Resistance fighters

For more than 100 years, antibiotic drugs have been successfully fighting diseases caused by pathogenic bacteria. These drugs (sometimes called antimicrobials) have saved the lives of countless people who might otherwise have died from infections. But this very success may have created a crisis of its own.

Because microbes constantly adapt to their environments, including mutating and acquiring new genes, some have evolved an ability to resist all the drugs used to defeat them, in effect becoming “superbugs.” In some instances, resistance means that drugs are less effective than usual, but sometimes it means they fail completely. In the U.S. alone, antibiotic-resistant infections occur annually in nearly 2 million people, causing more than 23,000 deaths.

“Antimicrobial resistance is one of the biggest problems we face in this century,” said Dr. Susan Sanchez, professor of infectious diseases in the College of Veterinary Medicine. Sanchez, pictured above holidng petri dishes with salmonella, also is chair of UGA’s One Health Initiative, an interdisciplinary approach that recognizes resistance can arise in and be complicated by interactions of humans, animals and the environment.

“Bacterial infections that are treatable today may kill people and their pets in the not-so-distant future if more antibiotics are not developed or we don’t find a way to stop the spread of resistance,” Sanchez said.

“However,” she continued, “we won’t solve this huge problem without an interdisciplinary research effort that provides an accurate picture of the complex interrelationships of antibiotic resistance in people, our pets and our food supply. Humans, animals and the environment-we are all in this together.”

Antibiotic resistance has become such a danger that the World Health Organization (WHO) last year declared it a threat to global health and human development. This February, WHO published its first-ever list of antibiotic-resistant bacteria that pose the greatest threat to human health.

The emergence of antibiotic resistance stems largely from overuse of antibiotics in humans and animals. And the numbers are staggering: In the U.S., one third to half of all antibiotics prescribed to humans are unnecessary or incorrectly prescribed. Antibiotic use in food animals is estimated to account for approximately 80 percent of the nation’s annual antimicrobial consumption.

In 2016, Congress appropriated $160 million to fight antibiotic resistance by increasing our ability to detect, prevent and control resistant infections. Focused through the lens of the One Health initiative, University of Georgia researchers are among those seeking answers to why microbes that affect animals and people build resistance to antibiotics.

Sanchez said UGA researchers’ findings could not only speed our understanding of why certain bacteria become resistant to antibiotics but also determine when they can be used appropriately by farms and veterinarians, and ultimately, improve the health of people and animals.

Resistance on the farm

The intensifying concern about antibiotic resistance has prompted significant changes in the use of antibiotics to prevent and treat illness in livestock and poultry. Over the past several years, farmers and ranchers have been urged to phase out the indiscriminate use of antibiotics in cattle, pigs and chickens raised for meat. Beginning this year, federal guidelines require veterinary oversight to authorize use of antibiotics important to human medicine in cattle feed and water, and these drugs are now prohibited for use in growth promotion.

Dr. Brent Credille, an assistant professor of beef production medicine at the College of Veterinary Medicine, became interested in antibiotic resistance after investigations in Georgia cattle with bovine respiratory disease showed they had an antibiotic-resistant strain of the bacterium Mannheimia haemolytica.

“Cattle in these herds would respond to almost nothing we had available,” Credille said. Yet, he said, “There was no history of exposure to those antibiotics.”

In a recent study published in the Journal of Animal Science, Credille and his team tested specific populations of calves in Georgia to determine the prevalence of antibiotic resistance. First, his team took upper airway swabs before the animals were mass administered an antibiotic for disease prevention. At that point, just 16 percent of calves carried the bacteria that cause respiratory disease. But when a second sample was taken 14 days later, almost 75 percent of the calves were carrying M. haemolytica bacteria, despite having received an antibiotic. Almost all of the bacteria found in these calves were of a multi-drug resistant strain, Credille said.

“There’s no question that the use of antimicrobials in beef cattle production affects resistance to multiple different antimicrobial drugs,” he said.

Credille frequently speaks to farm and agribusiness leaders about increasing antibiotic resistance in farm animals, advising them to focus on antimicrobial stewardship.

“Is there something that’s not an antibiotic that would work just as well? Could we use management to prevent the disease instead of just treating cattle all the time?”

As part of its mission to study problems of importance to the poultry industry-Georgia’s largest agricultural segment-UGA’s Poultry Diagnostic and Research Center (PDRC) studies the use of antibiotics fed to chickens. Unraveling the mysteries of antibiotic resistance in poultry has become a major focus.

A decade ago, a team led by Dr. Margie Lee, professor of infectious diseases in the College of Veterinary Medicine and director of the PDRC diagnostic lab, discovered that even chickens raised on antibiotic-free farms have high levels of antibiotic resistance to commonly used drugs. Her counterintuitive findings suggested that poultry come to the farm harboring resistant bacteria, possibly acquired as the chickens were developing as eggs.

About three years ago, Lee’s research turned to how feeding antibiotic alternatives-such as probiotics and prebiotics-to chickens might affect antibiotic resistance found in chicken litter. A mixture of chicken manure and sawdust or other bedding material, chicken litter is commonly used by farmers and gardeners to fertilize and condition soil. For organic farmers, it is especially desirable because of its high nitrogen content.

