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A Vision Into the Post-Apocalyptic Future of Antimicrobial Resistance

Sunday, March 19th, 2017

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About 4 million years ago, a cave was forming in the Delaware Basin of what is now Carlsbad Caverns National Park in New Mexico. From that time on, Lechuguilla Cave remained untouched by humans or animals until its discovery in 1986—an isolated, pristine primeval ecosystem.

When the bacteria found on the walls of Lechuguilla were analyzed, many of the microbes were determined not only to have resistance to natural antibiotics like penicillin, but also to synthetic antibiotics that did not exist on earth until the second half of the twentieth century. As infectious disease specialist Brad Spellberg put it in the New England Journal of Medicine, “These results underscore a critical reality: antibiotic resistance already exists, widely disseminated in nature, to drugs we have not yet invented.”

The origin story of antibiotics is well known, almost mythic, and antibiotics, along with the other basic public health measures, have had a dramatic impact on the quality and longevity of our modern life. When ordinary people called penicillin and sulfa drugs miraculous, they were not exaggerating. These discoveries ushered in the age of antibiotics, and medical science assumed a lifesaving capability previously unknown.

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Note that we use the word discoveries rather than inventions. Antibiotics were around many millions of years before we were. Since the beginning of time, microbes have been competing with other microbes for nutrients and a place to call home. Under this evolutionary stress, beneficial mutations occurred in the “lucky” and successful ones that resulted in the production of chemicals—antibiotics—to inhibit other species of microbes from thriving and reproducing, while not compromising their own survival. Antibiotics are, in fact, a natural resource—or perhaps more accurately, a natural phenomenon—that can be cherished or squandered like any other gift of nature, such as clean and adequate supplies of water and clean air.

Equally natural, as Lechuguilla Cave reminds us, is the phenomenon of antibiotic resistance. Microbes move in the direction of resistance in order to survive. And that movement, increasingly, threatens our survival.

With each passing year, we lose a percentage of our antibiotic firepower. In a very real sense, we confront the possibility of revisiting the Dark Age where many infections we now consider routine could cause severe illness, when pneumonia or a stomach bug could be a death sentence, when a leading cause of mortality in the United States was tuberculosis.

The Review on Antimicrobial Resistance (AMR) determined that, left unchecked, in the next 35 years antimicrobial resistance could kill 300,000,000 people worldwide and stunt global economic output by $100 trillion. There are no other diseases we currently know of except pandemic influenza that could make that claim. In fact, if the current trend is not altered, antimicrobial resistance could become the world’s single greatest killer, surpassing heart disease or cancer.

In some parts of the United States, about 40 percent of the strains of Streptococcus pneumonia, which the legendary nineteenth and early twentieth century physician Sir William Osler called “the captain of the men of death,” are now resistant to penicillin. And the economic incentives for pharmaceutical companies to develop new antibiotics are not much brighter than those for developing new vaccines. Like vaccines, they are used only occasionally, not every day; they have to compete with older, extremely cheap generic versions manufactured overseas; and to remain effective, their use has to be restricted rather than promoted.

As it is, according to the CDC, each year in the United States at least 2,000,000 people become infected with antibiotic-resistant bacteria and at least 23,000 people die as a direct result of these infections. More people die each year in this country from MRSA (methicillin-resistant Staphylococcus aureus, often picked up in hospitals) than from AIDS.

If we can’t—or don’t—stop the march of resistance and come out into the sunlight, what will a post-antibiotic era look like? What will it actually mean to return to the darkness of the cave?

Without effective and nontoxic antibiotics to control infection, any surgery becomes inherently dangerous, so all but the most critical, lifesaving procedures therefore would be complex risk-benefit decisions. You’d have a hard time doing open-heart surgery, organ transplants, or joint replacements, and there would be no more in vitro fertilization. Caesarian delivery would be far more risky. Cancer chemotherapy would take a giant step backwards, as would neonatal and regular intensive care. For that matter, no one would go into a hospital unless they absolutely had to because of all the germs on floors and other surfaces and floating around in the air. Rheumatic fever would have lifelong consequences. TB sanitaria could be back in business. You could just about do a post-apocalyptic sci-fi movie on the subject.

To understand why antibiotic resistance is rapidly increasing and what we need to do to avert this bleak future and reduce its impact, we have to understand the Big Picture of how it happens, where it happens, and how it’s driven by use in humans and animals.

