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The Prevention of Antimicrobial Resistance

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Antibiotics are common medication used to fight bacteria. As Maryn McKenna mentioned in her TED Talk What Do We Do When Antibiotics Don’t Work Anymore, many deadly infections could be cured within a few days when antibiotics became available. As we are now entering the post-antibiotic era, more and more people are dying of infections again because of antibiotic resistance, a phenomenon where bacteria become resistant to the drugs used to treat infections. Because bacteria develop this resistance so quickly, many pharmaceutical companies have also stopped creating new antibiotics. To make matters worse, the world is continuing to accelerate this inevitable biological process by misusing antibiotics in medicine and agriculture.

"Antimicrobial resistance is a serious problem that has led to people dying from common bacterial infections," said Andrew Read, Evan Pugh Professor of Biology and Entomology and director of the Huck Institutes of the Life Sciences, Penn State. "Many of our most important antibiotics are failing, and we are beginning to run out of options. We have created a therapy that may help in the fight against antimicrobial resistance, an 'anti-antibiotic' that allows antibiotic treatment without driving the evolution and onward transmission of resistance."

For instance, a major cause of antibiotic-resistant infections in health facilities is vancomycin-resistant [VR] Enterococcus faecium according to Valerie Morley, a postdoctoral scholar in the Huck Institutes of the Life Sciences, Penn State.

The normal flora of the gastrointestinal tract consists of the bacteria Enterococcus faecium. It can cause infection when it enters other sites in the body. Some common infections include sepsis, meningitis, endocarditis, wound infections, and pelvic infections. The bacteria can survive in extremely hot, salty, and acidic environments. In general, they do not pose any problems to healthy people; however, individuals with underlying health conditions or a weakened immune system are more likely to get sick. E. faecium has become more antibiotic-resistant over the last few years, so many antibiotics, such as vancomycin, are usually not effective in treating infections caused by the bacteria.

"E. faecium is an opportunistic pathogen that colonizes the human gastrointestinal tract and spreads via fecal-oral transmission," she said. "The bacterium is asymptomatic in the gut but can cause serious infections, such as sepsis and endocarditis, when introduced to sites like the bloodstream or the spinal cord."

One of the several remaining antibiotics that could treat VR E. faecium infection is daptomycin, which is used for the treatment of bacterial infections of the skin and underlying tissues caused by the bacteria through an intravenous route, as discussed by Morley. Daptomycin is mainly eliminated by the kidneys, but approximately five to ten percent of the dose is introduced to the intestines. This can result in the development of resistance to antibiotics.

The team of scientists at Penn State and the University of Michigan orally inoculated mice with various strains of daptomycin-susceptible VR E. faecium to determine whether systemic daptomycin treatment contributes to a rise in daptomycin-resistant VR E. faecium. A day after inoculation, the mice were given daily doses of either subcutaneous daptomycin, oral daptomycin, or a control mock injection for five days. The researchers also used different doses and routes of administration, including similar to clinical human doses, to increase the chances of observing resistance emergence. Furthermore, they gathered fecal samples from the mice to calculate the extent of the bacteria shedding into the environment and find daptomycin susceptibility of the E. faecium bacteria that were present in the excrements.

They discovered that only the highest doses of daptomycin uniformly lowered fecal VR E. faecium below the level of detection, while lower doses caused the shedding of VR E. faecium. The team also found that a strain obtained a mutation in a gene that has been recognized to be in association with daptomycin resistance, whereas another strain acquired various mutations that had not been associated with daptomycin resistance before.

Morley said, "Our experiments show that daptomycin resistance can emerge in E. faecium that has colonized the GI tract, and that this resistance can arise through a variety of genetic mutations."

Moreover, the team discovered that even when the daptomycin was administered through subcutaneous (under the skin) injection, the daptomycin-resistant bacteria were shed. The team then investigated if orally administered adjuvant cholestyramine, an FDA-approved bile-acid sequestrant (medication for reducing LDL cholesterol), in addition to daptomycin could significantly decrease daptomycin activity in the GI tract as well as prevent the emergence of daptomycin-resistant E. faecium in the gut. The sequestant was found to reduce fecal shedding of the bacteria in mice treated with daptomycin by up to 80 times.

"We have shown that cholestyramine binds the antibiotic daptomycin and can function as an 'anti-antibiotic' to prevent systemically administered daptomycin from reaching the gut," said Read.

Amit Pai, professor and chair of the Department of Clinical Pharmacy, University of Michigan, mentioned that there are no recently developed strategies that can reduce antimicrobial resistance other than the use of combination therapy, vaccine development for respiratory tract infections, and prevention of antibiotics misuse.

"These are blunt instruments for antimicrobial resistance reduction at the population level but do not readily translate to an intervention that can be used in individuals," said Pai. "Reducing selective antibiotic pressure on bacteria that reside in the colon is a potential individual-level strategy that deserves greater attention."

You can do your part in fighting antimicrobial resistance too. Instead of just waiting for the creations of new drugs to combat superbugs, we can change our behaviours in the meantime, whether it be using antibiotics appropriately or changing our diets to include foods that are raised without antibiotics.

Featured image is courtesy of Wix.

Article Author: Tanya Kor

Article Editor: Maria Giroux, Sherilyn Wen