To avoid prescribing high dosages of polymyxins and to make up for the antibiotic's weaknesses, the researchers decided to turn to new dosing strategies and multiple antibiotic combinations.
After conducting studies on dozens of combinations of more than 15 antibiotics paired with polymyxin B, the researchers discovered two effective treatments. Combinations of polymyxin B with either aztreonam or amikacin resulted in undetectable bacterial counts after 24 hours.
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The E. coli, however, was able to regrow to initial levels after 96 hours and a subpopulation of amikacin-resistant strains arose after 10 days when exposed to the combination of polymyxin B and amikacin. Polymyxin B and aztreonam pushed the E. coli into a persistent but nonreplicating state. Only the triple combination eliminated the E. coli strain and prevented regrowth.
"We knew that polymyxins alone couldn't work. Only the three drugs combined were able to work synergistically to suppress and kill the bacteria," says Bulman. "We overcame the bacteria by pushing it as far as possible with an agent that it was resistant to while simultaneously administering two other antibiotics."
The promising finding may provide a viable treatment against mcr-1 and ndm-5 strains.
The research was funded through a $4.4 million National Institutes of Health (NIH) grant awarded to Tsuji to develop new dosing regimens for polymyxins.
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