A Race Against Bugs
It was just after dawn when I felt the buzz on my hip. I broke stride, put down my coffee, and glanced at my pager: I was needed in the emergency room. It was 2014, an unseasonably warm October day, and the text induced a flurry of anxiety and excitement. After eleven years of training, I had accepted a position as a staff physician at NewYork-Presbyterian Hospital, a tertiary care center on the Upper East Side of Manhattan, and a patient had just arrived with a perplexing infection, one that had stumped the team in the ER.
A moment later, I was standing before a group of medical students and residents and my new patient. The young man writhing on the stretcher was an African American mechanic from Queens named Jackson, with dark-green eyes and a small Maltese cross tattooed onto his neck. He had been shot, and a large area surrounding the bullet, which was still lodged in his left leg, looked infected. As I peered into jagged edges of the entry wound just above Jackson’s knee, a student handed me a piece of paper. The printout revealed the results of a microbiological test, which caused my eyes to bulge. My patient, I discovered, was infected with a nimble and aggressive new bacterium that was resistant to every antibiotic at my disposal, except for one: colistin.
I had used the drug only a few times in my career and never with good results because it was so outrageously toxic. Colistin might kill bacteria, but it destroyed kidneys and other internal organs in the process, leaving many of my patients with just two options: dialysis or death. Antibiotics that had proven so effective just a short time ago were now useless, and if I wanted to save this young man’s leg, it was my only option. I shook my head and handed the paper back to my student. “Not good.” More than twenty thousand people die every year in the United States from antibiotic-resistant infections, and the pipeline of drugs to treat them is always on the verge of drying up. I crouched to meet Jackson’s eyes and carefully considered my words. “You have an infection,” I said. “A severe infection.”
The man’s gaze darted from me to the men and women standing in a horseshoe behind me. “How severe?” He took in a small breath of air and held it, waiting for me to say something. It felt like an hourglass had been flipped; suddenly the tiny room was very hot. I took off my white coat and rolled up my sleeves. “Quite severe.”
His eyebrows raised, and I reflexively extended my arm to hold his hand, but caught myself. I wasn’t supposed to touch this patient without protection. I pivoted back to my team. “Everybody out. Now.” I pointed toward the door. “I’ll be right back.” Just outside of his room, I put on a disposable yellow gown and a pair of purple nitrile gloves, and returned to the bedside alone. “It’s very hard to treat,” I said, “but not impossible.”
Jackson was now breathing very quickly, on the verge of hyperventilating, as sweat beaded on his forehead. He grasped his thigh, inches above where the bullet had entered. Beneath his fingertips, bacteria were rapidly multiplying, devouring muscle and bone.
“Am I gonna lose it?” he asked. “The leg?”
In truth, I wasn’t sure. Only colistin had a chance of destroying the infection, but there were no guarantees. The last person I prescribed it to died twelve hours after she received it. The one before that died while receiving it. “I don’t think so,” I said, as confidently as I could. I squeezed his sweaty hand and tried to imagine how I would summarize the nuances of the case for his wife and children. They would need to take special precautions just to be in the same room with him. “We’re going to get through this,” I said as his eyes began to water. “We will.”
I left the room, removed my gown and gloves, and addressed my team. “Start colistin,” I said. One of the residents frowned as she scurried to a computer to put in the order. Then we vigorously washed our hands and moved on to the next patient.
When rounds were over, I walked across the hospital to the office of my research collaborator, Tom Walsh, director of the Transplantation-Oncology Infectious Diseases Program. Walsh is a wisp of a man, pale and thin like a potato chip, with deep-set eyes, a warm smile, and a surprisingly firm handshake. His modest features are a notable contrast with my own: I have a high forehead, broad shoulders, and a nose that’s slightly too large for my face.
We make for an odd pair.
Walsh is one of the world’s leading authorities on obscure infections, and when he’s not caring for patients, he’s creating new antibiotics to treat them. We had met a few years after I graduated from medical school—I still have the elegant biochemical structures he drew for me during our first interaction—and I’ve been working with him ever since.
