Canada_IPAP - Impacts of antibiotic usage reduction in farmed animals

Antibiotics are used to prevent and treat bacterial infections in humans and animals. Antibiotics are natural products of microbes and have been present in the environment in small amounts for millions of years. Some environmental bacteria have therefore had time to evolve resistance to these antibiotics. Once we started using antibiotics to treat infections, we set off a chain of events that has led to pre-evolved resistance moving from its environmental origins into bacteria that cause disease. This "mobile" resistance can spread through bacterial populations, leading to long-term consequences when these bacteria cause infections. One example is the CTX-M enzyme, which gives resistance to 3rd generation cephalosporin (3GC) antibiotics. CTX-M was discovered 30 years ago, but it is now found in bacteria causing about 5% of urinary tract and bloodstream infections in humans in the UK.

3GCs are used to treat infections in humans and animals. However, because they are considered Highest Priority Critically Important Antimicrobials for use in humans, their use in farm animals in the UK has now almost stopped. This is because the Red Tractor farm assurance scheme, which is followed by 95% of UK farms, introduced new regulations around antibiotic use in mid 2018. One aim is to reduce the number of 3GC resistant bacteria in farm animals, which might spread to humans and cause resistant infections.

Some antibiotics, in contrast, are used to treat infections in farmed animals but never in humans (in the UK). One example is spectinomycin, which has been extensively used to treat sheep in the UK for decades. There are no rules specifically preventing the use of "farmed animal specific" antibiotics like spectinomycin, but in many countries, there is a general downward trend in antibiotic usage in farming. Furthermore, since late 2021, spectinomycin has no longer been available in the UK for treatment of sheep because its manufacturers have withdrawn it from sale. This might be expected to reduce rates of spectinomycin resistance in the UK sheep flock. We also see spectinomycin - and other farmed animal specific antibiotic resistance - in bacteria causing human infections, suggesting that there is a flow of resistant bacteria from farmed animals to humans. Maybe this will now start to reduce?

Moves to reduce antibiotic usage in farming are ongoing in many countries. This project aims to build a partnership between UK (University of Bristol) researchers and those in Canada (Universities of Montreal, Guelph, Calgary and Prince Edward Island) who are experts in antibiotic use and resistance in farmed animals, and/or in humans. In Canada, there has been variation in regulatory and industry-led changes to antibiotic usage in farming at provincial level, but generally, a downward trajectory in usage started later than it did in the UK.

Our partnership will be built though a variety of activities, but predominantly by collaborative research aiming to understand whether antibiotic usage reduction in farming is driving down antibiotic resistance levels on farms, and also in human infections. To do this, we will take advantage of natural experiments in the UK and Canada that are uniquely possibly for us to undertake, become of our ongoing involvement in large-scale longitudinal farm antibiotic usage and resistance surveillance projects, and the fact that antibiotic usage is being reduced in both countries at different rates and in subtly different ways.

It is very difficult to validly demonstrate a significant association between antibiotic usage reduction in farming on antibiotic resistance in bacteria on farms, and even more difficult to show and effect on human populations. This is because of all the potential confounding factors occurring in parallel that might also be driving down resistance. The value of our partnership is that we can pool our cutting edge technical expertise and so make these analysis possible.

In many countries, antibiotic usage is being reduced in farming. The objective is mainly to reduce selective pressures on farm, since it is known that humans ingest farm-animal origin bacteria in food, and through interaction with the environment; and it is known that colonising flora, most notably enteric bacteria such as Escherichia coli, can cause opportunistic extra-intestinal infections. In the UK, the use of highest priority critically important antimicrobials (e.g. 3rd generation cephalosporins and fluoroquinolones) was effectively stopped in cattle due to introduction of new regulations by the Red Tractor farm assurance scheme in June 2018. In sheep, spectinomycin use stopped in late 2021 because the only licenced product was discontinued from manufacture. It is important (and scientifically interesting) to find out if such antibiotic usage changes have a significant impact on antibiotic resistance levels in bacteria on farms, and on the prevalence of resistant infections in humans. Some have tried, but it is far easier said than done, mainly due to the intertwining of other farm management, human antibiotic usage and infection control practices going on at the same time, which confound these analyses. To unravel this, we need a partnership of epidemiologists, molecular modellers, bioinformaticians, and the comprehensive data sets uniquely available from longitudinal surveillance studies on farms and in human cohorts. In this project, we will build a sustainable partnership (and ECR network) of UK and Canadian researchers with internationally recognised excellence in these disciplines, and unique access to the required farm and human longitudinal surveillance studies and associated meta data. We will undertake six research projects to address the impact of antibiotic usage reduction (starting with those described above) on the prevalence and ecology of antibiotic resistance on farms and in humans. We will deliver impact through stakeholder engagement.