 So good afternoon, everyone. I'm Jeff Drazen. I'm editor-in-chief of the New England Journal of Medicine. We like to think of ourselves as the most trusted source of medical information in the world. To my left is Vanky Ramachankran and Ramakrishnan, who is an expert on ribosomes and antibiotics. We're going to hear about how antibiotics and ribosomes are related. And Jean Carlet from Paris, who has been leading the charge against antibiotics or against antibiotic use, if I might say. So imagine it's back in your youth. You remember the story of Martin Aerosmith written by Sinclair Lewis, the Nobel Prize-winning author. So in that story, Martin Aerosmith is a young physician, and he's just set up his practice in North Dakota. And one of his first patients is a call in the middle of the night. 2 o'clock in the morning, he tests trouble finding the house, and he finds a child with diphtheria. And the only way to treat this child in the later stages is to get an anti-serum. He can't get the pharmacist on the phone, so he drives 60 miles to the city, gets the antitoxin, comes back, treats the child, and with a half an hour, she's dead. Didn't help us practice. But this story, we've all had our own versions of this story. It's the middle of the night. Your child, imagine a five-year-old girl or boy, gets up and has a fever of 40 degrees Celsius and a sore throat and is rasping away. And he just looks terrible. And you're so concerned, you pick him up and take him to the emergency room. And there, the doctor examines the child, does a blood test, and says, I'm not exactly sure what's wrong, but just to be safe. Here's a prescription for an antibiotic. And I'm going to give him his first dose right now, intravenously. It gives you the dose of antibiotics. And you take the child home. You're at the pharmacy the first thing next morning, filling it. You've been fulfilled. You've helped do your job as a parent. We've all had this experience. So Jean, was this the right thing to do? Well, it looks simple, but in fact, it's a difficult case. Thank you for providing this case, because it shows the dilemma of GPs, in particular when there is some emergency, which is the case in this story. There is a very high likelihood that this disease is viral. It's almost true that it's viral. The only bacteria, which, if there is some inflammation of the throat, the tongue cells, would be streptococcus. But it's really very unlikely. And we will come back to the diagnosis a little bit later. But it's not something which is cool during the day, in the waiting room. It's something very acute for AM during the night. Fever is very high. I would just try to want to know what is, he looks terrible. Is it symptoms of severity, really, tachypnea? So all those things are very important. If the kid does not look terrible, it's an argument not to give antibiotics. If there is really symptoms, wheezing, or symptoms of severity, then it's different. And the patient, the parents looks very anxious because they came with the kids during the night, which is something which is unusual, in fact. Most parents would have probably waited until the next morning. And physicians, for example, with their kids, very likely would have not given antibiotics in this case, I think, at least for my kids. I never gave antibiotics to my kids for those kind of symptoms. But in fact, most physicians in France, I think that most physicians, I don't know in your country, for example, that would give antibiotics to this child, probably. And they would just say, well, it's one shot. I don't see really a lot of resistant microorganisms in my daily work. I will not really influence resistance. And, well, if it's really resistant to a very severe problem, I'm not really convinced. So they would find some arguments not to treat the kid with antibiotics. Of course, they are wrong. The resistance is really building every day with additional therapies, treatments. And we all have a responsibility for that as a prescriber. So it's something which is extremely important is to try really to consider antibiotic therapy as a civic act, because we are preparing resistance for the next generations, and in particular for our kids. So what could we do to try to convince physicians not to treat with antibiotics in this case? The first thing is information. Information is something which is very important. We had very wide campaigns in Europe for antibiotic consumption and resistance. One in Belgium, for example, induced a 36% decrease in antibiotic consumption. And in France, we had a 25% decrease. So this was targeting not only health care professionals but also consumers, citizens. And now there are more and more people, I think, citizens who really understand that antibiotics are not automatic and that they probably don't necessarily need antibiotics. And now we can imagine that more and more we will have some discussion between the patients, the parents, and the physician to try to come with some kind of agreement. The second is guidelines. Of course, guidelines is something which is very important and very helpful for physicians. The third is rapid diagnostic tests. This is very important. In this case, we have the search for streptococcal antigen, which is available. We can use it widely in France. It's freely available for every GP. The problem is that they don't use it. Only 20% of the GPs in France use this test, which is very efficient. And really, if it's negative, you are very sure that you can avoid antibiotics. So it's something which is very, very important but underused. Other ways of the education, of course, it's very important for students and also for kids. There are nice programs nowadays in Europe called eBug, which is a program for education of the kids related to infectious diseases, hygiene, and antibiotic resistance. And of course, continuous medical education is something which is key. And really, it should be something really mandatory. Those kind of modules should be mandatory. So Venki, you've been in the antibiotic business for a long time. Can you sort of help us understand antibiotic resistance, why use leads to resistance, and what you think we can do about it? Sure. But could I expand on Jean's points, please? So what you heard is the problem in a highly developed country. But even in Europe, there are countries in Southern Europe where you can buy antibiotics without a prescription at all. You don't even have to go to a doctor. And in developing countries, this is almost the norm. And in poorer countries, what happens is people cannot afford to go to a doctor. So they go to a pharmacist. The pharmacist says, oh, this is the best antibiotic for you. And they'll sell them the most advanced third generation antibiotic. Because they're poor, they won't buy a whole course. They'll only buy just enough so they start feeling better. And then that's how resistance spreads. They often will prescribe antibiotics prophylactically. Forget your sore throat and high fever. They'll prescribe it in case they might get a high fever, because they've gone through, say, childbirth, or they're in a hospital or something like that. So this is a global problem. And we cannot any longer separate developing countries from advanced countries. Because people are crossing over. They're bringing bugs back and forth. Resistance that emerges in one part of the world