In 2009, he moved from the National Institutes of Health (NIH), the federal agency responsible for biomedical research and disease prevention. Walsh brought with him an expansive research consortium—an international team of physicians and scientists who conduct experiments in test tubes, animals, and humans—to develop antibiotics. He is one of the only researchers in the world to oversee a laboratory of this scope; he is an expert in infectious diseases, oncology, pediatrics, internal medicine, pathology, microbiology, and mycology. No one else possesses his breadth of knowledge.…
He had called me that October morning in a fit of excitement, with news that Allergan, the pharmaceutical giant, wanted us to run a clinical trial: a large-scale human experiment with an unproven drug. The Dublin-based company was developing a promising new molecule and it wanted us to show it was not only safe but effective in treating humans infected with antibiotic-resistant bacteria, known colloquially as superbugs. They had become a persistent problem for us; superbugs didn’t really exist before the 1960s, and they were only sporadically seen in the world until the 1990s. But a combination of poor prescribing practices by doctors along with the indiscriminate use of antibiotics in commercial agriculture and farming exposed bacteria to our precious arsenal of effective drugs, and the microbes figured out ways to neutralize them. Superbugs were now everywhere—even on stray bullets in Queens—and they had become a leading cause of deadly infections in humans. “So what is it?” I asked Walsh as I entered his office. He leapt up from his messy desk, hurrying past framed diplomas and awards that covered every inch of the mahogany walls, to greet me. “What’s the drug?”
Superbugs were now everywhere—even on stray bullets in Queens.
Walsh looked exhausted—the man regularly slept only three hours a night—because we were in crisis mode, desperately searching for new antibiotics to treat our patients. I had grown accustomed to watching men and women succumb to infections that had been treatable just a few years ago. When Walsh shook my hand, he brightened. “Dalbavancin,” he said softly.
My fingers and wrists were still damp from the tense exchange in the emergency room; I wiped them on my khaki pants and sat down in the chair next to his desk. “You’re kidding.”
He handed me a thick manila folder. “I’m not.”
Just the word—dalbavancin—brought me back fourteen years, to my days as an undergraduate tinkering around in the laboratory of a future Nobel laureate named Tom Steitz [PhD ’67], a biophysicist who was known around campus as “the Michael Jordan of crystallography,” the branch of science that probes the atomic building blocks of life. Steitz studied protein synthesis, an essential function of nearly all living things, and his discoveries led to all sorts of new drugs, including a handful of antibiotics related to dalbavancin, called “dalba” for short. Like Tom Walsh, he was a visionary who could see drug development in ways that others couldn’t.
I connected with Dr. Steitz through his son, Jon, who had happened to be my teammate on the Yale University baseball team. He and I were pitchers and biochemistry majors, and we were both drafted out of college to play professional baseball; Jon was selected by the Milwaukee Brewers in the third round of the 2001 Major League Baseball draft, and I was taken the following year, in the twenty-first round, by the Anaheim Angels. We briefly thought we were destined for the big leagues.
A year later, after a stint playing minor league baseball in Provo, Utah, I was cut by the Angels and exchanged my baseball mitt for a stethoscope. I enrolled at Harvard Medical School in the fall of 2003, moving to Boston around the time Jon gave up the game and went to Yale Law School. A few weeks after classes began, I attended a lecture by a young and charismatic infectious disease doctor named Paul Farmer [MD ’88 PhD ’90], cofounder of the global nonprofit Partners In Health, and immediately knew what I wanted to do with the rest of my life. I was going to study infections to learn how to defeat them.
“Let’s get to work,” Walsh said, snapping me out of my reverie.
This was the moment everything changed, when I went from a passive observer of drug resistance to an active participant in the race to stop the expanding threat of superbugs. But before I could start the long and winding journey of a clinical trial, I had to familiarize myself with the painful lessons learned from generations of failed studies and appalling ethical lapses, as well as the remarkable scientific advances behind the work of Tom Steitz, Tom Walsh, and others…It’s an adventure dotted with clues that would help me unravel the mystery of Jackson’s infection.…
A maxim in medicine is that antibiotic resistance comes with a fitness cost, meaning that when bacteria become impervious to antibiotics—when they mutate into superbugs—they sacrifice something vital in return. Devoting resources to evasion leaves superbugs exhausted and unable to spread. It’s a phenomenon that infectious disease specialists count on, but it turns out this paradigm is changing: superbugs have recently become more fit and more virulent. In other words, they’re getting smarter and stronger.
This had profound implications for my dalba trial and the risk associated with participation. It was clear from the IRB’s terse wording that I had underestimated the possible dangers dalba posed to patients. I was offering a false sense of security by telling them that I could potentially cure their infection and shorten their hospital stay. But it was far from certain that this would, in fact, be the case. I hadn’t mentioned efflux pumps—the microscopic vacuum cleaners that bacteria use to suck up and expel antibiotics—or any of the other chemical modifications that they might use to neutralize dalba. I hadn’t mentioned that bacteria were becoming more aggressive and that my drug might not work. The protocol was in need of a drastic rewrite.
