The thoughtless person playing with penicillin treatment is morally responsible for the death of the man who finally succumbs to infection with the penicillin-resistant organism. I hope this evil can be averted.
—SIR ALEXANDER FLEMING, MD
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.
An article by Dr. Kirandeep Bhullar of Ontario’s McMaster University and seven others, published in the April 2012 issue of the peer-reviewed online journal PLoS One, received little notice outside the scientific community. But its implications were provocative and sobering.
When the bacteria found on the walls of Lechuguilla were analyzed by the article’s authors, many of the microbes were determined to have resistance not only 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, MD, 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: Returning to his lab at St. Mary’s Hospital in London in 1928 after a holiday, Dr. Alexander Fleming noticed that a fungus had corrupted one of his staphylococci culture petri dishes and that the staph colonies surrounding the fungus had been destroyed. This was every bit the equal of the observation that English milkmaids didn’t get smallpox.
Fleming grew this fungal mold in a pure culture and found that the result killed a range of disease-causing bacteria. The mold was from the Penicillium genus, so he called it penicillin. It was left to Drs. Howard Florey and Ernst Chain to figure out penicillin’s structure and transform it into a lifesaving medical agent. The three pioneers shared the Nobel Prize in Physiology or Medicine in 1945.
At around the same time that Florey and Chain were working in England, a team at a division of IG Farben in Germany (later to become Bayer) led by Dr. Gerhard Domagk was exploring the properties of red chemical dyes called sulfonamides: substances derived from coal tar that did not kill bacteria but inhibited their growth. They became the basis for a group of medicines known as sulfa drugs, the first of which was marketed as prontosil. In 1933, one of Domagk’s colleagues treated a ten-month-old baby boy with an almost always fatal S. aureus infection in his blood. The boy became the first person in history whose life was saved by an antimicrobial.
Ironically, two years later, Domagk’s six-year-old daughter lay near death from a massive infection after accidentally puncturing her hand with a sewing needle. Her doctor recommended amputating the arm in a desperate attempt to stem the infection. Instead, just as desperately, Domagk administered prontosil. Within four days, the little girl had recovered. Domagk was awarded a Nobel Prize in 1939.
Nor did it stop there, so great was this medical revolution. Dr. Selman Waksman, the Russian-born American biochemist and microbiologist who suggested the use of the term “antibiotic,” was awarded the Nobel Prize in 1952 for the discovery of streptomycin—purified from soil bacteria—the first such agent that could treat tuberculosis.
Today, heart disease and cancer are, by far, the leading causes of death in the United States. In 1900, they were relatively insignificant. This is not because our forebears pursued a healthier lifestyle, didn’t smoke, or followed a more prudent diet. It’s because back then infectious diseases didn’t give our two modern killers a chance to move in; they got to people earlier and more often than heart disease and cancer ever could. Antibiotics, along with the other basic public health measures we have described, 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. The discoveries of Domagk, Fleming, Florey, and Chain ushered in the age of antibiotics, and medical science assumed a lifesaving capability previously unknown.
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 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.
The World Economic Forum’s Global Risks 2013 report declared, “While viruses may capture more headlines, arguably the greatest risk of hubris to human health comes in the form of antibiotic-resistant bacteria. We live in a bacterial world where we will never be able to stay ahead of the mutation curve. A test of our resilience is how far behind the curve we allow ourselves to fall.”
In his book Missing Microbes, Dr. Martin Blaser explains how our use of antibiotics over the past eighty years is greatly altering the three-billion-year-old microbiome that resides in our bodies. He lays out with clarity and vision why what I call “supermicrobial evolution in our modern world” poses a real and new danger for our future encounters with infectious diseases. What we are dealing with, to put it plainly, is a slow-motion worldwide pandemic. 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 most comprehensive and accurate assessment of the future of antimicrobial resistance and the devastating impact it will have on humans and animals in the years to come is the Review on Antimicrobial Resistance, a detailed study commissioned by the British government of Prime Minister David Cameron and supported by my friends and colleagues at the Wellcome Trust. (Cameron reaffirmed the seriousness he places on this issue when he mentioned it on April 22, 2016, during a joint news conference with President Obama in London, as part of his enumeration of the top challenges facing the modern world.) The effort became known as AMR and was led by Lord Jim O’Neill, an internationally recognized macroeconomist, former chairman of Goldman Sachs Asset Management, and former British government minister.
