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The Search for Alternatives to Antibiotics

Ask any doctor or veterinarian to rate the important medical discoveries of the past century, and antibiotics would surely be at or near the top of the list. In this century, too, antibiotics are expected to remain an essential tool for treating animal and human diseases.

But the “miracle of antibiotics” is being threatened. There are clouds hovering over their use in both human health and animal agriculture — with antibiotic resistance casting perhaps the largest shadow.

According to the U.S. Centers of Disease Control and Prevention (CDC), antibiotic resistance occurs when bacteria change (or mutate) in a way that reduces, or even eliminates, the effectiveness of drugs such as antibiotics, chemicals or other agents that could otherwise be counted on to cure or prevent infections. On the health front, that matters because antibiotic-resistant bacteria survive and continue to multiply, causing more harm.

Over time, warns the Food and Drug Administration’s (FDA) Center for Veterinary Medicine, the use of antibiotics and other microbial drugs will further complicate health workers’ efforts to select the appropriate antimicrobial for treatment. FDA provides an animation explaining how antimicrobial resistance both emerges and proliferates among bacteria on its website.

In the case of food safety, foodborne antibiotic-resistant bacteria have already made their way into the food chain, which makes curing people sickened with the bacteria all that more challenging. According to a Sept. 2013 report released by the Centers for Disease Control and Prevention, of the 18 drug-resistant organisms highlighted as “alarming,” four are foodborne organisms: Campylobacter, E. coli, Salmonella and Shigella.

The report also pointed out that resistant bacteria in food-producing animals are of particular concern because these animals serve as carriers. Resistant bacteria can contaminate the foods that come from those animals, and people who consume these foods can develop antibiotic-resistant infections.

Are we headed for a post-antibiotic era?

Bacteria in a petri dish can’t grow near samples of antibiotics to which they are susceptible (left), but when they have developed resistance, the antibiotic cannot keep them from growing around it (right).
Image courtesy of CDC

In April this year, a report from the World Health Organization outlined a picture of the resistance problem on a global scale, warning that this serious threat is no longer a prediction for the future.

“It has happened right now in every region of the world and has the potential to affect anyone, of any age, in any country…and is now a major threat to public health,” says the report.

Dr. Keiji Fukuda, WHO’s assistant director-general for Health Security, put it this way: “Without urgent coordinated action by many stakeholders, the world is headed for a post-antibiotic era, in which common infections and minor injuries that have been treatable for decades can once again kill.”

He didn’t stop there. Pointing out that effective antibiotics have been one of the pillars allowing people to live longer, be healthier and benefit from modern medicine, he had this warning to share.

“Unless we take significant actions to improve efforts to prevent infections and also change how we produce, prescribe and use antibiotics, the world will lose more and more of these global public health goods, and the implications will be devastating.”

No wonder, then, that the search is on for alternatives to antibiotics.

A hot topic

“There is a huge amount of interest in this. It really is a hot topic,” Hyun Lillehoj, a research molecular biologist at USDA’s Agricultural Research Service, told Food Safety News.

An example of this interest, she said, is the audience of 600 people who attended her presentation about developing alternative strategies to reduce the use of antibiotics by using phytochemicals — a talk she gave during the 2014 Joint Annual Meeting this summer in Kansas City.

Phytochemicals are natural chemicals found in certain plants that are believed to benefit health. Feed additives derived from a wide variety of plants and herbs, such as garlic, cinnamon and other spices, have been shown in experimental clinical studies to benefit food animal health and production.

The Joint Annual Meeting that Lillehoj spoke at was hosted by the American Dairy Science Association, the American Society of Animal Science and the Canadian Society of Animal Science. Its theme was “Linking animal science and animal agriculture: Meeting the global demands of 2050.”

As for finding alternatives to antibiotics, Lillehoj, who in September was inducted into the Agricultural Research Service’s Science Hall of Fame, said that “there are many different strategies we can use.”

