The FDA’s Cara Fiore had marveled at the astonishing synchronicity of it all. She’d told Chip that to have obtained the FDA’s approval of phage therapy for a clinical use, they’d needed to have a patient with a multi-drug-resistant bacterial infection who was dying, a next of kin who agreed to pursue phage therapy, a doctor and a medical institution who would cut through the mountain of red tape, and a network of phage researchers who were willing to go flat-out to launch a phage hunt to identify, purify, and prepare a phage cocktail to the FDA’s rigorous standard. They couldn’t have dreamed of a better situation than the one Chip handed them. It occurred to me that there couldn’t have been a better person to lead the phage protocol than Chip, either. He was exactly the kind of person who could take on the old-timers in the medical establishment who had been influenced by the negative reviews about phages from the 1930s. Not only that, he was able to navigate the contemporary landscape to coordinate initiatives for rigorous, responsible, progressive phage therapy research and clinical studies; be a mentor in the medical field as it sought ways to help patients; and continue, as a physician himself, to practice the art and science of medicine on the cutting edge.
It struck me, especially from my perspective in global health, how Chip, and so many who had partnered with us through this odyssey, embodied the spirit and potential of medical science in the global age. Each in their own way had reached out to bring together the best from everyone and everything, everywhere. Chip told me later how, at the critical juncture when Tom’s phage therapy was temporarily halted, he’d called a renowned expert on the subject, his longtime colleague and friend Charles Dinarello, a professor of medicine at University of Colorado. When Charles didn’t answer the phone that Sunday morning, Chip had emailed him. Charles had answered within minutes from a Delta flight somewhere over Greenland. After a lengthy discussion, during which Charles offered to measure endotoxin in Tom’s blood, Charles ultimately concluded that endotoxins weren’t the cause of his septic shock episode. His reassurance had freed Chip to refocus on other possibilities.
So many times, this pickup team of doctors and scientists without borders had made the difference between life and death for Tom. I would never know them all, but I could feel the global village present with us at grand rounds.
Sir Isaac Newton famously said of his own accomplishments that if he could see further than others, it was because he had “stood on the shoulders of giants.” We were acutely aware of the shoulders on which the success of Tom’s phage therapy rested. Tom wasn’t the first person to be treated and cured with phage therapy, not by a long shot. Beginning with Félix d’Hérelle a hundred years ago, scientists around the world had spent their careers on phage research and its clinical applications, beginning with the Republic of Georgia, Russia, Poland, and more recently, Belgium. In the US, phage researchers like Betty Kutter from Evergreen State College had used phage therapy topically to successfully treat diabetic toe ulcers. Félix and his contemporaries died before their work could be fully appreciated, but all those on the phage front then and today had supplied essential pieces of the knowledge and expertise that had saved Tom’s life. Our “bold guess” to treat Tom intravenously with phage cocktails had paid off, but only because we had learned from the experiences of so many others—their successes and failures—and taken a calculated risk.
In truth, this was also a story about privilege. So many people who are dying of multi-drug-resistant bacterial infections don’t have the connections and resources to call upon that we did. If phage therapy is shown efficacious in clinical trials, our goal is to help ensure that it is scaled up in lower-and middle-income countries that bear the largest burden of the superbug crisis.
As fortunate as Tom was to survive his battle against one of the world’s most lethal superbugs, his was a worst-case scenario that showed just how fast we’re losing that battle globally and how unprepared our US medical and healthcare systems are for the crisis. The plasmid that confers resistance to the antibiotic colistin was reported in China in November 2015—the same time that Tom got sick. Once it was discovered, the Chinese stopped using colistin in livestock. But resistance to it had already spread to thirty countries and five bacterial species before anyone noticed. In Tom’s case, when we were in Frankfurt waiting for the antibiotic resistance profile to come back on Tom’s A. baumannii isolate, Chip said he’d be very surprised if it came back resistant to colistin, but by the time we got to San Diego two weeks later, Tom’s Acinetobacter was fully resistant to it. That’s how quickly these superbugs can develop resistance and catch us off guard.
