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Teaming up to tackle antimicrobial resistance

This article was originally posted by AgriLife Research.

This year, our country will see fewer approved uses for antibiotics in food animal production, following implementation of two guidelines from the U.S. Food and Drug Administration (FDA). These changes are among efforts around the world to combat a rise in antimicrobial resistance.

The push to use less antibiotics is surprising for some, considering that the advent of antibiotics helped add nearly 30 years to Americans’ life expectancy and decrease child mortality by 29 percent. And haven’t antibiotics made our food supply more abundant by helping livestock animals thrive?

Antibiotics and other antimicrobials — agents that inhibit the growth of bacteria, fungi, or viruses — are essential and widely used. Yet the spread of microbes that do not respond to antimicrobials threatens our ability to reap the benefits of many medications.

Antibiotic-resistant infections sicken at least 2 million people, kill an estimated 23,000, and cost the U.S. economy roughly $70 billion each year, according to the Centers for Disease Control and Prevention. While the exact causes and effects of antimicrobial resistance are still being studied, agriculture has an important role to play in understanding and mitigating the problem. Researchers, farmers, veterinarians, and national and international agencies are pursuing a wide swath of tactics to help control resistance. AgriLife Research in particular is involved at local, national, and international levels in many distinct ways:

  • conducting basic research,
  • promoting best practices,
  • developing new treatments against infections, and
  • promoting communication about and surveillance of outbreaks.

To help support and expand these life-saving efforts, we are requesting $6 million for 2018-2019 from the Texas Legislature. The scope of our efforts on antimicrobial resistance is vast. Below are several topics related to AgriLife researchers’ work.

Understanding resistance

Antimicrobial resistance is a complicated topic with no easy answers, says Dr. Elizabeth Parker, chief veterinarian for the Institute for Infectious Animal Diseases (IIAD) and AgriLife Research expert on livestock and animal health.

Antimicrobial resistance is an ancient phenomenon. Long before humans discovered antibiotics, microbes were producing substances that could hinder other microbes — these substances are the inspiration for all antibiotics used today. And for as long as microbes have been producing antibiotics, other microbes have been evading them. The discovery of each new antibiotic in the past 70 years has been followed by the discovery of bacteria that are not affected by it. We have seen the same phenomenon with antifungal, antiviral, and anti-parasite medications.

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Two types of bacteria found in the soil help explain how resistance to antibiotics develops. (Texas A&M AgriLife photo by Kathleen Phillips)

Antimicrobial-resistant (AMR) microorganisms are naturally found in humans, animals, soil, and water. When an antimicrobial kills non-resistant microbes, resistant microbes acquire more “living space” and multiply.

“Microorganisms have been around forever and it’s their job to survive,” Parker says. “They are continually modifying and changing.”

AgriLife scientists are finding new information on the exact mechanisms of resistance. This work can pave the way toward creating new treatments and optimizing older ones, refining best practices for treating infections, and much more.

For example, Dr. Paul Straight, AgriLife Research biochemist, has focused on understanding how communities of bacteria interact. In a study published in PLoS Genetics in December 2015, Straight and his doctoral student Reed Stubbendieck identified a novel antibiotic molecule and understood how resistance to that molecule arises, as well as the microbial genes that are responsible.

Building a detailed picture of competition between bacteria “helps us understand what happens in soil or inside a human intestine,” Straight remarked in an AgriLife Today story. Understanding microbial communities can help explain not only how resistance develops, but also how to control it.

Toward new treatments

Controlling resistance is highly important for a disease such as tuberculosis, where the world has seen a rise in cases that are resistant to most typical treatments, according to Dr. James Sacchettini, Texas A&M AgriLife Research biophysicist, director of the Center for Structural Biology, and director of the TB Structural Genomics Group at Texas A&M University.

Sacchettini’s lab has recently developed a technique for identifying features of Mycobacterium tuberculosisthat new drugs could target. Using this method, the lab identified bacterial genes previously unknown to be linked to drug resistance. These genes are not directly affected by existing tuberculosis drugs and provide clues toward the discovery of new treatments.

Transmission electron micrograph of multiple bacteriophages attached to a bacterial cell wall; the magnification is approximately 200,000. (Image credit: Dr. Graham Beards/CC-BY-SA-3.0)
Transmission electron micrograph of bacteriophages attached to and inside a bacterial cell; the magnification is approximately 200,000. (Image credit: Dr. Graham Beards/CC-BY-SA-3.0)

Inventive ways to combat AMR infections include more than just creating new antibiotics. Another way to kill bacteria involves phages — viruses that infect bacteria but are harmless to humans or animals. “Long before humans were here, bacteria and phages were fighting it out in the soil,” says Dr. Ryland Young, professor of biochemistry and biophysics and director of the Center for Phage Technology (CPT) at Texas A&M.