To gain a bit of perspective, I reached out to several experts to understand how they approach clinical trials and antibiotic research. I started with Brad Spellberg, chief medical officer of LAC+USC Medical Center, a top-flight, oddly punctuated health care and research center. Spellberg is a thoughtful and devoted physician-scientist; he’s also a provocateur. At a major conference in San Diego, I listened with delight as he stood at a podium, calling out pharmaceutical companies by name for the trials they should have done but were scared to attempt.…
Devoting resources to evasion leaves superbugs exhausted and unable to spread.
Spellberg and his colleagues believe that resistance already exists to all antibiotics, including those we have not yet discovered. To understand how this is possible, we might invoke the infinite monkey theorem, which argues that a monkey hitting keys at random on a computer keyboard for an infinite amount of time will eventually produce coherent text, including the complete works of William Shakespeare. By way of comparison, microbes are constantly mutating, hitting the proverbial keys in novel combinations, and those sequences produce enzymes and pumps that can deflect or destroy any antibiotic. Spellberg and his team have noted that antibiotic resistance has even been discovered “among bacteria found in underground caves that had been geologically isolated from the surface of the planet for 4 million years.” It’s a terrifying thought that called into question the very essence of my trial.…
“There are already widespread resistance mechanisms in nature to drugs we haven’t invented yet,” he told me one morning before rounds. “When we come out with a new antibiotic, people think new mutations occur after we start using the drug, but that is false. The much bigger problem is that there are low levels of preexisting resistance mechanisms that we can’t yet detect. When we dump a new antibiotic into the environment, we apply selective pressure and resistance grows.” Eventually we will run out of new drug targets. “We need to be smart about this,” he added. “Bacteria use antibiotics judiciously. Humans do not.”
Spellberg told me that the solution is to take the long view. “We don’t want a flood of new antibiotics,” he said. “We need a slow and steady drip.” Bringing a number of antibiotics to market simultaneously would be problematic, he explained, because resistance would occur in tandem. We desperately need more antibiotics, but it would be a mistake to test all of the best candidates simultaneously.…
I revised the dalba protocol, conceding that the risk had been understated, and resubmitted it. “Fingers crossed,” I said to Tom. The leitmotif of his expansive career had been to solve the unsolvable; I had faith that together we could steer our study through the latticework of approvals and regulations. “I feel pretty good about this.”
“Now we wait,” he replied.
I went back to seeing patients, and Tom returned to writing grant proposals. What struck me in the weeks that followed, as we waited for a response from the IRB, was the rising number of patients who were admitted to my hospital because oral antibiotics were no longer working. They had routine infections—pneumonia or urinary tract infections—that in prior years could have been treated at home with a week’s worth of pills. But the treatments simply weren’t strong enough. Bacteria really were getting smarter and stronger. In the week after I revised the protocol, Jackson passed in and out of my emergency room twice. He told me the infection prevented him from seeing his daughter’s dance recital and his son’s first basketball game. “Nothing seems to work,” he said. And he was right. He was coping with a chronic infection and hoped that he wasn’t spreading it to others.
This shift in the way we treat infections—from oral to intravenous antibiotics—was contributing to a burgeoning crisis at the hospital. Due to overcrowding, patients were waiting up to thirty hours in the ER just for a bed to open up. On some days, we had to turn ambulances away. There simply wasn’t the space for the additional bodies, and patients were instructed to look elsewhere. Jackson was just one of hundreds of patients I’ve cared for with a superbug infection. Many of these people died, and even more were left profoundly debilitated.…
There was no good way to predict who would contract an infection or who would succumb to the illness. We were all at risk because bacteria don’t discriminate—they attack all comers: the young, the old, and everyone in between. They were outfoxing us, and in some ways it felt like we were returning to a pre-antibiotic era, one in which a century of scientific progress had simply been erased. While waiting for a response from the IRB, I kept asking myself: Why is it so hard to make a new antibiotic?
Matthew McCarthy, MD ’08, is an assistant professor of medicine and a hospitalist at Weill Cornell Medicine in New York City. This article contains excerpts from his international bestseller, Superbugs: The Race to Stop an Epidemic, published by Penguin Random House’s Avery imprint in 2019. Excerpts appear with permission from the author and his publisher. Bracketed material added with permission.
Images: Mattias Paludi (illustration); Maya Rucinski-Szwec