The spread of colistin resistance was a failure on so many levels. Widespread use in livestock of a medically important antibiotic for humans was known to contribute to antibiotic resistance more than a decade ago. The lack of a surveillance system for detecting the emergence of colistin-resistant bacteria had hidden the growing threat for an unknown period. And the unavailability of rapid tests to diagnose bacterial infections and determine which antibiotic might work slowed any response time, giving superbugs an even greater head start. A 2016 report found that colistin was still being used in agriculture in countries like India, Vietnam, Russia, Mexico, Colombia, and Bolivia.
In the US, it wasn’t until 2017 that the FDA banned use of medically important antibiotics to promote growth in livestock. Although antibiotics used for prevention in the US are now under the control of veterinarians, many of these are unlabeled growth promoters, which continue to be one of the main contributors to the spread of multi-drug-resistant bacteria. And banning use of the antibiotics for that purpose here hasn’t kept some in the animal pharmaceutical industry from continuing to sell them as a growth enhancer in countries where regulation and enforcement has been more lax, exposing those consumers to greater risk and adding to the global factors contributing to antimicrobial resistance.
Experts now acknowledge that infectious diseases we thought we’d licked are making a comeback, and some infections that once were easily cured with antibiotics are almost untreatable now. What’s more, many routine procedures like colonoscopies and common surgeries like joint replacements now present a greater risk of infection by antibiotic-resistant bacteria present in hospital settings and equipment.
There is no new family of antibiotics on the horizon that promises to rescue us as penicillin once did. However, there is precedent for innovative breakthroughs in science and medicine when disasters strike and our backs are up against the wall. The urgency of war led to a number of medical advances in World War II, penicillin topping the list. If not for the mounting pressure to find a cure for battlefield wounds, would penicillin have been tested and scaled up at the time? When the pressure is on and conventional methods fail, alternatives get more serious attention, and that is often how old ideas get recycled, new discoveries are made, and new cures are developed.
Desperation was what pushed me to action, too. And that sense of urgency paired with possibility had spurred the actions by others who found a way to take what was known and push forward, which eventually made Tom’s one-man miracle possible. But with a bold guess comes risks, and the risk/benefit ratio is one that doctors take into account every day, as do the FDA, the ethics committees at hospitals and universities, and the loved ones who make the ultimate decision.
Tom and I, as well as Chip, Davey, and Connie, had witnessed this firsthand in the HIV epidemic. When there were no AIDS drugs available, researchers and clinicians pushed for clinical trials, whereas AIDS activists pressed for access to the experimental treatments. There were terrible clashes at first, and as a PhD student, I felt caught in the middle, seeing both sides. At the 1991 International AIDS Conference in San Francisco, I’d even participated in a “die-in” protest with ACT-UP activists outside the conference hall, when my researcher colleagues were inside, and faced off against police in riot gear as we all lay down on the pavement and had other activists outline our bodies in spray paint. My friends and even my PhD adviser, Randy,
were dying, waiting for drugs that could save them or give them even a little more time, whereas researchers were saying it was too early, too risky, to allow patients access to drugs that could turn out to be toxic. In the end, there was room for both. Clinical trials went forward, but a pathway for compassionate use was created on a case-by-case basis, where the FDA, ethics committees, doctors, and patients could weigh the potential benefits versus the risks based on each patient’s unique situation.
That was our hope when we arranged for Tom’s phage therapy protocol to provide data in a way that could be useful to other scientists and physicians. We were aware that the phage cocktails themselves—and administering them intravenously in particular—posed risks and set aside drug safety standards that might never be acceptable for general use. But what tipped the scales for us was the possibility that Tom’s case—even if it meant Tom’s death—could contribute to scientific understanding of phage therapy and to the impetus for needed clinical research.