Many people wondered why an economist was chosen to chair such an important medical study. But I believe he was the perfect choice, because every aspect of this problem is tied to economic issues—for governments, for the pharmaceutical industry, for world agriculture, and for the practice of healthcare, much of which is paid for through reimbursements. Macroeconomists are trained to look at the big picture. O’Neill is one of the world’s best macroeconomists. He is the man who coined the acronym BRIC for Brazil, Russia, India, and China and who has a firm understanding of what role those nations must play in the critical effort against antimicrobial resistance.
After studying the issues for more than two years, O’Neill and his highly talented team of researchers determined that, left unchecked, in the next thirty-five years antimicrobial resistance could kill 300 million 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.
The problem of drug resistance isn’t new. Dr. Max Finland, a world renowned professor at Harvard Medical School and a pioneer in the development and use of antibiotics for almost fifty years, convened eight international experts on infectious diseases in 1965 and asked the question “Are new antibiotics needed?” The results of that conference were published in a major medical research journal later that year. The conclusion reached by the group was a resounding yes: We need new antibiotics to cover diseases not yet well treated and because of the diminishing effectiveness of antibiotics available due to the emergence of antibiotic resistance. Our current discussions, therefore, are like déjà vu all over again.
The only difference between then and now is that whole fleets of antibiotics that were available in 1965 or discovered after that time are now additional clinical casualties of antibiotic resistance. The rate of that resistance now far exceeds the rate of new antibiotic development. In some parts of the United States, about 40 percent of the strains of Streptococcus pneumoniae, 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 million 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 S. aureus, often picked up in hospitals) than from AIDS.
Most of us can’t quite imagine that time before Domagk, Fleming, Florey, and Chain, in which our great-grandparents and, in some cases, even our grandparents lived, before the antibiotic era that has been our great gift since the late 1940s. But within ten to twenty years, we could well be moving into the postantibiotic era.
If we can’t—or don’t—stop the march of resistance and come out into the sunlight, what will a postantibiotic era look like? What will it actually mean to return to the darkness of the cave?
Well, for one thing, clearly, more people will get sick and more people will die from germs we’ve been able to combat for the past seventy years. But once we get down in the weeds, it’s even more chilling. Without effective and nontoxic antibiotics to control infection, any surgery becomes inherently dangerous, so all but the most critical, lifesaving procedures 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 backward, 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 postapocalyptic sci-fi movie on the subject.
How did we get here? 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 what the major drivers are.
They are, in ascending order of magnitude:
1. Human use in the United States, the United Kingdom, Canada, and the European Union—the countries that have done the most to foster antibiotic stewardship, though many challenges remain.
2. Human use in the rest of the world, where little has been done to curb resistance to date.
3. Use for animals in the United States, Canada, and Europe, where the food livestock, poultry, and fish industries have been largely unwilling to address the issue of overuse without serious pressure from government and the public health sector.
4. Use for animals in the rest of the world, which we don’t have reliable data on, but which we know is high and increasing.
Let’s take a look at each of our four categories of resistance by human and animal demographics and geography.
Think of an American couple, both of whom work full-time. One day, their four-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. They almost always are. 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. This is a real everyday problem, and it doesn’t seem like a big deal to write an antibiotic prescription to solve this couple’s dilemma, even if the odds that the antibiotic is really called for are minute.
But it is a classic “Tragedy of the Commons.” As Spellberg explained in his pioneering 2009 book, Rising Plague:
First described by Garrett Hardin in Science magazine in 1968, the “Tragedy of the Commons” applies to scenarios where an individual acts to significantly benefit [himself], and as a consequence accepts as a tradeoff a small amount of overall harm to society at large. If only one person is so acting, the total harm to society is small. But when everyone in society undertakes the same action, the collective harm to everyone becomes enormous.
Several surveys show that 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.
In the May 3, 2016, issue of the Journal of the American Medical Association, the CDC published the results of a study undertaken with the Pew Charitable Trusts and other public health and medical experts. The study found that in physicians’ offices and hospital emergency departments, at least 30 percent of antibiotic prescriptions are unnecessary or inappropriate. Not surprisingly, most are given for respiratory conditions such as colds, sore throats, bronchitis, and sinus and ear infections that are caused by viruses.
The CDC’s press release states, “These 47 million excess prescriptions each year put patients at needless risk for allergic reactions or the sometimes deadly diarrhea, Clostridium difficile.” This brings up another important point. Not only does overuse accelerate antibiotic resistance, but these agents are not completely benign. Like many drugs that treat serious conditions, they have side effects—in the CDC’s example, by possibly wiping out the “good” and necessary bacteria in the gut.
