species subsequently quickly became more globally widespread following the adoption of intensive farming practices which often included the imprudent addition of antibiotics to animal feed without veterinary prescription.

Regulation of antimicrobials

Australia has long recognised the importance of regulating the production and usage of antimicrobial therapeutic drugs.³ High level committees comprised of representatives from the Australian Government and its agencies in human medicine and agriculture, as well as human and veterinary health professionals informing regulation and providing national governance and leadership on antimicrobials in Australia have existed since the 1960s.^3,4 Australia’s first National AMR [Antimicrobial Resistance] Strategy was released in 2015,⁵ and, in March 2020, the updated Australia’s National Antimicrobial Resistance Strategy – 2020 and Beyond⁶ was released alongside a One Health antimicrobial resistance action plan⁷ that takes a One Health approach to mitigating AMR across humans, animals, food, agriculture and the environment. This strategy has been expanded to include the responsible usage of antifungals, antiparasitics and antivirals. The ‘2020 Strategy’ outlines seven key objectives including governance, AMR surveillance, AMR research, infection prevention and control, communication and engagement, antimicrobial stewardship, as well as global partnerships. Australia’s Animal Sector Antimicrobial Resistance Action Plan 2023–2028⁸ was developed as the plan for the animal sector to progress relevant activities under the ‘2020 Strategy’ and is inclusive of multiple animal sectors including both terrestrial and aquatic food and fibre producing animals, companion animals, zoological collections, laboratory animals and wildlife treated with antimicrobials.

Antimicrobial stewardship is one of the seven key objectives of the ‘2020 Strategy’ and represents the coordinated efforts to promote optimal antimicrobial usage that includes optimal drug selection, dose and duration of treatment that leads to the best clinical outcome while minimising the potential for resistance. World-wide, Australia has one of the most conservative approaches surrounding the regulation and usage of antimicrobials in food-producing animals. Most antimicrobials have been classified as Schedule 4 medicines since the 1970s and require a prescription from a licensed veterinarian.^9,10 Fluoroquinolones have never been registered for use in food-producing animals in Australia and label directives limit the administration of extended-spectrum cephalosporins to only individual animals with respiratory disease though there is some reported off-label use.^11,12 In food-producing animals, polymyxins are only present in two registered preparations with infrequent use as topical agents for ear and ocular conditions.

AMR surveillance in food production animals

Surveillance programs focused on AMR are vital within veterinary and food production sectors to detect emerging threats to human and animal health. AMR surveillance in food production animals in Australia is ad hoc with various industry-led studies in the red-meat industries, and government co-investment in studies in poultry, pigs as well as commercial barramundi and salmon. AMR in E. coli and Salmonella isolated from Australian food-producing animals substantially differs from what has been observed in other countries. Gram-negative bacteria isolated from Australian livestock have no or extremely low levels of resistance to a wide range of critically important antimicrobials.^13–15 Recent AMR surveys in poultry have also revealed low levels of resistance in key indicator bacterial species, including E. coli and enterococci, as well as the foodborne pathogen Salmonella spp.^16–18 To date, there have been no reports of carbapenem or colistin resistance in E. coli and Salmonella from Australian livestock and resistance to fluoroquinolones and extended-spectrum cephalosporins has been observed at only very low frequencies. Low levels of AMR are believed to be in part due to Australia’s unique geography, quarantine restrictions and governance regarding the use of critically important antimicrobials in food-producing animals. Effective ongoing surveillance, however, requires continuous repeated evaluation (rather than one-off surveys) and expansion to include pathogens of animal health significance so that AMR of human and animal importance can be effectively monitored and reported. Importantly, this strategy would provide the data needed to identify emerging AMR trends and contribute to public health and animal health related decision making.¹⁹

Antimicrobial usage practices in humans represent one of the most significant risks to the emergence of AMR in Australia. Given the global nature of the world’s economies and the extent of human travel, the contribution of reverse-zoonotic transfer of antimicrobial-resistant bacterial species (human to animals) cannot be discounted. For example, workers at an Australian piggery with close animal contact exhibited a higher risk for carriage of methicillin-resistant Staphylococcus aureus.²⁰ Despite the absence of fluoroquinolone usage in Australian food animal species, fluoroquinolone-resistant Campylobacter spp. were detected in broiler faeces collected from major poultry processing plants.²¹ Comparative genomic analysis revealed that these Campylobacter isolates clustered with international isolates previously detected in both humans and animals overseas.²¹

Movement of wild animals through natural migration and urban encroachment may also contribute to the emergence of AMR in Australia. Recent genomic analysis of fluoroquinolone and extended-spectrum cephalosporin-resistant E. coli and Salmonella isolates detected from Australian livestock has shown that these strains are very dissimilar to those previously observed in clinically ill humans in Australia but have previously been observed in humans and wild birds overseas.^22,23 These results suggest that the few fluoroquinolone- and extended-spectrum cephalosporin-resistant E. coli and Salmonella isolated from Australian food-producing animals are unlikely to have evolved locally but rather have potentially been introduced, by human carriers or wild birds.

Robotic platform technologies in AMR surveillance

Combining automation and genomics is the future of AMR surveillance. Current AMR surveillance strategies utilise the broth microdilution minimal inhibitory concentration (MIC) method,²⁴ which is labour intensive and costly. These limitations restrict the number of bacterial isolates that can be tested, ultimately decreasing the sensitivity of detection of emerging resistances, including to critically important antimicrobials. A high-throughput robotic antimicrobial susceptibility platform (RASP) has recently been developed representing a significant advancement in AMR surveillance. Combining laboratory automation from Tecan, spiral plating and colony picking with SciRobotics, MALDI-TOF from Bruker, and Illumina sequencing into a single high-throughput solution, it is possible to rapidly screen thousands of samples and study AMR in a large number of colonies, while adhering to internationally recognised standards (Fig. 1).²⁵ Comparison of MIC results between RASP and a human technician revealed a high degree of agreement.²⁵ With funding from the Australian Government Department of Health, Food Standards Australia New Zealand has recently used RASP to conduct a survey of AMR in retail food products.

Fig. 1.

Robotic antimicrobial susceptibility platform (RASP) workflow to isolate, identify, test and sequence bacterial isolates from faecal samples.

Industry engagement and communication

Industry engagement in the control and prevention of AMR is critical to reduce the public health and animal health impacts of antimicrobial use in all areas of intensive food production systems. Business management, veterinarians, farm managers and workers must be committed to implementing high standards of antimicrobial stewardship and biosecurity, and refining antimicrobial use to maintain bacterial susceptibility among pathogens in both intensive and extensive animal production systems. This approach will have a profoundly beneficial effect as healthy animals result in improved productivity and lower production costs (and, ultimately, lower costs to the consumer).

Conclusion

AMR in animals and food is a complex and multifaceted issue. Efforts to address this issue should focus on strengthening existing conservative regulations targeted at reducing unnecessary use of antimicrobials in humans and animals, improving biosecurity practices, implementing high standards of antimicrobial stewardship, raising awareness, education, and conducting research and surveillance. By taking a comprehensive and coordinated One Health approach to combating AMR, stakeholders can help to protect human and animal health, preserving the efficacy antimicrobials for future use.