Replacing Antibiotics in Livestock
By: Frank Klemens – GFRP Fund I, Big Idea Ventures (New York City, New York), Max Martin – Supercharger (Nashville, Tennessee), Kevin Wang – Supercharger (New York City, New York)
*Generation Food Rural Partners Fund, a BIV Fund, partners with 23 US-based universities pioneering research into breakthrough agricultural technologies, food technologies, and protein innovations to create new companies and create living-wage jobs in rural communities across the US.
*Supercharger is a New York Based Financial Technology company that automates investment research and machine learning capabilities for the private capital market.
Prontosil, invented by Bayer in 1935, was the first drug to successfully treat Gram-positive infections. Within three years, Prontosil and other sulphonamide-like compounds were being marketed for use in animals, first in Britain and then in the United States. Introduced as a defensive treatment for livestock diseases such as mastitis, sulphonamide antibiotic applications also benefited healthy animals. Studies in the 1940s confirmed that adding low doses of antibiotics such as Streptomycin to animal feed caused increased animal growth without an increase in feed quantity. Soon it was common practice for farmers to have all livestock on a low dosage of antibiotics, whether they were sick or not.
However, antibiotics pose risks over long periods as livestock develop antibiotic-resistant bacteria (AMR) in their gut, such as Salmonella and Campylobacter. When passed on to humans, this creates potentially serious health hazards. For example, the percentage of cases of nontyphoidal Salmonella unaffected by ciprofloxacin has risen from 3% to 9% between 2011 to 2020, according to CDC’s 2022 report. In 2020, NRDC found that medically important drugs are 44% more likely to be destined for cattle and swine than for human medical use, contributing to the rising threat of infections caused by antibiotic-resistant bacteria. This recent rise in antibiotic resistance has led the WHO to call it “one of the biggest threats to global health, food security, and development today.”
Agricultural antibiotics do not present a viable long-term solution. In the race to find an alternative, various new technologies are being developed within the startup sector. Probiotics, a potential alternative, are live microorganisms that can benefit the host by improving its digestive and immune systems. By providing a healthy gut microbiome, probiotics help prevent disease and improve overall health in livestock, reducing the need for antibiotics. Probiotics have also been linked to enhancing growth performance. However, while offering many benefits, probiotics are not a complete replacement for antibiotics. In fact, their relationship with antibiotic resistance is under scrutiny by scientists who hypothesize that probiotic bacteria can serve as a safe haven for antibiotic-resistant genes. So while probiotics could be a viable alternative to antibiotics, currently more research is needed before determining their long-term efficacy.
Another alternative comes in the form of bacteriophages, which are naturally occurring viruses that infect bacteria and can be used to specifically target pathogenic bacteria in livestock guts, reducing the overall bacterial load and helping to maintain animal health. Unlike antibiotics, which can kill both beneficial and harmful bacteria, phages only infect and kill specific bacterial strains. Thus this targeted treatment approach reduces the impact on non-pathogenic bacteria as well as the risk of antibiotic resistance. This reduces the selective pressure that drives the development of antibiotic-resistant bacteria. As phage therapy is still an emerging field, regulations, and infrastructure for the production and distribution of phages for use in livestock are currently limited in many countries.
Feed additives are another developing alternative to antibiotics. Utilized in several unique ways, these additives are typically composed of probiotics, prebiotics, and non-digestible food ingredients that stimulate the growth of beneficial bacteria in the gut. Shown to improve gut health and reduce the growth of harmful bacteria, prebiotics can be used in place of antibiotics in poultry. Feed additives can also be made up of natural alternatives made of organic acids, such as acetic and propionic acid, which are added to animal feed to lower gut pH and reduce the growth of harmful bacteria, helping to prevent or treat bacterial infections. While natural feed solutions such as essential oils, such as oregano, thyme, and cinnamon are currently unregulated, the regulations surrounding probiotic and prebiotic solutions vary by location. For example, probiotics in the US, which are regulated by the FDA, hold a Generally Regarded As Safe (GRAS) status. In Europe, however, the EFSA has assigned probiotics to the Qualified Presumption of Safety (QPS) status, which involves added safety assessment criteria compared to GRAS.