Infections might be treated with a cocktail of several different strains of phage that attack the same type of bacteria. “Any two phages targeting the same bacterium are likely to be as similar as a whale and a platypus,” Young says. While bacteria might develop resistance to one strain of phage at a time, they cannot evade many different strains at once. And unlike broad-spectrum antibiotics, phages used to treat an infection would have no effect on beneficial bacteria that are important for human and animal health.

The CPT works to advance the application of phages to combat bacterial infections, promote food safety, and protect against bacterial contamination. The center’s faculty and staff collaborate with academics, research enterprises, and companies. The CPT also provides protocols for phage-related research as well as bioinformatic tools for studying phage genomes.

Widespread clinical applications of phages are still a long way away in the United States, Young says, but phages are being used to treat infections on a case-by-case, “compassionate use” basis. When a patient is in danger of dying from an infection after all approved treatments have failed, a physician can ask the FDA for approval of phage therapy.

Phages are being used commercially to treat plant diseases and have been approved by the FDA for a number of food-safety applications, such as decontaminating foods and food preparation surfaces. Food safety can prevent food-borne infections and sidestep the need for antimicrobials.

Preventing infections through food safety

Raw oysters treated with electron-beam radiation may be less likely to cause food poisoning. (U.S. Department of Agriculture — Agricultural Research Service photo by David Kingsley)
Raw oysters treated with electron-beam radiation may be less likely to cause food poisoning. (Credit: U.S. Department of Agriculture — Agricultural Research Service, photo by David Kingsley)

Using phages is just one of many inventive ways to increase food safety. For example, Dr. Suresh D. Pillai, a molecular microbiologist and an AgriLife Research Faculty Fellow who directs the National Center for Electron Beam Research at Texas A&M, uses a completely different strategy for dealing with antibiotic resistant microorganisms. His center has been at the forefront of using high energy electrons (eBeam technology) to shred the DNA of antibiotic-resistant pathogens and other organisms in foods, animal feeds, water, and animal waste. His strategy is to permanently inactivate all pathogens, antibiotic resistant or not, so the issue of antimicrobial resistance becomes moot.  The center works with the government, private industry, and the International Atomic Energy Agency to expand this technology to address not only antimicrobial resistance but the bigger issue of microbial pathogens and spoilage organisms in foods, feeds, and wastes.

Pillai writes in a recent review that eBeam pasteurization technology significantly reduces risk of viral and bacterial infections deriving from contaminated foods. This technology can safely and without any chemical residues decrease or eliminate viruses, bacteria, insects, and parasites from various food items. The technology is gaining in popularity around the world, and irradiated raw oysters, spices, ground beef, and fruit are now available in U.S. grocery stores.

Antimicrobial stewardship in poultry production

Historically, poultry have often been treated with antibiotics for disease prevention, which improves growth. However, the poultry industry is largely moving away from this practice due to pressure from consumers, says Dr. Craig Coufal, associate professor and AgriLife Extension expert in poultry science.

A look inside Dr. Craig Coufal’s egg sanitizing machine. (Texas A&M AgriLife Extension Service photo by Robert Burns)
A look inside Dr. Craig Coufal’s egg-sanitizing machine. (Texas A&M AgriLife Extension Service photo by Robert Burns)

Coufal has been exploring alternative ways to reduce pathogens and keep chickens healthier. Eggs in hatcheries used to be injected with antibiotics because the practice led to fewer losses and healthier chicks. After many years of research, Coufal developed a machine for sanitizing hatching eggs with hydrogen peroxide and ultraviolet light, thus reducing losses due to microbial contamination. “A lot of people in the poultry industry are interested in this approach,” he says. Coufal has also evaluated an innovative and cost-effective method for heat-treating chicken litter, resulting in reduced microbial populations and healthier flocks.

He encourages producers to follow time-tested practices such as keeping young chicks warm and disinfecting their drinkers and feeders regularly. Antibiotics have sometimes been used to fix management problems that resulted in reduced bird health. “If you didn’t keep things exactly spic and span, you could sometimes address the problem with antibiotics,” Coufal says. Now, producers have an opportunity to revisit the basics of good husbandry.

The basics of good husbandry extend to the ways animals are handled, transported, and raised. For example, beef producers can raise healthier calves by implementing programs such as the Value Added Calf program, or VAC 45, where calves are weaned 45 days before they are sold and receive two sets of booster vaccines to enhance their immunity to disease — decreasing the need to treat them with antibiotics.

Judicious use of antimicrobials

Some drug-resistant infections take root in hospitals, where antibiotics are heavily used and patients with weakened immune systems abound. Other such infections appear when people overuse antibiotics outside the hospital setting. Yet others appear in livestock and can affect humans through contaminated meat or through plants that were fertilized with contaminated manure.

