Resisting resistance: Scientists race to stay ahead of disease-causing microbes
By Pat Melgares
Nearly 90 years ago, Scottish scientist Alexander Fleming discovered penicillin, heralding the dawn of antibiotics to fight infections and protect humans from emerging diseases.
History indicates that the use of penicillin likely saved the lives of many wounded soldiers during World War II, in addition to countless others suffering from previously untreatable ailments.
But disease-causing microbes have survived since the beginning of time largely because of their ability to adapt. In fact, it wasn’t long after Fleming discovered penicillin that he realized that microbes had already become resistant to the medicine.
In a world of bacteria, fungi, viruses and parasites, science can never rest.
Kansas State University researchers involved with antimicrobial resistance, or AMR, are ramping up efforts to tackle the growing and deadly problem.
“In the mid-1980s, we were so bold as to say the era of infectious disease is behind us, that we’ve conquered infectious disease,” said Mike Apley, the Frick professor of production medicine and clinical pharmacology in K-State’s College of Veterinary Medicine.
“Bacteria aren’t smart, but there are billions and billions of them and they have mutations — and some of those mutations select for resistance to antibiotics,” he said.
Microbes ‘adapt and survive’
That’s the essence of antimicrobial resistance, which threatens human and animal health as the wave of resistant bacteria grows while the world’s production of new antibiotics and the effectiveness of existing antibiotics diminish. An antibiotic will kill most microbes for which it’s designed, but the surviving microbes develop resistance, ultimately making the antibiotic ineffective to future strains of the illness.
“AMR is a natural phenomenon,” said Brian Lubbers, director of the Clinical Microbiological Laboratory in the Kansas State University Veterinary Diagnostic Laboratory. “Bacteria are responding to a pressure from the environment — antibiotics. The bacteria try to adapt and survive just like any species.”
“The concern for the future is if we get an infection in the hospital, we may not be able to deal with it,” said Apley, who was appointed in 2015 to the Presidential Advisory Council on Combating Antibiotic Resistant Bacteria. “That would be catastrophic in a lot of different ways.”
According to a 2013 report from the U.S. Centers for Disease Control, a little more than 2 million human illnesses are caused annually by bacteria and fungi that are resistant to some classes of antibiotics. The CDC reports that 23,000 of these illnesses result in death.
The CDC also reports that illnesses and deaths attributed to antimicrobial resistance cost Americans $20 billion in additional health care spending and $35 billion in lost human productivity.
Protecting animal agriculture
A.J. Tarpoff, a beef extension veterinarian and assistant professor in K-State’s animal sciences and industry department, said concerns regarding antimicrobial resistance have led some to point a finger at animal agriculture, where antibiotics are a reliable way to prevent and treat diseases in food animals.
Tarpoff notes, however, that the agriculture industry has long been a good steward of antibiotics, and that some of the criticism may be due to a growing disconnect from farm life.
“With most of our population so far removed from the farm, many people have lost the understanding of how we care for animals, how we raise them, how we feed them, what diseases affect them and how we treat them and control diseases,” he said. “The average consumer who walks into a grocery store doesn’t understand how we raise these animals.”
Even so, K-State scientists like T.G. Nagaraja and Raghavendra Amachawadi are discovering new ways to reduce the use of antibiotics and still give animals protection from common diseases.
They’ve worked on research that tests the efficacy of two common minerals — copper and zinc — as additives in animal feed.
“Copper is not an antibiotic, but it does inhibit bacterial growth,” said Amachawadi, a microbiologist and assistant professor of clinical sciences at the College of Veterinary Medicine. “Plus, copper is economical and a natural alternative to antibiotics.”
The researchers identified a novel copper resistance gene, tcrB, in Enterococcus, bacteria common in hospital-acquired infections. Amachawadi said their study showed a connection between copper and two classes of antibiotics commonly used in animal agriculture: tetracyclines and macrolides.
“We have also shown a positive dose response to zinc supplementation to MRSA, or methicillin-resistant Staphylo- coccus aureus, a common skin bacteria in humans more simply known as staph,” Amachawadi said. “The use of antibiotic alternatives are becoming popular, especially as antibiotics are phased out for growth promotion and production efficiency.”
