Steffanie Strathdee is an infectious-disease epidemiologist, and associate dean of global health sciences and professor at the University of California, San Diego, school of medicine. She also directs the new UC San Diego Center for Innovative Phage Application and Therapeutics and is an adjunct professor at Johns Hopkins and Simon Fraser Universities. She is the co-author of The Perfect Predator: A Scientist’s Race to Save Her Husband from a Deadly Superbug.
When I was an undergrad science student at the University of Toronto in the mid-eighties, I grew bacteria on petri dishes, marvelling at how quickly they multiplied to form multicoloured colonies that resembled art. My fellow students and I wore lab coats and gloves, but no other gear was required because most bacteria were considered relatively harmless. I never imagined that within the next 30 years, many of these bacteria would evolve to become “superbugs” that are increasingly resistant to antibiotics.
I’d evolved myself. I was now an infectious-disease epidemiologist and a professor with academic appointments in both the United States and Canada. But in November, 2015, during a holiday to Egypt with my husband Tom, my professional and personal lives collided. Tom came down with what first resembled food poisoning, but it turned out to be nothing of the kind. He’d suffered a gallstone attack and an abscess the size of a football had grown inside his abdomen. Inside it, one of those wimpy bacteria I had studied in class – Acinetobacter baumannii – was devouring Tom from the inside out. A. baumannii is nicknamed “Iraqibacter” because thousands of veterans returned with it from the Middle East. Many recovered from their battle wounds only to succumb to Iraqibacter, which had hitch-hiked on the military’s evacuation system, infiltrating hospitals the world over. Iraqibacter was now public enemy No. 1 on the World Health Organization’s (WHO) list of the deadliest superbugs. It’s a bacterial kleptomaniac that collects antibiotic-resistance genes and has sticky “fingers” that cling to lab coats, hospital linens and even body lice. By the time Tom was flown back home to San Diego, Calif., by air ambulance, his Iraqibacter strain had become resistant to all available antibiotics. There was nothing that modern medicine could do to stop it. Little by little, my husband was dying.
After months in the ICU, Tom was on life support and almost comatose, but he managed to squeeze my hand one day when I asked him if he wanted to live. Although I had a PhD, I was not an MD, and I studied HIV, not superbugs. I had no idea where to turn, so I did what anyone would do. I Googled it. Buried in the scientific literature was something that rang a bell from my virology class decades ago at U of T: bacteriophages.
Bacteriophages (phages) are viruses that have naturally evolved to attack only bacteria. They were discovered in 1917 by Félix d’Hérelle (1873-1949), who was a self-taught microbiologist inducted into the Canadian Medical Hall of Fame in 2007. After moving from Montreal to Mexico, Mr. d’Hérelle made a name for himself when he discovered a strain of bacteria that killed locusts. He developed it into the first organic pesticide. But when he plated the bacteria on a petri dish, he noticed clear zones surrounding some of the colonies where no bacteria could grow. Years later, after moving to Paris, Mr. d’Hérelle would deduce that these clear areas were caused by viruses that preyed upon the bacteria, which he named “bacteriophage” (derived from Greek, meaning “bacteria eater”). After dosing himself and his family with a purified suspension of bacteriophages with no ill effects, Mr. d’Hérelle used phages to treat a boy suffering from dysentery during an outbreak in Paris in 1919; the child was miraculously cured within 24 hours and after that, so were many others.
Phage therapy experienced a heyday in the 1920’s and thirties and Mr. d’Hérelle became somewhat of a celebrity as the inspiration for Sinclair Lewis’s Pulitzer Prize-winning book, Arrowsmith. But phage therapy had its downsides. Phages were finicky; they needed to be matched to the specific bacteria they infected, and if they weren’t handled properly they could be rendered useless. Our understanding of their biology was also basically non-existent back in those days. After the discovery of penicillin, phage therapy was largely abandoned in the West. Moreover, Mr. d’Hérelle was an egotist with a tendency to infuriate his peers. He’d helped establish the world’s first phage therapy centre in what is now the former Soviet Union, which didn’t help matters. In the heart of the Second World War, if you were advocating for phage therapy, you were labelled a “pinko commie.”
As far back as 1940, scientists had identified bacteria that had acquired antibiotic resistance, but the burgeoning pharmaceutical industry wasn’t worried. Their solution? Keep cranking out new antibiotics. But as more antibiotics were used, resistance was spreading faster than anyone imagined. In November, 2015, the same month Tom fell ill, a new gene conferring resistance to colistin, a “last resort” antibiotic, was discovered in China, where it had been routinely given to pigs to make them grow fatter. By the time the report was published, the colistin-resistance gene had been identified in 30 countries. Tom’s Iraqibacter strain had it, along with 50 other antibiotic-resistance genes.
Since it takes years and millions of dollars to develop a new antibiotic, the antibiotic pipeline has turned into a pipette dream. Not only is there diminished return on investment, but policy-makers have begun to advocate that new antibiotics should be “reserved” as a last resort. What incentive does Big Pharma have to develop a new drug that may scarcely be used? As a result, only four major pharmas continue to conduct research on new antibiotics.