But she also pointed out that there’s no silver bullet — no one answer or strategy — that will replace antibiotics, in large part because there are so many different conditions livestock and poultry are raised in and so many different breeds. A farmer in Tunisia, for example, is going to be facing different challenges than a farmer in China or in the United States.

“I believe scientists should be proactively working to develop science-based alternative strategies to reduce the use of antibiotics,” she said. “That is the focus of my research here for poultry.”

She was quick to say that many companies have already taken proactive steps to reduce their use of antibiotics.

Hyun Lillehoj, molecular biologist at ARS Animal Biosciences and Biotechnology Lab
Photo courtesy of ARS

As a trained immunologist with 20 years experience in this field, she believes that some important headway can be gained by taking a closer look at the immune system.

The immune system protects a person, an animal, or other organisms from becoming infected by dangerous foreign intruders. These “intruders” could include foodborne pathogens such as Salmonella, E. coli and Campylobacter.

Reading reports Lillehoj has co-written about research done on alternatives to antibiotics reveals that this is indeed a complex topic with no easy answers waiting in the wings. Much of it calls for yet more research.

Even so, Lillehoj said she sees huge opportunities to use immunology to benefit animal health.

“Why don’t we activate the immune system,” she posited, referring to an approach that would include modulating the immune system to enhance disease resistance and to treat sick animals.

Cyril Gay, a senior national program leader with the USDA, working with the agency’s National Animal Health Program, would agree. He describes what he refers to as the gut microbiome as a “promising new area of research.”

Simply put, the gut microbiome, which lives in the gastrointestinal system, contains tens of trillion of beneficial microbes, including an estimated 1,000 different species of bacteria. In humans, that’s ten times more than all the other microbes in and on the body. As such, the microbiome plays a critical role in human and animal health for many reasons: It helps digest certain foods, fights off microorganisms that could be harmful and plays an important role in the development of the immune system.

Gay said that one of the important questions being asked by scientists right now is whether shifts in populations of gut bacteria that result from certain dietary alternatives, such as probiotics and phytochemicals are associated with beneficial outcomes or are the result of interactions with the cells of the gut wall.

Probiotics are “live microorganisms which, when administered in adequate amount, confer a health benefit to the host,” according to Gut Microbiota Worldwatch. In humans, they are commonly consumed as part of fermented food, such as yogurt, and dietary supplements.

Both Gay and Lillehoj agree that finding alternatives to antibiotics in animal agriculture is going to take a keen understanding of the mechanisms of action, including an animal’s innate immune and digestive systems. As such, USDA has started a website as a resource on science-based information of the development of alternatives to antibiotics.

“What’s becoming more and more apparent is that there is a need to integrate nutrition, health, and disease research,” Gay said in an e-mail to Food Safety News.

Taking a similar tack, Loren Laine, professor of medicine at Yale University and president of the American Gastroenterological Association, told federal legislators during a videotaped presentation to Congress that “one of the most exciting and promising areas of science is the gut microbiome.”

And though he was talking about human health, his comments also pertained to animal health.

“There’s no question that understanding and manipulating the gut microbiome will be important in impacting diseases in the future,” he told the federal legislators.

What about organics?

Organic producers are not allowed to use antibiotics, or, if they do, in the case of treating a sick animal or bird, they can’t sell the meat, milk or dairy products as “organic.”

For George Vojkovich, co-owner of Skagit River Ranch, which produces and sells pasture-raised organic beef, broilers, pork and eggs, it all comes down to good animal husbandry.

His farming practices include building the soil, culling animals with genetic tendencies for certain health problems, using selective breeding, rotational grazing, planting a diversity of grasses and legumes and making sure the animals get the trace minerals they need.

“There’s no silver bullet in any of this,” he said in an interview at his ranch in Western Washington, echoing Lillehoj’s outlook. “We build an animal’s immune system through nutrition. We look at food as medicine for the immune system.”

