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A global health crisis may be on the horizon, as the golden era of antibiotics is under serious threat. We recently bore witness to the first case in the United States of a highly resistant, Escherichia coli so-called “superbug” (MCR1_NJ), coharboring two of the most worrying antibiotic resistance genes, encoding mobile colistin resistance (mcr-1) and a New Delhi metallo-β-lactamase (blaNDM-5). And worryingly, the medical community is vulnerable to this emerging bacterial threat because optimal treatment strategies are undefined.

However now, researchers at the University of Buffalo have discovered a novel combination of aztreonam, amikacin, and polymyxin B – a last resort antibiotic – was able to simultaneously kill E. coli bacterium strains carrying mcr-1 and ndm-5 genes within 24 hours while also preventing regrowth.

The rapid increase in antibiotic-resistant bacteria has resurrected the importance of polymyxins, a class of antibiotics that are effective but employed as a last resort because of the damage they can cause to the kidneys.

“The threat of Gram-negative bacteria, including E. coli carrying mcr-1, is worrisome,” remarked lead study investigator Zackery Bulman, Pharm.D., who is currently an assistant professor at the University of Illin

ois at Chicago College of Pharmacy. “We believe that the appearance of mcr-1 and ndm-5 in patients may be a harbinger for what is to come. The golden era of antibiotics isn’t over yet, but we wanted to help clinicians prepare therapeutically for the occurrence of these strains.”

Brian Tsuji, PharmD, principal investigator and associate professor in the School of Pharmacy and Pharmaceutical Sciences, continued: “That is why the mcr-1 and ndm-5 strains represent an urgent threat, because of the high-degree of resistance combined with the potential for rapid spread in the community setting. We had to work quickly and think outside of the box, beyond traditional antibiotic combinations.”

“This is the first study to propose therapeutic solutions with three drugs against superbugs harboring mcr-1 and ndm-5. The results will help prepare clinicians for future occurrences of these pathogens.”

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.

The E. coli, however, was able to regrow to initial levels after 96 hours and a sub-population 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 non-replicating 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,” said Zackery Bulman, PharmD, Assistant professor at the University of Illinois at Chicago College of Pharmacy. “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,”he added.

The promising finding may provide a viable treatment against mcr-1 and ndm-5 strains.

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