Why antibiotic resistance is becoming an unfixable problem

It's not that we don't know better
Grant Currin
A white blood cell devours antibiotic-resistant Staphylococcus aureus (left). Raw chicken (right).NIAID (left) Wikimedia / Ll1234 (right)

In 2016, a retiree in a Las Vegas hospital was suffering from a mysterious bacterial infection that cropped up after she broke her right femur during a trip to India. 

When the patient, the subject of a widely circulated note from the field published by the CDC, came back to the U.S., doctors couldn't kill the infection. They prescribed antibiotic after antibiotic. But none of the 26 drugs they tried kept the bacteria from colonizing her bloodstream.

The patient died of septic shock a few weeks after turning up at the hospital.

Microbiologist Sid Thakur, who directs the Global Health program at North Carolina State University, tells IE that doctors are coming up empty more often when it comes to bacterial infections.

“It’s really weird when a physician walks up to you and says ‘I’ve got nothing left to treat you with,’” Thakur says.

In 2019, the CDC reported that nearly three million people in the U.S. have an antibiotic-resistant infection, and at least 35,000 of them die, each year. Such infections kill more people across the world than HIV/AIDS or malaria. Statistical models predict tipping points when numbers will skyrocket. In less than three decades, it is estimated they will kill more people than cancer.

Modern medicine is losing its grip on bacterial infections. But it doesn’t have to happen.

Researchers and engineers know how to develop new antibiotics and lengthen the useful lifespans of the drugs already in use.

Microbiologist Lance Price, who founded the Antibiotic Resistance Action Center at George Washington University, tells IE that the antibiotic resistance problem is fundamentally a “market failure.”

Harmful bacteria are a huge problem for most living things

Humans only have to worry about a tiny sliver of the estimated one billion species of bacteria across the world, but the bugs that do cause problems have been responsible for a lot of human misery. Bacteria are behind notorious diseases like pneumonia, tuberculosis, cholera, tetanus, gonorrhea, and syphilis.

Killing bacteria isn’t that hard. Plenty of chemicals — or often just a pot of boiling water — can do the trick. Antibiotics have helped lengthen human life expectancy by eight years in the decades after they became widely available, owing to their ability to ravage harmful bacteria without damaging human cells. 

Destroying bacteria while leaving human cells unharmed remains a challenging biomolecular balancing act: eukaryotic cells, of which humans are made, and bacteria, are only related in the extremely distant past, after all, but have inherited many of the same cellular weaknesses.

Antibiotics work by targeting vulnerabilities that humans and bacterial cells don't share. For example, bacteria evolved to use an outer cell wall for structural support, but human cells didn’t. Penicillin stops bacteria from building that critical piece of cellular infrastructure, causing the single-celled organisms to burst without harming human cells. It can be thought of as a scalpel for jobs where even a scalpel would be a far too blunt instrument.

“A good comparison is chemotherapy,” Price says. An oncologist who prescribes chemo is “taking people to the brink of death with this poison” to weaken or kill the cancerous cells. Antibiotics enable doctors treating bacterial infections to avoid taking such extreme measures.

But there’s a drawback: Antibiotics are often an effective therapy, but they can have the effect of giving bacteria an evolutionary turbo-charge, which is also one of the biggest arguments against using antibiotics too frequently. (For instance, in the UK, the bar for prescribing antibiotic medicine is much higher than in the U.S. Neosporin Original Antibiotic Ointment, a staple of many American medicine cabinets, is usually only available in the UK with a prescription.) 

Antibiotics “create a pressure for bacteria to change,” Thakur explains. “And the change is in the form of becoming resistant” to the drug. That happens if a genetic variation protects some of the bacteria against whatever vulnerability the drug normally exploits.

"If you’re not killing the pathogen, then you’re basically selecting for the resistant versions,” Thakur says. Once those survivors reproduce to occupy the recently vacated space, “we have this massive resistant population that totally dominates the environment."

This evolutionary game isn’t anything new. Fungi started developing antimicrobial compounds — and applying selection pressure on bacteria — billions of years ago. It’s been a life-or-death competition of R&D programs driven by random genetic variation ever since.

Bacteria have a bit of an advantage: They don’t merely transfer genes from one generation to the next. They can also swap genes — including genes that harden them against antimicrobials — simply by coming into contact with each other.

“If you’ve got an E. coli that is resistant and an E. coli that is not resistant and they come in contact with each other, soon they’re both resistant,” Thakur says.

Researchers have identified one such “mobile genetic element” that can make bacteria resistant to the antibiotic colistin, which is the last option doctors have for treating some strains of E. coli and Klebsiella, Price says. (Klebsiella pneumonia is what scientists think the retiree who died in the Las Vegas hospital was battling.)

“We know that bacteria have the capacity to pick up that last gene and become untreatable,” he said. Something like that has already happened with tuberculosis.

What’s concerning now is that the volume of antibiotics in circulation today is driving the rapid evolution of bacteria to resist the antibiotics that are used by doctors all over.

Why we’re overusing — and underinvesting

The explosion in antibiotic use is the result of changing circumstances and misaligned incentives. There are a lot more humans who can be helped with antibiotics now than there were in 1941 when the first antibiotic for medical treatment became available. The human population has grown by nearly 350 percent in that period.

