In 2019, few would deny that the rising trend of antimicrobial resistance (AMR) represents a global health crisis. Decades of over-use and misuse of the world’s cornerstone antibiotics have given rise to drug-resistant infections that threaten to make critical medicines obsolete and turn even the most routine surgery into a minefield of risk. The statistics that have terrified the experts for years are increasingly becoming common knowledge, boosted by major communications campaigns by the likes of the World Health Organization (WHO) and the O’Neill Review on Antimicrobial Resistance.

Without concerted action, AMR could force up to 24 million people into extreme poverty by 2030, and cause ten million deaths a year by 2050, not to mention creating economic damage equal to the worst ravages of the 2008-09 financial crisis. Even today, around 700,000 deaths a year are attributed to antibiotic-resistant disease, with 230,000 lives claimed annually by multidrug-resistant tuberculosis alone.

The AMR crisis is an incredibly complex problem that requires a multi-faceted set of solutions. The pharmaceutical industry and research groups can play a vital role by investing in the discovery and development of new antibiotic classes and alternative treatments. Clinicians must exercise more caution to avoid the unnecessary prescription of antibiotics, while medical technology providers can work on new, rapid point-of-care diagnostics to help doctors quickly distinguish between bacterial and viral infections. The WHO describes this multi-sectoral strategy to tackle AMR as the ‘One Health’ approach.

Antibiotics in agriculture

A critical but often-overlooked component of the One Health approach is better control over the use of antibiotics in agriculture. Around 70% of the antibiotics used globally are administered to farm animals, such as cattle, swine and poultry. With demand for meat rising globally, farmers are under pressure to maximise their output, giving rise to intensive farming methods that put animals into closer proximity – often in poor conditions – and increases the risk of bacterial infections that can spread rapidly.

Farmers have traditionally addressed this problem by pre-emptively treating their livestock’s feed with antibiotics to protect their health and, in many cases, as a proven growth promotion agent to maximise the weight (and therefore profitability) of each animal.

But efficiency comes at a price: a growing body of scientific evidence has shown that excessive antibiotic use in farms allows for the development of resistant bacteria in animal herds, which can be transmitted to humans through contact with farm workers, or through the food chain. Media investigations have found resistant superbugs such as livestock-associated MRSA in supermarket foods sold in the UK.

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This is why agricultural practices are an important part of the One Health approach to AMR, as reflected in a report published in April this year by the UN Interagency Coordinating Group on Antimicrobial Resistance, which, as part of its broader recommendations, called for restricted use of antibiotics on livestock farms and phasing out the use of important antimicrobials as growth promoters.

“The report’s recommendations recognise that antimicrobials are critical to safeguard food production, safety and trade, as well as human and animal health, and it clearly promotes responsible use across sectors,” said UN Food and Agriculture Organization director-general José Graziano da Silva in April. “Countries can foster sustainable food systems and farming practices that reduce the risk of antimicrobial resistance by working together to promote viable alternatives to antimicrobial use, as laid out in the report’s recommendations.”

Pharma marketing to agribusiness

In recent years, some governments have started to crack down on agricultural uses of antibiotics, but regulation and enforcement varies significantly between regions. The EU has banned the use of antibiotics to fatten animals since 2006, and in October last year the European parliament approved a new set of restrictions, due to come into force in 2022, on using antibiotics on healthy animals or to replace poor animal husbandry. The US, meanwhile, banned the use of non-prescribed antibiotics as well as antibiotic-based growth promoters in January 2017.

The US Food and Drug Administration permits the use of antibiotics on livestock for disease control, but international bodies are trying to persuade industrial farming operations to limit antibiotic administration to healthy animals. Part of the picture lies in the marketing materials of the animal-focused pharmaceutical companies – many of which are divisions or spin-outs from mainstream pharma giants like Novartis, Merck and Pfizer – that sell medical products to farmers. Are drugmakers advertising their products in a way that encourages best practices in antibiotics stewardship?

