I’ve written about these types of claimsbefore. The first one–a claim that antimicrobial peptides were essentially “resistance proof,” was proven to be embarrassingly wrong in a laboratory test. Resistance not only evolved, but it evolved independently in almost every instance they tested (using E. coli and Pseudomonas species), taking only 600-700 generations–a relative blip in microbial time. Oops.
A very similar claim made the rounds in 2014, and the newest one is out today–a report of a “super vancomycin” that, as noted above, could be used “without fear of resistance emerging.” (The title of the article literally claims “‘Magical’ antibiotic brings fresh hope to battle against drug resistance”, another claim made in addition to the “no resistance” one in the Scripps press release by senior author Dale Boger). This one claims that, because the modified vancomycin uses 3 different ways to kill the bacteria, “Organisms just can’t simultaneously work to find a way around three independent mechanisms of action. Even if they found a solution to one of those, the organisms would still be killed by the other two.”
A grand claim, but history suggests otherwise. It was argued that bacteria could not evolve resistance to bacteriophage, as the ancient interaction between viruses and their bacterial hosts certainly must have already exploited and overcome any available defense. Now a plethora of resistance mechanisms are known.
Within the paper itself, the limitations are much more clearly laid out. Discussing usage of the antibiotic, the authors note of these conventional semisynthetic vancomycin analogs:
“However, their use against vancomycin-resistant bacteria (e.g., VRE and VRSA), where they are less potent and where only a single and less durable mechanism of action remains operative, likely would more rapidly raise resistance, not only compromising its future use but also, potentially transferring that resistance to other organisms (e.g., MRSA).”
So as they acknowledge, not really so resistance-proof at all–only if they’re used under perfect conditions and without any vancomycin resistance genes already present. What are the odds of that once this drug is released? (Spoiler alert: very low).
Alexander Fleming, who won the 1945 Nobel Prize in Physiology or Medicine, tried to sound the warning that the usefulness of antibiotics would be short-lived as bacteria adapted, but his warnings were (and still are?) largely ignored. There is no “magic bullet;” there are only temporary solutions, and we should have learned by now not to underestimate our bacterial companions.
Part of this post previously published here and here.
Yesterday, two article were released showing that MCR-1, the plasmid-associated gene that provides resistance to the antibiotic colistin, has been found in the United States. And not just in one place, but in two distinct cases: a woman with a urinary tract infection (UTI) in Pennsylvania, reported in the journal Antimicrobial Agents and Chemotherapy, and a positive sample taken from a pig’s intestine as part of the National Antimicrobial Resistance Monitoring System (NARMS), which tracks resistant bacteria related to retail meat products. Not surprising, not unexpected, but still, not good.
Colistin is an old antibiotic. Dating back to the 1950s, it’s been used sparingly over the decades because it can cause serious damage to the kidneys and nervous system. It’s also typically administered intravenously in humans, so you can’t just pop a colistin pill and be sent home from the doctor. Newer preparations appear to be safer, and because of the problem with antibiotic resistance in general and limited treatment options for multidrug-resistant Gram-negative infections in particular, colistin has seen a new life in the last decade or so as a last line of defense against some of these almost-untreatable infections.
Because of its sparing use in humans, resistance has not been much of an issue until recently. And while human use is relatively rare compared to other types of antibiotics, in animals, the story is different. Because colistin is old and cheap, it’s used as an additive to feed in Chinese livestock, to make them grow faster and fatter. (We do this here in the U.S. too, but using different antibiotics than colistin). So as would be expected, use of this antibiotic led to the evolution and spread of a resistant strain, due to the presence of the MCR-1 gene. By the first time they saw this resistance, it was already present in 20% of the pigs they tested near Shanghai, and 15% of the raw meat samples they tested. In this case, the gene is on a plasmid, which makes it easier to spread to other types of bacteria. To date, most of the reports of MCR-1 have been in E. coli, but it’s also been found in Salmonellaand Klebsiella pneunoniae–all gut bacteria that can be spread from animals via contaminated food products, or person-to-person when someone carrying the bacterium doesn’t wash their hands after using the bathroom.
So a question becomes, how exactly did it get here? And that’s very difficult to say right now. The hospital where the human case was reported notes that the patient reported no travel history in the past 5 months (so it’s unlikely that she traveled to China, for instance, and picked up the gene or bacterium carrying it there). The hospital says they’ve not found other MCR-1 positive isolates from other patients, but also that they’ve only been testing specimens for 3 weeks, so…yeah. Hard to say. People and animals (like the tested pig) can carry E. coli or other species that harbor MCR-1in their gut without becoming ill, so it may have been in the population for awhile (as they’ve seen in Brazil) before it came to the attention of medical researchers. Perhaps it’s been circulating in some of our meat products, or spreading in a chain of miniscule transfers of shit from person to person to person to person, for longer than we realize. Or both.
I was asked on Twitter yesterday, “Should I panic today or put that off until next week?” I’m not an advocate of panic myself, but I do think this is yet another concern and another hit on our antibiotic arsenal. It’s not widespread in this country and as mentioned, colistin is luckily not a first-line drug, so it won’t affect all *that* many people–for now, at least.
There are already papers out thereshowing bacteria that have both NDM-1 (or related variants) and MCR-1 genes. NDM-1 is a gene that provides resistance to another class of last-resort antibiotics, the carbapenems. (Maryn McKenna has covered this extensively on her blog). When carbapenems fail, treatment with colistin sometimes works. But if the bacterium is resistant to both colistin and carbapenems, well…not good. That hasn’t been reported yet in the U.S., but it’s only a matter of time, as McKenna notes.
It doesn’t mean that we’re out of antibiotics (yet) or that everyone who has one of these resistant infections will be unable to find a treatment that works (yet). But we’re inching ever closer to those days, one resistant bacterium at a time.
I’ve been involved in a few discussions of late on science-based sites around yon web on antibiotic resistance and agriculture–specifically, the campaign to get fast food giant Subway to stop using meat raised on antibiotics, and a graphic by CommonGround using Animal Health Institute data, suggesting that agricultural animals aren’t an important source of resistant bacteria. Discussing these topics has shown me there’s a lot of misunderstanding of issues in antibiotic resistance, even among those who consider themselves pretty science-savvy.
