This used to be the plot of science fiction movies: A virulent organism with no known cure quickly circles the globe, killing millions as public health officials scramble for a cure. COVID-19, of course, took the fiction out of the plot. While people today are trying to adjust to a new normal after this multiyear pandemic, infectious disease experts told Washington that other pathogens lurking in just about every hospital and community are poised to do more damage than SARS-CoV-2, which killed almost 7 million people worldwide as of August 2023.
During Congressional testimony, Infectious disease experts once again have stressed the importance of growing antimicrobial resistance (AMR), aiming to drive action to confront this growing threat and increase the armamentarium of antimicrobials.
“As we addressed the COVID-19 pandemic, another pandemic has been quietly brewing, not one from a single disease but rather one of resistance,” Mary Denigan-Macauley, PhD, the director of Health Care at the Government Accountability Office, testified before a subcommittee of the House Committee on Energy and Commerce in April.
At another subcommittee hearing held by the Senate Committee on Health, Education, Labor and Pensions in July, Christine Miller, the president and CEO of Melinta Therapeutics, reiterated the problem: “AMR remains a silent killer in hospitals every day. Every year we wait to address this crisis is another year more patients are at risk for losing their lives.”
Danger Zone
The numbers bear out the need for a new approach. In 2019, worldwide, AMR directly resulted in an estimated 1.27 million deaths, and AMR played a role in almost 5 million deaths, according to Helen Boucher, MD, FACP, FIDSA, the dean of the Tufts University School of Medicine and chief academic officer for Tufts Medicine, in Boston, who called AMR “one of the most significant health crises of our time, urgently needing solutions.”
The problem is exacerbating. If nothing is done to address AMR, the World Health Organization predicts the annual death toll from resistant infections will be 10 million people by 2050.
COVID-19 only aggravated the problem. A 2022 report by the CDC found the pandemic “pushed back years of progress made combating AMR in the U.S.,” noted Gareth Morgan, the senior vice president and global head of portfolio management and AMR policy at Shionogi.
The report “concluded that the threat of antimicrobial-resistant infections is not only still present but has gotten worse with resistant hospital-onset infections and deaths increasing at least 15% during the first year of the pandemic,” he said (Box).
“During COVID-19, you saw a major uptick in a lot of the resistant organisms that we had been making some progress against over the last five years,” explained James S. Lewis II, PharmD, FIDSA, the clinical supervisor for infectious disease at Oregon Health & Science University, in Portland, where he codirects OHSU’s antibiotic stewardship program.
“I think COVID made it worse” for a couple of reasons, Mr. Morgan added. “AMR is still predominantly a hospital issue and [admissions were] increasing—even though perhaps the number of people visiting community physicians was lower—and there were more people in intensive care, for example, on ventilators, where AMR becomes an issue.”
Use of empiric antibiotics also played a role, according to Margaret Koziel, MD, the chief medical officer at Innoviva Specialty Therapeutics.
“Hospitals were busy, and if a patient was admitted with a clinical diagnosis of pneumonia, there were a lot of people who were still using empiric antibiotics,” Dr. Koziel said. “The overall pressures in terms of using empiric antibiotics went up during that period for the inpatient side of the house.”
During the first year of the pandemic, nearly 40% of 29,400 people who died from an AMR infection became infected during their hospital stay, the CDC report found (bit.ly/3qowOZW-IDSE).
In addition, antibiotic stewardship programs, which made strides in ensuring proper use of antibiotics in hospitals prepandemic, were put on hold as pharmacists and ID specialists moved to caring for COVID-19 patients, according to Dr. Lewis (bit.ly/43TDhJW-IDSE).
AMR is the third-leading cause of death behind heart disease and cancer in the United States. For the 2.8 million annual U.S. AMR infections, it costs an estimated $55 billion a year, with $20 billion spent on care and another $35 billion in lost productivity (Infect Drug Resist 2019;12:3903–3910).
Medicare alone spends about $1.9 billion on the cost of caring for resistant organisms, according to Dr. Koziel. “It is not only a problem of resistance and the direct impact on patient length of stay and survival, but also the enormous impact on our healthcare system. Medicare could be doing other things with those dollars,” she added.
Again, one only has to look at COVID-19 to see how a healthcare emergency can damage the U.S. economy. “AMR is a national security threat,” Dr. Boucher told the Senate subcommittee. In addition to the impact on the economy, military service people are at increased risk for wound infections from pathogens that are multidrug resistant, and there is always the possibility that a resistant organism could be engineered as a bioweapon.