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 Spellberg, “The majority of the problem really revolves around fear. It’s not any more complicated than that. It’s brain-stem-level, sub-telencephalic, 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.
“You can say on a population basis that 95 percent of patients who present with these signs and symptoms have a virus. But when I have an individual in front of me and I’m going to see 10,000 of these individuals in my career, I’m going to be wrong sometimes. And if I’m wrong, the consequences could be really bad. That’s what drives most of it. And patients suffer from the same fear. They come, they don’t feel well, they want something. They don’t want to get into a philosophical debate. They want something that’s going to make them feel better. That’s why they ask for the prescription.”
Spellberg cited a couple of cases for us. In the first, he got a call from a chief resident in surgery, saying she had a patient with an infected gallbladder. The patient was taking the correct, fairly narrow-spectrum antibiotic—one that targets a limited number of bacteria—but her white blood cell count was going up (a sign of the body’s response to infection), her fever was continuing to rise, and the pain was getting worse. So the resident wanted to put the patient on piperacillin-tazobactam, known commercially as Zosyn—a powerful broad-spectrum antibiotic that kills Pseudomonas aeruginosa, one of the worst pathogens out there.
Spellberg asked why she would want to use that particularly valuable antibiotic when there was virtually no chance the patient had Pseudomonas. The resident explained that she wasn’t worried about Pseudomonas, but the patient was continuing to get worse.
“Yeah,” he replied. “But the patient’s getting worse because you need to take out her gallbladder.”
“Well,” she said, “there were a couple of trauma cases that bumped her from the OR so we couldn’t operate right away, and I just want to broaden the antibiotic.”
“This is completely irrational,” Spellberg says. “And the resident knows it’s irrational, but she’s afraid. She wants the Band-Aid of broad-spectrum antibiotics to make herself feel better.”
In the next case, he got a request from a resident for Cipro, another powerful broad-spectrum antibiotic, for a patient with gram-negative bacteria in her urine. Gram-negative is one of the two main classifications of bacteria, characterized by their type of cell membrane and identified by not reacting to a special lab stain. Gram-positive, not surprisingly, is the other type. They are named for the inventor of the staining technique, Danish bacteriologist Hans Christian Gram.
Spellberg asked what the patient’s symptoms were and was told there weren’t any. “So the question is: How do we treat asymptomatic bacteriuria [bacteria in the urine]? And the answer is: We don’t. This is cognitive dissonance staring us in the face. If this resident had this question on a board exam, he’d get it correct. But that’s a piece of paper and this is a patient staring him in the face, and he’s afraid. And we have not tackled the fear. We’ve got to figure out psychological ways of getting around the fear.”
Now, after hearing these two cases, you wouldn’t be out of line for thinking that doctors, particularly young doctors, just have to get it together and start thinking critically and rationally about each case. Then Spellberg throws one more case at us, one he heard at an infectious disease conference he attended:
A twenty-five-year-old woman came into the urgent care facility of a prominent healthcare 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 syndrome,” says Spellberg. “It clotted her jugular vein from a bacterial infection that spread from her throat to her bloodstream. This is about a 1-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 benefited from receiving inappropriate antibiotics.”
Mark’s brother Jonathan Olshaker, MD, is chief of the Emergency Department at Boston Medical Center, the largest safety-net hospital and busiest Level I trauma and emergency services center in New England. He is highly sensitive to the growing resistance problem, but also sensitive to doctors’ and nurses’ concerns about making mistakes that could hurt the patient.
“One thing no emergency physician wants to hear,” Jon says, “is ‘Remember that case you saw last week…?’ Because you know the next line is going to be, ‘Well, here’s what happened to him…’”
“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?” asks Spellberg.
The populations of the nations we have just discussed add up to about 868,798,000, or about 12 percent of world’s population. Even if we make significant strides in reducing the rate of increase in antibiotic resistance evolution in this “First World,” it will have only a short-term and limited impact on the eventual global catastrophe if we don’t make this an international priority.
The BRIC countries are all at about the same level of development. Their combined population is around 3,938,300,000, or about 54 percent of the world’s total. Then there is the rest of the planet; approximately 2,494,400,000 people, making up the remaining 34 percent. As much difficulty as we’re having controlling antibiotic resistance in “our” 12 percent of the population, for the remaining 88 percent, 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 over-the-counter sales of antibiotics without prescriptions are illegal in numerous places around the world, lax enforcement results in extensive sales in many low- and middle-income countries.
While we in the public health community would certainly like to see a complete cessation of antibiotic use without a doctor’s 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.
