Coronavirus Outbreak: Read an excerpt from Superbugs which outlines the difficulties of making antibiotics

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, writes Dr Matt McCarthy, author of Superbugs: The Race to Stop an Epidemic

Matt McCarthy April 20, 2020 14:46:13 IST
Coronavirus Outbreak: Read an excerpt from Superbugs which outlines the difficulties of making antibiotics

In Superbugs: The Race to Stop an Epidemic, author, researcher and physician Dr Matt McCarthy tells the exhilarating story of his race to find a treatment for superbugs, an antibiotic-resistant bacteria.

Today, as the world waits for doctors and researchers to find a cure against the novel coronavirus , the book offers insight into how such treatments are developed. In it, Dr McCarthy discusses the history of bacteria and antibiotics, from the discovery of penicillin by Alexander Fleming and the obscure sources, often found in soil samples, of new medicines, to DNA manipulation known as CRISPR. The book highlights how medicine arrived at this point of extraordinary breakthroughs coupled with extreme vulnerability. He also talks about the patients whose lives depend on a cure for superbugs being found in time.

The following excerpt is from the eighth chapter of the book, called 'Oversight,' and discusses the implications of superbugs getting stronger and smarter in his clinical trial. 

Superbugs: The Race to Stop an Epidemic is published by HarperCollins.

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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 neutralise 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. (He told the standing-room-only audience that Allergan lacked the “cojones” to conduct a bloodstream- infection study with one of its drugs.)

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. I reached out to Spellberg because I valued his skepticism, and I thought he might give me the most critical eye.

“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.

After surveying a handful of experts, including some who requested anonymity because of their relationships with Big Pharma, 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. One woman, a fifty-nine-year-old receptionist from Staten Island, told me that she knew a recurring spinal infection wouldn’t kill her, but she wished that it would. “I’m tired of playing this game,” she said, and noted that she now spent far more time in the emergency room than in her own apartment. “Enough is enough.”

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?

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