Organisms have many mechanisms for developing resistance and are capable of sharing these mechanisms among and between other organisms, Dr. Boucher explained. This became a problem not long after Dr. Alexander Fleming found that precious mold on a petri dish in 1928. Resistance was reported in 1942—before penicillin became widely used—and the battle against resistance began (Exp Biol Med 1942;51:386-389).
Even in a hospital with antibiotic stewards to educate and inform, antibiotics continue to be overused and misused, said Dr. Lewis, who is a member of the editorial advisory board of Infectious Disease Special Edition.
“I think diagnostic uncertainty drives a lot of the problem when providers are … not sure what the problem is,” Dr. Lewis said. They may assume the infection is viral, but there could be an additional bacterial superinfection complicating matters, he noted. “Even though that may be unlikely, what you see is this mindset that antibiotics cannot hurt; they can only help.”
Amy J. Mathers, MD, an associate professor of medicine and pathology in the Division of Infectious Diseases and International Health at the University of Virginia School of Medicine, in Charlottesville, said diagnostics are crucial to preserving antimicrobials. “As more antibiotic resistance emerges, we’re going to need diagnostics to make sure that we target these [strains] with ‘niche’ antibiotics,” she said.
While waiting for test results, “sometimes we have to use multiple antibiotics that the patient doesn’t need when we could be using more targeted [regimens], so the collateral damage of resistance, selection and overuse is occurring at that time,” she told the House subcommittee.
And once a broad-spectrum antibiotic is prescribed, especially to an ICU patient, there is a reluctance to de-escalate or deprescribe (Clin Infect Dis 2021;72[8]:1314-1322).
Some Things Never Change
For some, this is an old story; however, ID experts have been warning for decades about the threat of organisms so resistant that nothing can treat them, coming before Congress asking for help to create new antibiotics because the armamentarium was no match for the resistance. Congress responded with an influx of support for new antibiotic development, noted Cathy McMorris Rodgers (R-Wash.), the chair of the full House Committee on Energy and Commerce.
“In 2016, Congress appropriated an unprecedented $160 million of new investments for the CDC to fight AMR,” Ms. McMorris Rodgers said. “By fiscal year 2022, this appropriation had increased to more than $182 million.” In addition, the National Institutes of Health, and the Departments of Defense, Veterans Affairs, Environmental Protection and State have all allocated money for AMR.
“The fact that AMR continues to be a growing threat and a health burden despite this heavy investment of resources is alarming,” she said.
The investment was not in vain, experts assured, and they can point to programs like the 10 × ’20 Initiative (Clin Infect Dis 2010;50[8]:1081-1083), which supported the development of new antimicrobials. Several new antibiotics were brought to market, including ceftazidime-avibactam, cefiderocol, delafloxacin, eravacycline, omadacycline, plazomicin, imipenem-cilastatin-relebactam and meropenem-vaborbactam.
But it just wasn’t enough, they said.
However, a new payment model may address the predicament.
“We absolutely need to find a way to finance [antibiotics] because the traditional model that you see in other therapeutic areas when a new drug comes to market just doesn’t work for antibiotics,” said Amanda Jezek, the senior vice president for Public Policy and Government Relations at the Infectious Diseases Society of America.
“It’s important to understand that we do not have an innovation problem,” Ms. Miller testified. “The U.S. government recognized the need and has taken action to support research and development to address resistant infections.
“We also do not have an approval problem,” she said. “Congress already enacted a policy to streamline regulatory [review of] antimicrobials, and companies are getting innovative products approved, but are failing after launch. What we do have is a commercial marketplace problem that is fundamentally unique to antimicrobials driven by reimbursement and access challenges.”
Despite providing new weapons in the antimicrobial armamentarium, many hospitals decided not to put them on their formulary because they were more expensive than the current antibiotics. And when they did put them on formulary, physicians were reluctant to use them because they were unfamiliar with them, they were similar to other antibiotics already available or they were worried about possible adverse events.
“Hospital formularies and stewardship committees are rightly or wrongly price-sensitive,” Dr. Lewis said. “When these molecules come to market, they have to be priced at a level that is considerably higher than the generic antibiotics that are available.”
Moreover, “several of these newer compounds that did come forward were largely mirror images of each other,” he said.
Pavel Raifeld, the CEO of Innoviva Inc., attributes the formulary and coverage pushback to only incremental improvements of some of the newer compounds. “I think one of the hard truths about some of the recently approved antibiotics is that they might not be as truly differentiated from existing branded or generic products as one could have hoped,” he said.
