Finding alternatives in the face of resistance

Dr. Cyril G. Gay has seen substantial money and labor invested in researching antimicrobial resistance but far less in finding new tools to treat and prevent diseases.

“We really need to shift, in a significant way, our investment to focus on providing solutions,” he said.

Dr. Gay is a national program leader for the Agricultural Research Service in the Department of Agriculture, and he chaired the organizing and scientific committees for a September 2012 World Organisation for Animal Health (OIE) symposium in Paris on alternatives to antimicrobials in agriculture. He expects those working in agriculture will have fewer antimicrobials available as bacterial populations become more resistant to existing products and regulations increasingly restrict uses.

“Antibiotic resistance has always been around,” he said. “We’re looking at bacteria and their ecological niches, where, essentially, they produce these substances to be able to compete in the environment, whether we’re looking at the gut microbiome, in the soil, in plants, or what have you.”

Dr. H. Morgan Scott, a professor of epidemiology at the Kansas State University College of Veterinary Medicine, said that, as governments in Europe and North America restrict antibiotic use, particularly in farm animals, they increase opportunities for alternatives.

He likened the current jostling of proposed replacements for antibiotics to the land grabs that occurred as people settled the Old West.

Determining potential

Heavy metals, lytic enzymes, disinfectants, vaccines, genetic selection, probiotics, and peptides are among the interventions and technologies cited at conferences and in articles and commentaries as potential additions to the current antimicrobial arsenal, both for human and animal medicine.

For example, Dr. Guy H. Palmer and Douglas R. Call, PhD, wrote in a recent commentary for the Institute of Medicine that the best ways to limit antimicrobial use in food animal production involve reducing demand through improvements in vaccination protocols, husbandry, sanitation, and biosecurity.

“Similarly, expanded research investment in livestock probiotics, immunostimulants, and vaccines will provide alternatives that can reduce the need for antibiotics with less chance of unintended consequences for food availability and access,” the commentary states. “Regulation accompanied by viable alternatives will have a much higher likelihood of success.”

That commentary is available at iom.edu/Global/Perspectives/2013/AntimicrobialResistance.

While veterinary medicine has effectively used vaccines to prevent diseases, the profession needs additional tools that can be used as treatment alternatives to antibiotics, Dr. Gay said.

Concern extends across species

Dr. Mark Papich, a professor of clinical pharmacology at the North Carolina State University College of Veterinary Medicine, said charitable and pharmaceutical organizations have funded research into the causes of resistant bacteria in companion animals but have not yet provided conclusive answers.

“If we knew what caused it, we could stop it,” he said.

Methicillin-resistant Staphylococcus pseudintermedius is becoming an increasing concern in companion animal medicine, particularly in connection with skin infections in dogs, Dr. Papich said. MRSP is the bacteria most commonly connected with resistant infections at the NCSU veterinary teaching hospital, he said. Among the others are antimicrobial-resistant Escherichia coli—including extended spectrum beta lactamase–positive E coli—and resistant Enterococcus.

The hospital most often encounters such organisms in treating urinary tract, skin, wound, and post-surgical infections.

That lack of identified causes of resistance increases the difficulty in finding alternatives to antimicrobials for treatment, Dr. Papich said. But he noted that veterinary dermatologists have provided good examples of alternative treatments in the use of ointments, topical treatments, shampoos, and disinfectants on infected skin, where the products are used as adjuncts or replacements for systemic antimicrobial administration.

“They help tremendously to allow us to use fewer systemic antibiotics and also to help us decrease the use of our antibiotics overall, and that’s incredibly important,” Dr. Papich said.

Antimicrobial use in pet care also has been a concern for the AVMA, which plans to develop antimicrobial stewardship programs similar to those used in human health care. The AVMA Executive Board voted in January to create the 10-member Task Force for Antimicrobial Stewardship in Companion Animal Practice, which will develop education materials and promote appropriate use.

Dr. Gay said a range of technologies also could prove to be effective at fighting viruses or parasites, and some, such as phyto-chemicals from plants, could be used to alter gastrointestinal bacterial populations. All could help with disease treatment and prevention across animal species, and prebiotics, probiotics, and phytochemicals could improve agricultural animals’ health and increase their nutritional efficiency and growth, he said.

“We’re at the stage where we’re starting to understand the mechanisms by which these products may work,” he said.

In an article in the May-June 2012 issue of Agricultural Research Magazine, Dr. Gay wrote that naturally occurring phage endolysins and bacteriocins are easy to genetically modify, making them prime candidates for producing novel antimicrobials. ARS researchers created a combination of three such antimicrobials to kill S aureus with simultaneous lytic activities.

Another article in that issue stated that ARS scientists had studied the use of vitamin D to reduce bacterial counts and clinical signs in cows with mastitis, selective breeding of chickens for disease resistance, and addition of chlorate-based compounds to water to reduce gut E coli populations in cattle.

Regulatory approval

Dr. Steven D. Vaughn, director of the Office of New Animal Drug Evaluation in the Food and Drug Admin­istration’s Center for Veterinary Medicine, said the FDA has adopted a new process to better work with developers of new technologies, such as genomics and stem cell and gene therapies, that could help animals survive infectious diseases. When organizations present a proof-of-concept study for such a technology, the FDA assembles teams that understand the technologies and report what information the sponsor will need to provide to show that its product would be safe, effective, well-manufactured, and properly labeled, he said.

FDA officials also have been talking with researchers about ways to ensure the agency has an efficient, predictable approval process, and the agency can waive some fees for developers of innovative products.

Many technologies, including those involving alteration of an animal’s immune system or gastrointestinal microbiome, could be useful across many species, Dr. Vaughn said. Enzymes extracted from one species also could be used to fight disease in others.

More medical interventions are needed to stay ahead of development of resistant microorganisms, and some microorganisms will survive any intervention, Dr. Vaughn said.

“The key is to maintain a strong discovery pipeline for interventions for infectious diseases,” he said.

But Dr. Vaughn cautioned that some alternatives to antibiotics treat disease and kill bacteria through the use of mechanisms similar to those associated with antibiotics, increasing selection pressure that favors bacteria resistant to both. Dr. Scott expressed similar concerns and said available evidence from European studies suggests use of high concentrations of zinc and copper in feed, for example, has co-selected for tetracycline resistance in methicillin-resistant S aureus and vancomycin-resistant Enterococcus, respectively.

“Is the heavy metal—as an alternative to the antibiotic—effectively creating the same problems that the antibiotic is?” Dr. Scott asked.

While Dr. Scott noted that some researchers are bullish about the potential uses for naturally occurring peptides, he expressed concern that bacterial populations eventually could develop resistance to those as well, greatly increasing treatment difficulty. He noted that he was speculating that such a change would be less likely to occur and slower to develop than other resistances, but bacteria have proved able to adapt and thrive in altered environments as humans have discovered and adapted antimicrobial products.

Dr. Gay noted that antibiotic interventions have had tremendous impact, and it behooves humanity to invest more in the fight.