Welcome back. This is Kieve again. This is the first of our two case studies. We're going to be looking at the use of antibiotics in industrial food animal production. You may have heard in your epidemiology classes about the epidemiologic transition, which was a shift from infectious disease as a leading cause of death in the US population to non-infectious chronic diseases as primary causes of death among our population. And there are a number of advances that are cited as reasons for that transition. Among those are development of vaccines, basic sanitation, clean water and food safety advances and the development of antibiotics to treat infections. So, as you can see from this figure, antibiotics play a really key role in minimizing infectious diseases and mortality. We use antibiotics for a variety of purposes. The ones you're likely most familiar with are the treatment of infections in humans. We also use antibiotics for the production of animals for a variety of reasons that I am going to go into. And we use them in both terrestrial animals like cows, chickens, and pigs, but we also use them in the production of fish which we're not going to go into great detail on today. Antibiotics are also used for some other purposes that people tend to be less than familiar with. Like the production of crops and also the production of ethanol. All uses of antibiotics contribute to the development of antibiotic resistance. And that means, the ability of bacteria to resist treatment with antibiotics. Certain uses, that we're going to go into in great detail, are believed to contribute more to the development and propagation of resistance than others. We've been talking about industrial food animal production today, it's a big focus of ours. But I just want to start off by saying the extent of the problem of antibiotic resistance in society, that can be tracked back to the use of antibiotics in food animal productions, has yet to be specified. And it's incredibly challenging to do that, but I'm going to make a case to you that I believe it is largely responsible for what we see, although not fully. This is a table from a paper by Ellen Silbergeld and colleagues that shows a list of the different types of antimicrobial drugs, including antibiotics that are registered for use as feed additives in the United States. Now you may be familiar with a number of these drugs because those same drugs, a good number of them, are also used routinely to treat infections in humans. So we're not using For the most part, drugs that were designed specifically for animals, we are using the same drugs that we might use to treat infections when we get them. These are some usage estimates for antibiotics broken up by whether they were used for treatment of infections in humans or for other purposes in animals. The first column is an estimate that was put together by the Animal Health Institute which is a trade organization for the animal production industry. And you'll see that they believed in 2000 that the majority of antibiotics that were sold in the US were used for treatment of humans. The Union of Concerned Scientists produced different estimates the following year. They're a public health advocacy organization and it was their estimation that the majority of antibiotics that were sold in the US were used For non-therapeutic or non-treatment based purposes in animals. And they believe the smaller fraction were used to actually treat animals and treat humans. In 2008, the Animal Health Institute released revised information about the fraction of antibiotics it believed were used in animals. They did not release an estimate for humans, but they estimated that 27.8 million pounds per year were administered to animals for either non-therapeutic or therapeutic purposes. They did not try to figure what fraction went to what. The following year, real sales data were released by the FDA for both human and animal drugs. And it turns out that the majority of drugs that are sold in the US are intended for animals. And a smaller fraction are used in humans. These, unfortunately, are the best data we have, in terms of antibiotic administration to animals, at a very, very crude level. We don't have specifics on what fraction are used in animals for non-therapeutic purposes, although inferences can be made, and we'll talk a little bit about those in a bit, as to what they're being used for. As you can imagine, this is a very hot topic in the public health literature. Wanted to talk a little more specifically about antimicrobial use in food animals. The Food and Drug Administration of the Center for Veterinary Medicine has listed 4 purposes for which antibiotics can be used in the production of food animals. They are treatment-controlled prevention and production uses. Now treatment, as you might expect, the treatment of a veterinarian-diagnosed disease in a diseased animal. Control corresponds to the administration of drugs to a flock of animals in which at least one member of the flock has been diagnosed as having a disease by a veterinarian. The term prevention is very nuanced, but refers to the use of antimicrobials or antibiotics in a flock, in which no animals have been diagnosed by a veterinarian as having a specific disease. But under the circumstances where it is reasonable to expect that disease may occur. And some may argue that this condition very well characterizes what a food animal production site looks like under the industrial model. And then production use is the use of antibiotics in food animals with the intention of either achieving growth promotion of feed conversion. Feed conversion is the use of antibiotics to maximize the amount of growth per unit of feed administered to the animals whereas growth promotion is the attempt to speed growth of the animal to bring it to market weight more quickly. And the figure here on the right. Relates back to the data I showed you before from FDA, that it released in 2010, corresponding