Antibiotic-resistant bacteria are multiplying. To stop them, we must preserve the drugs we have—and find new antibiotics now.
Mary Millard lives with an antibiotic-resistant infection, caused by bacteria known as Pseudomonas aeruginosa, that she acquired during heart surgery in 2014.
“I was 55 and super healthy, and I started getting atrial fibrillation,” recalls Millard, who lives near Baton Rouge, Louisiana. “I could feel my heart jumping around in my chest.” She was scheduled for surgery, but went into massive cardiac arrest just before the surgery and ended up on an ECMO heart-lung machine. “That’s when I acquired the infection,” she says. Such infections can be difficult to eradicate, especially if they involve any type of medical device such as a prosthetic joint or vascular graft, and the symptoms can flare up repeatedly and unexpectedly.
Since being infected, Millard says, “I’ve had 28 CT scans and hundreds of X-rays. I developed sepsis in 2014 and again a year later.” At the time she was given a 98% chance of dying. “People think: ‘I’m healthy; I’ll never get an infection.’ But it can happen to anybody.”
Over the past decade, there has been an explosion in infections from antibiotic-resistant bacteria—the so-called superbugs that have evolved to outsmart the working mechanisms of antibiotics and develop resistance to them, continuing to grow instead of being killed by the medicine. These bacteria have increasingly grabbed headlines worldwide—carbapenem-resistant Enterobacteriaceae (CRE), Klebsiella, and, perhaps the most commonly known, methicillin-resistant Staphylococcus aureus (MRSA)—and can have a terrifying aftermath.
Superbugs threaten all of modern medicine: As they become increasingly common, patients getting routine surgery or care such as cancer treatment risk acquiring an infection that’s difficult or impossible to treat.
Christina Fuhrman’s story is another cautionary tale. In 2012, after a root canal, her dentist sent her home with a prescription for an antibiotic as a safety measure.
“I didn’t have an infection. And I thought nothing of taking that antibiotic as a preventive follow-up to my root canal,” the Missouri resident remembers. It’s a decision she regrets to this day.
Over the next couple of weeks, she developed “fatigue that was like nothing I had ever experienced before: exhaustion, abdominal pain, and horrible diarrhea.” Eventually, she became so dehydrated that she had to be hospitalized.
Fuhrman was diagnosed with a Clostridioides difficile, or C. diff, infection—a major health threat that, according to the U.S. Centers for Disease Control and Prevention (CDC), is almost always caused by a side effect of antibiotic use. C. diff, essentially an extreme overgrowth of normal bacteria thrown out of balance by antibiotics, most often strikes seniors who are hospitalized or living in a nursing home. But Fuhrman, a healthy and independent 31-year-old, had six long hospital stays over the next seven months, fighting the devastating infection that easily could have ended her life.
All told, antibiotic-resistant bacteria infect at least 2.8 million Americans each year and kill at least 35,000 of them, according to the CDC; approximately another half million people will be diagnosed with C. diff, with roughly 15,000 dying from it.
Millard and Fuhrman are both Stand Up to Superbugs ambassadors with The Pew Charitable Trusts’ antibiotic resistance project, sharing with members of Congress their personal stories of fighting drug-resistant superbugs and complications from antibiotics use to urge lawmakers to act to help preserve the effectiveness of existing antibiotics and develop urgently needed new ones. For more than a decade, the project has worked to preserve the effectiveness of antibiotics, reduce unnecessary use of these drugs—including their use for growth promotion in agricultural animals—and spur the creation of new types of antibiotics.
So how did resistance to antibiotics—drugs that transformed modern medicine for the better—become such a problem?
Alexander Fleming, who discovered penicillin in 1928, predicted some two decades later that bacteria treated with the drug would evolve, leading to penicillin-resistant organisms. He was right.
“This is what bacteria do. It’s evolution at work,” says Dr. Cheryl Quinn, a drug discovery expert who has worked with Pew’s antibiotic resistance project. “They develop resistance to whatever you throw at them. All these millions of bacteria are always generating mutations.”
The bottom line is that every time an antibiotic is used, it contributes to the development of resistance and diminishes that drug’s effectiveness, says Kathy Talkington, who directs Pew’s public health programs. “Over time, all antibiotics become less effective, but when antibiotics are overused or misused, either for human health or in animal agriculture, the contribution toward antibiotic resistance intensifies,” she says.
