Late last year, one of Dr.’s patients. Vance Fowler – a man in his 60s who had returned to North Carolina from visiting his family in Nepal – died of a bacterial infection. He is being treated at a top US hospital with access to the strongest antibiotics. But the infection, a drug-resistant strain of E. coli, grew stronger.
“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 medicine.”
Health officials have warned the public about antibiotic resistance for decades. That’s made even more urgent by an upcoming World Health Organization report tallying just a few new antibiotics in development.
Preliminary data from the report, released by the WHO this month, paints a dire picture: 27 new antibiotics for the most dangerous 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 in a report from the trade organization Pharmaceutical Research and Manufacturers of America.
Of the antibiotics in trials, only six of them are considered by the WHO to be innovative enough to overcome antibiotic resistance, and only two are capable of targeting the most resistant bacteria. Agency officials will present the full report at the European Congress of Clinical Microbiology and Infectious Diseases next month.
There’s no telling whether some new drugs in clinical trials will work, either. Between 2017 and 2021, only one new antibiotic, cefiderocol, was approved that can treat superbugs in the WHO’s most critical list, including strains of Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae. These pathogens can cause a range of potentially serious infections in the lungs, urinary tract, ears, blood, open wounds, or even the brain and spinal cord.
The resistance is growing
Drug-resistant bacteria are growing more commonly. 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 types of drug-resistant gonorrhea are on its list of urgent superbugs, such as Clostridioides difficile, or C. diff, which can cause life-threatening diarrhea and inflammation of the colon. The CDC estimates that 12,800 people die from C. diff each year.
One of the most common superbugs in the US, methicillin-resistant Staphylococcus aureus, or MRSA, kills 9,800 people each year. MRSA can spread quickly in long-term care facilities and hospital settings, where cases have occurred up 13% in the first year of the Covid pandemic.
Infections from drug-resistant Shigella bacteria, which often result in severe diarrhea and abdominal pain, are also increasing at an alarming rate. In February, the The CDC warned that last year, 5% of Shigella infections are “extensively drug resistant” — meaning they don’t respond to certain antibiotics — up from zero percent in 2015. Shigella can be spread sexually, particularly among men who have sex with men.
Bacteria are not the only culprits. In the US, antifungal drug-resistant infections from the fungus Candida auris increased by 60% in 2020, According to the CDC.
Identified by the WHO 12 resistant superbugs are considered “major pathogens,” and the CDC tracked a list of 18 drug-resistant bacteria and fungi.
Globally, more than 5 million people die from antibiotic resistance, more than the number of deaths from HIV, tuberculosis and malaria combined, said Valeria Gigante, team leader of the WHO’s antimicrobial resistance division.
Antimicrobial resistance is one of the leading global health threats facing humanity.
“Antimicrobial resistance is one of the leading global health threats facing humanity,” he said. “We should no longer call it a silent pandemic. We must be loud and clear: this is indeed a pandemic.
Bacteria and fungi are more likely to develop resistance when they are more exposed to antibiotics or antifungals. In the case of Fowler’s patient, the particular strain of E. coli bacteria has a gene that produces a protein called NDM-1, which can destroy even the strongest, last-resort antibiotics, called carbapenems. Today, most strains of E. coli — there are more than 700 — are not deadly. But beyond E. coli, some strains of Klebsiella, Enterobacter and Acinetobacter already have this gene, and according to Fowler, more may acquire it soon.
“They don’t need a passport to travel,” Fowler said. And bacteria can shuffle DNA “like baseball cards.”
“Maybe five or 10 years down the road, the US will be facing resistance patterns that are 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 new antibiotics to develop was just two to three years, down from the 11-year average from 1930 to 1950. Resistance peaked in the early days of the pandemic when many health systems overuse antibiotics, which have no effect 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 to test a drug’s safety and effectiveness, then recoup that money in sales once it’s approved — “is not works for antibiotics,” says Ramasubramanian.
Developing a new antibiotic can take up to two decades and typically costs $568 million to $700 million according to PhRMA. And only 1 in 30 of these drugs are ultimately approved to treat patients. But unlike drugs meant for widespread use, there is an international push to use fewer antibiotics. Excessive or unnecessary antibiotic use increases the likelihood that a pathogen will develop resistance.
“With a new antibiotic, we say, ‘don’t use it,’ or ‘use it sparingly so it lasts longer,'” Ramasubramanian said. “It’s not an attractive proposition for anyone in the industry.”
Some countries have launched what they call “antibiotic stewardship programs.” This encourages doctors to prescribe drugs only when there is a clear need. In the US, for example, the CDC offers training courses and guidelines to help curb antibiotic use and prevent resistance.
Even in cases where antibiotics are absolutely necessary, they are often prescribed for only days or weeks, making them less profitable than long-term, daily use. medications for chronic conditions such as blood pressure or diabetes.
“At the end of the day, the ‘supply and demand’ model cannot be sustained for antibiotics,” Fowler said.
There is no easy answer
If drug makers don’t start developing new antibiotics soon, the world could be facing a “doomsday scenario,” WHO officials have warned.
More people may die from infections that are once treated, such as bacterial pneumonia, gonorrhea or salmonella. People who need antibiotics the most, such as immunocompromised people and those undergoing cancer treatment, will be most vulnerable.
“We have entered the post-antibiotic era,” Ramasubramanian warned in a statement on March 15. “The current antibacterial pipeline is insufficient to make a difference in dealing with the ongoing threat of antibiotic resistance.”
Fowler, who was not involved in the WHO report, agreed with the organization’s use of bold “doomsday” language. “WHO is 100% spot-on,” he said. “I’m glad 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, funding and government policy can help move the needle. For example, some countries have created new economic models for incentivizing antibiotic development.
In the US, lawmakers are debating a law called the PASTEUR Act that would pay pharmaceutical companies under contract to make these critical new drugs available.
“Fundamentally it’s a Netflix-like subscription model,” Fowler said. Drug companies no longer have to rely on the meager profits they get from selling their antibiotics on the commercial market. The proposed model was controversial and did not become law, but it is an example of the kind of “new economic model” that WHO officials like Gigante want policymakers to explore.
US taxpayer dollars are already supporting some new research into antibiotics. For example, Fowler leads a program called the Antibacterial Resistance Leadership Group, which funds new tests with grants from the National Institutes of Health.
“It’s a tremendous amount of money, but there’s a great deal more that’s needed,” he said.
Better tests might help
Beyond calling for new antibiotics, WHO officials want to see better, faster, ways of diagnosing bacterial infections. Right now, for the first 48 hours or so after a patient has an infection, “you don’t know what germ you’re treating,” Fowler said.
The more quickly and accurately doctors pay attention to the specific bug infecting their patients, the less likely they are to prescribe antibiotics that won’t work, which can cause more resistance.
The diagnostic process involves collecting a swab, sending it to a lab, growing the bacteria from that swab until there is enough of a test, then, while still in the lab, testing a bunch of different antibiotics to see which one will work. It can take days or weeks, and sick patients can’t wait that long.
“This is not through any lack of good clinical practice, but modern infection treatment in 2023 is an educated guess,” Fowler said. “It’s scary when you think about it.”