The surprise in store for us was that it happened so quickly. When Tom’s case was first covered in the news in April 2017, after Biswajit presented it in Paris, our story went viral on social media.
Within a few days, I received the first call for help from a woman whose family member was suffering from a multi-drug-resistant Acinetobacter infection in China. That was soon followed by others with chronic urinary tract infections, lung infections associated with cystic fibrosis, and complications following surgeries, like sepsis. All had superbugs and all wanted phage therapy. Desperately. I turned to Chip, Theron, and Ry for help. Some patients died before we could obtain their samples to find matching phage. A few went to the Eliava Phage Center in Tbilisi. And in a growing number of cases, we were able to help.
Later that year, Belgian researchers working with Jean-Paul Pirnay and Maia Merabishvili reported on successful intravenous phage therapy to treat a patient with a life-threatening multi-drug-resistant infection. In early June, based on the success of Tom’s case, phage therapy was used successfully to treat another patient at UCSD who was battling a lung infection following a double lung transplant. Tom and I met John Willson and his family one day when we were visiting the TICU nurses and doctors. As we stood bedside with several of John’s family members donned in the all-too-familiar yellow gown and blue gloves, John’s daughter Jolynn embraced us and held our hands.
“Thank you for your courage,” she said. “Because of you, my dad is still alive.”
However, the “shoulders of giants” are often those of the most vulnerable among us. During Tom’s recovery, Chip was contacted about using a modified version of the protocol to help a two-year-old boy, working with Theron and Biswajit’s phage lab at the Navy. The boy’s parents decided to try phage therapy after being presented with Tom’s case, and it was working; his infection cleared. Sadly, he died of his underlying heart problem, but his case added to the body of evidence that phage therapy is worth a closer look.
Just weeks after the grand rounds presentation, I received a call from the father of a young woman not much older than Cameron. Mark Smith asked if I could help his daughter Mallory obtain phage therapy. A cystic fibrosis patient, Mallory had recently had a double lung transplant after battling a chronic superbug infection with an uncommon but nasty bacteria, Burkholderia cepacia. The infection had come back and was now attacking her new lungs. Cystic fibrosis patients have a genetic mutation that means they can’t clear mucus from their lungs, which breeds infection. They receive a lot of antibiotics, which, over time, fuels resistance.
Mallory’s mom, Diane, sent me a photo of herself and Mark with Mallory from her hospital bed in Pittsburgh, where she had recently celebrated her twenty-fifth birthday. I pinned it to my screensaver for inspiration. Chip, Theron, Biswajit, Ry, and one of his colleagues at Texas A&M were all in, but a few were skeptical that we could find phages against B. cepacia. And B. cepacia phages were tricky. They tended to be temperate rather than lytic, meaning that even if they matched Mallory’s superbug, they could integrate into the bacterial DNA—essentially merge with it—without killing it. Since there was no time to sequence the phages, Ry, in particular, was worried that these phages could carry harmful toxin or antibiotic resistance genes. Still, the Smiths were willing to try it if we could find phages to match. They had reached out to the only phage researcher they could find who had published on B. cepacia, Dr. Jon Dennis from Alberta, Canada. He too, was on board. But we would need a phage cocktail, which meant launching a wider net. It felt like déjà vu. Could we do it all again?
The PubMed database didn’t identify any other researchers who studied B. cepacia phages. After racking my brain about how to find more phage researchers who could help, I turned to Twitter. Maybe we could crowdsource phages for Mallory. My tweet was retweeted 432 times and found several other phage researchers who stepped up to the plate. Mallory’s parents had her bacterial isolate sent to their labs, which included Texas A&M and Adaptive Phage Therapeutics (APT), a new phage therapy startup in Maryland that Carl Merril and his son Greg had launched after witnessing the success of Tom’s case. After working around the clock for several days, Dr. Dennis and APT, working with Biswajit and the Navy lab, both found matching phages. We were exhilarated; success appeared within reach. But before the phages could be purified and amplified, Mark called with terrible news. Mallory’s condition had worsened considerably, and her doctors said they could only keep her alive for a few more days. Mark and Diane decided to take whatever phage preparation was available, even though it wasn’t fully purified or amplified, and give it a try. A few small vials were raced to Pittsburgh. Mallory only received a few micro doses before her doctors decided that it was too late. When she was taken off life support, we were all crushed.