I think this is partly an issue of, perhaps, hating to agree with one’s “enemy.” Vani Hari, the “Food Babe,” recently also plugged the Subway campaign, perhaps making skeptics now skeptical of the issue of antibiotics and agriculture? Believe me, I am the farthest thing from a “Food Babe” fan and have criticized her many times on my Facebook page, but unlike her ill-advised and unscientific campaigns against things like fake pumpkin flavoring in coffee or “yoga mat” chemicals in Subway bread, this is one issue that actually has scientific support–stopped clocks and all that. Nevertheless, I think some people get bogged down in a lot of exaggeration or misinformation on the topic.
So, some thoughts. Please note that in many cases, my comments will be an over-simplification of a more complex problem, but I’ll try to include nuance when I can (without completely clouding the issue).
First–why is antibiotic resistance an issue?
Since the development of penicillin, we have been in an ongoing “war” with the bacteria that make us ill. Almost as quickly as antibiotics are used, bacteria are capable of developing or acquiring resistance to them. These resistance genes are often present on transmissible pieces of DNA–plasmids, transposons, phage–which allow them to move between bacterial cells, even those of completely different species, and spread that resistance. So, once it emerges, resistance is very difficult to keep under control. As such, much better to work to prevent this emergence, and to provide conditions where resistant bacteria don’t encounter selection pressures to maintain resistance genes (1).
In our 75-ish years of using antibiotics to treat infections, we’ve increasingly found ourselves losing this war. As bacterial species have evolved resistance to our drugs, we keep coming back with either brand-new drugs in different classes of antibiotics, or we’ve made slight tweaks to existing drugs so that they can escape the mechanisms bacteria use to get around them. And they’re killing us. In the US alone, antibiotic-resistant infections cause about 2 million infections per year, and about 23,000 deaths due to these infections–plus tens of thousands of additional deaths from diseases that are complicated by antibiotic-resistant infections. They cost at least $20 billion per year.
But we’re running out of these drugs. And where do the vast majority come from in any case? Other microbes–fungi, other bacterial species–so in some cases, that means there are also pre-existing resistance mechanisms to even new drugs, just waiting to spread. It’s so bad right now that even the WHO has sounded the alarm, warning of the potential for a “post-antibiotic era.”
This is some serious shit.
Where does resistance come from?
Resistant bacteria can be bred anytime an antibiotic is used. As such, researchers in the field tend to focus on two large areas: use of antibiotics in human medicine, and in animal husbandry. Human medicine is probably pretty obvious: humans get drugs to treat infections in hospital and outpatient settings, and in some cases, to protect against infection if a person is exposed to an organism–think of all the prophylactic doses of ciprofloxacin given out after the 2001 anthrax attacks, for example.
In human medicine, there is still much debate about 1) the proper dosing of many types of antibiotics–what is the optimal length of time to take them to ensure a cure, but also reduce the chance of incubating resistant organisms? This is an active area of research; and 2) when it is proper to prescribe antibiotics, period. For instance, ear infections. These cause many sleepless nights for parents, a lot of time off work and school, and many trips to clinics to get checked out. But do all kids who have an ear infection need antibiotics? Probably not. A recent study found that “watchful waiting” as an alternative to immediate prescription of antibiotics worked about as well as drug treatment for nonsevere ear infections in children–one data point among many that antibiotics are probably over-used in human medicine, and particularly for children. So this is one big area of interest and research (among many in human health) when it comes to trying to curb antibiotic use and employ the best practices of “judicious use” of antibiotics.
Another big area of use is agriculture (2). Just as in humans, antibiotics in ag can be used for treatment of sick animals, which is completely justifiable and accepted–but there are many divergences as well. For one, animals are often treated as a herd–if a certain threshold of animals in a population become ill, all will be treated in order to prevent an even worse outbreak of disease in a herd. Two, antibiotics can be, and frequently are, used prophylactically, before any disease is present–for example, at times when the producer historically has seen disease outbreaks in the herd, such as when animals are moved from one place to another (moving baby pigs from a nursery facility to a grower farm, as one example). Third, they can be used for growth promotion purposes–to make animals fatten up to market weight more quickly. The latter is, by far, the most contentious use, and the “low hanging fruit” that is often targeted for elimination.
From practically the beginning of this practice, there were people who spoke out against it, suggesting it was a bad idea, and that the use of these antibiotics in agriculture could lead to resistance which could affect human health. A pair ofpublications by Stuart Levy et al. in 1976 demonstrated this was more than a theoretical concern, and that antibiotic-resistant E. coli were indeed generated on farms using antibiotics, and transferred to farmers working there. Since this time, literally thousands of publications on this topic have demonstrated the same thing, examining different exposures, antibiotics, and bacterial species. There’s no doubt, scientifically, that use of antibiotics in agriculture causes the evolution and spread of resistance into human populations.
Why care about antibiotic use in agriculture?
A quick clarification that’s a common point of confusion–I’m not discussing antibiotic *residues* in meat products as a result of antibiotic use in ag (see, for example, the infographic linked above). In theory, antibiotic residues should not be an issue, because all drugs have a withdrawal period that farmers are supposed to adhere to prior to sending animals off to slaughter. These guidelines were developed so that antibiotics will not show up in an animal’s meat or milk. The real issue of concern for public health are the resistant bacteria, which *can* be transmitted via these routes.
Agriculture comes up many times for a few reasons. First, because people have the potential to be exposed to antibiotic-resistant bacteria that originate on farms via food products that they eat or handle. Everybody eats, and even vegetarians aren’t completely protected from antibiotic use on farms (I’ll get into this below). So even if you’re far removed from farmland, you may be exposed to bacteria incubating there via your turkey dinner or hamburger.
Second, because the vast majority of antibiotic use, by weight, occurs on farms–and many of these are the very same antibiotics used in human medicine (penicillins, tetracyclines, macrolides). It’s historically been very difficult to get good numbers on this use, so you may have seen numbers as high as 80% of all antibiotic use in the U.S. occurs on farms. A better number is probably 70% (described here by Politifact), which excludes a type of antibiotic called ionophores–these aren’t used in human medicine (3). So a great deal of selection for resistance is taking place on farms, but has the potential to spread into households across the country–and almost certainly has. Recent studies have demonstrated also that resistant infections transmitted through food don’t always stay in your gut–they can also cause serious urinary tract infections and even sepsis. Studies from my lab and others (4) examining S. aureus have identified livestock as a reservoir for various types of this bacterium–including methicillin-resistant subtypes.
How does antibiotic resistance spread?
