Have We Entered a Post-Antibiotic Age?

Up until the coronavirus pandemic, tuberculosis (TB) had been the leading cause of death by a single infectious agent for centuries. It may be no surprise, then, that drug-resistant TB is a major contributor to antimicrobial resistance worldwide and is one of the leading causes of antimicrobial-related deaths.

There is (relatively) good news in the TB story. Although about a half million new cases of drug-resistant TB occur each year, that number has remained relatively stable for the past two decades. “There has been a huge global effort toward addressing drug-resistant TB, and a lot of progress has been made in developing better diagnostic tests and better treatment,” says Sarita Shah, MD, professor of epidemiology and global health and a director of the Emory/Georgia TB Research Advancement Center’s Clinical & Population Science Core. “As a result, more people are getting diagnosed and started on the correct treatment than ever before.”

The bad news is that drug-resistant strains of TB are becoming more resistant. “Through our early work with laboratories that are part of a global network, we showed that drug-resistant TB is becoming resistant to more and more drugs,” says Shah. “We came up with a term for it—extensively drug-resistant tuberculosis, or XDR-TB. These are strains of TB that are not resistant to just one or two antibiotics, but four or more, making it much more difficult to treat and cure.”

Treatment of normal, nondrug-resistant TB requires a regimen of four different antibiotics taken for six months. While this is difficult enough, treatment of drug-resistant TB involves four or five antibiotics, one of which is given by daily injection. It’s easy to imagine the difficulties in following doctors’ orders, particularly when the medications make you feel even sicker because of side effects. In many countries, including the U.S., one or more of the prescribed drugs could become out of stock. The patient might not be able to afford all the drugs or have transportation to get them. As such, many assumed adherence failure was the primary driver of drug-resistant TB, including XDR-TB.

However, work by Shah and her colleagues looking at XDR-TB in South Africa was instrumental in demonstrating that most people who get drug-resistant TB don’t develop it from failing to follow their treatment regimen. Rather, they get infected at the outset with an already resistant strain of TB. “That was a real sea change in the way we think about drug-resistant TB,” says Shah. “People who had never had TB before were showing up with XDR-TB, so it wasn’t because of failure to take medications correctly.”

Currently, Shah’s team is working to test another assumption: that most drug-resistant TB is transmitted in hospitals, health care facilities, or homes. Shah believes transmission often occurs in community settings. Her research team is also monitoring for the emergence of resistance to new drugs for TB—how often it is happening and what molecular mutations are causing the resistance—in the hopes that knowledge could be used to make new diagnostic tests and tailor treatment accordingly.

Additionally, Shah hopes her findings will help inform interventions. While regimen compliance and development of new TB antibiotics as resistance develops are important in LMIC populations, more emphasis should be placed on stopping the spread of TB in the first place and addressing social determinants that increase vulnerability to TB disease.

“This requires investing in efforts like community wide infection control; water, sanitation and hygiene; nutrition; and health care access” says Shah. “It’s hard to get people to invest in these things. They are not flashy or exciting. TB has survived for millennia, and it is going to continue to find ways to become resistant. I hope the research that we are doing will help us stay just one step ahead of it.”

Elizabeth Rogawski McQuade, PhD, assistant professor of epidemiology, studies pediatric enteric (intestinal) disease in low-resource settings. She has a lot of material to work with. Enteric infections are a leading cause of death in children in LMICs, and they are a likely contributor to the development of antibiotic resistance.

“Diarrhea from enteric pathogens is just so common and so recurrent in children in these settings,” says McQuade. “At the same time, antibiotics are readily available without a prescription in many of these places. In South Asia, for example, you can pretty much walk into any pharmacy and get antibiotics. So these children may be getting an antibiotic when they don’t need one. Or they may be getting the wrong antibiotic. Or they may not take an appropriate dose. It’s totally the Wild West in many places when it comes to using antibiotics.”

It's little surprise, then, that enteric pathogens in these settings develop AMR, and many antibiotic stewardship activities in these settings have focused on curtailing the overuse of antibiotics for diarrhea.

McQuade contends that focus needs to be expanded to include overuse of antibiotics for respiratory diseases as well. The reason: Children in LMICs tend to have a host of pathogens—many asymptomatic—residing in their guts. “When a child takes antibiotics for a respiratory infection, all the bacteria in their gut gets exposed to those antibiotics, not just the bacteria causing the illness,” says McQuade. “That means they all can become resistant and be passed to others.”