Antibiotic-resistant food-borne bacteria “are the most direct link between antibiotic use in agriculture and potential impacts of resistance on human health,” says Dr. H. Morgan Scott, professor in the Department of Veterinary Pathobiology at the Texas A&M College of Veterinary Medicine & Biomedical Sciences (CVM).

An illustration of carbapenem-resistant Enterobacteriaceae, a family of germs that includes Salmonella and E. coli. Image credit: CDC/James Archer
An illustration of carbapenem-resistant Enterobacteriaceae. Enterobacteriaceae are a large family of germs that includes Salmonella and E. coli. (Image credit: CDC/James Archer)

Scott has long worked to study and combat antimicrobial resistance. He works with agencies such as the World Health Organization, and he has recently received a $1 million research grant from the USDA National Institute of Food and Agriculture to better define and encourage antimicrobial stewardship.

Using any antibiotic, for any purpose, increases resistance in the long run. While working to decrease agriculture’s reliance on antibiotics, we must keep in mind the situations where not using antibiotics would prolong suffering or cause the death of an animal. Deciding which uses of antibiotics are the most judicious is the quandary underlying antimicrobial stewardship.

As of January 2017, drug manufacturers and animal agricultural groups have voluntarily implemented FDA guidelines to change how medically important antimicrobials are administered to animals. Through these guidelines, the FDA “indicated that they no longer believe the use of antibiotics to promote growth is a ‘judicious use,’” Scott says. Manufacturers also have changed drug labels to ensure the oversight of a veterinarian before medically important antimicrobials can be put into water and animal feed.

Scott promotes the idea that those in the agricultural industry become antimicrobial stewards, following their own ethical principles such as “First, do no harm,” rather than rigid rules, which sometimes contain loopholes.

One such loophole remains on the product labels of some antibiotics, Scott says. According to these product labels, animals cannot be slaughtered for a certain number of days after completing treatment, making sure that no antibiotic residues contaminate the meat. Yet the labels do not address the problem that antimicrobial-resistant bacteria may be present in elevated numbers beyond this withholding period.

“What are the obligations of farmers, ranchers, and veterinarians to voluntarily withhold those animals from market until resistance returns to normal, which it will after some additional period of time?” Scott says. “Those are things we are exploring at the moment.”

Appealing ethical frameworks have already been developed, he says. For example, livestock producers might try to keep resistant microbes from escaping the farm at levels higher than baseline. “Zero is not feasible because there is resistance to all antibiotics somewhere in the world. But baseline is a measurable metric,” Scott says. Let’s say that before treatment, 10 percent of bacteria are resistant to a certain antibiotic. After antibiotic treatment you would aim to restrict manure, food, and water runoff leaving the farm until the levels are once again no higher than 10 percent.

This approach would add costs due to monitoring levels of AMR bacteria, Scott says, but it provides a foundation for a comprehensive program of antibiotic stewardship.

Seeking solutions at every level

IIAD’s Parker has extensive experience working with national and international groups. She is using that experience to help build IIAD’s and A&M’s network of collaborations to better understand and control infectious diseases in animals, including AMR infections.

One global collaboration is the tripartite partnership between the World Health Organization, the World Organization for Animal Health (OIE), and the Food and Agriculture Organization of the United Nations (FAO). These agencies have created a global action plan that links human- and animal-related efforts in combating antimicrobial resistance. In addition, OIE is assisting countries by reviewing veterinary services laws and regulations that are helpful for this topic and identifying gaps. OIE is also developing a global database on the use of antimicrobials in animals. FAO is assisting countries in developing national action plans, Parker says, and IIAD is poised to help these global efforts. The United States already has such an action plan: The U.S. National Action Plan for Combating Antibiotic-Resistant Bacteria.

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IIAD program coordinator Sarah Caffey, MPH (right), works with swine industry representatives during an AgConnect® Emergency Exercise. (Image credit: Lesa Muehlstein/IIAD)

IIAD has also been creating software tools such as AgConnect®, which enables producers, veterinary practitioners, diagnostic laboratories, wildlife biologists, and other data providers to contribute to an animal health and disease detection and control surveillance system. Mobile applications that feed data into AgConnect® have fields to help track judicious use of antibiotics.

At a local level, AgriLife and CVM scientists participate in AgriLife Extension programs that educate everyone from kids in 4-H to veterinarians and producers. They also work with state associations for beef cattle, dairy, swine, and poultry producers.

The world is certainly seeing an increase in antibiotic resistance, says CVM’s Scott. A person can no longer go to a hospital with a bacterial infection and know with certainty that an antibiotic is available to treat them. That is a massive shift from just a decade or two ago.

“We all have a role to play and we all have a responsibility for this,” he says. “What we can do in our corner of the world is to know that what we are doing is of the highest ethical standards and follows best principles and relies on the best science.”

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