As antibiotic resistance continues to grow, some researchers have begun investigating “alternative” therapies—methods that do not rely on additional, stronger antibiotics.
At Penn State University, researchers are focusing on capturing off-target antibiotics—in tandem with the antibiotic—to mitigate resistance. Antibiotics are labeled as “off-target” when they appear in the body away from the infection site.
The current study focused on infections that originate in health care settings. Resistance comes about because 5% to 10% of the antibiotics, administered intravenously, end up “off-target” in the gastrointestinal tract. There, the off-target antibiotics are no match for the number of bacteria, which survive the medication and evolve to be unaffected by the drugs meant to kill them.
“Antibiotics drive antibiotic-resistance,” said Andrew Read, senior vice president for research, and co-author of the current study. “If you can inactivate antibiotics where they are not needed, you eliminate the driver of antibiotic resistance. An anti-antibiotic could in principle prevent resistance to antibiotic from ever emerging in the gut.”
Read and colleagues showed this is possible using the FDA-approved drug sevelamer, which is typically prescribed to help bind excess phosphorus in the blood of people with chronic kidney disease undergoing dialysis. The idea is that the sevelamer can find and bind the off-target antibiotics, preventing them from interacting with bacteria in the gut.
The work builds off previous studies by Read that showed cholestyramine—a drug approved by the FDA to treat high cholesterol—could inactivate daptomycin, an antibiotic used against gram-positive bacteria, including MRSA. While cholestyramine was success in binding daptomycin, it failed to remove vancomycin, another common antibiotic used against gram-positive bacteria,
Thus, in the current study, the team turned to another promising candidate: sevelamer. Recently published in Small, the researchers administered vancomycin or saline solution via injection to mice with Enterococcus faecium, a type of gut bacteria known to quickly evolve antibiotic resistance. At the same time, they fed the mice oral suspension of sevelamer. The researchers then analyzed the genetic content of fecal matter from the mice.
The results showed that sevelamer captured low concentrations of daptomycin within minutes and vancomycin within hours. The sevelamer was able to block antibiotic activity of daptomycin in vitro, and vancomycin in vitro and in vivo.
“This introduces sevelamer as a more versatile and effective adjunctive therapy for reducing resistance evolution in infections that can originate in health care settings,” said corresponding author Amir Sheikhi, assistant professor of chemical engineering at Penn State. “To the best of our knowledge, this is the first demonstration that an FDA-approved drug can effectively block vancomycin-driven resistance emergence in live organisms, presenting a novel and scalable strategy to combat antimicrobial resistance in health care settings.”
Since sevelamer is already FDA-approved, it has a well-established safety profile, making it a strong candidate for clinical application.
Next, Sheikhi said the team plans to conduct clinical trials to evaluate sevelamer’s effectiveness in human patients receiving vancomycin or daptomycin. They also plan to explore whether sevelamer might prevent resistance evolution of other types of antibiotics excreted into the gastrointestinal tract.