But when Lee and colleagues analyzed the data from farms where the birds had been treated with the antibiotic alternatives and no antibiotics, they discovered no difference. “Basically, nothing reduced the concentration of antibiotic resistance,” Lee said.

Lee’s explanation is not terribly encouraging. “What we’re tilling into the soil are antibiotic-resistant genes at incredibly high numbers,” she said. “I think we’re going to see many more antibiotic-resistant infections coming from people who eat a lot of organic produce. I can’t see how the produce won’t be contaminated by this.”

To address this problem, Lee recommends a focus on remediation. She has advised the U.S. Department of Agriculture to take that route in its antibiotic resistance research program, which could lead to new rules for users of chicken litter.

“We have polluted the environment,” she said. “What do you do to fix it?”

In our food 

The CDC estimates that 48 million Americans-1 in 7-get sick from food or beverages every year, chiefly from food contaminated with bacteria originating from animal intestines. Food can come in contact with bacteria at any point along the “farm-to-fork” chain — from the farms and fields where food is raised until the time it is consumed. If those bacteria are resistant to antibiotics, the resulting infection may not respond to antibiotics.

“The main issue with antimicrobial resistance in zoonotic foodborne pathogens is antibiotic use at the farm level,” said Francisco Diez-Gonzalez, director of the Center for Food Safety at UGA’s campus in Griffin. There, Diez and other scientists conduct research to detect, control or eliminate pathogenic microorganisms or their toxins in foods.

The current thought, Diez said, is that limiting the use of antibiotics on the farm — whether growing produce or raising cattle or poultry-is going to contribute to reducing the presence of antibiotic resistance in bacteria.

Salmonella, Diez said, is “the number one bacterial pathogen in the U.S. — and probably in the world — because it is ubiquitous in nature, and it’s hard to get rid of.”

While eggs, raw milk, meat and poultry are the most common sources of contamination, Salmonella may also contaminate fresh produce through contact with infected animals or other environmental sources. It even survives in foods that have almost no water, Diez said. Recent outbreaks have been detected in foods ranging from chocolate and nuts to dried spices, and even flour.

Its widespread presence means foodborne illnesses from Salmonella are common: It sickens 1 million Americans annually. While most Salmonella infections in humans are limited to acute gastrointestinal illness, it can cause severe infections requiring treatment with antibiotics.

And, Diez said, multiple strains of Salmonella now show resistance to five or more antibiotics used in humans.

There is, however, a glimmer of good news about Salmonella. Ongoing surveillance by the National Antimicrobial Resistance Monitoring System — a collaborative effort of CDC, the U.S. Department of Agriculture and the U.S. Food and Drug Administration — has recently shown steady or declining antibiotic resistance of some strains of Salmonella found in humans, poultry and meat. While some of these trends are promising, the emergence of antibiotic resistance traits continues to be a concern.

In our pets 

On any given day in the Athens Veterinary Diagnostic Lab in the College of Veterinary Medicine, researchers test samples sent in by veterinarians across the state from sick or wounded animals, ranging from domestic animals to wildlife to zoo animals.

Being on the front lines of animal disease diagnosis, Sanchez has spotted trends, such as new strains of Salmonella, ahead of health agencies like CDC. She was among the first researchers to identify methicillin-resistant Staphylococcus aureus (MRSA) strains that were horse- and dog-specific after seeing the illnesses in pets whose owners were sick first.

“We’ve seen an increase in antibiotic resistance in many bacteria found in dogs, similar to what’s happening in people,” Sanchez said. “That’s concerning, and we need to do something about it.”

The extent of the problem is unknown, however, because there are no regulations to track antibiotic use in companion animals. Sanchez said a broad team effort is needed to find the resistant organisms so that researchers can better guide veterinary practitioners on treatment of sick pets. As part of CDC’s Developing Healthcare Safety Research program, UGA’s Athens Veterinary Diagnostic Lab will collect information about antibiotic resistance in dogs to create a searchable database.

And in our water

The third pillar of One Health — environment — is often overlooked because it’s not as well defined as “animals” and “humans.”

Erin Lipp, professor of environmental health science in the College of Public Health, said that neglect is unfortunate because the environment is “the integrator of all these things.”

Lipp studies water, waterborne disease and microbial ecology of pathogens. And water, she said, “is the ultimate integrator.”

She said runoff from agricultural land and septic systems, and even discharge from water treatment systems, all eventually end up in streams, rivers and oceans where people and animals are exposed through drinking, swimming and other activities. The runoff includes antibiotics to prevent and treat disease in animals and humans.

Wastewater is especially concerning, Lipp said. “It’s a big milieu of bacteria, where they can exchange and acquire genes that may be resistant to antibiotics.”

In collaboration with UGA’s Marine Extension, Lipp and student researchers are studying how triclosan, an antibacterial ingredient found often in soaps, cosmetics and some plastics, affects natural bacterial populations, especially Vibrio, in southeastern coastal waters. Triclosan reaches the coast through sewage discharge.

Lipp’s research group found an increase in antibiotic resistance to triclosan among Vibrio and will be continuing its research to find out if triclosan resistance also can result in resistance to other antibiotics.

Lipp noted that while triclosan is being phased out of consumer products, “the half-life of triclosan is decades,” meaning it will persist in the environment for many years to come.