“We overuse antibiotics, and we drive the evolution of drug-resistant bacteria,” Price says.

Reason one: Patients demand antibiotics

One reason is that patients often demand them — even if they won’t help. Most people have “positive experiences of getting better” after taking antibiotics, so it’s common to pressure their doctor to write a prescription, even if it won’t do anything.

“I don’t want a one-star review, so I’m gonna write a prescription because that’s what people want."

On the other side, many doctors are thinking to themselves “I don’t want a one-star review, so I’m gonna write a prescription because that’s what people want,” Price said.

Overprescription is far from the only problem, though. Antibiotics are sold on the market, just like pretty much everything else. That means higher sales of antibiotics to animals or humans, higher profits for the manufacturers.

Price calls it “quarterly thinking” because many of the people making these decisions are focused on making their company’s quarterly earnings reports look as good as possible by selling as many antibiotics as they can.

Manufacturers “actively market an antibiotic and push for it to be used because they want to recoup their [research and manufacturing] cost,” he said. If the drug has been around for a long time, the sales are mostly profit.

But humans aren’t the only species popping pills. In the US, roughly 65 percent of medically important antibiotics are sold for use in agriculture. Livestock producers routinely give livestock antibiotics because the animals are less likely to get sick, which drains profits. Adding antibiotics to feed also causes livestock to grow larger more quickly, though researchers aren’t entirely sure why.

Federal regulation briefly caused the amount of medically important antibiotics used in agriculture to decrease to as low as 12.25 million pounds (5.55 million kilograms) in 2017, but recent data show the number is once again on the rise.

This practice is dangerous, but it’s common because agricultural companies benefit from it, at least in the short term. The drug manufacturers say “‘we make money when we sell them to animal producers,’ and the animal producers say ‘we can grow meat more efficiently if we use antibiotics,’” Price explains. The result is a lot of antibiotics exerting a lot of selection pressure on bacteria.

This is an especially important part of the problem because demand for meat is growing fast, and the livestock population is growing with it. In the 1960s, average animal protein consumption was about six grams per person per day. That number has now quadrupled, according to Thakur.

Reason two: There aren't enough new antibiotics

All of this might be sustainable — at least for a while — if new antibiotics that bacteria hadn’t yet grown resistant to were constantly becoming available the way they did in the middle of the 20th century, but today hardly anyone is investing the time and money it takes to develop new ones. The last time an entirely new kind of antibiotic was discovered was in the late 1980s.

The reason is that return on that investment isn’t large or reliable because pathogens quickly grow resistant, Thakur says. “You wait ten years [for the drug to be approved], you invest a couple of billion dollars, and the next day the pathogen becomes resistant to it,” he explains.

“The sort of golden age of developing antibiotics is gone."

When bacteria grew resistant to penicillin, there were more drugs in the development pipeline to take its place. That’s not the case anymore. “The sort of golden age of developing antibiotics is gone,” Price says.

Many of the bacteria that have plagued our ancestors since long before they evolved into modern humans haven’t disappeared. And they don’t just live and reproduce in people and livestock.

“There's a huge reservoir of these resistant pathogens and genes in the environment,” Thakur says. Practically every teaspoon of water, a gram of soil, and animal on the planet is hosting bacteria — many of them infectious pathogens. They hide out in built spaces, like hospitals, too. No part of this massive, global ecosystem can be understood on its own, Thakur says. “It's a huge problem because it's a complex problem.”

And it’s starting to catch up with us.

There are many possible futures

Antibiotics aren’t the only treatment that can help with bacterial infections. One of the most promising alternatives is phage therapy, which uses viruses to target bacterial cells.

Naturally occurring phages that evolved to feast on bacteria are one option, and it’s a frontier of bioengineering. Price’s colleague, Cindy Liu, is leading research on using benign bacteria that occur naturally in the body to “​​act as biological bouncers that prevent the colonization of bad bacteria like staph” he says.

Such therapies might be especially helpful in combatting bacteria that are harmless and normal in certain parts of the body but dangerous when they take hold somewhere else. For instance, E. Coli is a normal part of the microbiome in the intestines, but it causes a lot of problems when the microbe manages to set up shop higher up in the digestive tract.

What's the solution for the overuse of antibiotics?

Price says we shouldn’t write off antibiotics, though. The right combination of policy changes and investment in the public and private spheres could ensure that humans have useful antibiotics well into the future. A big part of the story is regulating the agricultural use of antibiotics, which the federal government has tried to do.

Another place where easy gains might be made is by reducing the antibiotics prescribed to humans by investing in rapid tests. It’s another area where incentives aren’t aligned in the public’s interest, Price says.

Price says that pharmaceutical manufacturers haven’t put a lot of energy into developing diagnostic tests that could quickly determine if a patient's illness is bacterial before they're prescribed an antibiotic.

That’s because insurance companies would rather spend a few dollars for an antibiotic than the hundred dollars such a test might cost. The tests remain so expensive because investors have little incentive to develop them if insurance companies won't pay up.

If it sounds circular, it’s because it is.

The whole crisis can be solved by “using the drugs we have better and then bringing some new drugs to market,” Price said.

If the money is there, the engineers, researchers, and clinicians can do the rest.

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