Late last year, one of Dr. Vance Fowler’s patients — a man in his 60s who’d returned to North Carolina from visiting his family in Nepal — died of a bacterial infection. He’d been treated at a top U.S. hospital with access to the strongest antibiotics. But the infection, a drug-resistant strain of E. coli, surged on.
“Antibiotic resistance is a real problem that, with little or no warning, can affect the lives of any of us at any time,” said Fowler, an infectious disease specialist at Duke Health. “We don’t have enough drugs.”
Health officials have warned the public about antibiotic resistance for decades. That’s become more urgent in light of an upcoming World Health Organization report tallying only a handful of new antibiotics in development.
Preliminary data from the report, released by the WHO this month, paint a dire picture: Just 27 new antibiotics for the most threatening infections are in the clinical trial stage of drug development. In contrast, there were more than 1,300 cancer drugs in clinical trials in 2020, according to a report from the trade organization Pharmaceutical Research and Manufacturers of America.
Of the antibiotics in trials, the WHO considers only six of them innovative enough to overcome antibiotic resistance, and just two capable of targeting the most resistant bacteria. Agency officials will present the full report during the European Congress of Clinical Microbiology and Infectious Diseases next month.
There’s no telling whether this handful of new drugs in clinical trials will work, either. Between 2017 and 2021, just one new antibiotic, cefiderocol, was approved that could treat the superbugs on WHO’s most critical list, including strains of Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae. These pathogens can cause a range of potentially severe infections in the lungs, urinary tract, ears, blood, open wounds, or even the brain and the spinal cord.
Resistance on the rise
Drug-resistant bacteria are growing more common. In the United States alone, the Centers for Disease Control and Prevention estimates more than 2.8 million people develop drug-resistant infections each year, and more than 35,000 people die as a result. Certain drug-resistant strains of gonorrhea are on its list of urgent superbugs, as is Clostridioides difficile, or C. diff, which can cause life-threatening diarrhea and colon inflammation. The CDC estimates 12,800 people die of C. diff each year.
One of the most common superbugs in the U.S., methicillin-resistant Staphylococcus aureus, or MRSA, kills 9,800 people each year. MRSA can spread rapidly in long-term care facilities and hospital settings, where cases spiked 13% during the first year of the Covid pandemic.
Infections from the drug-resistant Shigella bacteria, often resulting in severe diarrhea and stomach pain, have been climbing at an alarming rate, too. In February, the CDC warned that last year, 5% of Shigella infections were “extensively drug-resistant” — meaning they didn’t respond to a number of antibiotics — up from zero percent in 2015. Shigella can spread through sexual contact, particularly among men who have sex with men.
Bacteria aren’t the only culprit. In the U.S., antifungal drug-resistant infections from the fungus Candida auris increased 60% in 2020, according to the CDC.
The WHO has identified 12 resistant superbugs deemed “priority pathogens,” and the CDC tracks a list of 18 drug-resistant bacteria and fungi.
Globally, more than 5 million people die from antibiotic resistance, outnumbering deaths from HIV, tuberculosis and malaria combined, said Valeria Gigante, the team lead of WHO’s antimicrobial resistance division.
Antimicrobial resistance is one of the top global health threats facing humanity.
“Antimicrobial resistance is one of the top global health threats facing humanity,” she said. “We shouldn’t call it a silent pandemic anymore. We should be loud and clear: it is indeed a pandemic.”
Bacteria and fungi are more likely to develop resistance the more they’re exposed to antibiotics or antifungals. In the case of Fowler’s patient, the specific E. coli bacteria strain had a gene that makes a protein called NDM-1, which can break down even the strongest, last-resort antibiotics, called carbapenems. Right now, most E. coli strains — there are more than 700 — aren’t deadly. But beyond E. coli, several strains of Klebsiella, Enterobacter and Acinetobacter already have this gene, and according to Fowler, more may soon acquire it.
“They don’t need a passport to travel,” Fowler said. And bacteria can swap DNA “kind of like baseball cards.”
“Maybe five or 10 years down the road, the U.S. will be facing resistance patterns reasonably similar to what we’re facing in India or Greece,” said Dr. Venkatasubramanian Ramasubramanian, president of the Clinical Infectious Diseases Society of India. Both countries have seen outbreaks of bacteria resistant to the strongest, last-resort antibiotics. “It’s a matter of time.”