In sum–in a lot of different ways. Resistant bacteria, and/or their resistance genes, can enter our environment–our water, our air, our homes via meat products, our schools via asymptomatic colonization of students and teachers–just about anywhere bacteria can go, resistance genes will tag along. Kalliopi Monoyios created this schematic for the above-mentioned paper I wrote earlier this year on livestock-associated Staphyloccocus aureus and its spread, but it really holds for just about any antibiotic-resistant bacterium out there:
And as I noted above, once it’s out there, it’s hard to put the genie back in the bottle. And it can spread in such a multitude of different ways that it complicates tracking of these organisms, and makes it practically impossible to trace farm-origin bacteria back to their host animals. Instead, we have to rely on studies of meat, farmers, water, soil, air, and people living near farms in order to make connections back to these animals.
And this is where even vegetarians aren’t “safe” from these organisms. What happens to much of the manure generated on industrial farms? It’s used as fertilizer on crops, bringing resistant bacteria and resistance genes along with it, as well as into our air when manure is aerosolized (as it is in some, but not all, crop applications) and into our soil and water–and as noted below, antibiotics themselves can also be used in horticulture as well.
So isn’t something being done about this? Why are we bothering with this anymore?
Kind of, but it’s not enough. Scientists and advocates have been trying to do something about this topic since at least 1969, when the UK’s Swann report on the use of Antibiotics in Animal Husbandry and Veterinary Medicine was released. As noted here:
One of its recommendations was that the only antimicrobials that should be permitted as growth promotants in animals were those that were not depended on for therapy in humans or whose use was not likely to lead to resistance to antimicrobials that were important for treating humans.
And some baby steps have been made previously, restricting use of some important types of antibiotics. More recently in the U.S., Federal Guidelines 209 and 213 were adopted in order to reduce the use of what have been deemed “medically-important” antibiotics in the livestock industry. These are a good step forward, but truthfully are only baby steps. They apply only to the use of growth-promotant antibiotics (those for “production use” as noted in the documents), and not other uses including prophylaxis. There also is no mechanism for monitoring or policing individuals who may continue to use these in violation of the guidelines–they have “no teeth.” As such, there’s concern that use for growth promotion will merely be re-labeled as use for prophylaxis.
Further, even now, we still have no data on the breakdown of antibiotic use in different species. We know over 32 million pounds were used in livestock in 2013, but with no clue how much of that was in pigs versus cattle, etc.
We do know that animals can be raised using lower levels of antibiotics. The European Union has not allowed growth promotant antibiotics since 2006. You’ll read different reports of how successful that has been (or not); this NPR article has a balanced review. What’s pretty well agreed-upon is that, to make such a ban successful, you need good regulation and a change in farming practices. Neither of these will be in place in the U.S. when the new guidance mechanisms go into place next year–so will this really benefit public health? Uncertain. We need more.
So this brings me back to Subway (and McDonald’s, and Chipotle, and other giants that have pledged to reduce use of antibiotics in the animals they buy). Whatever large companies do, consumers are demonstrating that they hold cards to push this issue forward–much faster than the FDA has been able to do (remember, it took them 40 freaking years just to get these voluntary guidelines in place). Buying USDA-certified organic or meat labeled “raised without antibiotics” is no 100% guarantee that you’ll have antibiotic-resistant-bacteria-free meat products, unfortunately, because contamination can be introduced during slaughter, packing, or handling–but in on-farm studies of animals, farmers, and farm environment, studies have typically found reduced levels of antibiotic-resistant bacteria on organic/antibiotic-free farms than their “conventional” counterparts (one example here, looking at farms that were transitioning to organic poultry farming).
Nothing is perfect, and biology is messy. Sometimes reducing antibiotic use takes a long time to have an impact, because resistance genes aren’t always quickly lost from a population even when the antibiotics have been removed. Sometimes a change may be seen in the bacteria animals are carrying, but it takes longer for human bacterial populations to change. No one is expecting miracles, or a move to more animals raised antibiotic-free to be a cure-all. And it’s not possible to raise every animal as antibiotic-free in any case; sick animals need to be treated, and even on antibiotic-free farms, there is often some low level of antibiotic use for therapeutic purposes. (These treated animals are then supposed to be marked and cannot be sold as “antibiotic-free”). But reducing the levels of unnecessary antibiotics in animal husbandry, in conjunction with programs promoting judicious use of antibiotics in human health, is a necessary step. We’ve waited too long already to take it.
(1) Though we know that, in some cases, resistance genes can remain in a population even in the absence of direct selection pressures–or they may be on a cassette with other resistance genes, so by using any one of those selective agents, you’re selecting for maintenance of the entire cassette.
(2) I’ve chosen to focus on use in humans & animal husbandry, but antibiotics are also used in companion animal veterinary medicine and even for aquaculture and horticulture (such as for prevention of disease in fruit trees). The use in these fields is considerably smaller than in human medicine and livestock, but these are also active areas of research and investigation.
(3) This doesn’t necessarily mean they don’t lead to resistance, though. In theory, ionophores can act just like other antibiotics and co-select for resistance genes to other, human-use antibiotics, so their use may still contribute to the antibiotic resistance problem. Studies from my lab and others have shown that the use of zinc, for instance–an antimicrobial metal used as a dietary supplement on some pig farms, can co-select for antibiotic resistance. In our case, for methicillin-resistant S. aureus.
(4) See many more of my publications here, or a Nature profile about some of my work here.
I’ve been working on livestock-associated Staphylococcus aureus and farming now for almost a decade. In that time, work from my lab has shown that, first, the “livestock-associated” strain of methicillin-resistant S. aureus (MRSA) that was found originally in Europe and then in Canada, ST398, is in the United States in pigs and farmers; that it’s present here in raw meatproducts; that “LA” S. aureus can be found not only in the agriculture-intensive Midwest, but also in tiny pig states like Connecticut. With collaborators, we’ve also shown that ST398 can be found in unexpected places, like Manhattan, and that the ST398 strain appears to have originated as a “human” type of S. aureuswhich subsequently was transmitted to and evolved in pigs, obtaining additional antibiotic-resistance genes while losing some genes that help the bacterium adapt to its human host. We also found a “human” type of S. aureus, ST5, way more commonly than expected in pigs originating in central Iowa, suggesting that the evolution of S. aureus in livestock is ongoing, and is more complicated than just ST398 = “livestock” Staph.