In an analysis commissioned by AMR, the London School of Economics found that in just four economically emerging nations on three continents—India, Indonesia, Nigeria, and Brazil—nearly 500 million cases of diarrhea are treated with antibiotics each year, a number expected to rise to more than 600 million by 2030. This gives us some sense of the scope of the problem, as well as underscoring the effects of unsafe water and unsanitary conditions. And what happens if the growing resistance problem means that at some point in the future, we can’t treat these diarrheal cases with antibiotics affordable in the developing world?
Many of the antibiotic compounds in the developing world are produced in loosely regulated 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 one another.
To get some perspective on the challenge of resistance in the developing world, let’s look at tuberculosis, one of the most devastating diseases of the nineteenth and early twentieth centuries. In various parts of the world, particularly Asia, tuberculosis has gone from being a disease largely treatable with antibiotics to a disease with some strains that are now labeled MDR (multidrug resistant), XDR (extensively drug resistant), or TDR (totally drug resistant).
And this is not just happening far from our shores. “I’ve been there for TB patients,” states Dr. Tom Frieden, director of the CDC. “I’ve cared for patients in the US for whom there are no drugs left. It is a feeling of such horror and helplessness. This is not where we need to be.” If we are confronted with this problem in the United States, imagine the challenges for the developing world.
Maryn McKenna, one of the leading independent journalists on public health and author of Beating Back the Devil and Superbug, tells us that “in various places in the US, anywhere with populations from areas around the world where these strains are seen, we are now having TB patients having pieces of their lungs removed. That’s nineteenth-century medicine!” She has been studying antibiotic practice, policy, and resistance for more than a decade. So far, the problems have far outpaced the solutions.
But all of the world’s use of antibiotics for humans is a relatively small percentage of total use. The United States, 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.
We buy antibiotics for ourselves by the gram in little white or orange plastic bottles, sometimes in small blister packs. Industrial farmers and cattle ranchers buy antibiotics by the ton.
There are four applications for antibiotic use in raising food animals, all of which, to one extent or another, result from the way we go about protein-food production in the modern world. 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.
In the late 1940s, fishermen near Lederle Laboratories in New York State noted that trout seemed to be larger than before. When Dr. Thomas Jukes, a prominent biochemist, investigated the apparent phenomenon with his colleague Dr. Robert Stokstad, they found that the antibiotic Aureomycin in the runoff from Lederle’s plant was the cause. After experimentation with livestock and poultry produced similar results, the serendipitous discovery was hailed as an agricultural breakthrough.
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 report found mounting evidence that the use of antibiotics for growth promotion may provide only very modest benefits to farmers in the high-income countries, usually less than 5 percent additional growth.
How does this antibiotic use affect us? The AMR team reviewed 280 published, peer-reviewed research articles that address the use of antibiotics in food production. Of these published studies, 139 came from research groups at academic institutions; 100, or 72 percent, found evidence of a link between antibiotic use in animals and antibiotic resistance in humans. Only seven articles, 5 percent, found no link between antibiotic use in animals and human infections.
In 2015, alarmed by reports of growing resistance, the Obama administration established the Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria—PACCARB, since every government entity seems to get an acronym attached to it. It is headed up Dr. Martin Blaser, whose seminal work on the microbiome we discussed in chapter 5. But even this first-rate panel of experts could not come up with a workable recommendation for curtailing agricultural use. While noting that the Food and Drug Administration has made recent efforts to reduce antibiotic use in animals, requesting veterinary oversight and an end to using antibiotics to encourage growth, the members conceded that there was nothing mandatory about these efforts and there was little evidence that they had had any effect since they were introduced in 2012.
One of the panel members, Dr. Michael Apley, a veterinarian at Kansas State University and an expert in agricultural uses of antibiotics, advocates that all such use be left in the hands of veterinarians and calls for much more study of the issue. So far, we have essentially left these matters in the hands of vets, and made only limited progress.
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. Dr. Jaap Wagenaar, 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 licensed veterinarians. 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 members of the developing world have adopted our meat-centric diet, they have also adopted our agribusiness formula for producing that meat, making heavy use of antibiotics for animal growth.
As a result, resistance is developing at an alarming rate. Fluoroquinolones (so named because of the fluorine atom in their central molecular structures) belong to a family of broad-spectrum antibiotics and include Cipro and other compounds whose scientific names end in “floxacin.” In a 2016 presentation at NIH, Ramanan Laxminarayan, a widely respected economist and epidemiologist who specializes in research on the impact of infectious diseases and drug resistance, noted that in 1990, there was a 10 percent resistance rate in the common pathogens found in animal production. By 1996, the rate was over 80 percent.
For quite some time, many of us in the public health field have been attempting to determine just how widespread the use of antibiotics in animals is in the United States and what those antibiotics are used for, but the food-animal producers have been reluctant to give us figures or administration data. Large meat producers claim it is proprietary data and they are afraid it will be used to blame the industry for the rise of superbugs. Martin Blaser puts the annual use of antibiotics for animals at 14,000 tons, compared to 4,000 tons for humans. The mere fact that we have to use measures like total tons of antibiotics, which is such a crude estimate of use and doesn’t tell us anything about types of antibiotics or where and how they are administered, is clear evidence that we desperately need better data. We believe antibiotic dosing for growth is being phased out in the United States, but how much is unclear. We do know that overall, according to various reliable sources, antibiotic use in American agribusiness is growing faster than livestock production. Between 2009 and 2014, antibiotic use increased by 22 percent.
I would liken our need for clear data on this to the need for hospitals in the United States to report the frequency of healthcare-associated infections in their institutions. Hospitals are now required by the federal government to report this data, but that wasn’t always the case, and there was a great deal of reluctance and pushback by the hospitals when the requirement was proposed. Today, the reporting system is in place and is a major reason why hospitals are taking extra measures to prevent patients from becoming infected while being cared for in their hospitals. The details of antibiotic use in food animals, beyond the raw numbers, are vital public health information, and as far as I am concerned, that trumps proprietary claims any day. Without the information, we can’t even establish a safe target for future use.
On May 10, 2016, the US Food and Drug Administration finalized a rule that revises annual reporting requirements for companies selling antibiotics for agricultural use. In addition to the overall estimates they now submit on the amount of antimicrobial drugs they sell to food-animal raisers, they must now break the number down by species: cattle, swine, chickens, and turkeys.
The FDA’s statement promises, “The new sales data will improve the agency’s understanding of how antimicrobials are sold and distributed for use in major food-producing species and help further target efforts to ensure judicious use of medically important antimicrobials.”
This is all well and good and could help us get a handle on the agricultural dimension. But it took forty years to get even this far. We don’t have forty more years for the rest of the world to get on board. Focusing only on reducing antibiotic consumption in the United States, Canada, and the European Union would be like patching three square feet of the twelve-foot-square hole the iceberg ripped in the Titanic’s hull and congratulating ourselves that we once again have a seaworthy vessel.
Antibiotic use is growing rapidly beyond the First World and is already leading to huge problems. Blaser estimates that 81,000 tons of antibiotics per year are used in China for humans and an equal amount for agriculture. China also exports another 88,000 tons annually. In China and other Asian nations, serious regulatory oversight is virtually nonexistent. The New Delhi–based Centre for Science and Environment found that 40 percent of seventy samples of chicken meat bought in that city’s markets from September 2013 to June 2014 contained antibiotic residue. Blaser has found no data he considers reliable for India.
We do have enough information to consider that India may be the largest producer of antibiotics in the world and, in turn, the greatest user and exporter of these drugs.
Maryn McKenna cites India and China as the largest practitioners, with India “completely stuck in dysfunction on this.” Many of her own findings were borne out by an investigation Bloomberg News undertook in 2016.
We see another frightening example of the mess we’re in, 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 it was not used unless absolutely necessary because of potential kidney damage. It’s not being used for people in China, but it is being used in agriculture—thousands of tons a year. Likewise, in Vietnam it is approved only 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 Dr. 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 one another. 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.
Dr. Jianzhong Shen, professor of veterinary medicine at the China Agricultural University in Beijing, told Bloomberg reporters Natalie Obiko Pearson and Adi Narayan, “The selective pressure imposed by increasingly heavy use of colistin in agriculture in China could have led to the acquisition of mcr-1 by E. coli.” This does not mean that all or even many of the countless E. coli strains around the world will take on resistance, but it is disturbing in its implications for how resistance is spreading through indiscriminate antibiotic use in agriculture.
Just as we were completing this book, the colistin-resistant E. coli made itself known in the United States—in the urine of a forty-nine-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, the 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 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 defies all imagination,” commented Dr. Timothy Walsh, professor of medical microbiology at Cardiff University in Wales.
In 2011, the Indian government released a document entitled “National Policy for Containment of Antimicrobial Resistance,” which called for a ban on over-the-counter sales of antibiotics for humans and on nontherapeutic use for livestock. The recommendations caused such an outcry from industry stakeholders that they were quickly withdrawn.
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.