Researchers uncover new approach to stopping antibiotic resistance

Finding a way to preserve antibiotic effectiveness and simultaneously prevent antibiotic resistance can help stop the spread of bacterial diseases, especially in hospital settings. 

A team of researchers from Pennsylvania State University and the University of Michigan (Ann Arbor) has come up with a proof-of-concept way to do this. Their novel approach involves using an oral drug, cholestyramine, to bind to the antibiotic in the colon and disable it. This prevents bacteria in the colon from encountering the drug, developing resistance, and being shed in the feces where they can spread to another host.

To treat systemic infections, antibiotics are injected directly into the bloodstream. Some of the antibiotic drug enters the gastrointestinal tract, and kills off the target pathogens that harmlessly live there. Resistance develops once the antibiotic-susceptible bacteria are killed off, leaving only those superbugs that developed mutations to keep them alive. 

The research was published in the journal eLife on Dec. 1.

The researchers looked at the bacteria Enterococcus faecium, a common pathogen that colonizes the GI tract and spreads via fecal-oral transmission to cause life-threatening infections in the bloodstream, spinal cord or urinary tract.

Intravenous daptomycin is an effective antibiotic used against E. faecium, but its effectiveness has been increasingly limited by bacterial resistance. The previous antibiotic used, vancomycin, resulted in a now-prevalent resistant strain of E. faecium.

First the researchers established the connection between daptomycin use and the increase of resistance to E. faecium in mice. The mice were given daptomycin intravenously and subcutaneously to treat an induced infection. Most of the dose is eliminated by the kidneys, the researchers state, but they hypothesized that a small amount (5% to 10%) of the dose reaches the intestines and could drive resistance to daptomycin.

Their experiments showed that the hypothesis was correct. The researchers examined the fecal shedding of the mice and found bacterial mutations associated with daptomycin resistance.

The next step, was to use the "therapeutically unnecessary intestinal daptomycin exposure," the authors write, as "an opportunity to intervene" and stop the evolution of resistance.

The researchers chose the drug cholestyramine, an inexpensive drug that's been used for 50 years with few side effects and has been approved by the Food and Drug Administration. Their hypothesis was that cholestyramine, which is used to remove bile acids in the intestine, will bind with daptomycin in the intestine and thereby prevent resistant strains from developing. This reduction of resistance could reduce the possibility of transmitting daptomycin-resistant bacteria in health care settings.

The researchers conducted four experiments in mice to test if oral cholestyramine reduced daptomycin resistance, and they found it to be effective. 

"It reduced the fecal shedding of daptomycin-resistant E. faecium by up to 80 fold," the researchers state.

The authors write that this proof-of-concept method has "appealingly low risk to patient health while offering large potential gains to hospital infection control."

There are many more steps required before this therapeutic approach is used with human populations. The authors note that more study is needed to determine the timing of giving the cholestyramine, the dosage and possible interactions. There are also likely to be other drugs that can sequester antibiotics in the intestine, they note, as well as other pathogen-drug combinations.

Among other drugs in development, the researchers report, is DAV-132, an "activated charcoal encased in zinc-pectinate beads," that is currently in a stage-1 clinical trial.

There is major potential for this novel approach to the deadly problem of antibiotic resistance, and currently there aren't other successful methods to combat resistance.