to 2009 sales. That shows that about 80% of antimicrobials that were sold in the US, were use for food animal production. Let's talk a little bit more about prevention and growth promotion. When antibiotics are administered for these two purposed, they tend to be administered at lower doses, so these are doses that are lower than what you'd expect to actually successfully treat A diagnosed infection. They're given for longer periods of time, often nearly matching the life span of the animal. They're administered primarily through feed and water and they can be administered without the oversight of a veternarian. Many of these drugs are available Over the counter and do not require a veterinary prescription. And data that were gathered from FDA, upon request from Congresswoman Louise Slaughter, revealed that of the 80% of the antimicrobials sold in the US each year, 74% of those Were administered through feed to entire flocks and not to single animals. 16% were administered through water and 10% were administered through other routes, like direct injection. There are concerns related to dosing precision when one thinks of feeding animals antimicrobials through feed and water. And I'm going to talk a little more about those in a bit., So now let's talk a little bit more about antibiotic resistance. I mentioned earlier on in this section that any use of anti-microbials has the potential to select for bacteria that are resistant to antibiotics. There are 4 mechanisms by which antibiotic resistance can develop and then can be propagated through bacterial populations and we're going to go through each of these very quickly. The first of these is selection for resistance, so imagine this pool of bacteria. The bacterion that is purple. has genes that allow it to resist the presence of an antibiotic. So if you administer that antibiotic, the susceptible bacteria all die off, but you'll notice the one purple bacterium is still alive, and it can use the resources that are available in the microbial ecosystem to propagate, so what you're left with is bacteria that resist that antibiotic. And so when you imagine that we're feeding animals multiple antibiotics at very low doses, so doses that are likely not high enough to kill off resistant bacteria, we're rapidly selecting bacteria that can survive in the presence of those drugs. There are also mechanisms by which bacteria can share genetic material. And develop resistance in a fashion that's considered to be horizontal. Horizontal differs from vertical, in that, these are not progeny of bacteria that are producing exact copies of themselves. But these are bacteria sharing genes. So the first, is, there's three different mechanisms by which this happens. The first is transformation. By which one bacterium releases DNA and that DNA is absorbed by another bacterium. That bacterium then contains the genes that allow it to resist the present of antibiotics. Phage viruses are also capable of infecting bacteria and spreading certain genes that confer resistance from one bacterium to another. The last is through bacterial conjugation, is when two cells share genetic material by direct contact with one another. The last two slides I showed you were mechanisms by which bacteria That are resistant to antibiotics. Can propagate in a system where antibiotics are administered. Or can share genes between each other, that allow them to resist the presence of antibiotics, or antimicrobial drugs. Now, there's also the concern that administration of antibiotics can actually generate new mutants among bacterial populations. There is research that was published in 2010 that shows that, administration of anti microbial drugs. At concentrations that are lower than what you would expect to exert selective pressure, like the first slide I showed you, are actually capable of generating reactive oxygen species that can lead to point mutations on bacterial DNA, that allow for creation of new genes that can also confer resistance. And in many cases those mutations can confer resistance to two different antibiotics. So at certain concentrations we were able to achieve the selective pressure, and then we killed the susceptible bacteria, but at lower concentrations we may be generating new mutants that mean new genetic mechanisms by which bacteria can resist antibiotic pressure. So it can be a concern that we We aren't even achieving selective pressure in these bacterial populations. There's also the concept of the resitome or reservoir of resistance and what that means is that as I've mentioned bacteria can horizontilly share genetic material and they can share the abillity to survive antibiotics with one another. And this reservoir of resistance means that bacteria that may not even be pathogenic Can harbor genes that can confer resistance when shared horizontally with other bacteria. So we're not just concerned about the bugs we're the most commonly infected with, but we're concerned about the entire bacterial community that can readily share genes between themselves. One recent piece of research that was fairly notable is the concept of bacterial altruism. And what this particular study from Nature in 2010 showed, is that certain bacteria that have a mutation that allow for them to be resistant to a particular drug, can share chemical signals with Bacteria that are believed to be susceptible to that drug and those chemical signals can be absorbed and allow these formally susceptible bacteria to actually survive in the presence of the antibiotic. So this is another mechanism by which bacteria can survive antibiotic pressure and go on to potentially find a way and to environmental pathways that can, for them to get in contact with humans. So we published a paper in 2010 that looked at feed and water delivery as a mechanism for delivering a predictable dose to food animals. And if you remember back a few slides data released by the FDA to Louise Slaughter indicated that the majority of antibiotics that