Phages: A promising alternative in the age of antibiotic resistance?
Steffanie Strathdee, PhD, thought they would “just ride it out.”
The infectious disease epidemiologist believed her husband, Thomas Patterson, PhD, a professor in the department of psychiatry at the University of California, San Diego, had fallen ill with food poisoning after eating seafood and drinking water during a vacation in Egypt. She realized she may be wrong when Patterson was unable to keep anything down, including the ciprofloxacin Strathdee gave him.
“After he started complaining of back pain, I started to realize, ‘You know what, maybe this isn’t food poisoning, and I need medical help,’” Strathdee, the associate dean of global health sciences and a professor in the department of medicine at UC San Diego, told Infectious Disease News.
Since Strathdee is not an MD, they called for a doctor to come to the cruise ship where they were staying, and Patterson was given IV antibiotics and fluids, Strathdee explained. But his condition worsened. Patterson went into shock and was taken to a local clinic, where he was diagnosed with pancreatitis. However, after he was medevacked to Germany, a CT scan revealed he had an abscess “the size of a small football” in his abdomen and the suspicion was that a gallstone had blocked one of his bile ducts, leading to pancreatitis, Strathdee said.
“They removed the gallstone and I’m still thinking ‘OK, you know, this is pancreatitis. They took the gallstone out, so everything should be fine, right?’” she said.
However, the doctors in Germany showed her a flask full of dark, murky fluid taken from the abscess, suggesting her husband had an infection. They soon discovered the cause: Acinetobacter baumannii, which was initially found to be partially susceptible to only three antibiotics, and resistant to 12.
“We knew we were in a bunch of trouble then,” Strathdee said. “They threw all the antibiotics that they had that were susceptible to stabilize him, and then we got him medevacked home to San Diego.”
Further sensitivity analysis showed the infection had become resistant to those last three antibiotics, including carbapenems and colistin. The situation worsened after one of the catheters placed in Patterson’s abdomen to drain the fluids dislodged, pouring infected fluids into his abdomen and sending him into septic shock. He was placed on a ventilator and in a medically induced coma.
“I realized that there was nothing else that they could do, and that we were going to just lose him, and it was just agonizing,” Strathdee said. “I asked him one day [that] if he wanted to live, to squeeze my hand, but I didn’t even know if he could hear me. When he squeezed my hand, I realized, ‘OK, this is great, he wants to live,’ but now it’s up to me to try to find something, because there’s nothing else that our doctor friends can do.”
‘A forgotten cure’
Strathdee searched PubMed for alternative therapies for multidrug-resistant A. baumannii and stumbled on bacteriophages.
Bacteriophages, or phages, are viruses that target and consume bacteria. Many phages are kept in research labs and can be shipped all over the world for trials and emergency use if needed, although it is also possible to isolate new phages from environmental sources, explained Dwayne Roach, PhD, assistant professor of cell biology and Conrad Prebys Chair in Virology at San Diego State University.
“Phages exist wherever bacteria live. Thus, both are found in every habitat on Earth,” Roach told Infectious Disease News. “In humans, phages are currently being used for treating bacterial infections that are not responding to traditional antibiotics, as a last resort treatment. There are several examples where phage therapy has been successful when a personalized medicine approach has been implemented.”
Strathdee contacted physicians and researchers with phage libraries — most of whom could not help — and was sent phages from Texas A&M and the U.S. Navy that matched Patterson’s infection. (The Navy and U.S. Army have both been exploring phages to treat service members who return from the Middle East with multidrug-resistant infections, according to Strathdee. She said the Army declined her request.) The phages from Texas A&M were applied first through Patterson’s abdominal drains. He was no worse, but no better. The second cocktail made of phages sent from the Navy was added intravenously 2 days later and performed exactly as doctors had hoped, Strathdee said.
“He woke up 3 days later, lifted his head off the pillow and kissed his daughter’s hand,” said Strathdee, who, with her husband, recently published a book on their story, The Perfect Predator: A Scientist’s Race to Save Her Husband from a Deadly Superbug.
“You know, phage therapy is a forgotten cure that was discovered over 100 years ago and has been used in parts of the Soviet Union for decades, and yet they’re not available in the West, so we’re hoping to move phage therapy into clinical trials so we can give the FDA the evidence they need to decide if phage therapy can be scaled up,” she said.
In January, the FDA gave researchers from UC San Diego clearance for the first clinical trial in the United States to test an IV-administered bacteriophage-based therapy against drug-resistant bacteria.
Saima Aslam, MBBS, associate professor of medicine at UC San Diego, and a colleague of Strathdee’s, is leading the trial.
“Phages represent a very exciting and innovative field in infectious diseases. Despite phages being around for most of the 20th century, we are only now learning of clinical applications that are pertinent to the current era of multidrug-resistant infections,” Aslam told Infections Disease News. “This includes a wide range of applications ranging from diagnostics to therapeutics in medicine.”
Aslam and colleagues will test phage therapy as an adjunct to antibiotics for the treatment of staphylococcal ventricular assist device (VAD) infections.
“Currently, it is almost impossible to eradicate such infections. The bacteria make a biofilm, or slime layer, on the device surface [and] antibiotics do not treat biofilm-based infections well due to a variety of reasons,” Aslam explained. “However, phages penetrate and kill biofilm-embedded bacteria well and so we think we may be able to cure such VAD infections when we add phages to the antibiotics.”
During the pilot trial, the team will treat 10 participants with antibiotics plus IV phages for 6 weeks. According to Aslam, if this approach works, the same principles could be applied to a variety of other device infections. Aslam said future trials will explore using phages in patients with multidrug-resistant Pseudomonas aeruginosa infections and assess safety and treatment outcomes.
Is phage therapy safe?
Recently, researchers who tested bacteriophages against pathogenic gut bacteria found them to be safe and tolerable, with no side effects, according to a presentation at the American Society for Nutrition Scientific Sessions and Annual Meeting.
Elsewhere, a systematic literature review by Lynn El Haddad, PhD, from the department of infectious diseases, infection control and employee health at the University of Texas MD Anderson Cancer Center, and colleagues found that phage therapy was an overall safe and effective treatment for infections caused by multidrug-resistant pathogens.
However, questions remain. According to Roach, little is known about how the human immune system reacts to phages. The ongoing studies, along with Strathdee and Patterson’s experience, show that the treatment may be promising.
“It’s a therapy that could be offered fairly cheaply as well if the purification aspects can be streamlined, and so it offers huge hope in the developing world,” Strathdee said. “That’s my biggest hope, that phage therapy would be offered to people dying of multidrug-resistant bacterial infections in developing countries.” – by Caitlyn Stulpin
- Haddad LE, et al. Clin Infect Dis. 2018;doi.org/10.1093/cid/ciy947.
- Wallace T, et al. Results of the bacteriophage for gastrointestinal health (PHAGE) study. Presented at Nutrition 2018; June 9-12; Boston.
Disclosures: Aslam and Roach report no relevant financial disclosures. Strathdee reports being a stockholder in Adaptive Phage Therapeutics and AmpliPhi Biosciences.