The challenge of finding a viable alternative to agricultural antibiotics has generated much commercial and research activity. What follows is a list of some of the most prominent startups working on agricultural antibiotic alternatives.
AgThera develops novel antimicrobial products to eliminate both antibiotic-resistant bacteria and hard-to-treat viruses. Their core product is an antimicrobial protein (AMP) that kills pathogens in poultry such as Salmonella. The AMP improves farmers’ feed conversion ratio, while also reducing mortality. They are currently developing a line of AMPs for swine producers that is capable of treating diarrheagenic E. coli, Lawsonia intracellularis, and Streptococcus suis.
Pando Nutrition uses CRISPR technology to analyze the cattle microbiome and produce genetically engineered probiotics tailored to cattle performance. Their first product, MicroMethane, increases cattle productivity and reduces me thane emissions. It has been shown to reduce feed costs by 30%, cut methane emissions by 50%, and eliminate the need for antibiotics in treated cattle.
Elogium, a Latvian-based startup, specializes in probiotic solutions for broiler producers. Their probiotic feed additive increases the weight of poultry by up to 10% and reduces 96% of Campylobacter and Salmonella pathogens. The combination of these effects both increases the revenues of Elogium’s clients and helps them to comply with food safety regulations imposed by governments worldwide.
Phage Pharm is a leading professional enterprise in the industrialization of bacteriophages. Currently, their products cover the fields of poultry, livestock, aquatic products, vegetables, and fruits. They have also created the original “Nuo’an Model”, a leading technical service platform to provide bacterial butler services for farmers, and provide bacterial culture, isolation, purification, identification, drug resistance, and bacteriophage sensitivity detection services.
Mootral focuses on feed supplements that improve greenhouse gas emissions and lessen the need for antibiotic use in agriculture. Their first product, Mootral Ruminant, is a proprietary blend of garlic and citrus extract and is produced in pellet form. It is proven to reduce up to 38% of methane emissions in real farm conditions. It can also help increase yields, improve animal health, and reduce the number of flies.
Nutrivert is developing a postbiotic alternative to antibiotics in livestock. Their antibiotic-free feed additive, while still under testing, promises to increase livestock feed conversion efficiency, enabling customers to get better output from their livestock.
Mileutis creates and commercializes natural peptides for animal health. Their first products, Imilac and Milac, are residue-free intramammary solutions for cattle with mastitis and intramammary infections during the lactation period. Mileutis’ solutions significantly reduce antibiotic use in cattle while increasing productivity.
Along with startups, academic and research institutions, including partner universities of the Generation Food Rural Partners Fund, have been developing cutting-edge alternatives to agricultural antibiotics. For example, Purdue University’s Mohamed Seleem has created a technology that repurposes non-antibiotic drugs to treat bacterial infections. Similarly, at the University of Missouri, Shuping Zhang and Ming Yang have developed a set of beta-defensin peptide analogues as alternatives to antibiotics. These peptides have been “custom synthesized to enhance their broad spectrum antimicrobial properties as anti-infective therapeutics, food preservation agents, and vaccine adjuvants.” University-based research such as this is vital for establishing and developing the technologies needed to create alternatives to antibiotics.
The rise of antibiotic alternatives in livestock has led to several VC investments in the past three years in innovative startups. In early 2020, agricultural accelerator Sparklabs Cultiv8 poured $1 million into postbiotic developer Nutrivert. NovaQuest Capital Management’s $20 million investment into Israeli livestock peptide producer Mileutis in October 2020 has proven to be one of the largest in the space. However, smaller funding rounds have also attracted attention, such as Commercialization Reactor’s 2021 €50 thousand pre-seed investment into Elogium, a producer of broiler probiotics.
|VC/Funding Source||Notable Investments||Lead Investor?||Funding Round||Date|
|Commercialization Reactor||Elogium||Yes||Pre Seed||9/10/2021|
|National Science Foundation||AgThera||Yes||Grant||4/2/2020|
|FJ Labs||Mootral||No||Series A||7/20/2022|
|Earthshot Ventures||Mootral||No||Series A||7/20/2022|
|Novaquest Capital Management||Mileutis||Yes||Venture||10/19/2020|
While the ultimate question of which antibiotic alternative will gain the most traction among farmers remains to be answered, a broad shift away from continual antibiotic use is all but inevitable. As of 2021, probiotics seemed to be farmers’ primary alternative, with the market for probiotics in animal feed being estimated at $4.8 billion compared to the essential oil and plant extract for livestock market at $2.8 billion and the considerably smaller prebiotics in animal feed market at $25 million. While one solution may pull away with the lion’s share, each method brings its advantages, and ultimately a variegated approach may suit most farmers best.