are going to food animals are delivered through feed and water and we were concerned that Those types of delivery mechanisms for antibiotics are really poor ways to predictably deliver a dose to a food animal. There are a lot of reasons why we think there would be an uneven delivery of dose to food animals as a result of administering antibiotics through feed and water. They have a lot to do with feed mixing, it's very challenging to create a very homogenous feed in terms of concentrations of antimicrobials. We also know through animal science research that certain dominant structures Arise in animal populations, even in food animal production settings where some animals may eat more than others or not. There are also concerns over food animal production facility workers in their delivery of the feed, whether they are very precise, in their formulations of water based feeds, especially. And there are concerns that there may be variability in differences among animals in terms of drug absorption and pharmacokinetics. So we think that there are reasons to believe that the doses that are delivered to animals are really not the doses that are intended to be delivered to animals. And given some of the concerns that we spoke of before, There are issues related to every possible outcome in this case. So the first is that over administration of drugs, which is probably the least of those concerns, may lead to potentially drug residues in food animal products and in some cases, clinical toxicity in animals. The scenario that we believe is most likely to occur is the under administration of a given antibiotic to food animals and the concern there is that we are not providing a concentration that even is capable of selecting for resistant bacteria but instead may induce some of those genetic mutations that lead to New genes that allow for a resistance to a variety of different drugs. The final concern is over intermittent dosing where there may be variability in the amount of drug delivered and this impredictability of the dose delivered may lead to any of these other scenarios: over administration, under administration, That may continue to put pressure for antimicrobial selection, and in many cases if the intent is to actually treat disease, there may be failures in that disease treatment. So certainly there are concerns with the nature of administer of antimicrobials to food animals in this context. We've talked now, about how administration of antibiotics to animals can lead to the development and propagation of antibiotic resistance among bacterial populations, so let's talk about how those bacteria can find their way into the environment and potentially cause problems for people. So, this is a nice figure from a 2008 Silbergeld paper looking at how resistant bacterial can be generated and find their way into the surrounding environment. So, if you look at the center toward the top of the figure, this is an animal production facility. This is a swine facility and this figure nicely details how bacteria can move from that facility. So, the first thing I'd like to call your attention to are the transport trucks and depending on the type of animal operation and the type of transport trucks, the truck itself can spread resistant bacteria into the community as we discussed before, but it can also bring any bacteria that are present on the animals or in animal waste to the processing plant where the animals are, are converted from animals into meat. And so, there are certainly concerns for workers in those processing plants and of course the output of those processing plants, the meat. To harbor bacteria that are resistant to antibiotics and studies have shown that some bacteria survive processing and reside on meat that's then shipped to stores. We've also talked a little bit about animal production site workers who, depending on the type of facility and the options for hygiene after the work shift. Those workers are capable of carrying bacteria that are resistant to antibiotics into communities. The last mechanism that I'd like to highlight here is The spreading of animal manure onto cropped fields. Of course, we talked before about how animal manure can harbor a variety of chemical and micro-biological hazards. Among those micro-biological hazards are bacteria that are resistant to drugs. And, and when that manure is spread on crop land, some of those bacteria can reside on some of the crops that are grown on the crop land. And, of course, workers in those fields who are harvesting or Spreading the manure can come into contact with the waste and become carriers or become infected with some of the pathogens that might be present there in. Let's talk for a minute about why resist infections are particular troublesome from a public health perspective. The biggest challenge is that an infection that's resistant to antibiotics Maybe more challenging to treat in a clinical setting. A resistant infection is characterized by responding very poorly to at least one antibiotic. In many cases it's resistant to a wide variety of antibiotics which in some cases may lead to mortality in infected persons. Estimates exist to characterize the burden from hospital acquired infections. And so these are not infections that we believe originate from food animal production sites. We've estimated about 19,000 deaths occur per year from those. There are a variety of factors that challenge why we can't characterize the contribution of food animal production to deaths from infection each year. When we're dealing with an infection that tends to be resistant, we find that the hospital stays are considerably longer and cost more money. One particularly well-conducted study looked at differences between Methicillin-resistant Staphylococcus aureus infections as compared to those that were susceptible to Methicillin. And it, that study found that hospital stays were increased by about 2 weeks and the average cost of those hospital stays was