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An inexpensive FDA-approved drug, cholestyramine, taken in combination with an antibiotic prevents the antibiotic from driving antimicrobial resistance, according to new research by scientists at Penn State and the University of Michigan. The team’s findings appear today (December 1) in the journal eLife.
“Antimicrobial resistance is a serious problem that has led to people dying of 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 major antibiotics are failing and we are starting to run out of options. We have created a therapy that can help in the fight against antimicrobial resistance, an ‘anti-antibiotic’ that allows for antibiotic treatment without driving evolution and transmission in ahead of the resistance. “
According to Valerie Morley, a postdoctoral fellow at the Huck Institutes of the Life Sciences, Penn State, a major cause of antibiotic-resistant infections in healthcare facilities is vancomycin resistant. [VR] Enterococcus faecium.
“E. faecium it is an opportunistic pathogen that colonizes the human gastrointestinal tract and spreads via fecal-oral transmission, “he said.” The bacterium is asymptomatic in the intestine but can cause serious infections, such as sepsis and endocarditis when introduced to sites such as the bloodstream or the spinal cord. “
Morley noted that daptomycin is one of the few antibiotics left for the treatment of VR E. faecium infection, but VR E. faecium is rapidly becoming resistant to daptomycin as well. Daptomycin is administered intravenously to treat infections caused by VR E. faecium. The antibiotic is mainly eliminated by the kidneys, but 5-10% of the dose enters the intestine, where it can drive the evolution of resistance.
To investigate whether systemic daptomycin treatment actually induces an increase in daptomycin-resistant VR E. faecium, the team inoculated mice orally with different daptomycin-sensitive VR strains E. faecium. Starting one day after inoculation, the researchers gave the mice daily doses of subcutaneous daptomycin, oral daptomycin, or a sham control injection for five days.
The team used a range of doses and routes of administration, including those that would be similar to clinical human doses, to maximize the likelihood of observing the emergence of resistance. Next, they collected fecal samples from the mice to measure the extent of VR E. faecium release into the environment and to determine the susceptibility to daptomycin of E. faecium bacteria that were present in the stool.
Researchers found that only higher doses of daptomycin consistently reduced fecal VR E. faecium below the detection level, while lower doses produced VR E. faecium shedding.
From the bacteria that were eliminated, the team found that one strain acquired a mutation in a gene that had previously been described in association with daptomycin resistance, while another acquired several mutations that had not previously been associated with resistance to daptomycin. daptomycin.
“Our experiments show that daptomycin resistance can emerge E. faecium that it colonized the gastrointestinal tract and that this resistance can arise through a variety of genetic mutations, ”Morley said.
The team also observed that daptomycin-resistant bacteria were eliminated even when daptomycin was administered subcutaneously.
Finally, the team investigated whether orally administered adjuvant cholestyramine – an FDA-approved bile acid sequestering agent – could reduce daptomycin activity in the gastrointestinal tract and prevent the emergence of resistant daptomycin. E. faecium in the intestine. They found that cholestyramine reduced the fecal shedding of daptomycin-resistant VR E. faecium in mice treated with daptomycin up to 80 times.
“We have shown that cholestyramine binds to the antibiotic daptomycin and can work as an ‘anti-antibiotic’ to prevent systemically administered daptomycin from reaching the gut,” Read said.
Amit Pai, professor and chair of the Department of Clinical Pharmacy, University of Michigan, noted that no new strategies have been developed to reduce antimicrobial resistance beyond the use of combination therapy, the development of vaccines for upper respiratory tract infections. and lower and simply reducing the unnecessary use of antibiotics.
These are blunt tools for reducing antimicrobial resistance at the population level but do not easily translate into an intervention that can be used in individuals. Reducing the selective pressure of antibiotics on bacteria residing in the colon is a potential individual strategy that deserves more attention. “
Amit Pai, Professor and President, Department of Clinical Pharmacy, University of Michigan
Source:
Journal reference:
Morley. VJ, et al. (2020) Adjunctive therapy administered with an antibiotic prevents the enrichment of antibiotic-resistant clones of a colonizing opportunistic pathogen. eLife. doi.org/10.7554/eLife.58147.
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