As with many health-conscious solutions, the main driver of a shift away from agricultural antibiotics proves to be the continual progression of government regulation and public opinion. The U.S. and Europe have spent the past two decades shifting towards stricter regulation of non-medical antibiotic use in agriculture. 2006 saw the EU ban the use of antibiotics for growth-promotion purposes. In 2017, the FDA began implementing the Guidance for Industry #213, also known as the Veterinary Feed Directive (VFD). This guidance requires veterinary oversight of antibiotics delivered via feed or water and forbids the constant use of low-dose antibiotics. More recently, in 2021, the FDA published Guidance for Industry #263 which put in motion a framework to remove any remaining medically important antimicrobials from OTC marketing channels, closing loopholes from their 2017 decision. More regulation such as this will lead to greater opportunities for research and development in this space, boosting better and safer solutions for probiotics, phages, and other feed additives.
Exact cost comparisons between antibiotics and alternatives are difficult to calculate with precision, but studies from the Wageningen Economic Research Group from 2019 typically find that alternatives are expensive interventions at current prices. A 2015 USDA study found that “replacing antibiotics used for production purposes or disease prevention may thus require more labor, capital, or material on farms, raising production costs.” With questions lingering about whether probiotics, the largest antibiotic alternative by market size, offer a significant improvement in stopping antibiotic resistance, farmers may be unwilling to take on the burden of cost increases to make the switch. However, beyond individual farmers, it is important to keep in mind that in 2019 in the United States alone, 2.5 million antimicrobial resistance infections resulted in an estimated annual economic cost of more than $55 billion. Ultimately, the massive size of the antibiotics market, close to $50 billion in 2021, is a driving factor in creating cheap treatment options for the agricultural industry. However, as money continues to pour into alternatives, their cost will likely drop to a more competitive level.
Beyond cost discrepancies, a unique challenge of antibiotic replacements is a lack of standardization in their product formulation. Inconsistencies in the formulation of alternative treatments make it difficult for farmers to compare products, leading to purchasing confusion and disparities in treatment. A lack of product understanding among farmers often leads to low adoption and trust in products. Another hurdle in the adoption of new antibiotic replacement products is that the performances of alternatives are often inconsistent. Noelle Noyes, a veterinary epidemiologist at the University of Minnesota Twin Cities, describes the problem by saying that although there are many alternatives on the market, “we just haven’t identified even which bacteria need to be in those formulations, or the dosage, timing, or route of administration.” Additionally, a lack of standardization can make it difficult for regulatory agencies to approve alternative treatments, which can further limit their availability and use.
Non-medical use of antibiotics in livestock is facing ever-increasing regulatory hurdles, creating a blue ocean opportunity for innovation in alternatives for the promotion of livestock growth and treatment. The stronger the tie between antibiotic use in livestock and antimicrobial resistance becomes, the larger this opportunity grows. In recent years, antibiotic alternatives have come in the form of probiotics, bacteriophages, and other feed additives. While probiotics are currently the most popular alternative, the lack of a comprehensive evidence base for their ability to improve society’s dire AMR situation calls their alternative monopoly into question. In reality, a mixed strategy of all three alternatives outlined above, combined with responsible antibiotic use, has the potential to keep farmers productive and lower dependence on antibiotics for non-medical purposes. In terms of technology. Companies like Pando Nutrition and Mootral are using cutting-edge genomic technology such as CRISPR to produce high-efficacy products that can increase farmer productivity without the need for antibiotics, while also cutting methane emissions in the process. Their commitment to research and highly targeted products gives hope for solutions that avoid the pitfalls of antibiotics while offering farmers tangible benefits.