Serious bacterial infections like pneumonia can be life threatening. For decades, however, most serious cases could be successfully treated with antibiotics. That is until some bacteria mutated and developed resistance to antibiotic treatment. Some of these, like bacterium Klebsiella pneumoniae ST258, have gotten so good at it that they have rendered antibiotic treatment virtually useless. The high rates of morbidity and mortality associated with untreated K. pneumoniae infections led the Centers for Disease Control (CDC) to include it on its list of the biggest antibiotic resistance threats in the United States. Now, bacterial resistance has emerged against even the newest drug combinations, leaving some patients with few or no effective treatment options.
As a result, a team of scientists working at Rocky Mountain Laboratories in Hamilton, in collaboration with labs at the National Cancer Institute in Bethesda, Maryland (all part of the National Institute of Allergy and Infectious Diseases), decided to take another look at a different kind of therapy that has been pursued for over a century, but research on which got eclipsed by the roaring success of antibiotics once they arrived on the scene.
That old way of treating bacterial infections involved using viruses to attack the bacteria, instead of antibiotics. This type of treatment was known as bacteriophage therapy, or “phage therapy” for short. What scientists found at RML, based on their experiments with mice, was that using viruses instead of antibiotics to tame troublesome drug-resistant bacteria is a promising strategy.
Dr. Shayla Hesse, lead author of the study results recently published by the American Society for Microbiology in the journal mBio [mBio DOI: 10.1128/mBio.02530-19 (2020)] initiated the project in Bethesda, Maryland under a Fellowship grant. According to Hesse, the first step involved identifying a good candidate among viruses that might infect the bacteria. Although viruses that infect bacteria can be found in small amounts almost anywhere, she decided it made sense to go look in a place, in an ecosystem, where bacteria growth is being controlled. Sure enough, she found what she was looking for in samples of raw sewage obtained from a wastewater treatment plant prior to treatment.
After that, she said, “it was time to move from ‘in vitro’ experiments to ‘in vivo’ experiments.” That is, it was time to leave the petri dishes behind and see what happens in a live animal, like perhaps a mouse.
This is what led Dr. Hesse to contact Dr. Frank DeLeo at Rocky Mountain Laboratories in Hamilton about conducting some experiments on mice. DeLeo, chief of the Laboratory of Bacteriology at RML, dedicated three labs to the project. In their experiments they used two different bacteriophage viruses individually and then together to successfully treat research mice infected with multidrug-resistant Klebsiella pneumoniae sequence type 258 (ST258).
They treated the mice with either phage P1, phage P2, or a combination of the two, all injected at different times following ST258 infection. The scientists had isolated phages P1 and P2 in 2017 from raw sewage that they screened for viruses that would infect ST258—an indication that phages can be found just about any place. Phages P1 and P2 are viruses from the order Caudovirales, which naturally infect bacteria.
Each of the three experimental treatment regimens helped the mice recover from ST258 infection. The scientists noted that the dose of phage provided was less vital to recovery than was the timing of when the dose was received. Mice treated one hour after infection showed the strongest recovery, followed by those treated eight hours after infection and then those treated at 24 hours. Control mice treated with saline all quickly developed severe disease and died.
The scientists also checked the blood and tissue of phage-treated mice for the presence of ST258 bacteria and found there were significantly fewer bacteria at all time points regardless of the treatment method used, as compared to control mice.
Unfortunately, the scientists also found that ST258 bacteria recovered in the blood and tissue samples of phage-treated mice already had begun developing phage resistance, a finding they are continuing to investigate. It appears that, just as viruses may mutate their way around vaccines, bacteria may be able to mutate around infection by viruses.
The group also is studying how phage therapy results compare between samples of ST258-infected mouse blood and human blood, and is examining whether components of human blood can interfere with phage efficacy. Just because something works in mice doesn’t mean it necessarily works in humans. A lot of things have to be considered before it can actually be tested on humans.
“This study represents a first step in evaluating the use of phage therapy for treatment of severe K. pneumoniae ST258 infection in humans,” said Dr. DeLeo.
Michael Howell can be contacted at: [email protected] or (406)239-4838.
Photo ID: A human neutrophil interacting with Klebsiella pneumoniae (pink), a multidrug–resistant bacterium that causes severe hospital infections. Credit: NIAID