Human Use

Think of an American couple, both of who work fulltime. One day, their 4-year-old son wakes up crying with an earache. Either mom or dad takes the child to the pediatrician, who has probably seen a raft of these earaches lately and is pretty sure it’s a viral infection. There is no effective antiviral drug available to treat the ear infection. Using an antibiotic in this situation only exposes other bacteria that the child may be carrying to the drug and increases the likelihood that an antibiotic resistant strain of bacteria will win the evolutionary lottery. But the parent knows that unless the child has been given a prescription for something, the daycare center isn’t going to take him and neither partner can take off from work. It doesn’t seem like a big deal to write an antibiotic prescription to solve this couple’s dilemma, even if the odds the antibiotic is really called for are minute.

While the majority of people understand that antibiotics are overprescribed and therefore subject to mounting resistance, they think the resistance applies to them, rather than the microbes. They believe that if they take too many antibiotics – whatever that unknown number might be—they will become resistant to the agents, so if they are promoting a risk factor, it is only for themselves rather than for the entire community.

Doctors, of course, understand the real risk. Are they culpable to the charge of over- and inappropriately prescribing antibiotics? In too many cases, the answer is Yes.

Why do doctors overprescribe? Is it about covering their backsides in this litigious society? Is it a lack of awareness of the problem? According to Brad Spellberg, “The majority of the problem really revolves around fear. It’s not any more complicated than that. It’s brain stem level, sub-telencephalonic, not-conscious-thought fear of being wrong. Because we don’t know what our patients have when they’re first in front of us. We really cannot distinguish viral from bacterial infections. We just can’t.”

Spellberg cited a case, one he heard at an infectious disease conference he attended. A 25-year-old woman came into the urgent care facility of a prominent health care network complaining of fever, sore throat, headache, runny nose and malaise. These are the symptoms of a classic viral syndrome and the facility followed exactly the proper procedure. They didn’t prescribe an antibiotic, but instead told her to go home, rest, keep herself hydrated, maybe have some chicken soup, and they would call her in three days to make sure she was all right.

She came back a week later in septic shock and died soon after.

“It turns out she had Lemierre’s disease,” says Spellberg. “It clotted her jugular vein from a bacterial infection that spread from her throat to her bloodstream. This is about a one-in-10,000 event; it’s pretty darn rare. But it’s a complication of an antecedent viral infection, and it’s a known complication. So this patient, ironically, would have benefitted from receiving inappropriate antibiotics. How many times do you think doctors need to have those things happen before they start giving antibiotics to every person who walks in the door?”

As much difficulty as we’re having controlling antibiotic resistance in the First World, for the rest, we believe the situation to be a whole lot worse.

In many of these countries, antibiotics are sold right over the counter just like aspirin and nasal spray; you don’t even need a doctor’s prescription. While we in the public health community would certainly like to see a complete cessation of antibiotic use without a prescription, how do we tell sick people in developing countries that they first have to see a doctor, when there may be no more than one or two physicians for thousands of individuals, and even if they could find one, they couldn’t afford the visit in the first place? Taking an action in a vacuum, such as banning over-the-counter sales without improving infrastructure, simply isn’t viable.

We also have to understand the inordinate burden antibiotic resistance places on the world’s poor. Current effective antibiotics now out of patent may cost only pennies a dose. When those are no longer useful, new compounds will cost many dollars a dose – far more than the poor can afford.

Many of the antibiotic compounds in the developing world are produced in loosely or unregulated manufacturing facilities, where there is no way to gauge quality control. And millions of poor people are living in tightly packed urban slums with inadequate hygiene and sanitary conditions, which generate both more disease and more opportunity for microbes to share resistance characteristics with each other.

Animal use—for food and pets

All of the world’s use of antibiotics for humans is a relatively small percentage of total use. The US, Canada and Europe use about 30 percent of our antibiotics on humans. The rest we use on animals—specifically, animals we kill for food or companion animals and pets.

We produce our food animals in very large numbers and raise them densely packed together, whether we’re talking about chicken and turkey operations, cattle and swine feedlots, or industrial fish farms. While these animals are less likely to catch infectious diseases when large production operations use high levels of biosecurity—the practice of limiting the ways that disease-causing germs can contact the animals—when these germs do get introduced their spread is rapid and extensive. So we use antibiotics to treat the resulting infections. But we also use them to prevent infections in the first place, or to control them by dosing healthy animals so they don’t catch anything from the sick ones. And then we use them to enhance growth.