As for cost, his customers are happy to pay $6.75 a pound for the ranch’s turkeys and $20 or more for its whole broiler chickens. But Vojkovich said that the benefits of eating food raised organically is actually an investment in health.

Surveys have repeatedly shown that consumers who seek out organic foods are willing to pay higher prices for it.

Oregon dairy farmer John Bansen, who switched over to organic dairying 15 years ago, said he did have some apprehensions about doing so. When he was raising his cows conventionally, he used antibiotics to prevent mastitis when drying up his cows after their milking cycle was over.

“All of the articles said you needed to treat them with antibiotics, so every cow got treated,” he said. “I never really knew that I actually needed to do that. I just listened to the so-called experts.”

For him, raising healthy cows is a matter of making sure that the good bacteria outnumber the bad bacteria.

“It can’t be about ‘no bacteria,'” he said.

He also believes that when the bacteria in the gut is healthy, the whole cow is healthy.

“You don’t want to subtract from a cow’s natural immune function,” he said. “Our job isn’t to replace her immune system with antibiotics and vaccines.”

He makes sure not to push his cows past what’s “biologically doable” to get more milk from them.

“If an animal is stressed, it has trouble fighting harmful bacteria,” he said.

He has his doubts about whether this can be achieved in what he calls “industrial-sized” farming operations.

“When you overcrowd animals, it whistles in problems,” he said.

Big vs. small

Although many people believe that smaller “family-size” farms are the only places where animals and poultry can be raised without an excessive use of antibiotics, veterinarian Charles Hofacre, professor at the University of Georgia’s Center for Food Safety in the Avian Medicine Department, would disagree.

He said that raising animals and poultry in large-scale farming operations without pumping them full of antibiotics is being done every day and has been done for the 30 years that he’s been a poultry veterinarian.

“A small subset of very vocal people feel we should not raise food animals in a way to make a safe and affordable supply of meat to help feed the world, so they make it sound like the animals are not being well-taken-care-of,” he said.

Hofacre and another veterinarian explain antibiotic use in the poultry industry and antibiotic resistance in a video. Hofacre and another veterinarian explain how the health of the birds in a 25,000-bird broiler operation is maintained and monitored and the role of veterinarians in this sort of operation.

Farmers and consumers united in desire for solutions

For farmers, the fear is that if antibiotics are overused, their animals or poultry will become immune to these drugs, something that some farmers have already seen. As a result, they’ll have fewer options to turn to when they need to treat a sick animal.

Another concern farmers have is that many consumers are seeking out meats and poultry products from animals that haven’t been treated with antibiotics. (This trend is happening even though any meats or poultry or dairy products showing traces of antibiotics are banned from the marketplace.)

Then, too, farmers are seeing ever-increasing regulatory restrictions on the use of subtherapeutic antibiotic growth-promoters in animal production. The U.S. Food and Drug Administration recently released guidance intended to phase out, by 2016, the use of medically important antibiotics in food animals for growth enhancement. It has also proposed a directive that ensures that all antibiotics administered to food-producing animals are given only under the care and prescription of a licensed veterinarian.

Veterinarian Hofacre told Food Safety News in an email that the pharma companies are not doing research on producing any new antibiotics for food animals because they don’t see that there’s going to be any chance for approval — unless there is an antibiotic that doesn’t have a human equivalent.

“That means we will have fewer options to treat animals when they get sick,” he said. Pointing to work done by Scott Russell at the University of Georgia, Hofacre said that “sick birds have a higher chance of having foodborne bacteria, so we need to keep them healthy. That is why so much of what a poultry veterinarian does is preventive medicine.”

Meanwhile, two classes of antibiotics, flouroquinolones and cephalosporins, which the FDA deems to be critically important to human medicine — especially for treating foodborne illness in humans — have been phased out of chicken production for a number of years, according to the National Chicken Council.

