Incentive structures to save us all from pathogens
Incentive structures to save us all from pathogens
Antibiotic resistance and a path forward
Before the pandemic hit, scientists had been warning for years about the possibility of a breakaway virus that could cause mass death and destruction, pointing to how unprepared we were and how inadequate our PPE stockpile was. Despite all these warnings, when COVID-19 hit, we were dramatically underprepared.
Another threat that lurks in the background is the ongoing evolution of antibiotic-resistant pathogens, made more real this week by the publication of a study in Nature about the increase in prevalence of drug-resistance in a fungus known to cause lung disease.
Antibiotics everywhere
Before Alexander Fleming accidentally discovered penicillin in 1928, infected wounds could quickly turn gangrenous or fatal. Especially on the battlefield, wounds comprised a significant portion of deaths. But with penicillin—and with the mass production of it during World War II—these deaths effectively ceased.
(I’m a huge nerd for WWII-era scientific funding and progress stories, and one of my favorites is how manufacturers were struggling to find a strain of penicillium mold that was amenable to mass production. They searched everywhere, every mold spore they could find. The winning candidate was, of all things, found on a cantaloupe in a Peoria grocery store.)
Now, less than 100 years after antibiotic use became the standard of care for a wide variety of illnesses and infections, we face the possibility of a return to the pre-antibiotic era, as many of the pathogens we treat have evolved resistance to the first- and second-line antibiotics doctors prescribe. The CDC reported in 2019 that, already, more than 35,000 people in the U.S. die annually due to antibiotic-resistant pathogens.
Part of the problem is that antibiotics were as close to a silver bullet-type drug as scientists have ever discovered. This class of drugs was able to cure—with amazing speed and limited side effects—illnesses as varied as gonorrhea, stomach ulcers, and sepsis.
Doctors became used to ordering antibiotics when a patient presented with an infection or bacterial illness. A study by the CDC using IQVIA data found 251.1 million antibiotic prescriptions in the U.S in 2019, which works out to 765 prescriptions per 1,000 patients.
And widespread antibiotic use isn’t just a factor in human medicine. After the war, animal researchers discovered that low doses of antibiotics cause livestock to grow bigger. It’s not entirely clear why; a few guesses are that antibiotics clear latent infections, or that the drugs kill bacteria in the animal’s microbiome that would otherwise absorb a portion of nutrients from the feed. (For more on the history of this, see the work of Maryn McKenna. She also reviews some of the history in this podcast with Scientific American.) Either way, in 2019, 6.1 million kilograms of antibiotics were sold to farmers for their livestock.
At the same time, the world has suffered an “antibiotic discovery void,” with the no novel classes of antibiotics discovered since the 1980s.
This gap is at least in part because many companies are wary of investing in antibiotic research. Any novel antibiotics would have to be held as a back-up for the most recalcitrant pathogens. As such, there’s a very limited market for new antibiotics. The case of Achaogen is striking. The company developed a new antibiotic, Zemdri, which became the first antibiotic designated by the FDA as a “breakthrough therapy.” The World Health Organization added Zemdri to its list of essential drugs. And then, lacking the revenue to do additional clinical trials and market the drug, the company went bankrupt.
What steps have been taken to date
From the beginning of the antibiotic era, scientists suspected antibiotic resistance could be a problem. But like many other problems in medicine, it’s hard to turn the ship—a problem that becomes more acute when you’re racing to keep up with pathogens.
In 2015, the Obama administration decided the problem needed a coordinated response. Following an executive order from the White House, multiple agencies developed the U.S. National Plan for Combating Antibiotic-Resistant Bacteria, or CARB. It’s seen some success. Not only has the amount of antibiotics given to livestock gone down (from 2015-2019, the FDA tracked a 36% decrease), but the coordinated government agencies also increased the amount of screening for antibiotic-resistant bacteria in animals, funded studies to reduce transmission on farms, and significantly reduced the rate of urinary tract infections in nursing homes.
The PASTEUR Act, introduced in 2021, could be an additional solution.1 The Act would set up a subscription payment model for the federal government to fund novel antibiotic drugs, with payments for years after discovery. By financially incentivizing research, the hope is that more companies could start working on scientific breakthroughs without worrying about the market on the other side of the discovery.
There may also be a role for AI in determining which molecule candidates to invest more time and resources in. This graphic, from a 2021 article in Nature, outlines the steps at which AI could theoretically be involved (denoted by asterisks). With Moderna having determined the basic structure of its successful mRNA vaccine in just two days, the future of drug discovery is looking brighter.
Conclusion
Antibiotic-resistant pathogens deserve our attention. But similar to my conclusion in a recent article about value-based oncology, the answer appears to be enabling scientists to do their jobs. Even more than value-based oncology, the problem and solution seem pretty simple—we need more research into novel antibiotic candidates, and there’s a way for the government to spend a relatively small amount of money to incentivize that. Of course, maintaining a stockpile of PPE would’ve been pretty simple too—but I’m choosing to be hopeful about our war with pathogens.
This information shouldn’t be taken as investment advice (obviously), and the opinions expressed are entirely my own, not representative of my employer or anyone else.
The acronyms of some of these bills are out of control. Also, it’s unclear to me why it’s PASTEUR and not FLEMING, considering the latter discovered the first antibiotic. Free Life from Everlasting Menace caused by Infectious gram-Negative Germs? It’s right there! I’m available for hire, Congress.