multiplied by about a factor of 5. So, they are a considerably increased health burden relative to susceptible infections which are far easier to treat. There have been numerous estimates that the societal burden, economically speaking, of these resistant infections and the highest estimate that we've seen thus far, is about $30 billion per year. But the majority of estimates range in the tens of billions per year. So given some of the problems we've just described in terms of human health consequences related to antibiotic resistant infections. There has been a real reluctance on the part of the Food and Drug Administration to curtail antibiotic use in food animal production. But what's encouraging is that Other places in the world have taken a closer at some of these problems and implemented policies intended to limit the use of antimicrobials in food animal production. And although we don't have a lot of data thus far in how those have worked out, what we have seen that shows a little bit of promise. So I think one of the leaders in minimizing antimicrobial use in food animal production is Denmark, who phased in legislation over time that would eliminate the use of growth promoting antibiotics in swine production. They have also eliminated that use in poultry production as well. And they started phasing in those various policies in 1998 and they have evaluated the impacts both on producers, in terms of economics but also on changes of indicators of animal health and potential human risk. And so I'd like to talk about those for just a moment. Across the board, indecators of animal health have actually shown a beneficial effect attributed to the elimenation of non-thereputic antibiotics. So they've seen increases in weight gain. The animals have been brought to market weight more quickly and they've seen reductions in animal mortality in swine. One pretty stunning figure is that they've shown that consumption of antibiotics since the ban While initially there was a little bump, an increase in antibiotic consumption, over time they saw a net decrease by 50% of antibiotic consumption by the industry. They've looked at some zoonotic microorganisms as indicators of resistance among bacterial populations and animal pathogens and they've found reductions in most zoonotic bacteria which is promising. And the national academies recently held an ad-hoc committee to examine the problem of antibiotic use in food animal production. And in the proceedings that came out of that ad-hoc committee, It was noted that Denmark was a helpful example to examine when thinking about policies to implement here in the states. So let's talk about the policies that have been implemented thus far in the US that relate to food animal production and antibiotic use. So the first is the mechanism that allowed for the collection of antibiotic sales data that I showed you before. This is the Animal Drug User Fee Act. Now the majority of this act Is focused around providing FDA with full-time employees that can work to examine animal drug applications for approval. But, Congresswoman Louise Slaughter pushed for an addition to that act that required the agency to released aggregated sales data for antibiotics in food animal production. The resolution of those sales data is a little poorer than we'd like, we would Hope for data on geographic locations of sales, sales by the type of administration, like through feed, through water, through injection, and those data have not been released publicly, but it is good to have some sense of the volume of antimicrobials sold for those purposes. So that's been useful and that act is up for reauthorization this coming year. The next piece of policy I'd like to talk about is a bill that's been proposed for the last few years called PAMTA or the Preservation of Antibiotics for Medical Treatment Act. And the purpose of this bill would be to eliminate the use of medically-important antibiotics, so those are the antibiotics that are routinely used in human medicine, from use in food animal production. And this bill, unfortunately, has been fairly not viable over the past couple of years given the current composition of Congress. But there's hope that at some point in the future this may become Politically viable. The last bill is the STAAR Act, or Strategies to Address Antimicrobial Resistance Act that's been introduced a few sessions in a row. And, and this would call for data collection and dissemination on antibiotic use both in human and animals similar to what FDA released, but with a little bit more detail. This would also fund an inter-agency task force that would deal with issues related to antibiotic resistance and it would call for real-time monitoring from federal agencies. And unfortunately this act has also had limited political viability. So in sum antibiotics as I mentioned before are one of the major advances that allowed us to transition away from infectious disease being a leading cause of mortality in the states to dealing more with chronic diseases. We're using the same antibiotics to raise food animals as we're using to treat infections in humans. And the majority of those antibiotics, in animals, we believe are being used for non therapeutic purposes, which is especially troubling. The way antibiotics are used in food animal production has been shown repeatedly to promote the propagation and emergence of resistant bacteria. And as I showed you in a figure earlier, there are a wide variety of environmental pathways by which bacteria that are present on farms, find their way into the surrounding environment, and can infect people. And we've promoted some policies to collect information about antibiotic use, and to limit. The use of certain antibiotics in the food animal production context, but unfortunately, we haven't seen a lot of success with those policies thus far. That concludes the antibiotics case study. Next up, we'll talk about the use of arsenic-based drugs in food animal production.