However, with all of this research, there’s been a big missing link that I repeatedly get asked about: what about actual, symptomatic infections in people? How often do S. aureus that farmers might encounter on the farm make them ill? We tried to address this in a retrospective survey we published previously, but that research suffered from all the problems that retrospective surveys do–recall bias, low response rate, and the possibility that those who responded did so *because* they had more experience with S. aureus infections, thus making the question more important to them. Plus, because it was asking about the past, we had no way to know that, even if they did report a prior infection, if it was due to ST398 or another type of S. aureus.
So, in 2011, we started a prospective study that was just published in Clinical Infectious Diseases, enrolling over 1,300 rural Iowans (mostly farmers of some type, though we did include individuals with no farming exposures as well, and spouses and children of farmers) and testing them at enrollment for S. aureus colonization in the nose or throat. Like previous studies done by our group andothers in the US, we found that pig farmers were more likely to be carrying S. aureus that were resistant to multiple antibiotics, and especially to tetracycline–a common antibiotic used while raising pigs. Surprisingly, we didn’t find any difference in MRSA colonization among groups, but that’s likely because we enrolled relatively small-scale farmers, rather than workers in concentrated animal feeding operations (CAFOs) like we had examined in prior research, who are exposed to many more animals living in more crowded conditions (and possibly receiving more antibiotics).
What was unique about this study, besides its large size, was that we then followed participants for 18 months to examine development of S. aureus infections. Participants sent us a monthly questionnaire telling us that they had a possible Staph infection or not; describing the infection if there was one, including physician diagnosis and treatment; and when possible, sending us a sample of the infected area for bacterial isolation and typing. Over the course of the study, which followed people for over 15,ooo “person-months” in epi-speak, 67 of our participants reported developing over 100 skin and soft tissue infections. Some of them were “possibly” S. aureus–sometimes they didn’t go to the doctor, but they had a skin infection that matched the handout we had given them that gave pictures of what Staph infections commonly look like. Other times they were cellulitis, which often can’t be definitively confirmed as caused by S. aureus without more invasive tests. Forty-two of the infections were confirmed by a physician, or at the lab as S. aureus due to a swab sent by the patient.
Of the swabs we received that were positive, 3/10 were found to be ST398 strains–and all of those were in individuals who had contact with livestock. A fourth individual who also had contact with pigs and cows had an ST15 infection. Individuals lacking livestock contact had infections with more typical “human” strains, such as ST8 and ST5 (usually described as “community-associated” and “hospital-associated” types of Staph). So yes, ST398 is causing infections in farmers in the US–and very likely, these are flying under the radar, because 1) farmers really, really don’t like to go to the doctor unless they’re practically on their deathbed, and 2) even if they do, and even if the physician diagnoses and cultures S. aureus (which is not incredibly common–many diagnoses are made on appearance alone), there are very limited programs in rural areas to routinely type S. aureus. Even in Iowa, where invasive S. aureus infections were previously state-reportable, we know that fewer than half of the samples even from these infections ever made it to the State lab for testing–and for skin infections? Not even evaluated.
As warnings are sounded all over the world about the looming problem of antibiotic resistance, we need to rein in the denial of antibiotic resistance in the food/meat industry. Some positive steps are being made–just the other day, Tyson foods announced they plan to eliminate human-use antibiotics in their chicken, and places like McDonald’s and Chipotle are using antibiotic-free chicken and/or other meat products in response to consumer demand. However, pork and beef still remain more stubborn when it comes to antibiotic use on farms, despite a recent study showing that resistant bacteria generated on cattle feed yards can transmit via the air, and studies by my group and others demonstrating that people who live in proximity to CAFOs or areas where swine waste is deposited are more likely to have MRSA colonization and/or infections–even if it’s with the “human” types of S. aureus. The cat is already out of the bag, the genie is out of the bottle, whatever image or metaphor you prefer–we need to increase surveillance to detect and mitigate these issues, better integrate rural hospitals and clinics into our surveillance nets, and work on mitigation of resistance development and on new solutions for treatment cohesively and with all stakeholders at the table. I don’t think that’s too much to ask, given the stakes.
Eleven years ago, two scientists made a bet. One scientist wagered that a new type of antimicrobial agent, called antimicrobial peptides, would not elicit resistance from bacterial populations which were treated with the drugs. Antimicrobial peptides are short proteins (typically 15-50 amino acids in length) that are often positively charged. They are also a part of our body’s own innate immune system, and present in other species from bacteria to plants. It is thought that these peptides work primarily by disrupting the integrity of the bacterial cell, often by poking holes in them. Sometimes they work with the host to ramp up the immune response and overwhelm the invading microbe. Because the peptides are frequently targeted at the bacterial cell wall structure, it was thought that resistance to these drugs would require a fundamental change in membrane structure, making it an exceedingly rare event. Therefore, these antimicrobial peptides might make an excellent weapon in the fight against multiply drug-resistant bacteria.
Additionally, the remarkable diversity of these peptides, combined with the presence of multiple types of peptides with different mechanisms of action present at the infection site, rendered unlikely the evolution of resistance to these molecules (or so some reasoning went). However, evolutionary biologists have pointed out that therapeutic use of these peptides would differ from natural exposure: concentration would be significantly higher, and a larger number of microbes would be exposed. Additionally, resistance to these peptides has been detailed in a few instances. For example, resistance to antimicrobial peptides has been shown to be essential for virulence in Staphylococcus aureus and Salmonella species, but we didn’t *witness* that resistance develop–therefore, it might simply be that those species have physiological properties that render them naturally resistant to many of these peptides, and were never susceptible in the first place.
Studies both in the laboratory and in the clinic confirm that emergence of resistance against antimicrobial peptides is less probable than observed for conventional antibiotics, and provides the impetus to develop antimicrobial peptides, both natural and laboratory conceived, into therapeutically useful agents.
Certainly in the short term, resistance may be unlikely to evolve for reasons described above. However, if these peptides are used over an extended period of time, could the mutations necessary to confer resistance accumulate? This was the question asked in a new study by Dr. Zasloff along with colleagues Gabriel Perron and Graham Bell. Following publication of his 2002 paper where he called evolution of resistance to these peptides “improbable,” Bell challenged Zasloff to test this theory. Zasloff took him up on the offer, and they published their results in Proceedings of the Royal Society.