Antimicrobial resistance (AMR) is not just a problem in lower- and middle-income countries. It’s a global crisis. At least 700,000 people die each year from superbug infections globally. The Canadian Institute for Health Research (CIHR) estimates that 250,000 Canadians develop hospital-acquired infections. Of these, about 8,000 die. That’s more than the number of deaths from motor-vehicle accidents, HIV/AIDS and breast cancer combined. Globally, the problem is getting worse because of overuse of antibiotics in livestock and in people. By 2050, it’s estimated that 10 million people, or one person every three seconds, will die from superbug infections unless urgent action is taken.
The possibility of living in a postantibiotic era where simple surgeries or scrapes could lead to an infection that requires limb amputation or results in death has rekindled interest in alternatives to antibiotics. Phage therapy has been offered for decades in the republic of Georgia and Poland, but due to the lack of rigorous data from clinical trials, it’s not yet licensed by the U.S. Food and Drug Administration, Health Canada or most health agencies in Europe, who still consider it experimental.
So when I proposed phage therapy to the doctors treating Tom in San Diego in early 2016, most of them had never heard of it. And they were skeptical. But with the help of the internet, I managed to find phage researchers – a global village of total strangers – who embarked on a phage hunt to see if they could find some to match Tom’s bacterial strain.
Phages are the most abundant organisms on the planet, and since they’re found wherever you find bacteria, some of the best places to find them is in sewage, barnyard waste and garbage dumps. Two research teams, one from Texas A&M and the other from the U.S. Navy Medical Research Center, rose to the challenge and each developed a phage cocktail personalized for Tom’s Iraqibacter.
As an infectious-disease epidemiologist, watching my husband die from bacteria that used to seem wimpy was like a cruel joke. Injecting him with a legion of viruses derived from sewage to cure him of his superbug infection sounded downright preposterous. But three weeks after my appeal for help, we obtained emergency approval from the FDA for compassionate use of phage therapy. Three days after we injected phages into his bloodstream, Tom miraculously woke from his coma and began his long recovery. He’s now almost fully recovered and back at work.
When news of Tom’s case became public, the story went viral, and in a good way. People started contacting me and his doctors from all over the world, asking us to help save their loved ones from superbug infections. We were able to help some, but others died before we could get phages to them in time. In response, my colleagues and I founded the non-profit Center for Innovative Phage Applications and Therapeutics (IPATH) at UC San Diego (UCSD) in 2018. Its goal is to move phage therapy into clinical trials, and in the meantime, to help people obtain experimental phage therapy if they have superbug infections that are no longer responding to antibiotics. To date, IPATH has treated six patients at UCSD and several others in the United States and internationally.
Why isn’t Canada at the forefront of research on phage therapy, since Mr. d’Hérelle was the first to use it 100 years ago? The University of Toronto published one of his monographs in 1922 and it’s not buried in the library; I bought my copy on Amazon. I posed this question to a few Canadian phage researchers. The only one to be actively working on phage therapy, Dr. Jonathan Dennis, told me he had received funding for his research at the University of Alberta through CIHR’s Novel Alternatives to Antibiotics initiative, but the program ended in 2012 and no new funding has replaced it. The CIHR spent just $280-million on AMR over 17 years, marginally more than what it spends each year on cancer. Professor Sylvain Moineau at Laval University in Quebec City maintains one of the world’s most important phage repositories, but he continually struggles to keep it funded. Research and innovation are one of four pillars of the Public Health Agency of Canada’s (PHAC) framework for action on AMR that was developed in 2015. PHAC spent only 1.2 per cent of its budget on AMR programming in 2016-17, but plans to implement its action plan later this year.
On the plus side, the Canadian government gave $9-million last year to the WHO to combat AMR in developing countries and began to ban the use of “medically important” antibiotics in livestock last year. But surveillance of AMR varies widely by province, and there are no official estimates of the number of Canadians who die from superbugs each year. Things are no better in the United States, where a recent report estimated that at least 153,000 people died from superbug infections in 2010, nearly sevenfold higher than the numbers reported by the U.S. Centers for Disease Control and Prevention. In contrast, Britain and several European countries are taking leadership roles in curtailing unnecessary use of antibiotics in humans and agriculture by testing new initiatives tied to specific milestones.
IPATH has fielded calls from a half-dozen patient requests for phage therapy from four Canadian provinces; some have trekked to Poland and Georgia to obtain it. Dr. Dennis and IPATH are currently working to find phages to treat a Canadian patient who is battling a multidrug-resistant bacterial infection associated with cystic fibrosis. If Health Canada grants approval for compassionate-use phage therapy for Canadians suffering from life-threatening superbug infections that no longer respond to antibiotics, they would not need to seek it in other countries.
Tom didn’t plan on being a poster child for the superbug crisis any more than I planned on being an advocate for phage therapy research. We can’t afford to bury a promising alternative to antibiotics for another 100 years. Canada should take a leading role, not a back seat, in the prevention and treatment of AMR, and should be scaling up research and programs to address it. This includes building on the legacy of early formative work on phage therapy to build the evidence base needed to determine if it is a viable adjunct or alternative to antibiotics. Since AMR is a more immediate threat to human health than climate change, the superbug crisis is going to get worse unless immediate action is taken at a global level.