Not in all cases, according to a recent investigation by the New York Times. In June, the newspaper reported on marketing materials distributed by pharma firm Elanco at last year’s World Pork Expo in Des Moines, Iowa, which ran under the tag ‘Pig Zero’. The campaign encouraged farmers to ‘proactively’ treat swine herds en masse rather than attempting to track down infected individuals. The recommended treatment was the company’s Denagard (tiamulin) in combination with chlortetracycline (CTC), which is from an antibiotic class categorised by the WHO as highly important for human health.

“When it comes to treating disease on your operation, isolating the source can be difficult,” read an Elanco brochure. “So, protect the population with the proactive choice that’s right for your herd and best for your business.”

The materials also highlighted the difficulty of enforcing legislation proscribing the use of antibiotics as growth promoters, as the brochure trumpeted the weight-gain benefits of treating pigs with Denagard/CTC as a side benefit, while not technically being sold as a growth promotion agent.

Antibiotic alternatives

Elanco, which did not respond to a request for comment, has stopped distributing the Pig Zero marketing materials, and chief executive Jeffrey Simmons told the New York Times that the company is working on antibiotic alternatives.

Elanco has drawn attention to its development of animal-only antibiotics such as Inteprity, which is used to prevent mortality among poultry with necrotic enteritis, and its launch of antibiotic alternatives including vaccines, enzymes and Imrestor, a protein used to support dairy cows’ immune systems against clinical mastitis in the first 30 days after calving.

“Could we eliminate the need for broad-spectrum antibiotics [in livestock]? I think it’s possible,” Elanco’s head of R&D Aaron Schacht told the New York Times.

Indeed, there is a plethora of therapeutic and prophylactic options on the table to help address the over-use of antibiotics in industrial farming. These include vaccines to immunise herds from certain bacteria and viruses, thereby reducing primary antibiotics use, as well as misdiagnosis and mistaken use in the case of viral infections. For example, more than 70% of US farms vaccinate nursery-age pigs against Mycoplasma pneumonia, and nearly 60% of US beef cows are vaccinated against chlostridial diseases caused by C. chauvoei.

Other approaches include introducing bacteriophages – viruses that are harmless to animals but hunt down and kill bacteria – as well as prebiotics and probiotics to promote healthy bacteria in animals’ gut microbiomes. Even gene editing, a new frontier even in human health, is starting to emerge as a potential solution to some issues. In June last year, scientists at Edinburgh University used gene editing to breed pigs that were resistant to porcine reproductive and respiratory syndrome (PRRS), one of the most pervasive and costly diseases affecting the swine industry. The researchers used gene editing techniques to cut out a section of the CD163 gene from the pigs, removing the corresponding receptor through which pigs are infected with the virus.

In some ways, the sheer number of options for reducing antibiotic use on animals – along with the many variables that may define their effectiveness or lack thereof – is one of the challenges facing researchers and the industry. Alternatives including vaccines and probiotics are already used for certain agricultural indications, but a great deal more research needs to be done to work out exactly which alternatives will work best for which animals, and in which circumstances, as a July 2017 report published by Pew Charitable Trusts concluded.

“In several instances, efficacy has been evaluated only experimentally, which probably neither reflects real-world husbandry conditions on commercial operations nor the target animals,” the report noted. “Potential unintended consequences have generally not been well-studied.”

Identifying appropriate alternatives and the best use of them will take an effort of coordination as well as research, with industry associations and governments sharing data and best practices. For farms operating on slim profit margins, the effect on costs will also need to be considered, and support offered where necessary.

Strong results have already been achieved on an individual basis in the campaign to introduce reliable alternatives to livestock antibiotics. These results must be built upon and shared these innovations need to be joined by other, more basic improvements to animal husbandry and biosecurity to counter the risks presented by modern, highly industrialised farming methods. The global AMR crisis connects to every living system on earth, and tackling individual issues in isolation – whether in human or animal health – is unlikely to solve the problem.