The WHO says the rate of antibiotic resistance is accelerating. From 1970 to 2000, the average time it took for resistance to develop to new antibiotics was just two to three years, down from the 11-year average from 1930 to 1950. Resistance skyrocketed during the early days of the pandemic when many health systems overused antibiotics, which have no impact on Covid because it is caused by a virus, not a bacterium.
Where are all the new drugs?
The economic model for new drugs — pharmaceutical companies invest large sums upfront to test a drug’s safety and efficacy, then earn that money back in sales once it’s approved — “doesn’t work for antibiotics,” Ramasubramanian said.
Developing one new antibiotic can take up to two decades and usually costs $568 million to $700 million according to PhRMA. And just 1 in 30 of these drugs are ultimately approved to treat patients. But unlike medicines meant for widespread use, there’s an international push to use fewer antibiotics. Excessive or unnecessary antibiotic use ups the odds of a pathogen developing resistance.
“With a new antibiotic, we say, ‘don’t use it,’ or ‘use it sparingly so it lasts longer,’” Ramasubramanian said. “It is not an attractive proposition for anyone in the industry.”
Some countries have rolled out what they call “antibiotic stewardship programs.” These encourage doctors to prescribe the drugs only when there’s a clear need. In the U.S., for instance, the CDC offers training courses and guidelines to help curb antibiotic use and stave off resistance.
Even in cases where antibiotics are truly necessary, they’re often prescribed for just days or weeks, making them far less lucrative than long-term, daily-use drugs for chronic conditions such as blood pressure or diabetes.
“At the end of the day, the ‘supply and demand’ model is not tenable for antibiotics,” Fowler said.
No easy answer
If drugmakers don’t start developing new antibiotics soon, the world may be facing a “doomsday scenario,” WHO officials warned.
More people could die from once-treatable infections, such as bacterial pneumonia, gonorrhea or salmonella. Those who need antibiotics most, like immunocompromised people and those undergoing cancer treatment, will be most vulnerable.
“We have arrived in the post-antibiotic era,” Ramasubramanian warned in a statement March 15. “The current antibacterial pipeline is woefully insufficient to make a difference in tackling the ongoing threat of antibiotic resistance.”
Fowler, who wasn’t involved in the WHO report, agreed with the organization’s use of bold “doomsday” language. “The WHO is 100% spot-on,” he said. “I was thrilled to see them make such a strong statement because I think it’s true.”
While there’s no single fix for catalyzing new antibiotic development, Gigante said, government funding and policy could help move the needle. For instance, some countries have devised new economic models for incentivizing antibiotic development.
In the U.S., lawmakers are debating a legislation called the PASTEUR Act that would pay pharmaceutical companies contractually to make these critical new drugs available.
“It would fundamentally be a Netflix-like subscription model,” Fowler said. Drug companies wouldn’t have to rely on the minimal revenue they’d get selling their antibiotics on the commercial market. The proposed model has been controversial and hasn’t become law, but it’s an example of the type of “new economic model” WHO officials like Gigante want policymakers to explore.
U.S. taxpayer dollars do support some new antibiotics research already. For instance, Fowler leads a program called the Antibacterial Resistance Leadership Group, which funds new trials with grants from the National Institutes of Health.
“It’s an enormous amount of money, but there’s a great deal more that’s needed,” he said.
Better tests could help
Beyond calling for new antibiotics, the WHO officials want to see better, faster, ways of diagnosing bacterial infections. Right now, for the first 48 hours or so after a patient comes in with an infection, “you don’t know what germ you’re treating,” Fowler said.
The more quickly and accurately doctors zero in on the specific bug infecting their patients, the less likely they’ll be to prescribe antibiotics that won’t work, which could cause more resistance.
The diagnostic process involves collecting a swab, sending it to a lab, growing the bacteria from that swab until there’s enough to test, then, while still in the lab, trying out a bunch of different antibiotics to see which will work. It can take days or weeks, and the sickest patients can’t wait that long.
“It’s not through any lack of good clinical practice, but the state-of-the-art in treating infection in 2023 is an educated guess,” Fowler said. “It’s frightening when you think about it.”