In November 2012, 18-year-old Meredith Littlejohn was a high school senior eagerly awaiting college acceptance letters, prom, and graduation when she was diagnosed with acute myeloid leukemia, a type of rapidly progressing blood and bone cancer.
Littlejohn underwent four rounds of chemotherapy and went into remission. But by June, her cancer had returned, and she resumed treatment. With her immune system waning due to the chemotherapy, Littlejohn contracted an infection caused by the bacteria Pseudomonas aeruginosa. But the bacteria causing her infection had evolved to evade many common antibiotics that would normally have cured her. Littlejohn’s doctors treated her with colistin, a last-resort antibiotic used for hard-to-treat infections. But even the colistin was not effective against the bacteria.
By October, the infection spread to her lungs and then to her bloodstream. A year after her cancer diagnosis, 19-year-old Littlejohn died from her infection.
Drug-resistant infections like Littlejohn’s are becoming more common. This phenomenon where bacteria evolve to survive antibiotics is called antibiotic resistance, or antimicrobial resistance more broadly because viruses and fungi can also evolve to survive antivirals or antifungals.
Common infections are becoming harder or even impossible to treat, and lifesaving medical procedures from surgery and cesarean sections to chemotherapy are becoming much riskier.
The World Health Organization (WHO) has identified antimicrobial resistance as one of the century’s top global health threats. Already some 2.8 million Americans contract drug-resistant infections each year resulting in 35,000 deaths, according to the Centers for Disease Control and Prevention (CDC). Globally, the death toll is estimated to be just over 1 million.
While antimicrobial resistance is a natural consequence of evolution, researchers believe that we are accelerating this process because antibiotics are so readily used across the globe. Antimicrobials are used not only to treat infections in humans but also to prevent infections in farm animals or sometimes just to rapidly fatten them up. In developing countries or places facing humanitarian crises, infections are more common because of a lack of access to clean water and proper sanitation infrastructure. In some places with poor regulation around pollution, waste from health facilities or pharmaceutical manufacturing is simply dumped into nearby waterways, creating a perfect environment for pathogens to evolve resistance.
Given the wide variety of factors that contribute to the rise of antimicrobial resistance, many solutions — from improving infection prevention and implementing policies that reduce unnecessary antibiotic use — need to be implemented. New antibiotics are also critically needed. But very few pharmaceutical companies are working to develop new ones because they are not profitable. Congress is now mulling renewed legislation to revive the antibiotic research and development field. The bill — called the Pioneering Antimicrobial Subscriptions to End Upsurging Resistance Act, or PASTEUR, a nod to the famous chemist and microbiologist Louis Pasteur – is widely supported by politicians on both sides of the aisle and by many public health organizations. However, some are concerned that the act will restrict access to badly needed antibiotics worldwide further exacerbating global inequities.
The pharmaceutical industry got its start developing antibiotics. But today, few companies are interested in developing new ones. All the major American and European pharmaceutical companies have shuttered their antibiotic development programs and many smaller firms have gone bankrupt trying to develop antimicrobials. Since 2017, the US Food and Drug Administration and the European equivalent have approved only 12 new antibiotics, but 10 of those were similar to existing drugs to which pathogens have already developed resistance.
Pharmaceutical companies don’t want to make antibiotics because they are not profitable in our current economic model for drug development, experts say. Companies typically invest billions of dollars into researching and developing new drugs, which includes covering the cost of large clinical trials required for FDA approval. Companies recoup this investment when a successful drug reaches the market and starts selling to patients and consumers. How much money a drug will make is based on the cost of the drug, the number of people who need the drug, the length of time patients take the drug for, and the amount of the drug they need.
Here lies the problem with antibiotics: They’re generally affordable, and most people aren’t taking them all the time.
Even though humans and animals everywhere are susceptible to infectious diseases, infections occur only periodically and when they do, taking antibiotics for a week or two typically cures the infection — unless, of course, it is a drug-resistant infection. That limited treatment period makes the volume of antibiotic sales too low for companies to turn a large profit or to even recover the cost of drug development, explained Ryan Cirz, the CEO of Revagenix, a pharmaceutical company developing antibiotics.
The alternative, at least in the US, would be to hike the price of antibiotics to thousands of dollars per dose, but that doesn’t go over well with the public or health insurance companies, when the average price is anywhere from $40 to $200 without insurance. (In Europe, governments set the price of medicines.)
Given the risks posed by antimicrobial resistance, many governments are now working to create new models to incentivize and encourage antimicrobial research and development. The Pasteur Act is one of those efforts. Last year, the US Senate proposed a revamped version after a similar bill failed to pass in 2021. The new version of the Pasteur Act has less funding — it’s capped at $6 billion, versus $11 billion.
Essentially, the Pasteur Act would allow the US government to enter into subscription-style arrangements with companies manufacturing antibiotics. Once an antibiotic receives FDA approval, the US government would pay the pharmaceutical company anywhere from $750 million to $3 billion over five years to keep manufacturing the antibiotic, said Erin Duffy, the chief of research and development at CARB-X, a nonprofit dedicated to accelerating antimicrobial development. The US government would then provide that antibiotic to federal health insurance beneficiaries — such as veterans or seniors on Medicare — free of charge. (The act also calls for the Department of Health and Human Services to encourage private health insurance companies to also enter similar subscription-style contracts to procure antibiotics that receive funding through the act.)
“You’re sort of delinking that sales and volume thing,” Duffy said.