And, in fact, they do. McQuade and her colleagues looked at data from a previous large cohort of children in eight low-resource countries. The study collected, among other things, monthly stool samples and detailed information on illnesses and antibiotic use. By analyzing this data, McQuade and her team determined that each asymptomatic pathogen they looked at had more than seven antibiotic exposures per year.

“This is called bystander exposure, and we found that it is shockingly common,” says McQuade.

She found respiratory infections accounted for more bystander exposure than enteric infections, suggesting antibiotic overuse in both instances needs to be targeted. But she acknowledges that both are a tall order.

“It’s really hard to change treatment practices,” she says. “Once a child is sick, it’s really hard to withhold antibiotics if they could help. That’s even true in high-resource settings like the U.S., but even more so in low-resource settings where the children are already so vulnerable.”

Which leads McQuade to another area of interest—vaccines. Indeed, vaccines have already been shown to effectively reduce antibiotic use and improve AMR in rotavirus and pneumonia. Her team is looking at the promise of a potential vaccine for Shigella, the leading cause of diarrhea in children.

The team did a simulation study to quantify the impact of potential Shigella vaccines on antibiotic use. The vaccine would be expected to prevent about a third of antibiotic treatments for Shigella diarrhea episodes and bystander exposures due to shigellosis treatment. However, because the reductions in total antibiotic use are expected to be small, vaccines in combination are likely needed.

Says McQuade, “By doing this type of study, we hope to show policymakers and ministries of health that investments in vaccines could result in a huge impact on levels of AMR, which is a huge priority.”

Worldwide, efforts to curb AMR have focused on reducing antibiotic misuse in humans and developing new antibiotics. While that strategy may work well in high-resource countries, or the so-called Global North, it likely will not prove as effective in the lower resource settings of the Global South.

“So often, people think we just need to reduce antibiotic use in humans and that will solve the problem,” says Nadimpalli. “But it turns out antibiotic use isn’t as high in some settings in the Global South as previously thought. In fact, more children in LMIC countries die from inadequate access to antibiotics each year than drug-resistant infections, so there must be more to the story than that.”

Nadimpalli thinks that story needs to include how animal and environmental reservoirs contribute to the spread of AMR pathogens—a “One Health” perspective that recognizes that the health of people, the health of animals, and the environment are connected.

In many LMICs, a growing middle class is fueling demand for meat. In response, more and more farmers are using more and more antibiotics to promote growth in their livestock, poultry, and aquatic animals. The connection between animals and humans tends to be more intimate in lower resource settings than in high. Pigs and chickens roam freely in the yards and even homes of small farms, which tend to be close to population centers rather than far removed. Consumers interact with livestock in live and wet markets. And food safety regulations in these areas tend to be quite lax.

To see if this proximity could lead to “leaks” of AMR pathogens between animals and humans, Nadimpalli and her research team looked at strains of antibiotic-resistant Escherichia coli collected from people and meat products sold at markets in Cambodia. They found strikingly similar genes in both, suggesting they had been exchanged at some point between humans and animals.

“In these types of settings, we have to find ways to block that circular transmission of bacteria between humans and animals,” she says.

That circle can also include the environment. Inadequate sanitation and hygiene measures mean water sources can become contaminated with animal and human waste carrying AMR pathogens. Humans can consume or bathe in this water, and it can also be used to grow vegetables that might be eaten raw.

Plugging those leaks will require investments in water, sanitation, and food safety infrastructure.

“Ensuring consistent access to clean water and sanitation can improve people’s health and well-being in so many ways,” says Nadimpalli. “We've suspected that it could also help antibiotic resistance, but our findings show that access to clean water and safe disposal of fecal waste is actually critical—for both humans and food animals—if we want to have a fighting chance at preserving antibiotics for human health.”

Nadimpalli acknowledges these types of improvements are big-ticket items requiring huge investments. “A lot of funding flows from the Global North and focuses on the priorities of high-income countries, specifically reducing antibiotic use,” she says. “But what is needed in the Global South is very different. The greatest need is reducing the burden of infectious disease, and that requires investing in clean water and basic sanitation. Otherwise we are fighting a losing battle.”

Story by Martha Nolan
Designed by Linda Dobson
Illustration by Kathleen Fu
Portrait Photography by Bita Honarvar