For decades we have given food-production animals repeated doses of certain antibiotics to make them grow bigger and fatter, producing more meat per animal. This practice is known as growth promotion. The FDA has implemented a voluntary plan with the agriculture industry to phase out the use of certain antibiotics for growth promotion. The European Union banned this use in 1969, though they still use antibiotics for infection prophylaxis, control, and treatment. The AMR found mounting evidence that the use of antibiotics for growth promotion may only provide very modest benefits to farmers in the high-income counties, usually less than 5 percent additional growth.

How does use of this affect us? The AMR team reviewed 280 published, peer-reviewed research articles that address the use of antibiotics in food production. Of these, 72 percent found evidence of a link between antibiotic use in animals and antibiotic resistance in humans. Only 5 percent, found no link between antibiotic use in animals and human infections.

Certain enlightened nations like Sweden, Denmark, and the Netherlands have limited agricultural use and set up comprehensive surveillance systems to determine the rates of antibiotic resistance in human and animal disease-causing germs. Jaap Waganaar, Professor of Clinical Infectiology at Utrecht University, points out that while the Netherlands has traditionally had the lowest rate of antibiotic use for humans in the European Union, as a major agricultural exporter, it was the highest on the animal side. To combat this, the health ministry set prospective standards to be met year by year, mandating full and transparent reporting by the industry. Antibiotics for animal use must be prescribed by certified veterinarians. And for the most powerful antimicrobial agents, there must be confirmation that there is no reasonable alternative to their use.

Most other nations have not attempted to institute such progressive practices. As the developing world has adopted our “meat-centric” diet, they have also adopted our agribusiness formula for producing that meat, making heavy use of antibiotics for animal growth.

We see another frightening example of the mess we’re in China, with the use of colistin, an absolute last-ditch antibiotic for bacteria that react to nothing else. It was isolated in Japan in 1949 and then developed in the 1950s, but not used unless absolutely necessary because of potential kidney damage. They don’t use it for people in China, but are using it in agriculture—thousands of tons a year. Likewise, in Vietnam it is only approved for animal use, but physicians obtain it from veterinarians for their human patients.

Colistin is used for people, though, in much of the rest of the world, including India. As other antibiotics with fewer harmful side effects have become resistant, colistin is about the only agent still effective against certain bloodstream infections in newborn infants. In early 2015, as reported by Bloomberg, physicians treating two babies with life-threatening bloodstream infections at King Edward Memorial Hospital in Pune, India, found that the bacteria were resistant to colistin. One of the babies died.

“If we lose colistin, we have nothing,” stated Umesh Vaidya, head of the hospital’s neonatal intensive care unit. “It’s an extreme, extreme worry for us.” Some hospitals in India are already finding that 10 to 15 percent of the bacterial strains they test are colistin-resistant.

What is worse, some bacteria can share independent little hunks of DNA, called plasmids, with each other. And on one such plasmid, Chinese researchers found a gene known as mcr-1 that conferred colistin resistance. More recently, they have detected NDM-1—for New Delhi metallo-beta-lactamase—an enzyme that protects bacteria against an important class of antibiotics called carbapenems, used mainly in hospitals against already multidrug-resistant bugs.

Recently, colistin-resistant E. coli, made itself know in the United States—in the urine of a 49-year-old woman in Pennsylvania. When an article documenting this unhappy development appeared shortly after in Antimicrobial Agents and Chemotherapy, a journal of the American Society for Microbiology, CDC’s Tom Frieden said, “It basically shows us that the end of the road isn’t very far away for antibiotics—that we may be in a situation where we have patients in our intensive-care units, or patients getting urinary tract infections for which we do not have antibiotics.”

Many of the largest chicken-growing concerns in India, including ones that supply meat for the nation’s McDonald’s and KFC outlets, use one of several antibiotic cocktails that combine colistin with such other vital antibiotics as ciprofloxacin (Cipro), levofloxacin, neomycin and doxycycline. According to an article by Ms. Pearson and Ganesh Nagarajan, “Interviews with farmers indicated that the drugs, permitted for veterinary use in India, were sometimes viewed as vitamins and feed supplements, and were used to stave off disease—a practice linked to the emergence of antibiotic-resistant bacteria.”

“The combination of colistin and ciprofloxacin is just stupidity on a scale that defines all imagination,” commented Timothy Walsh, Professor of Medical Microbiology at Cardiff University in Wales.

What are the implications of all of this? The end result could very well be untreatable bacterial infections going directly into the world food supply. This would be the ultimate Frankenstein scenario.

Excerpted from Deadliest Enemy: Our War Against Killer Germs, Copyright © 2017 by Michael T. Osterholm and Mark Olshaker. Used with permission of Little, Brown and Company, New York. All rights reserved.

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Henry Sapiecha