The World Health Organization says antimicrobial resistance is one of the top 10 global public health threats facing humanity today, and calls superbugs a global health threat requiring urgent action. The organization published a fact sheet in November warning that for some of the most common bacterial infections—including urinary tract infections, sepsis, sexually transmitted infections, and some forms of diarrhea—“high rates of resistance against antibiotics frequently used to treat these infections have been observed worldwide, indicating that we are running out of effective antibiotics.”
To make matters worse, new antibiotics aren’t being developed fast enough to take the place of those that are being rendered useless—not by a long shot. “Every FDA-approved antibiotic in use today,” notes Pew’s Talkington, “is based on a scientific discovery from 1984 or earlier.”
That’s why Pew’s antibiotic resistance project has worked to improve the stewardship of existing antibiotics, minimizing the inappropriate use of these drugs both in human medicine and in animal agriculture, and also ensuring that the right dose is given for the right duration in order to maintain their effectiveness as long as possible. The project also works to develop and promote policies that lead to the creation of new types of antibiotics, a critical step toward ensuring that people will always have antibiotics that are effective.
Antibiotics save lives, and patients should take them when needed. But recent research from Pew and the CDC shows that nearly 1 in 3 antibiotics prescribed at doctor’s offices and other outpatient settings is unnecessary. That’s some 47 million unnecessary prescriptions a year, all contributing to antibiotic resistance.
Over-prescribing in inpatient settings is also a concern, especially at a time when more than half of all patients admitted to U.S. hospitals are given antibiotics. Underscoring that finding, a recent Pew study found that 52% of all patients admitted to U.S. hospitals with COVID-19 during the first six months of the pandemic were prescribed antibiotics.
Talkington says that minimizing inappropriate antibiotic use in hospitals is essential in the fight against antibiotic resistance.
Beginning in 2018, Pew partnered with the CDC and other health experts to evaluate antibiotic use in U.S. hospitals in order to set national targets to improve prescribing. The findings, published last year, were startling: They showed that 79% of all antibiotic prescriptions for community-acquired pneumonia and 77% of those for urinary tract infections were inappropriate, using an unrecommended antibiotic, for example, or using a drug for too long. The panel recommended a national target to reduce inappropriate use for each of these conditions by 90%.
Meeting those national reduction targets will require widespread adoption of effective antibiotic stewardship programs.
Among Pew’s antibiotic resistance project’s partners is the Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X), a global nonprofit public-private partnership dedicated to accelerating antibacterial research to tackle the threat of drug-resistant bacteria. Pew has worked closely with CARB-X, which is based at Boston University, since its inception in 2016; the organization’s executive director, Kevin Outterson, has been studying antibiotic resistance for almost two decades.
Outterson likens antibiotic stewardship to infrastructure. “You can stop maintaining a bridge, and it’s hard to say exactly when it’s going to fail. Antibiotics are slowly degrading, and every year that we kick the can down the road, the solution becomes more difficult,” he says. People understand that you need to invest in repairing roads, bridges, and other infrastructure, he says, adding that we should likewise build a system to ensure that antibiotics—which he calls the most powerful drugs ever invented—are there when we need them.
“It takes 10 to 15 years to go from a good idea to an antibiotic with FDA approval,” Outterson notes. In the meantime, “we need to maintain the infrastructure we have. Instead of waiting for the bridge to collapse and then building a new one, let’s maintain it.”
But building a new bridge—or, in this case, developing new antibiotics—remains a crucial part of the fight against superbugs. And the news there is not encouraging.
Between the 1940s and the 1970s, 29 new classes of antibiotics were developed. But in the 1980s, just two new ones were created—and there have been none since. Those novel classes of antibiotics—that is, drugs that are new and significantly different from existing drugs—are needed to overcome increasing resistance, especially to bacteria such as Acinetobacter baumannii, which are Gram-negative and so particularly difficult to treat because they have a defense mechanism (called an efflux pump) that jettisons the medicine back outside the cell.
That’s why Pew’s antibiotic resistance project is working not just on stewardship but also on supporting the development of new antibiotics.