Zasloff had egg on his face. Resistance not only evolved, but it evolved independently in almost every instance they tested (using E. coli and Pseudomonas species), taking only 600-700 generations–a relative blip in microbial time. Oops.
Well, everything old is new again. A very similar claim has been making the rounds recently, originating from the press release for a new paper claiming to have found bacteria’s “Achilles’ heel,” advancing the claim that “Because new drugs will not need to enter the bacteria itself, we hope that the bacteria will not be able to develop drug resistance in future.” A grand claim, but history suggests otherwise. It was argued that bacteria could not evolve resistance to bacteriophage, as the ancient interaction between viruses and their bacterial hosts certainly must have already exploited and overcome any available defense. Now a plethora of resistance mechanisms are known.
Alexander Fleming, who won the 1945 Nobel Prize in Physiology or Medicine, tried to sound the warning that the usefulness of antibiotics would be short-lived as bacteria adapted, but his warnings were (and still are?) largely ignored. There is no “magic bullet;” there are only temporary solutions, and we should have learned by now not to underestimate our bacterial companions.
After this post on antibiotic resistance, many of you may have seen an exchange on Twitter calling me out for being “knee-jerk” about my call to action to do something about the overuse of antibiotics. In that post, I focused on antibiotic use in agriculture, giving only brief mention to human clinical use. There are a number of reasons for this, and while I didn’t discuss them extensively on Twitter, I did want to provide an overview here in order to better explain my position and concern about antibiotic use in agriculture.
How are antibiotics used in animal production?
To start, some background on the issues. Antibiotics are used in agriculture in a number of different ways. Like humans, they’re used to treat disease when animals get sick. This type of use isn’t disputed for the most part–no one wants animals to die from treatable disease, nor do they want sick animals to enter the food chain. Antibiotics can also be used to prevent disease, such as when animals are stressed (as when they’re moved from farm to farm) and disease has a tendency to break out, or if a few animals in the herd are sick and owners want to prevent the rest of the herd from falling ill. This type of use is somewhat controversial, and many have argued that this type of use is only necessary because hygienic conditions on farms aren’t up to snuff–and that if better husbandry was practiced, this prophylactic use could also be significantly decreased or eliminated. Others argue that it’s necessary even with good husbandry.
The practice which is most widely disputed is the use of antibiotics for growth promotion. We’ve known for roughly 60 years that animals, when fed antibiotics at low doses (below the level required for disease treatment), grow to their slaughter weight faster (and therefore, with less food input). This is the “low-hanging fruit;” the practice that even some in industry agree could end with pretty much no (or minimal) side effects to industry; and the practice that the European Union has already ended. It’s also the target of FDA guidance 213, which asks the phamaceutical industry to voluntarily phase out the use of growth promotant antibiotics in feed and water given to livestock. Twenty-five of 26 companies have agreed to this already, so again, there’s really not much dispute that this is a process that will be ending, after over 60 years of use and 45 years after a government report suggested that rising rates of antibiotic resistance in humans was tied to agricultural antibiotic use in the Swann report. (Maryn McKenna has a great timeline of other developments here).
Why am I (and many others) concerned about the use of antibiotics in agriculture?
First, and most compelling to me, is the fact that between 70-80% of all antibiotics used in the United States are used in agriculture. I’m linking to a PolitiFact report because they drill down into the caveats with that number in more detail than I want to go into for this post, but I will note that it’s tough to get good numbers because the industry won’t release them, and that the numbers we do have include drugs that are not used in human medicine–but that doesn’t mean they may not be important. More on that later.
Second, this is my area of expertise. I study antibiotic-resistant pathogens in the agricultural environment, so naturally this is my interest and where I know the literature the best. Third, antibiotic use in agriculture just isn’t as intensively studied when it comes to methods to reduce antibiotic-resistant microbes that may emerge from this setting. In the hospital and clinics, patients need a prescription to get antibiotics. The amount of antibiotics that are prescribed are tracked and those data are available. Hospitals often have stringent infection-control policies put in place to reduce the generation and spread of antibiotic-resistant “superbugs.” Hell, there’s enough research on these policies that my colleagues have a blog devoted just to that topic. In human medicine, no one is ignoring the generation and spread of resistant pathogens.
None of these control and monitoring policies are present on livestock farms as a matter of routine. Rather, as my colleague Lance Price has noted more than once, if he was going to try to create a superbug, farm use of antibiotics–subclinical dosing of thousands of animals at a time–would be an ideal way to create one.
What if we remove “growth promotant” antibiotics?
What remains an issue is what will happen after growth-promotant antibiotic use is stopped. There is already a “natural experiment” going on in the EU, where such antibiotics were banned back in 2006. As I noted here, the results have been mixed when antibiotics have been removed from agricultural practices. Sometimes resistance persists, sometimes it goes down. A modeling paper examined the use of antibiotics for agricultural use, and suggested that their biggest impact happens before we even realize it via surveillance, and by the time we notice it, it may be too late to make much of a difference, which is depressing. So even if antibiotics are banned for growth promotion purposes, there is a chance that we won’t see much of a dent in antibiotic resistance overall–or if we do, it may take years to see it decrease. This is an argument against removal of these sub-therapeutic uses–if we can’t 100% guarantee it will help, why change the status quo?–but at this point, even the current status quo is better than an ever-increasing arc of resistant bacteria.
Another concern that persists and muddies the waters is that no meaningful reduction in antibiotic use in animals will occur, but that rather antibiotics used for growth promotion will just be repackaged as “prophylactic” use, which will still be allowed under the new guidance. The industry says this won’t happen, but without meaningful and transparent surveillance, how can we know if it is or not?
Additionally, other sources of low-level antibiotics may still be present on farms and in feed, such as the use of distiller’s grains in animal feed which may still contain some antibiotics. And even if antibiotics that are important for human medicine are removed altogether, resistance still may linger or even climb if we allow for other classes of antimicrobials (such as ionophores, which are part of that group I mentioned above that are used in agriculture but not in human medicine) to still be used on the farms. Why could this be an issue? Right now, we really don’t know if any of these drugs co-select for resistance to important human medicines. For example, in some cases, antibiotic resistance genes are together as cassettes that can move around between bugs, such as on a plasmid or other mobile genetic element. That’s why using tetracycline on a pig farm can select for methicillin resistance–not because the drugs are the same (they’re totally different classes), but because the resistance genes come as a package deal. Is this happening with ionophores? Don’t know. It’s a messy area and makes any clear-cut cause-and-effect research very difficult to carry out.