“In certain cases, [companies] developed enough data for approval, but perhaps not enough data to ensure rapid adoption. As a result, physicians often do not know exactly where to use these products, making it difficult for these companies to generate revenue and subsequently raise capital. This creates a vicious cycle for these companies that discourages innovation in the industry as a whole.”
Even infectious disease experts were hesitant because they were worried organisms would develop resistance to these new antibiotics, and so decided they should be held until there were no options.
Unfortunately, as Mr. Raifeld pointed out, this is not a sustainable business model for pharmaceutical companies. If people don’t buy the products, companies not only cannot recoup their research and development (R&D) investment, they also are not profitable.
Kevin Outterson, JD, a professor of law and the executive director of CARB-X, which is a global nonprofit accelerator for antimicrobial innovation created under the U.S. National Action Plan by the Biomedical Advanced Research and Development Authority, reiterated that business fact when he testified before the House. “A new drug that isn’t used much in the early years cannot make money,” Mr. Outterson said. “In the last decade, seven antibiotics have come to the market sponsored by small companies. All of those companies—100%—have gone either bankrupt or the economic equivalent of their R&D investors losing their shirts—even after approval from the FDA.”
Mr. Outterson compared this market dynamic to having a fire extinguisher waiting to be used. “Doctors are doing the right thing by being careful with the newest antibiotics. They put them on the shelf behind glass like a fire extinguisher. Let me tell you, the fire extinguisher company gets paid at the moment that fire exchanger hangs on the wall,” Mr. Outterson told the House subcommittee.
Push and Pull
Although the story is not new, ID experts think they have found a new way to pay for antibiotics that could enable innovation and the development of new drugs, as well as support their judicious use after they are approved. This should encourage companies to either stay in the market or return to it.
They are called pull incentives. Prior funding worked on push incentives: money provided for R&D to push new development. Pull incentives are post-marketing funds that help a company maintain viability after approval.
“Five years ago, we all thought that the answer to the broken market was push funding [to help] companies with their research and development programs,” Mr. Morgan told Infectious Disease Special Edition. “But we started to see issues, such as the Achaogen bankruptcy, which has just become a classic example of where companies go through the development process, often using a lot of public funding, and then, after a year or so on the market, become bankrupt because they cannot fund that period of market introduction when there’s negative cash flow and little use of their new antibiotic.”
(Achaogen spent more than $1 billion and 15 years bringing plazomycin to market. The company went bankrupt in 2019 shortly after it was approved.)
“I think what we realized was that push funding is a great help, but what we really need is pull funding,” Mr. Morgan said.
Pull funding is a novel way to pay for antimicrobials, Dr. Boucher, from Tufts, explained. “Congress can revitalize antimicrobial innovation by paying for the value of antimicrobial drugs, instead of volume under a subscription model approach,” she said. Companies would make their antibiotics available, and they would receive a predetermined amount of money on an annual basis, similar to the way consumers use content streaming services like Netflix.
“We must change the way we pay for antibiotics after more than a decade of studying the problem,” Mr. Outterson said. “The G7 governments, the wealthy governments of the world, are creating antibiotic pull incentives to reward innovation while allowing the antibiotic to be used carefully. If Congress creates a subscription program, Americans will get the new antibiotics they need. They will be on the shelf ready to go like that fire extinguisher. But companies will also get what they need, which is [to avoid] bankruptcy.”
Under the PASTEUR Act (Pioneering Antimicrobial Subscriptions to End Upsurging Resistance) now before both houses of Congress, the subscription service would only be available for truly innovative and promising new antimicrobials. In addition, the PASTEUR Act would also support stewardship efforts so important to the preservation of these products.
Every ID expert learns pretty quickly to “never bet against the bugs,” Dr. Koziel said, adding it would be unrealistic to think that resistance could not develop among even new antimicrobials.
“Our weapons keep getting deactivated,” so it is important to keep the pipeline of antimicrobials filled with new and innovative antimicrobials,” she said. “I do think that with a combination of tools, education, new therapeutics and better diagnostics, we can bring AMR down so that we have a usable armamentarium.”
Mr. Morgan added: “The U.S. has an opportunity to be a leader on this issue, particularly with PASTEUR. We call AMR the silent pandemic, because it is killing an awful lot of people worldwide, yet few people [outside of ID] know about it.”
The sources reported no relevant financial disclosures outside of their employment.
This article is from the August 2023 print issue.