For example, in years past, research and development efforts for new antibiotics were effectively siloed, and when companies stopped doing R&D, their information got locked away—forcing scientists to keep repeating basic efforts instead of building upon existing data and moving forward toward new potential discoveries. So in order to help facilitate innovation, Pew created the Shared Platform for Antibiotic Research and Knowledge (SPARK), a cloud-based, virtual laboratory that allows scientists to share data and observations, learn from past research, and generate new insights into how molecules enter and stay inside of Gram-negative bacteria. Since its launch in 2018, SPARK has garnered data contributions from academic, governmental, nonprofit, and industry sources, including major pharmaceutical companies such as Merck and
Novartis, and been a resource for more than 800 users from 63 countries.
Pew has also worked to track the pipeline of antibiotics in clinical development—drugs that are either approved, discontinued from development, or remain stagnant. This visual pipeline tool underscores the long-standing concerns of scientists, doctors, public health officials, and others about the dangerously low number of antibiotics in development to address current and future patient needs, particularly for treating the most urgent bacterial threats.
“The pipeline of antibiotics in development is broken,” Talkington says, urging that action be taken soon if we want to ward off disaster.
As for what that disaster would look like: The United Nations warns that without major change, by 2050 drug-resistant disease could cause 10 million deaths a year, along with catastrophic damage to the global economy. And some infections are already closer to being untreatable, such as the sexually transmitted disease gonorrhea.
So why don’t drug companies develop new antibiotics, since there’s clearly a need for them? It’s a matter of resources.
“Developing a new antibiotic can cost $1.3 billion over 10 to 15 years for a drug that—if it’s approved—would ideally be used only when absolutely necessary and in the smallest dose possible,” says Talkington. That’s not exactly a recipe for a profitable product.
So it’s the perfect storm: the rise of antibiotic-resistant superbugs plus a broken pipeline for bringing new antibiotics to market.
“There are far too few drugs in development with even the potential to treat the most dangerous superbugs. And that’s unlikely to change without meaningful government intervention to fix what has become a broken antibiotic market,” Talkington says.
“There’s widespread consensus that government intervention is necessary to fix the broken antibiotic-development pipeline,” says Talkington. “What’s needed is a policy like the Pioneering Antimicrobial Subscriptions to End Upsurging Resistance (PASTEUR) Act, which is aimed at delinking—in other words, removing—antibiotic revenues from sales figures.”
That’s why, Talkington says, the federal government must get involved in a public-private partnership for funding the development of novel antibiotics, and why Pew is urging Congress to pass the PASTEUR Act to help develop the next generation of life-saving antibiotics.
The act was introduced in the House of Representatives and Senate last June, with bipartisan support, by Senators Michael Bennet (D-CO) and Todd Young (R-IN) and Representatives Mike Doyle (D-PA) and Drew Ferguson (R-GA). As of the end of the year, the bill had 19 co-sponsors.
The act would establish a subscription model to decrease a company’s costs for developing new antibiotic drugs, including a federal payment that is not connected to the sale of the drugs, to ensure the company gets a sufficient return on its investment while minimizing pressure to sell more.
“A company says: ‘We want to develop this.’ And the government says: ‘Great, when you bring it to market, you will get a financial incentive, regardless of how much of the drug you sell,’” Talkington says.
Outterson, from CARB-X, concurs. “For most of the last two decades, we’ve been looking at why the private business model for developing antibiotics is broken. It’s almost beyond doubt now that public funding is essential. The problem is, you develop a brand-new highly effective antibiotic, you bring it to market and the right thing to do is to use as little as possible for five or 10 or 20 years. That’s a great thing for public health, but a terrible thing for the company. We need a new way to think about this model so that companies developing these drugs don’t go bankrupt in the process.”
Under the PASTEUR Act, “the company makes the same amount of money no matter how much of the antibiotic is used,” he says. “And we put that new antibiotic on the shelf as a fire extinguisher: We don’t want to use it until we have to.”
Superbugs have forever changed the lives of patients like Mary Millard, whose world has been turned upside down by the waning power of antibiotics. But experts say that unless antibiotic resistance is seen as the crisis that it is, we all run the risk of living in a post-antibiotic world.
“Our great-grandparents lived in a world where a minor cut could kill you,” Outterson says. “Let’s not return there.”
Kathleen Cahill is a Maryland-based writer and editor.