The challenge of making new antibiotics
Right now, the US government offers grants to fund early-stage drug research and development; other funders, such as NGOs, step in when promising candidates near final stage clinical trials. But the Pasteur Act uniquely promises to fund select antibiotics at a critical, tenuous time in the pipeline: right after FDA approval.
In that post-approval window, scientists and regulators have evidence that a drug is effective and safe. But there are still several costly hurdles to overcome to get a drug stocked in pharmacies across the country. For one, pharmaceutical companies are legally required to conduct a clinical trial amongst children within five years of FDA approval. That can cost upward of $80 million, according to Cirz. “So that will bankrupt you immediately,” he said.
What is even more costly is scaling up manufacturing capacity. During clinical trials, pharmaceutical companies are making drugs at a research site. But once a company receives FDA approval, it must move production to large-scale commercial manufacturing spaces. This all comes with a huge price tag, in the realm of $100 million, says Cirz. Additionally, many antibiotics being developed now are meant to be given intravenously to treat the most severe infections, which means they must be placed in sterile vials — another pricey expense.
The Pasteur Act aims to provide funding in this critical five-year period. “It’s trying to stabilize the fact that we can’t generate enough revenue to pay our bills at approval,” Cirz explained. Pharmaceutical companies developing antibiotics still won’t see the same kind of profit margins as a drug like Humira, a drug for rheumatoid arthritis, which brought in $21.2 billion in 2022. But that $750 million to $3 billion infusion of funds would be enough for companies to recoup their investment in research and development and to maybe invest in other antibiotics, Duffy said.
The Pasteur Act will not fix the system
While the act has bipartisan support in Congress and hundreds of health organizations to back it, some global health stakeholders, such as Doctors Without Borders, have cautioned against the act’s approach. They warn that antibiotics developed under this model would be more costly and inaccessible in developing countries where the burden of antimicrobial resistance is higher than in the US.
The Pasteur Act will certainly help resolve major hurdles for US pharmaceutical companies — that’s what it’s intended to do. However, antimicrobial resistance is a global problem. The emergence and spread of drug-resistant pathogens in other countries may one day present a threat to Americans. Therefore, some health organizations criticize the proposed legislation for not thinking more about the global implications of such a law
Many other developed countries with established pharmaceutical industries such as Japan, Canada, and the UK have implemented or are working to roll out their own incentives to spur antibiotic development. The Pasteur Act dwarfs these. This could potentially drive pharmaceutical companies to flock to the US market to make drugs deemed important there and not in other places.
“The size of the Pasteur Act is going to be so large that it ultimately draws developers to only focusing on the United States, only developing the drug so that it can be used appropriately in the United States, and only registering the drug in the United States, because that’s ultimately going to be sufficient revenue and incentive for what otherwise is not a very profitable market,” explained Rohit Malpani, a senior policy advisor at the Global Antibiotic Research and Development Partnership, or GARDP.
Cirz added that with a steady influx of Pasteur Act funds, pharmaceutical companies may be less interested in investing additional funds to figure out ways to manufacture their antibiotics more cheaply. Usually companies would continue investing so they can increase their profit margins by lowering manufacturing costs, but if profit margins are set by the US government, then there’s less incentive to make an approved drug cheaper, when it can divert attention to making even more drugs. Without that innovation for affordable production, the act may unintentionally prohibit developing countries such as India from being able to independently manufacture the drug.
Finally, while Americans with federal health insurance plans are guaranteed access to antimicrobials that receive support from the act, the proposed legislation does not provide any stipulations or guidance for ensuring global access to these drugs. Pharmaceutical companies are left to make decisions regarding pricing, manufacturing, and distribution of whatever antibiotics might be funded by the program, argued Ava Alkon, global health advocacy and policy adviser at Doctors Without Borders.
“What the act doesn’t do is attach any meaningful conditions to facilitate affordable access to people outside of those federal programs, and certainly not outside of the US,” said Alkon.
“From our years of work on access issues around the world, this generally results in products being sold to the highest bidder and being inaccessible in many contexts where they’re needed,” she said.
The concern about distribution is rooted in a long history of inequitable access to antibiotics. Between 1999 and 2014, 21 new antibiotics were developed. Only 12 of them were registered in more than 10 countries, most of which were high-income countries in the global north.
However, there is a bit of a tricky dynamic at play here. Because antibiotic use is one major factor accelerating the development of resistance, reducing the use of antibiotics in other countries — for instance, by restricting the sale of antibiotics there — would help preserve the effectiveness of any new antibiotic including those that receive support from the Pasteur Act. Of course, this presents a huge ethical and perhaps diplomatic question: “Is it the job for Congress to do the Pasteur Act to save every other country?” Cirz asks.
If the Pasteur Act were intent on ensuring equitable global access to new antibiotics, then the committee created by the Pasteur Act to select drugs for investment could strengthen global considerations by, for instance, requiring that pharmaceutical companies license their drug in developing countries, as GARDP recommended. Or the committee could designate some funds for antibiotics that will treat drug-resistant infections that may not be prevalent in the US but are common in lower-income countries.
While the Pasteur Act may not solve all the multifaceted challenges around antibiotic development and antimicrobial resistance, it still represents progress in solving one of the most daunting and intractable public health challenges of our time.
“There’s no question it will help me be economically successful as a drug developer,” Cirz said. “Does it fix the system? I worry it doesn’t, and I worry it creates new problems. But, at this point, everyone’s desperate for something to happen.”