For consumers, the main fear is that they’ll be infected with antibiotic-resistant bacteria when they eat an infected animal’s meat. That’s especially worrisome because some of the antibiotics that would normally be effective against a foodborne pathogen such as Salmonella, E. coli or Campylobacter can’t, or won’t, be able to be used to treat the sick person. And some of these bacteria can also be resistant to more than one antibiotic.

Although the CDC points out that the majority of drug-resistant infections occur in hospitals, it also says that there’s growing concern over antibiotic-resistant infections from food.

New task force formed

Two agricultural heavy-hitters — the Association of Public and Land-grant Universities and the Association of American Veterinary Medicinal Colleges — have joined forces to create the Task Force on Antibiotic Resistance in Production Agriculture, according to to a Nov. 17 press release from The Ohio State University’s College of Food, Agricultural and Environmental Sciences.

The task force is made up not only of representatives from universities and veterinary colleges but also from animal agriculture and the pharmaceutical industry.

The goal of the task force is to help advise the federal government on a research agenda and also to help provide information to the public about the use of antibiotics in production agriculture.

Growing concerns about antibiotic resistance in veterinary and human medicine among scientists and the public provided the necessary push to create the task force.

“The task force will draw on the expertise of its members to serve as a knowledgeable and important source of advice for the federal government as it develops its plans,” said Dr. Lonnie J. King, chair of the task force and dean of The Ohio State University College of Veterinary Medicine, in a press release. “It can also make recommendations on further research that should be undertaken to develop alternative solutions for some antibiotic use in production agriculture.”

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Did you know?  

Antibiotic resistance: Sometimes it’s ‘natural’

If you think of bacteria as living beings that — like us — do whatever is necessary to survive, you’ll understand how antibiotic resistance is sometimes a natural response to that same survival instinct.    Here is some information from a June 2014 USDA report, Antibiotic Resistance in Agriculture, published in Crops, Soil and Agriculture.

The research was focused on environmental sources of  antibiotic resistance from bacteria that live in soil and water. According to the report, researchers are only now beginning to understand the complex relationships between antibiotic resistance in the environment and common agricultural practices such as using animal manure or biosolids for fertilizer or reclaimed wastewater for irrigation.  

  • Bacteria evolved antibiotic resistant genes naturally over millennia of evolution in order to survive in a hostile environment. These genes typically express proteins that give the bacterial cells the ability to either break down antibiotics or prevent their entry into the cells.
  • Genes that code for antibiotic resistance have been found in ice cores from the time of the woolly mammoths.    
  • Naturally resistant antibiotic resistant bacteria have also been found in soil from a 4-millions-year-old cave in New Mexico.  Even more amazing, the soil contained bacteria that was resistant to a suite of modern antibiotics — even some recently developed antibiotics.  
  • The same kinds of  antibiotic resistant genes in cattle and chicken waste have been found in Antarctic ice and the Sargasso Sea. In other words,  antibiotic resistant genes occur not only in agricultural environments but also in non-agricultural environments.  
  • Antibiotic resistance can occur in meat products from antibiotic-free animals. So even though putting limits on the use of antibiotics in agriculture is a good start, it is not necessarily going to be enough to keep antibiotic resistant bacteria from getting into the food chain.    
  • When antibiotics are used to trigger growth (weight gain) in animals, up to 75 percent of the dose is shed in the feces. As a result, these antibiotics may kill susceptible bacteria in the soil and water, thus potentially enriching the environment in antibiotic resistant bacteria.  
  • Just because antibiotic resistance is found in an environmental sample doesn’t necessarily mean it poses a threat to human health.  
  • A lot more research on naturally occurring antibiotic resistance in non-agricultural environments is necessary in order to identify increases (or decreases) triggered by agricultural practices.    

Information supplied here thanks to: Jean McLain , associate director of the Water Resources Research Center at the University of Ariizona and Lisa Durso, research microbiologist at USDA’s Agricultural Research Services, Lincoln, Neb. 

© Food Safety News
  • B. Obama

    This is an important issue! Kudos to Dr. Hyun Lillehoj and others for their efforts!