To make matters even messier, because there’s so much transport of animals across state, national, and international lines, even if antibiotics are reduced in one place, new resistant bugs could be imported from elsewhere where no reduction in antibiotic use has taken place, mucking up the data and making it appear that antibiotic withdrawal has had no effect.
Furthermore, there is no directive for companies to actually track and report antibiotic usage differences after growth-promotant antibiotics are removed. We can’t even get good data on the industry as a whole, much less finer-level data describing how much goes to pigs, how much to cattle, how much on Iowa pig farms versus North Carolina, or for Smithfield versus Hormel farms, etc. It’s a surveillance nightmare. Even if we did have this data, surveillance of resistant pathogens is quite limited, especially on the farms themselves. Most of the data we have comes from NARMS–the national antimicrobial resistance monitoring system, which examines gram negative pathogens in people, meat samples, and live animals (taken at slaughterhouses). It’s a start, but what if we don’t see an effects in these organisms–but might in other commensal pathogens, or in the microbiome as a whole? Or in gram positives like my pet bug, Staphylococcus aureus? NARMS right now would miss those, and so might lead to false impressions of how reduction in antibiotics is really affecting resistance in the bacteria originating on farms.
Soooo….as you can see, this is a messy area. However, as I noted on Twitter, one should look at the totality of the research rather than searching for any particular “smoking gun” publication (a fallacy, I might add, that is employed by many types of science “skeptics”). There have been many, many papers that have shown, usually in ecological studies, that use of antibiotics on the farm is linked to generation of resistant bacteria, and that these bacteria (and associated resistance genes) can spread to humans via food, water, environmental runoff/contamination, air, and other mechanisms. Pew Health has an extensive bibliography of many of these studies here, and it’s barely even scratching the surface when it comes to publications in this field. In the end, though it’s messy, it breaks down to a simple truth: antibiotic use leads to antibiotic resistance, and reduced use is a goal to strive for–be it use in humans or in animals.
It’s a parent’s worst nightmare. Your healthy child is suddenly ill. The doctors you’ve trusted to treat him are unable to do anything about it. Drugs that we’ve relied upon for decades are becoming increasingly useless as bacteria evolve resistance to them. New drugs are few and far between. Old drugs, shelved because of their toxic side-effects, are being brought in as last resorts–kidney failure, after all, is better than certain death.
Unfortunately, this is increasingly the state of medicine today, and people are dying from it. The World Health Organization even recently sounded the alarm, noting that “the world is headed for a post-antibiotic era”–and it takes a lot of consensus to get the WHO to act, so this is a Big Deal.
I was in Washington, DC last week for two days to discuss the issue with other “supermoms” and dads (farmers, physicians, researchers, and parents whose children had experienced antibiotic-resistant infections), and to share information with legislators and government agencies. (I also brought William, 4 months old, for an extra dose of adorableness).
Some of the “super” attendees might be familiar to readers. I had the pleasure of meeting Russ Kremer, who has been profiled in several articles and documentaries. Russ raised pigs in confinement, dosing them with antibiotics from birth to slaughter until he was gored by a boar, resulting in a very difficult-to-treat infection that almost cost him his life. David Ricci was also present. His story was profiled in the Frontline documentary, “Hunting the Nightmare Bacteria.” He contracted an infection with bacteria carrying the NDM-1 genes, making them resistant to almost all known antibiotics, and required multiple surgeries and treatment with some of these last-line drugs over many months.
There were also participants you may not have read about previously, like Amanda Hedin and Everly Marcario, who both lost children to antibiotic-resistant infections. I’ve written before about the immense sadness that comes at times when studying infectious disease, noting that I have a freezer full of bacterial isolates that, while important for study, frequently mark someone’s illness or death. It’s important work, but heart-wrenching at times.
However, we have very little funding to study such infections. My colleague Eli Perencevich recently estimated the amount of money spent on antibiotic-resistant infections versus HIV/AIDS, and the answer is that it’s vastly less. Antibiotic resistance needs to be a priority on many fronts. The FDA has recently made some headway into possibly reducing antibiotic use on farms, though optimism is mixed regarding how much that will actually help things. Hospitals and clinics are working with physicians to encourage and enforce best practices for antibiotic prescribing in these settings.
In January of this year the British Chief Medical Officer urged her government to add threat posed by superbugs to the official list of “Apocalypses to Worry About” along with catastrophic terrorist attacks and massive flooding. With typical British understatement, its actual name is the National Risk Register of Civil Emergencies but a very stark picture was painted of a post-antibiotic world in which routine operations, such as hip replacements, could prove fatal. In September, The Centers for Disease Control in the US issued a similar statement which estimated that 23,000 people die every year in the US from antibiotic resistant infections. So what is it that has Dame Sally Davies and so many others so worried?
“Superbug” is a term used to describe bacteria which are resistant to many common antibiotics which are used to treat infection. Resistance to these drugs makes treatment more difficult and has increased mortality rates. As resistance to individual antibiotics becomes more prevalent the number of deaths is only set to increase, especially because there is a dearth of research into new antibiotics. Antibiotics are used medically in the short term, so don’t offer the same kind of return on investment for the pharmaceutical companies as drugs for chronic diseases or long-term treatments, such as anti-depressants or hypertension medications. Even more worryingly of all is that strains of potentially deadly infectious bacteria, such tuberculosis have already been identified that are resistant to every potential drug.
Against this background the FDA’s announcement of a plan to phase out the agricultural use of antibiotics is very welcome. Many animals raised for human production are fed antibiotics as a matter of course to boost growth rates. The animals are not suffering from infection, but the drugs can help them grow faster, resulting in a more efficient production of meat for the market. For most drugs, there is a mandatory withdrawal period during which the animals are fed no antibiotics so that they will clear out of the meat prior to slaughter. However, the antibiotics can impact the food supply and human health in other ways. Not only is there concern about meat contaminated with resistant bacteria but the standard agricultural practice of using animal waste as fertilizer only increases the risk of releasing resistant bacteria into the environment contributes to the spread of resistance. This is of particular concern if the land fertilized in this manner is subsequently used to grow food crops that are typically consumed raw. Previous recalls due to bacterial contamination have included spinach and cantaloupe melons. The potential for harm would only have been greater if these cases had involved superbugs, but this possibility is becoming more and more likely. Resistant bacteria that are spread onto crops via animal manure fertilizer have been demonstrated to not only persist in the soil but to also pass the genes for antibiotic resistance onto other species. As we have no control over this genetic transfer it is quite possible that they spread to even more pathogenic species.
