The answer to combating resistance to antibiotics may be in the sewers.
That’s where researchers are gathering viruses whose favorite food is bacteria, known as bacteriophages. Instead of infecting humans, many types of phages attack harmful bacteria, such as E. coli.
“From any liter of sewage, we could get phage against any of those E. coli strains after it’s gone through particulate filtration,” researcher and The Evergreen State College professor Elizabeth Kutter told a group of Aberdeen High School students last week. “We let it go through the first part of the process but not the UV rays and stuff.”
Aberdeen High School science teacher David Brunke has worked in Kutter’s lab in the summertime and Kutter came to his class to talk about the research.
A Seattle native, Kutter has been working with phage since 1963, as a graduate student of biophysics at the University of Rochester.
“I was immediately fascinated,” Kutter recalled.
The viruses are the most abundant living entities on the planet, she explained, ten-fold more so than bacteria. At any given time, a quarter of all ocean bacteria are infected. A milliliter of coastal water will contain from 10 to 100 million viruses.
“You drink them, you eat them, you have them in your gut,” Kutter said. “They’re everywhere. They’re what keeps the various types of bacteria under control.”
Phages were used to help identify DNA as the building block of life. From 1975 to 1980, Kutter served on the National Institutes of Health Recombinant DNA Advisory Committee, which provided safety and ethical advice on DNA research.
She joined Evergreen in 1972, its second year. Her phage lab opened when the lab building was completed in 1973, and she is now the chair of the Phagebiotics Research Foundation.
One of their major concerns is the growing resistance of bacteria to antibiotics. An estimated 50 to 60 percent of hospital-acquired infections are from antibiotic-resistant bacteria. The cost of fighting that resistance is estimated at $32 billion per year in the U.S. alone, Kutter said.
“People are very worried we may get back to a time when there aren’t any antibiotics available that work,” Kutter said.
Phage was first isolated in France, from soldiers recovering from dysentery. Scientists at the Pasteur Institute found many soldiers who survived the illness had phage in their stool. In 1919, it was used to treat typhoid in chickens.
Despite her vast experience with the viruses, Kutter didn’t know about their application in disease treatment until she spent four months in the Soviet Unionin 1990, visiting the Republic of Georgia.
“That’s when I learned, although I had been working with phage all this time, that they were being used as antimicrobials,” Kutter said, and had been in that country since the 1920s.
At the Eliava Institute, in the mid-1990s, Kutter witnessed some of the incredible therapeutic applications. In 1996, Chief Surgeon Guram Gvasalia treated a diabetic man with such severe ulcers on his foot, it was nearly split down to the bone. He was expecting to have it amputated. Instead, after three days of topical treatment with phage, all signs of pus were gone and the wound was on its way to healing.
In 2000, Alfred Gertler of Toronto, Canada, sought treatment for his shattered, severely infected ankle in Georgia.
“Four years later, there were still holes in both sides of his ankle and staph was still draining out of it,” Kutter recalled.
It wasn’t a case of resistant staph — tests showed that Gertler’s strain was responding to the drugs. But they weren’t getting to the part of his bone where the infection was living, just keeping the infection isolated.
“It’s not just antibiotic resistance we need to worry about, it’s getting the antibiotics where they can do some good,” she said.
Doctors flushed the wound with a phage solution, and packing it with strips of phage-soaked artificial skin.
“Within three days, there was no bacteria coming out anymore,” Kutter said.
Dr. Randolph Fish, a podiatrist, has been treating a few patients with diabetic foot ulcers with phage through a compassionate use exemption at his Tacoma office. He’s working to obtain the same permission from Grays Harbor Community Hospital to conduct similar studies locally.
“Phage have the unique advantage that they can be carried throughout the body and then multiply wherever they find their target bacteria,” Fish wrote in his presentation at the National Wound Care Conference earlier this year.
Fish treated four patients with severe ulcers, with exposed or infected bone, who had been treated with antibiotics. The next step in their cases would have been amputation of toes or feet. Many diabetic patients have poor circulation to their extremities, which makes it difficult for drugs to be carried to the ulcerated area through the blood stream.
Fish thoroughly cleared the dead tissue from the wounds, then packed them with gauze. The gauze was then soaked with a phage preparation, then wrapped. That preparation was left on for 48 hours, then the patients switched back to regular dressings for a week, then another round of phage, until the wound became too small to pack.
It didn’t take long in the sample patients. A 92-year-old man with ulcers in several toes was treated for just more than a month. Instead of losing his toes, the wounds were closed and healing. None of the four patients had any recurrence within six months.
If phages are such potent treatments to serious infections, why aren’t they more widely used?
In Europe, they are, but one stumbling block that stalled their U.S. development is a general sense of fear surrounding viruses since the 1980s.
“When the AIDS epidemic came, here was something that was a virus that had gotten into the blood and things, so the Legislature in its great wisdom said you couldn’t make anything with viruses,” Kutter said.
Phage is not approved by the FDA, and can’t be used by most doctors except with special permission. Naturopaths have access to therapies that are approved in other countries and may use phage.
The safety of phage therapy is well documented in decades of cases around the world. But that presents a problem in developing it for the U.S. American medicines are mainly developed by private drug companies in expensive, double-blind trials. Most companies take on that expense because they will be able to patent a drug if it makes it through the long process to FDA approval.
Because many types of phage are in established use, companies would likely not be able to patent them despite funding trials.
“It’s hard to get private investment when patents are so hard,” Kutter said. “It’s not accidental that in France, where they’re doing a big study … the funding is coming mostly from the French army and the European Union.”
Phase 1 trials like the ones Fish is conducting could help to change U.S. usage by doing some of the preliminary research.
“This could be a key step toward doing the appropriate studies — it could happen in this city,” Kutter said. “Isn’t that cool?” she told the students.