“When I first heard about phage therapy,” Mark told me at the reception after Mallory’s funeral, “I had an idea. I asked Mallory’s doctors if we could treat her before she had her lung transplant, so we could clear her infection and give her new lungs a chance. But they had never heard of this treatment. They thought it was too risky and dismissed it. But I can’t help but wonder if it could have worked.”
We had an opportunity to try Mark’s idea. In early 2018, Chip and Dr. Saima Aslam from UC San Diego treated a cystic fibrosis patient with phage therapy, a woman the same age Mallory would have been. But this time, she received phage therapy before she received a lung transplant, with the hopes that if her infection could be cleared, her new lungs would avoid reinfection. Her phage treatment worked beautifully, and she returned home to wait for her lung transplant.
We may have learned as much from Mallory’s death as we have from Tom’s survival. As Ry liked to say, “phage therapy 2.0 is on its way.”
One morning in summer 2018, incredulous upon hearing news of the US federal government’s plans to stop public reporting of hospital-acquired infections and to continue the use of preventive antibiotics in citrus groves, Tom and I sat, discouraged, before heading into work for the day.
“This superbug crisis is bigger than us,” I told Tom. “Why aren’t people paying attention?”
Tom watched me pensively. “Look at it this way,” he said. “You’re an infectious disease epidemiologist, right? But until Iraqibacter almost took me down, it wasn’t like you were going around sounding the alarm bells about the superbug crisis.”
He had a point. And by dosing Tom with Cipro in Egypt without a doctor’s oversight, my misuse of antibiotics was part of the problem. I had been clueless in Frankfurt and even here, to truly comprehend what we were up against—what Tom and his medical team were up against.
I had always told my students that being ensconced in the ivory tower of academia could render scientists out of touch. If people like me who are supposed to know better are oblivious to the urgent threat superbugs pose to human civilization, how can we expect to inspire global action for change? As a species, are we ignoring the signs? Suffering from collective denial? Or do we just think that we huma
ns are supreme beings that can outsmart any microbe?
A post-antibiotic era. That’s how some of the world’s top health officials, including former CDC director Tom Frieden, describe the global threat of antimicrobial resistance (AMR). By 2050, one person could die from a superbug infection every three seconds each year, making AMR a more immediate threat to humankind than climate change.
In 2018, the world’s leading health agencies worked together to stop an Ebola outbreak that threatened to spiral out of control and announced that globally, more than half of people living with HIV were now receiving HIV antiretrovirals. But despite urgent calls for action, little progress has been made to curb the global spread of AMR. New strains of antibiotic-resistant bacteria continue to be reported along with the spread of “extremely” drug-resistant bacteria associated with diseases like tuberculosis, gonorrhea, and typhoid.
Healthcare systems and the pharmaceutical industry are on the hook, too. A recent CDC report found that in US outpatient clinics, antibiotics were inappropriately prescribed almost half the time. In 2018, the first detailed analysis of pharma action against AMR found that of twenty-eight antibiotic candidates in late stages of clinical development, only two had plans to ensure that the product will be used wisely. Less than half of companies with antibiotics on the market are involved in AMR surveillance, and of eighteen major antibiotics manufacturers, just eight had set limits on antibiotic wastewater discharge. Meanwhile, the death toll from antimicrobial resistance in the US alone has been grossly underestimated in past analyses, and is now estimated to have been more than 150,000 in 2010—a seven-fold increase over previous reports. Roughly one-fifth of infections occuring in Europe, North America, and Australia are believed to be due to antibiotic-resistant bacteria.
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