For an American couple, it began with a 2015 dream trip to the Valley of the Kings in Egypt. It turned into the curse of the pharaohs. The husband developed a pan-resistant Gram-negative infection that turned septic, and at one point his wife asked him if he wanted to keep fighting for life hooked up to machines.

“I knew he was already on a ventilator and on three pressors — that this was the trifecta of organ system failure,” says Steffanie Strathdee, PhD, at that time an epidemiologist at the University of California San Diego (UCSD). “I decided to have a conversation with [my husband] Tom, and I asked him if he wanted to live.

“Even though he was in a coma and I wasn’t sure if he could hear me, I asked him to squeeze my hand if he wanted to live and then I would leave no stone unturned. And he squeezed my hand.”

Strathdee, for reasons that will become clear, now is co-director of the Center for Innovative Phage Applications and Therapeutics (IPATH) at UCSD.

She told her story recently at the 2021 virtual meeting of the Association for Professionals in Infection Control and Epidemiology (APIC), beginning when her husband became violently ill during the Egypt vacation.

“I just assumed that he had food poisoning, but it was more serious than that,” she said. “He was rushed to the closest clinic — there was no hospital in Luxor, where we were based.”

The clinic staff diagnosed him with pancreatitis, saying they thought he might have a gallstone blocking his bile duct, and stabilized him enough to be medevacked to Germany.

“He was too weak to be sent home to the U.S. right away,” Strathdee said.

The German clinicians did a computerized axial tomography scan and found a “giant abscess the size of a small football in his abdomen,” she said. “They removed a gallstone. The abscess in his abdomen was full of this putrid, stinking fluid and that meant that it had been there for quite some time.”

The infecting organism was cultured, and Strathdee awaited word on what they were dealing with.

Bad News

“The doctor came back — and he was in full PPE (personal protective equipment) this time — and he said, ‘Look, I’m sorry to tell you this bad news, but this is the worst bacteria on the planet,” she said. “’This is Acinetobacter baumannii.’”

Initially, it was partially sensitive to a few antibiotics, but as treatment continued, it became pan-resistant, what the Centers for Disease Control and Prevention calls “carbapenem-resistant Acinetobacter,” which it gave its highest threat level of “urgent” in 2019.1

“Well, that’s when I started to get a bit worried,” she said. “I realized that my husband was now a poster child for this post-antibiotic era that we’re entering, where by the year 2050, one person every three seconds, or 10 million a year, are going to be dying from superbugs.”

The physicians in Germany stabilized her husband as best they could and he was medevacked back to the United States and hospitalized at UCSD.

“So now my colleagues were caring for him, but Tom was hospitalized for months,” she said.

One day, an internal drain slipped and contamination spread within the patient. “He went into septic shock because it had dumped all that infected fluid into his abdomen, into his bloodstream,” she said. “Sepsis is a horrible thing to witness. Well, from that moment on, he was fully colonized with Acinetobacter baumannii and this organism had acquired even more resistance, so it was now pan-resistant. So the doctors said look, there’s nothing that we can do.”

This is the point the handheld exchange between wife and husband occurred, with Tom squeezing Stephanie’s hand to express the will to keep fighting.

The Search Begins

“I went home and I did what anybody would do, I hit the internet and I used PubMed, our National Library of Medicine’s wonderful search engine, and put in the key words ‘multidrug resistance, Acinetobacter baumannii,’” she told APIC attendees. “Up popped this paper about something called phage therapy. I vaguely remembered what this was from my classes in microbiology back in the 1980s.”

Phages have been going in and out of style since they were discovered a century ago. After it was discovered that these viruses could kill bacteria, a French-Canadian microbiologist, Félix d’Hérelle, dubbed them bacteriophage for something that, translated from the Greek, “devours” bacteria. Bacteriophages had something of a treatment heyday in the 1930s, but fell out of favor with the discovery of penicillin and the dawn of the antibiotic age in the 1940s. However, bacteriophages seem poised for a renaissance as bacteria evolve resistance to antibiotics and more infections threaten to become untreatable.

Under electron microscopy, bacteriophages can be seen to have a “head” containing nucleic acid, a stem body, and spidery legs or fibers. It’s not unlike an oil drilling rig in appearance and it is designed to penetrate and invade bacterium.

“The phage attaches to the bacterium through a receptor, and it drills into it and its genetic material, usually DNA, takes over the bacterial cell wall and turns it into a phage manufacturing plant,” Strathdee said. “Now if this is the lytic cycle of the phage, the phage makes progeny called virions, and when given the kill signal, they burst out and then they go on to attack new bacteria. They only attack the bacteria that they’re a match to. If there are no matches, the reticuloendothelial system, usually the liver and the spleen, filter out these phages and there are no side effects.”

The next step in her quest was to find bacteriophages that matched A. baumannii, sending out an urgent request that was answered by phage researchers at Texas A&M University, the U.S. Navy, and others. Four matches initially were found.

“Nobody really knows at this point how many phages you really need to have a cure, but you definitely want to have different phages that will attack different receptors, and we didn’t have the time to sequence the phages to know if we did,” she said. “But the more phages, the better, was what we thought.”

However, it was found that the level of the level of endotoxins in some of the phages may be high enough to trigger septic shock.

“Luckily, San Diego State researchers who had been studying phage had the perfect setup with an octanal extraction and they were able to reduce the endotoxin level to what we thought was probably safe,” she says.

Miracle or Virus?

After titrating the doses to about a billion phages per dose, the first phage doses were injected into the catheter in the patient’s abdomen. They waited a few days and injected phage doses in his peripherally inserted central catheter line.

“And three days later, even though he had been in multisystem organ failure and in a deep coma, he lifted his head off the pillow and opened his eyes and kissed his daughter’s hand,” she said. “Well, everybody in the ICU (intensive care unit) freaked out. Nobody could believe that a guy could come back from near-death like this. And, in fact, the head of the ICU said she’d never seen somebody so close to death that has made a near full recovery.”

As a result of the case, the ensuing publicity, and the attendant funding, UCSD founded IPATH in 2018.

“We’ve gone on to treat over a dozen phage therapy patients at UCSD, and we’ve consulted on numerous other cases internationally,” she says. “Our goal is really to disseminate our knowledge, to be able to treat other patients. We’ve published a number of case reports and are moving toward clinical trials now.”

Those trials may be instrumental in getting the Food and Drug Administration to license phage therapy beyond compassionate use. The potential for enlisting viral phages against resistant bacteria is promising, particularly as it may be used in support of antibiotic stewardship programs.

“Can you imagine having an ever-expanding phage library that maps onto a superbug library?” she says. “You’ll be able to go back to that library and match a new phage to the bacterial mutants that arise.

We should be treating phage like a living antibiotic and moving it through all of those translational studies that we need to be able to take it to Phase III trial.” To that end, the National Institutes of Health is planning a $12 million bacteriophage therapy trial using a network of research institutions.

REFERENCE

  1. Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States 2019. Updated Dec. 2019. https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf