Octavian Report: 2016’s Review on Antimicrobial Resistance predicts as many as 10 million annual deaths from AMR, the resistance of bacteria to antibiotics, by 2050. How credible do you find that estimate?
Laurie Garrett: I think it’s reasonable, based on what we know about current AMR death rates — which is that it’s very confusing right now. Very, very few hospitals actually report AMR incidents. Private hospitals all over the world don’t want anybody to know if they have such things going on because then likely patients will go to a different rival hospital. Many countries have no mandatory reporting at all, or the capacity to even track AMT incidents for lack of laboratory resources. And finally, the food industry tends as a rule to do their very utmost to have nobody know what they’re finding in livestock or in poultry or in whatever it is they produce; they tend to kill the animals if they spot any drug-resistant bacteria in them without reporting it rather than risk having them get out into the food chain or risk a PR crisis.
So we often have no idea. If a college co-ed comes down with a urinary tract infection involving an E. coli strain that is multidrug-resistant, we don’t know if it gets reported. If she just goes to the local clinic and gets treated, does anyone do a resistance assay? If it does get reported, does anybody link it to her food consumption and go back to the supermarket and determine what’s going on? In general, the answer is no, no, and no. So to answer the question will it be 10 million, 100 million, or five million deaths from AMR annually by 2050, let me say that the problem is we don’t even know how many millions are coming down with AMR-associated disease now. It’s a very large number. We know that.
OR: What are the big socioeconomic drivers of AMR?
Garrett: The number-one problem, without a doubt — and I mean log-scale number-one above everything else — is the use of antibiotics as growth promoters in the livestock and aquaculture industry (and increasingly in crop farming as well). The industry will tell you that the compound they’re putting routinely in the feed of every single chicken or every single cow or every single pig is not identical to an antibiotic available in your pharmacy. That it’s one hydroxy group different or that it has an attached chlorine element. But the truth is they are in the body biologically identical, and the compounds used as growth promoters are directly responsible for a surging rate in antibiotic resistance.
In particular, as we noted in an expert brief that was posted on the CFR’s website on this topic in April, we now have two broad classes of plasmids that have emerged. One class is known as the NDM or New Delhi Mutations. It was first noted in 2008 and is now pretty much everywhere in the world and has mutated into more than 19 subtypes. The other class is called MCR, first noted in China in about 2015. It has now already mutated into two subtypes and is seen in at least 31 countries — including the United States.
These plasmids are transposable units that jump from bacterium to bacterium, from species to species. So they are, as we call them, promiscuous genetic elements. They’re not confined to a given species line. They could spur very, very broad-spectrum resistance against a huge range of drugs, to the point of creating incurable diseases.
In both cases they’ve arisen out of the livestock industry in India and China, where the use of growth promoters is so ubiquitous and so completely unregulated that there are places in China where antibiotic-resistant plasmids come out of the water faucet and antibiotic residue comes out in drinking water. Where the rivers literally run with antibiotic resistance. We’re really at a dire, dire turning point right now if we don’t manage to take action well beyond the namby-pamby crap we’ve been saying for the last 20 years — “Please doctors, minimize your use of antibiotics and prescribe appropriately.” That’s so 1980’s. The situation is way beyond whether or not a given pediatrician overprescribes antibiotics. They are in the food chain, they are in the environment, they are in the water, they are in the air. We can show that antibiotic-resistant bacteria are carried in air streams and go from one part of the planet to another. It is out of control.
OR: Where geographically and with what particular bacteria might we expect a pandemic to begin?
Garrett: It doesn’t work that way. Pandemics tend to be viral, and that’s because viruses transmit completely differently. The whole problem with antibiotic resistance, the reason it hasn’t been taken seriously, the reason the livestock industry has gotten away with destroying the antibiotic revolution, is because it creeps and crawls and slowly acquires in any given bacterial species, in any given setting, in any given food or hospital or geography. What we’ve seen is a steady march towards disaster, towards apocalypse, but it’s decades in the making. When you get to the level of senior policy, of legislators, of presidents, all problems that grow incrementally draw less attention because they don’t look as urgent as problems that suddenly flash (like an Ebola epidemic). It’s not a pandemic that will arise. Bacteria are so resilient, so mutable, so capable of altering their entire evolutionary course that we’re seeing dramatic changes in bacterial populations all over the world already.
Let’s look at it this way. Before the age of antibiotics, my aunt in the 1920’s scraped her knee and got an infection that went into the bone and resulted in osteomyelitis. She was a child; it must have been excruciatingly painful. For the rest of her life she walked with a limp and with difficulty. Most people assumed she had been a polio victim. But it was because antibiotics didn’t exist. This routine scratch of the knee crippled her for life.
We’re not used to thinking about this anymore. We’re not used to imagining how dangerous it is, and pulling out a bottle of Mercurochrome and another bottle of iodine every time one of the kids gets a scratch. We’re not accustomed to thinking when somebody starts coughing, “Maybe it’s not just a cold. Maybe there’s pneumococcus in there. And if there is maybe we have to come up with something radical to do with you, like isolate you from the rest of the household — because antibiotics don’t work anymore.” This is what we’re facing. It won’t be a pandemic. It will be a steady erosion in the toolkit of fighting diseases with more and more bodies mounting up. This is in fact already happening.
OR: Do you see the possibility of a full-scale return to the pre-antibiotic era?
Garrett: In some cases we’re already there. If you get a Clostridium difficile infection right now and it has one of these plasmids in it, the standard therapy is to take the excrement of a healthy person and do what’s called a fecal transplant: transplanting feces from a healthy individual into you so that your microbiome will alter and you will have beneficial bacteria that will fight off the Clostridium difficile bacteria because antibiotics won’t work against it anymore.
OR: What can we do to stop this, and are any high-level groups undertaking those efforts?
Garrett: The number-one thing we need to do is completely ban the use of antibiotics as growth promoters. The industry is screaming and yelling because they’re so hooked on it. It’s already in the feed, commercial producers have already mixed it in for them, and the animals do — depending on what kind of animal you’re looking at, whether it’s aquaculture salmon or it’s turkeys for Thanksgiving — get incrementally larger as a result of being treated every single day with antibiotics. We don’t even know why this happens, but when all this started back in the 1950’s it was simply an observation that paid out big, and a few key companies went crazy. The profits were huge.
You could literally now raise animals without having them ever go out and forage for food, and they would be fat and go to the market. So now all of a sudden you could have giant industrial pig farms where a pig never walks more than 15 inches in any direction in its entire lifetime. You could have industrial-scale warehouse chicken rearing, where the chicken never sees the sun. These were all possible because the feed bulked the animals up so much and that made mass-scale agricultural production cheap and possible and limited the real estate expense of raising animals. You can go down a huge list of pluses for the industry. But it has to be banned, and the industry has to rethink what it’s doing. I say “the industry,” but we’re talking hundreds of different industries that are involved.
By the way, adding these growth promoters now is very expensive. The increment of added size for the animals in many cases is less than three percent of total animal weight. And so it’s becoming less and less financially wise, and it certainly is less and less wise for the health of the planet and of human beings.
OR: Is there regulatory or legislative pushback against this?
Garrett: Yes, everywhere. It’s a huge thing, it’s a giant confrontation. This has been going on for a while. The FDA under Obama initiated a whole set of moves aimed at phasing out the use of growth promoters in the industry. USDA traditionally defends the agricultural industry, and FDA traditionally is about the safety of pharmaceuticals, and they often come to blows on this with USDA saying, “What right do you have to say what our farmers do? You’re a drug regulator.” And the FDA’s saying, “Yes, but your farmers are using drugs.” And the USDA says back, “No, no, they’re not drugs, they’re growth promoters.” This has been an ongoing dispute for a couple of decades. They reached a point where there was hope, at least in the United States, that limitations would indeed go in place. But then Obama went out and we have a new administration and we haven’t heard a peep from anybody in either the FDA or the USDA about what is likely to transpire on this front under the Trump administration.
Overseas we’ve seen some remarkable things. The Dutch and the Swedes in particular banned almost all growth promoters long ago. They have very vibrant livestock industries. In some of their animals, the yield rates are even higher than those seen in, say, France where they use a ton of this stuff. They have far less drug-resistant human infection, far lower rates of death due to bacterial infection in their hospitals. Across the board they’ve seen benefit with no real economic hardship to their farmers. They have pushed hard, the Swedes and the Dutch, all throughout the E.U. to try and get a Europe-wide law. Dame Sally Davies, the former Minister of Health under Tony Blair in the U.K., has led a powerful initiative in the U.K. to try and ban a lot of agricultural uses.
Agricultural uses now also involve the applications to plants and to seeds. So you could acquire drug-resistant bacteria from your next pile of nuts or strawberries. It’s not just chickens anymore. The British government under David Cameron had been leading an initiative globally to stem the tide of agricultural use and had brought it to the Security Council and the General Assembly. Last September the United Nations General Assembly passed a resolution to combat antibiotic resistance, antimicrobial resistance, and called for a phase-out over the next 15 years of all agricultural uses other than direct veterinary treatment. The problem is that Cameron went out of power, Brexit passed, the Brits became less of a force behind all of this, and nothing has really been put in place in the U.N. system that represents any way of really regulating any of it. So at the moment it’s all good intentions and aspirations — but not much else.
OR: If this faltering of political will continues, what will be the short- and medium-term consequences?
Garrett: We are already seeing them. Let me give you an example. When I was a child, some of the diseases that are common we didn’t have vaccines for. When I was a kid antibiotics were considered really miraculous substances that were used as indicated by doctors. But they were very well aware of the miracle of penicillin and tetracycline. They used them when there was a really good reason to believe you had strep throat as opposed to a virus. I never had an antibiotic — no doctor felt the need to prescribe it — until I had tonsillitis at the age of six. Somehow I, and most of my generation, managed to get all the way into elementary school before we ever had to have an antibiotic.
Today it’s almost impossible in the United States to find a two-year-old who hasn’t already had two, three, or even four giant rounds of broad-spectrum, very powerful antibiotic treatment. In most cases it’s for ear infection. That kind of ear infection was almost unheard of 40 years ago; now it’s routine. Hardly any kid makes it to first grade without having gone through bouts of antibiotic treatment for ear infections. On the first round, the doctor may give the parent these droplets that the children hate; the parent has to go into combat with their 18-month-old to get them to swallow the stuff. And it seems to work. They stop taking them perhaps prematurely, and the kid’s fine. But they didn’t kill off all the bacteria, they just brought the worst symptoms under control — and meanwhile the remaining bacteria acquired resistance to that first round of treatment.
Six months later the kid’s back, the ear infection’s worse, the kid is screaming. There’s concern about it getting into the brain and leading to encephalitis. So they go to a higher, broader-spectrum, more powerful antibiotic formulation. Now the child is two years old and is flailing around and screaming and doesn’t want to take these drops. Mom and dad go into combat every night with child. Finally they think they’ve got it under control. Maybe the pediatrician said, “You have to really, really do it right this time.” But once again a resistant strain arises.
Pediatricians will tell you they see more hearing loss in children now. Eight, 10, 11-year-olds showing hearing loss that’s a result of bouts of bacterial infection when they were toddlers. That’s just one example. Consider urinary tract infections. About 15 to 18 million Americans every year get a urinary tract infection, most of them women, and an increasing percentage of those infections are drug-resistant. Some are so drug-resistant that basically nothing works. You just wait it out in pain and hope — if you’re lucky, you’re young, and you’re healthy — that your immune system goes into combat mode and you defeat the microbes. Or maybe not.
There was a woman who died in 2016. She had been traveling in India. She got a broken leg and was treated in India for her broken leg. She came home to Las Vegas and there was an infection associated with her broken leg and the treatment. It looked like it had just been a little scratch that perhaps one of the medical instruments had made when they were fixing her bone. But it became so drug-resistant she went through 26 different rounds of completely different formulations of antibiotics. She died. Nothing worked. We’re seeing this more and more. There are people trying to keep tally of all of this and there are various interactive trackers you can see online that will show you trends in drug resistance around the world.
The bottom line is that it’s just getting harder to keep hospitals clean, because it now turns out that some of the disinfectants we use actually select for resistant bacteria and promote resistance. The chlorine we use for water-waste treatments, so that we don’t dump antibiotic-resistant factors into our oceans and our rivers, turns out to select for resistant microbes and actually enhances the amount of resistance we’re dumping into our environment.
We need an all-hands-on-deck approach that where the world takes the U.N. resolution seriously and the pharmaceutical community steps up to the plate and the biotech community steps up to the plate. We need an all-out push by NIH and all its counterparts around the world. The World Health Organization underscored this. For the first time in the history of the organization they released a list of 12 of the most dangerous pathogens — non-viral — on earth. All of them because they’ve become so drug-resistant that people are dying in record numbers. You can see that list on their website. So the sense of urgency is there in the public health community, but it’s not yet there at all in higher tiers of policy making, on Wall Street, and in the pharmaceutical industry where it needs to be.
OR: Where do you rank AMR on the scale of global health threats?
Garrett: Let me provide an example that is not bacterial, but is illustrative of how complicated trying to answer that question can be. Yellow fever has been around as long as we know in human history. It’s carried by mosquitoes; it’s a virus. It’s a nasty virus. If you are unvaccinated, I believe the mortality rate is 30 percent. I’ve seen people with yellow fever. You hemorrhage. The individual looks like an Ebola victim, which is why a lot of yellow fever is misdiagnosed. But then we developed a vaccine that really, really works. And not only does it really work, it only costs 27 cents and it confers lifetime immunity. There was good reason to believe when this vaccine rolled out in the 1960’s that we could effectively stop yellow fever on the whole planet. The World Health organization and everybody else issued these special yellow papers you had to carry anywhere you traveled in the world that stipulated when and where you’d been vaccinated. Many countries would not allow you in, especially in Africa, without a valid yellow fever vaccination slip certified by the World Health Organization.
Today we have a rampant yellow fever epidemic in Brazil and in several other places in the world. Cases are now turning up in Sao Paulo and Rio de Janeiro. Why? For one thing, people have gotten lax about vaccinations — just look at the anti-vaccine movement that’s made a huge comeback and has caused surges in measles, mumps, and whooping cough all over the United States and much of the rest of the developed world with its ridiculous hocus-pocus. The vaccination rate for yellow fever has similarly dropped off. Two, the vaccine’s so cheap that nobody wants to bother to make it. And finally, the virus could always hide in monkeys, and that’s what we’re now seeing: the Amazon region plagued by what’s known as sylvatic yellow fever. It’s coming from the monkeys via mosquitoes to people.
But here’s the final kicker: it is urbanizing. This is something we never saw before. This is why the Ebola epidemic in 2017 was so hideous: it was an urban epidemic for the first time in human history. We don’t know what an antibiotic-resistant scourge would look like in the modern world. We can only draw so many assumptions from what we know it was like in the 1920’s and 1930’s when the world population was an incremental piece of what it is today. When most people lived in rural areas, not urban. When a visit to the family doctor was a rare experience — and when you did go, you went to some little guy’s shop with a shingle hanging out on the street.
Today when someone gets sick they go to a waiting room with their sick child and sit there for 16 hours surrounded by another 100 or 200 people. They then get into a facility that is operating at hyperspeed with sometimes marginal forms of hospital hygiene. And if they’re really sick and they get hospitalized, they’re going into a facility where infection control is very, very difficult to maintain, especially if the people on the ward are under highly stressed conditions like advanced cancer or pneumonia or are in post-op ICU or neonatal ICU. These are all places where we see outbreaks of drug-resistant bacteria now. We see them go screaming through a ward. One by one every patient — boom, boom, boom, boom, down the line. The infection is often carried on the hands of well-intentioned doctors and nurses. We now know it can be on their coat, it can be in their shoes. It’s almost impossible to completely scour your body free of salmonella, of methicillin-resistant Staphylococcus aureus, of streptococcus, of Enterococcus faecalis.
These are really hard bugs to get rid of. They exist in the environment because they have acquired the capacity to latch onto any surface. If there’s so much as a molecule of H2O around they can live there. We don’t know what it means to be talking about the spread of bacterial disease in the modern age of air conditioning and of people living in giant towers and cities where you can’t even open your windows. In the 1930’s nobody had air conditioning and nobody lived and worked in offices and buildings where they shared the air space of every single other person in the entire building. What we see now is an increase in Legionnaires’ disease, for example, which is really an air-conditioning disease. We see more and more our air-conditioning systems themselves become giant bacterial biofilms with disease scourges spreading through the system.
So to answer your question, you would have to set your baseline assumptions of how commonly bacterial disease spread with fatal outcome. Let’s just stick with fatal. We won’t even talk about people who got crippled like my aunt or rendered deaf or blind because of bacterial infection. You could look at how people lived and what the rate of transmission was in the 1930’s, but then you’d have to add in all these factors to reflect 21st century living: increased human population, antibiotics in our food and water, social interactions on the subway or on airplanes, and on and on and on. As you can see, it’s an almost impossible calculus to make.
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