Nagaraja, university distinguished professor of diagnostic medicine and pathobiology at the College of Veterinary Medicine, noted that the researchers also found that bacteria eventually were developing resistance to copper and zinc.
“That is a significant finding,” Nagaraja said, “because no one expected that there could be a relationship between resistance to copper and zinc and antibiotic resistance.”
The findings led the two scientists to further pursue studies on other nonantibiotic alternatives, such as probiotics — naturally extracted, beneficial bacteria found in milk, cheese, yogurt and other foods — and vaccines.
“When you give antibiotics in feed and water, it goes to the gut, which has a lot of bacteria that are then exposed to a high concentration of antibiotics, so they are more likely to develop resistance,” Nagaraja said. “If you inject the same drug, it’s mostly under the skin, which means the gut bacteria are not exposed as much.”
Other recent projects further illustrate K-State’s efforts in deterring antimicrobial resistance.
In early 2016, K-State scientists were the first to note that feed ingredients could serve as a vector for disease. They have since conducted trials on feed additives that could reduce or eliminate the risk of contaminated feed infecting animals, including the use of medium chain fatty acids and other enriched products.
Another breakthrough occurred in late 2015 when Raymond “Bob” Rowland, a professor of diagnostic medicine and pathobiology, announced that he and colleagues at the University of Missouri had developed pigs that were resistant to the industry’s most deadly disease, porcine reproductive and respiratory syndrome, or PRRS.
The project took more than 10 years to develop as the scientists worked to breed pigs that lacked a vital protein that had previously made them susceptible to the disease.
“At the very least, the development of PRRS-resistant pigs is a new tool for improving pig well-being and reducing economic losses,” Rowland said. “At the most, it could be the beginning of a revolution that will eradicate many of the most important livestock diseases that affect global animal and human health communities.”
Veterinarians help producers
In fall 2016, the U.S. Food and Drug Administration awarded $1.5 million to Apley and his colleagues to monitor antibiotic use in beef cattle feedlots and dairies. Data will be collected from 30 feedlots and 32 dairies in California, Kansas, Texas, Colorado, Nebraska, Iowa, Pennsylvania and Minnesota.
“We are fortunate to have the collaborative assistance of both the beef and dairy industries, and the U.S. Department of Agriculture’s Center for Epidemiology and Animal Health,” Lubbers said. “With their help, we aim to create usable systems that can be adopted by agriculture to understand and continuously improve our antibiotic use practices.”
On Jan. 1, 2017, new FDA regulations expanded the veterinary feed directive, which requires producers to receive written guidance from a veterinarian to use medically important antibiotics in animal feed.
“Most producers out there already have this relationship with the veterinarian, called a veterinary client patient relationship,” Tarpoff said. “What the veterinary feed directive does is reaffirms the relationship with their vet. They always go to their veterinarian for recommendations or questions pertaining to animal health. Now it takes it a step further to make the relationship stronger.”
Joel DeRouchey, an extension livestock specialist at K-State, said the university regularly communicates with producers in Kansas about the veterinary feed directive and research findings. He is involved with a project that established a website, KSUantibiotics.org, to provide information, fact sheets and more to help livestock producers, veterinarians, consumers and others.
“The information is unbiased and comes from many agencies,” DeRouchey said. “We are providing new information all the time so that everyone in the industry can know what is being communicated to livestock producers about using antibiotics in a correct manner.”
Management and livestock health
Aside from making sure the agriculture industry is using antibiotics appropriately, Tarpoff said veterinarians and extension specialists constantly review best management practices for keeping animals healthy.
“Through biosecurity, we can prevent introduction of disease so that we should never have to treat them,” he said. “We are looking for ways that we can change management strategies to decrease stress on animals, where their immune system stays stronger for longer so that they never succumb to a disease.”
Management also includes keeping pens clean, improving conditions during transportation, properly timed vaccines that don’t include antibiotics, and even immune-modulators that boost the animals’ immune systems.
“The issues have been brought to light and now we have an action plan of how we’re going to combat some of these issues,” Tarpoff said. “It’s not just one thing — it’s not just the veterinary feed directive, it’s not just the regulation — but we have innovation and education.
“Between that and the push from industry and consumers, we’re going to win. It will be a win for the industry. It will be a win for everyone.”