The FDA’s proposal to limit antibiotics in cattle feed would seem like good news then. However, the most significant caveat with this plan is that it is voluntary and as such is dependent on the cooperation of the drug producers and farmers. Two of the largest antibiotic producers, Zoetis and Elanco, have indicated that they will no longer labelling their products as suitable for growth promotion. Any subsequent use of these antibiotics for growth promotion would be “off-label” and something that the FDA can and does regulate. However, as with all regulation the devil will be in the details. We do not know yet what the change in labelling will actually say. If their new label can be interpreted in such a way that cattle are still regularly fed antibiotics then nothing will have been achieved.
For example, in Denmark they found that after introducing a ban on antibiotic use for growth promotion in cattle that the quantities of antibiotics actually increased. Animals no longer fed a sub-therapeutic level of antibiotic became more susceptible to infection and thus need therapeutic treatment more often. At first glance this might seem as if little has changed but antibiotics taken at therapeutic levels for the prescribed duration will result in fewer occurrences of resistance to the antibiotic in question. Anybody who has been told by their doctor to ensure that they take the full course for an infection will know this. By reserving antibiotic use for therapeutic use only, where it is needed in greater quantities to fight infections, not only will there be fewer superbugs released into the environment, but the drug companies will stand to increase their sales. This might explain their willingness to cooperate with these proposals. Their other option would be to switch production to antibiotics which are not regarded as being important for human health (such as the ionophores) as these are not covered by these new proposals. However, this is something that would presumably involve some cost to them.
It is also worth comparing the timescale for voluntary phase-out (three years) with the length of time it would take the FDA (presumably in collaboration with the USDA) to implement a strategy for an obligatory regulatory framework, which might have more teeth in terms of enforcement, but which is not yet on the table. The FDA has many admirable qualities but turning on a dime is not one of them. This process would take at least that long if not longer. What we do not know at this point is whether there are plans for the FDA to pursue such mandatory regulation if this voluntary arrangement is found not to be working. Such efforts would presumably require specific budgeting and it seems unlikely that this will happen any time soon given the current state of Congressional deliberations on budget matters. Another possible mandatory option would be Louise Slaughter’s PAMTA bill which is currently with the Health Subcommittee.
If our goal is to reduce the spread of antibiotic resistant bacteria from agriculture then the FDA plan may in fact be the best option, and it is certainly better than doing nothing. Mandatory regulation seems unlikely at this point. However, accountability is still vital to the success of this voluntary agreement. What form could this accountability take? The FDA must be prepared to state publicly if insufficient progress is being made. Also, it is to be hoped that increased demand from major chains like Chipotle, McDonalds and KFC will help. If they were to make this demand then cattle production would change at a much faster pace than that proposed currently. This means that consumers are in a position to contribute by choosing to support suppliers of meat produced in a way consistent with these new guidelines.
Tim Fothergill, Ph.D. is a microbiologist with over a decade of experience in researching the mechanisms for the spread of antibiotic resistance. This interest has led him to the intersection of antibiotic resistance in bacteria and policy, where his is now looking at the implications and consequences of legislation and regulation around antibiotic use. As a result, he has become concerned that the threat posed by overuse of antibiotics needs to be taken more seriously. But it’s not all doom and gloom: his interest in instrumentation and general microbiology extends to brewing his own beer.
Tuberculosis (TB) is a major disease burden in many areas of the world. As such, it was declared a global public health emergency in 1993 by the World Health Organization (WHO). It is a bacterial disease that is transmitted through the air when an infected individual coughs, sneezes, speaks, or sings. However, not all individuals who contract the disease will display symptoms. This separates the infected into two categories, latent and active. Latent individuals are non-infectious and will not transmit the disease, whereas active individuals are able to transmit the disease.
TB is a significant concern in patients diagnosed with HIV, since individuals diagnosed with HIV and latent forms of TB infection is more likely to develop the disease, then the HIV negative individuals. In addition, in people living with HIV, TB is one of the leading causes of death. (CDC, 2012) The fact that latent forms of the disease are capable of becoming fully active forms given the right stimulus represents a high risk to individuals living in poor conditions, which is widely present in developing nations. It is of even greater concern to individuals who have immune system diseases, such as HIV. Individuals with latent TB infection depend on robust immune system responses to prevent the infection from going into active form. HIV and similar diseases targets and weakens immune systems so that the response to infections becomes weaker, providing increased risk of TB infections and the activation of latent forms.
TB is a major concern not only because of its status as a global epidemic. While there are many forms of prevention and treatment for the disease, such as antibiotics and vaccine, these treatments are not overly effective in combating and controlling the spread of the disease. TB is widespread and has a high chance of becoming resistant to any treatment that it is exposed to, especially antibiotics and other chemotherapeutic drugs such as isoniazid. Several of these strains already exist and each has varying levels of resistance, including Multidrug-Resistant (MDR) and Extensively Drug-Resistant (XDR). MDR is a strain that is resistant to two of the most often used and potent TB drugs, isoniazid and rifampin; whereas XDR is MDR strains that have developed resistance to any fluoroquinolone and at least one of three second-line drugs such as kanamycin or capreomycin. Also, the vaccine that has been developed for preventing TB is not overly protective, and sometimes fails to protect against infection. (CDC, 2012) The vaccine is not designed to prevent the infection of TB; instead, it is aimed towards boosting and speeding up the immune system response to any new infection so that the infected individual remains in latent forms. (Russell, et al., 2010)
The increasing trends in the resistance of TB to various treatments is a serious concern as it have major impacts in controlling the spread of the disease in many regions. This condition worsens with MDR and XDR TB. With regular, normal strains of TB, latent and early infections could be combated and controlled by a successful chemotherapeutic treatment even in patients with immune system diseases. However, with MDR and XDR TB, the strains are able to fully develop in an individual with weakened immune system, as evident in areas where incidence of TB and HIV is high, such as South Africa. (O’Donnell, et al., 2013) For cases with MDR and XDR strains, the weakened immune systems are not potent enough to prevent infections or keep them in latent form. Additionally, the active forms of these strains are resistant to common, and in some cases, advanced treatments.
