Late last year, one of Dr. Vance Fowler’s patients, a man in his sixties who had returned to North Carolina from visiting his family in Nepal, died from a bacterial infection.
“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.”
He would be treated in an upper-tier American hospital that had access to stronger antibiotics. But an infection from a strain of E. coli that resists drugs, was the risk.
Health officials have cautioned the public of antibiotic resistance for decades. The problem is now even more urgent.
The forthcoming report from the World Health Organization, which counts just a handful of new antibiotics under development.
Preliminary data in a report released this month by WHO paints a bleak picture: Only 27 new antibiotics are currently in clinical trials.
Comparatively, there were more than 1,300 drugs in clinical trials for cancer by 2020, according to a report from trade group Pharmaceutical Research and Manufacturers of America.
Of antibiotics in trials, WHO considered just six to be sufficiently innovative to overcome antibiotic resistance, and just two capable of targeting the most resistant bacteria.
Agency officials have prepared a comprehensive report to be shared at the European Conference on Clinical Microbiology and Infectious Diseases next month.
From 2017 through 2021, only one new antibiotic, cefiderocol, has been approved, which may be capable of treating superbugs which WHO views as most critically important, including strains of Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae.
These pathogens lead to a number of potentially serious infections in the lungs, urinary tract, ears, blood, open wounds, and even in the brain and spinal cord.
Drug-resistant bacteria are becoming increasingly common. In the U.S. alone, the Centers for Disease Control and Prevention estimates that over 2.8 million people contract a drug-resistant infection every year, with over 35,000 deaths.
Some drug-resistant strains of gonorrhea are on its urgent superbug watchlist, as is Clostridioides difficile, or C. diff, which can cause life-threatening diarrhea and colon inflammation.
The CDC estimates that 12,800 people die from C. diff every year. One of the more common superbugs in the United States, methicillin-resistant Staphylococcus aureus, or MRSA, kills 9,800 people every year.
MRSA can spread quickly in long-term care facilities and in hospital settings, where cases spiked 13% in the first year of the Covid pandemic. Bacteria are not the only culprit. In the United States, antifungal infections caused by Candida auris, a fungal species, increased by 60% in 2020, according to CDC data.
WHO has identified 12 resistant superbugs that are considered “priority pathogens,” while CDC is monitoring a list of 18 resistant bacteria and fungi.
More than five million people worldwide are dying because of antibiotic resistance, according to Valeria Gigante, who leads a group in the WHOs Antimicrobial Resistance Division.
Bacteria and fungi are more likely to build up resistance the more they are exposed to antibiotics or antifungals.
In the case of Fowler’s patients, one particular strain of e.coli had a gene that made a protein called NDM-1, which could degrade even a powerful, last-resort antibiotic called carbapenem. Right now, most strains of E. coli—there are more than 700—lack lethality.
But in addition to E. coli, some Klebsiella, Enterobacter, and Acinetobacter strains already carry the gene, and according to Fowler, others could get it soon.
The WHO worries that antibiotic resistance is increasing rapidly. From 1970 to 2000, the average time for a resistance to develop in a new antibiotic was two or three years, compared with an 11-year average between 1930 and 1950.
Resistance spiked dramatically during the early pandemic, as many health systems were overusing antibiotics, and this had no effect against Covid, since it was caused by a virus, not a bacteria.
The economic model of new drugs—pharmaceutical companies investing a lot upfront to verify the safety and effectiveness of the medicine, then making back the money through sales after approval—”does not work with antibiotics,” according to Ramasubramanian.
It can take up to two decades to develop a single new antibiotic, typically costing between $568 and $700 million, according to the PhRMA.
And only one out of every 30 such drugs is eventually approved for treatment in patients. But, in contrast with drugs designed to be widely used, an international push is underway to make less use of antibiotics. Excessive or unnecessary antibiotics are using up chances that pathogens will evolve resistance.
Some countries have implemented what they refer to as “antibiotic stewardship programs”. These incentivize doctors to prescribe drugs only if there is a demonstrable need. In the United States, for example, the CDC offers courses and guidelines that can help curb antibiotic use and prevent resistance.
Even in cases when antibiotics are really needed, they are typically prescribed only for days or weeks at a time, making them much less profitable than longer-term, day-to-day drugs used to treat chronic conditions like high blood pressure or diabetes.
More people may be dying of infections that once could have been treated, like bacterial pneumonia, gonorrhea, or Salmonella. Those most in need of antibiotics, like the immune-compromised and people in cancer treatments, would be the most affected.
In the United States, legislators are debating legislation called PASTEUR, which would pay drug companies under contract to make these crucial new drugs available.
U.S. taxpayer dollars are supporting some of this new antibiotic research right now. Fowler, for example, leads a program called the Antibacterial Resistance Leadership Panel, which funds new trials through grants from the National Institutes of Health.
In addition to calling for new antibiotics, WHO officials would like to see better, faster ways of diagnosing bacterial infections.
Right now, in the first 48 hours or so after an infected person comes in, “you have no idea which bacterium you are treating,” Fowler said.
The faster doctors can pinpoint a particular bug that is infecting a patient, the less likely they are to prescribe antibiotics that don’t work, potentially leading to increased resistance.
The diagnostic process involves collecting a swab, sending it to the lab, growing the bacteria on that swab until they have enough for testing, then, still in the lab, trying a bunch of different antibiotics to see which ones work. This could take days or weeks, and the sickest patients cannot wait that long.