A preclinical study led by researchers from Monash University has discovered that a combination of phage and antibiotic therapy may be the most effective to combat antibiotic-resistant bacteria.
“We have been able to confirm that, even in complex living systems, treatment with our characterised phages can reliably steer bacteria towards a phage-resistant variant that is re-sensitised to antibiotics,” said study author Dr Jeremy Barr on May 8.
Phage therapy is the use of bacteriophages, also known as viruses that kill bacteria to clear a bacterial infection, and in recent years there has been a growing interest in the use of the therapy as a potential treatment for antibiotic-resistant superbugs.
In the team’s previous work, the researchers used phage therapy to kill antibiotic-resistant A. baumannii, and in doing so, they found that phage-resistant mutants emerged, with the resistant mutants reverting back to being re-sensitised to antibiotics they were once resistant to.
“While A. baumannii rapidly became phage-resistant, in doing so, they were also re-sensitised to the same antibiotics they use to resist,” said lead study author Dr Fernando Gordillo Altamirano.
He told The Epoch Times in an email that the team hypothesised the re-sensitisation of bacteria to the anti-biotics was a form of “evolutionary trade-off.”
“Bacteria can only evolve to escape a limited amount of threats before they start experiencing ‘side effects’, i.e. trade-offs, from that process,” he said.
Re-Sensitisation A ‘Repeatable’ Process
Under this hypothesis, the team conducted a preclinical trial on mice models, exposing infected mice to combinational therapy and observed that the combined therapy “significantly improved treatment outcomes than either antibiotics or phage therapy alone,” confirming their hypothesis.
Additionally, by isolating phage-resistant bacterial colonies from the mice and comparing them with bacteria that have undergone the same treatment in the lab, the researchers found changes to the same gene across both groups, indicating that the mechanism of an “evolutionary trade-off” is a repeatable pathway.
The team also observed a “synergistic” effect of combination therapy, where the two therapies together had far superior results compared to isolated administration.
Whilst there are some concerns that combination therapy may breed superbugs that are both phage and antibiotic-resistant, Barr wrote that “phages are incredibly diverse and numerous while antibiotics are limited and exhausted,” making the concern unlikely.
“Phages and bacteria have been participating in an evolutionary war for billions of years, and still neither has won, and both continue to co-exist. It is for this reason that there likely will always be a phage available to treat a bacterial infection.”
Though he noted there are some concerns that the combination therapy may select for bacteria that are capable of broad defence against phage therapy, potentially limiting researchers’ capacity for phage therapy, Barr hopes that researchers have “learned lessons from the antibiotics crisis” and become smarter on using these agents.
Altamirano told The Epoch Times that knowing about the mechanism of antibiotic re-sensitisation allows researchers “to make informed, rational, even smart therapeutic choices when moving phage therapy to the hospital setting.”
“As a field, we will have a much deeper understanding of how phages work,” wrote Barr. “We will use this new knowledge in combination with existing treatments to enhance and improve our capacity to treat and kill some of the world’s most deadly bacterial pathogens.”