With the increasing development of drug-resistant TB, the most effective way to combat TB is not only through vaccines and treatments. Instead, strict public health policy is needed to properly maintain control and combat the spread of TB. With a well-structured public health system, we can ensure that the long treatment of TB is complete, since most of the increase in the resistance to treatment often results from issues during treatment. Events such as patient non-compliance to the treatment and inadequate health-care supervision can all result in the development of new strains of the bacteria that have developed resistance to the treatments that was used. (Russell, et al., 2010) Also, a well-structured public health system can maintain better supply and quality of drugs throughout the treatment process, as well as the prevention and detection of possible new drug resistant strains. More importantly, it can maintain better surveillance and ensure patient compliance during the treatment process, which would help in reducing the development of drug resistant strains. The surveillance systems can also target comorbid diseases such as HIV to reduce risk factors for activating latent forms of the disease in patients with HIV and similar diseases.
CDC, 2012. Tuberculosis (TB). [Online]
Available at: http://www.cdc.gov/tb/topic/basics/default.htm
[Accessed 13 2 2013].
O’Donnell, M. R. et al., 2013. Treatment Outcomes for Extensively Drug-Resistant Tuberculosis and HIV Co-infection. Emerging Infectious Disease [Internet], 19(3).
Russell, D. G., Barry 3rd, C. E. & Flynn, J. L., 2010. Tuberculosis: What We Don’t Know Can, and Does, Hurt Us. Science, 328(5980), pp. 852-856.
The ecology of antibiotic resistance on farms is complicated. Animals receive antibiotic doses in their food and water, for reasons of growth promotion, disease prophylaxis, and treatment. Other chemicals in the environment, such as cleaning products or antimicrobial metals in the feed, may also act as drivers of antibiotic resistance. Antibiotic-resistant organisms may also be present in the environment already, from the air, soil, or manure pits within or near the barns. Ecologically, it’s a mess and makes it more difficult to attribute the evolution and spread of resistance to one particular variable.
A new paper emphasizes just what a mess it really is, and what animals are exposed to in addition to “just” antibiotics. Led by Keeve Nachman at the Johns Hopkins University Center for a Livable Future, his team took a different approach to examining farm exposures, by looking at “feather meal.” What is feather meal, you may ask? I did when I met with Keeve last month at Hopkins as we discussed his research. Well, feathers are one obvious byproduct of chicken slaughtering, and waste not, want not, right? So feathers are processed into meal, which can then be used in a number of ways–among them fertilizer, and as an additive to feed for chickens, pigs, fish, and cattle.
We already knew that chickens receive antibiotics in their food and water supplies, just as other farm animals do. It was also known that some antibiotic residues persisted on chicken feathers–another potential driver of resistance in farm animals. However, Nachman and colleagues wanted to assess what other chemicals may be present in this feed meal besides antibiotics, and also whether those antibiotic residues persisted in the feather meal after processing/treatment of the feathers. As lead author David Love notes:
Why study feather meal? We know that antibiotics are fed to poultry to stimulate growth and to make up for crowded living conditions in poultry houses, but the public does not know what types of drugs are used and in what amounts. It turns out that many of these drugs accumulate in poultry feathers, so by testing feathers we have a non-invasive way of learning about what drugs are actually fed to poultry.
To do this, they examined 12 feather meal samples from the U.S. (n=10) and China (n=2). All 12 samples contained at least one antibiotic residue, and some contained residues of 10 different drugs (both of those were from China). While many of the antibiotics were ones used in poultry farming (or their metabolites), they also found drugs they did not expect. Most significantly, this included residues of fluoroquinolones, which they found in 6 of 10 U.S. feather meal samples. Why is this important? Fluoroquinolone use was banned in U.S. poultry production as of 2005 because of the risk to human health–so where are these residues coming from? The authors make a few suggestions for this:
These findings may suggest that the ban is not being adequately enforced or that other pathways, for example, through use of commodity feed products from livestock industries not covered by the ban, may inadvertently contaminate poultry feed with fluoroquinolones. Furthermore, if feather meal with fluoroquinolone residues is fed back to poultry, this practice could create a cycle of re-exposure to the banned drugs. Unintended antimicrobial contamination of poultry feed may help explain why rates of fluoroquinolone-resistant Campylobacter isolates continue to persist in poultry and commercial poultry meat products half a decade after the ban.
Interestingly, the authors tested whether antibiotic residues at the level they found could influence bacterial growth, and found that they did inhibit growth of wild-type E. coli, but allowed a resistant strain to flourish.
Besides antibiotic residues, a number of other chemicals were also detected, including many I’d never thought to associate with farming. In the U.S. samples, they found caffeine–apparently chickens may be fed coffee pulp and green tea powder, which may account for this finding; acetaminophen (Tylenol), which can be used to treat fevers in poultry just as it can for humans; diphenhydramine (the active ingredient in Benadryl), which apparently is used for anxiety issues in poultry; and norgestimate, a sex hormone. Any kind of health significance to these (either to people or to the animals who are ingesting these via feather meal) is uncertain. In an interview with Nick Kristof in the New York Times, Nachman noted:
“We haven’t found anything that is an immediate health concern,” Nachman added. “But it makes me question how comfortable we are feeding a number of these things to animals that we’re eating. It bewilders me.”
So what we’re seeing here are the presence of antibiotics and other drugs in feather meal, which is spread around as a fertilizer or fed to many species of domestic animals as an additive. It’s difficult to keep up with these additional feed additives–in addition to feather meal, many animals could also receive distiller’s grains in their diet, ethanol by-products which are another potential source of antibiotic residues.
This, my friends, is a clusterfuck.
Though I’ve focused on the U.S. data here, the paper notes that the Chinese samples are relevant as well–while most feather meal used here is domestically produced, we do import some, and about a quarter of what we import is from China, where antibiotics that are restricted or banned in the U.S. may still be in use. Furthermore, farmers may not even know this is in the feed they’re using, as many mixes are proprietary. (And if farmers don’t know, you can imagine how difficult it is for a researcher to determine if this is playing a role in antibiotic resistance or other public health issues on these farms).
Love, D., Halden, R., Davis, M., & Nachman, K. (2012). Feather Meal: A Previously Unrecognized Route for Reentry into the Food Supply of Multiple Pharmaceuticals and Personal Care Products (PPCPs) Environmental Science & Technology, 46 (7), 3795-3802 DOI: 10.1021/es203970e