quickly appears in other parts of the world. So I think it's a problem that has to be tackled internationally, nation by nation, of course. But also, there have to be some concerted efforts to tackle the sort of policy issues involved with antibiotics. Now, the question about how antibiotics work and why resistance emerges is you can think of antibiotics as small molecules that bind to very large targets. These large targets are typically enzymes in a bacterium that is doing something critical for the bacterium. And the small molecules tend to fit in a tight pocket in these large molecules so that the large molecules unable to do its job. So it's a little bit like throwing a spanner in the works of a machine. It gums up the machine, and it stops it, and it can't work. Now, the way resistance, so it depends on a tight fit. So imagine there's a cavity, and here's the antibiotic. It depends on a tight fit between the antibiotic and its binding pocket. Now, you can disrupt that fit in many ways. You can break down the antibiotic so that it's broken into little pieces, and it's no longer a tight fit. That's exactly how penicillin resistance works. The penicillin beta-lactam ring is cleaved off into two pieces. And so you no longer have an effective penicillin-like antibiotic. In other cases, you might actually add extra groups to the antibiotic. You might modify the antibiotic. The cell develops or acquires enzymes which will modify the antibiotic. Now it no longer fits the pocket correctly. And a third one is to modify the pocket itself. And so the antibiotic, when it tries to go into the pocket, doesn't fit. And finally, cells sometimes have pumps. These are things in the membrane of cells, of the bacterial cell, that take antibiotics and pump them out of the cell. And when they acquire these pumps, then if you give them the antibiotic, it's quickly extruded from the cell, and so it's no longer effective. The point is, there are multiple ways in which antibiotic resistance can occur. And the only sort of constant thing is that, no matter how good the antibiotic, resistance always seems to emerge. And for instance, vancomycin was thought to act in a way that resistance could not actually occur. But 30 years after vancomycin was discovered, eventually resistance to vancomycin did develop. There's been a report of a new antibiotic, which seems very promising. And again, the suggestion is that because of the way it acts, it may be very hard to acquire resistance. And I believe that it may well be very hard to acquire resistance, but I wouldn't bet on resistance never emerging, even to such a compound. So have we overused antibiotics? I know that in my practice, in intensive care medicine, people come in with an undefined illness, but if it's characterized by fever and a lack of an immune response because of an altered host, we get out every antibiotic in the book. And if that doesn't work, we add a few more. And we know we're doing this in the goal of trying to save lives. And when we clone out a resistant antibiotic, right? It's Darwin inaction. The bacteria that is resistant to the antibiotics is the one that succeeds, and now it's in the hospital environment. So are we making mistakes? Should we change the way doctors are taught to treat these infections? Is the treatment of that single immunocompromised host worth it for the rest of the community, or should we be lying off? Wondering whether there are other things that physicians can do to fight infections other than give antibiotics. Well, there is something which is very important is diagnosis. So there are, sometimes people don't really try to have a precise diagnosis. They just treat fever. It's exactly the opposite that you should do. Never treat just fever and try to have the diagnosis as soon as possible so that even if you start antibiotics, you can afterwards, after two days, for example, de-escalate, stop antibiotics if there is no infection. So this is extremely important. And to try to do the diagnosis before starting antibiotics. So it's in the ICU, it's something that we always try to do at least in the ICUs in my country really reach a diagnosis. I completely agree. I think rapid diagnostic kits are going to be very helpful and it may be possible to have different types of diagnostic kits depending on the region, depending on which are the most common bacterial infections in a particular region. You may have a sort of array or a library and you take a sample and you can immediately tell if one of the sort of six more most common infections are present or not. And I think that seems to me a very rational way to go. And this is an area where, of course, industry can greatly help by the development of these kits. So I think we're learning more and more about the fact that we live in a microbiome. There's one of us in hundreds of millions of bacteria in our gut, on our skin, in our environment. There are more bacteria in you than there are you in you. Yeah, I know people have told me to bug off on many occasions. One of the questions is, is there a long lasting effect? Let's say you have a diagnosed infection that there's an antibiotic to treat, but we know that if you don't treat it, you're gonna get better in three or four days. If you do get treated, you might get better in one or two days. And that one or two days of additionally being ill isn't going to kill you. You might be sick. But is the modification of your internal microbe structure by the antibiotic something that lives on after your antibiotic treatment? And is that worth the risk? I'm not sure I know, but I do know that certain antibiotics have altered your microbiome so much that they've lodged bacteria like clostridium difficile in your gut, which are then very hard to treat with antibiotics. And in fact, they've been treated by introducing normal antibiotics into your gut, and which then sort of drive out the disease causing antibiotic. So... You misspoke, you said normal antibiotics, but I think you meant normal bacteria. Sorry, normal bacteria, that's right. By introducing normal bacteria, which are normally present in your gut, but which have been eliminated due to antibiotics. If you reintroduce them, they have the effect in many cases of driving out disease causing bacteria by out-competing them in your gut. So I think this whole microbiome research is taking on a very interesting turn, and that may be yet another way to treat infections, certainly intestinal bacterial infections. So a little bit of background for those of you without medical training. There's an organism called clostridium difficile. That's the name of the family, and it's got many actors, some of which are really bad, some of which aren't so bad. But when you take an antibiotic, this organism is not sensitive to it, and so it overgrows, and it produces a toxin, which gives people terrible diarrhea. In fact, it can be fatal. So a side effect of antibiotic therapy can be worse than the disease itself. So Jean, how do you deal with these kinds of problems? How do you work to avoid antibiotic-associated illness? Well, it's not easy to avoid this completely because as soon as you have some elimination in the gut of the antibiotic, you might have this problem. There are antibiotics which are heavily eliminated in the gut, like septriaxone, for example, and it's worth trying to avoid this antibiotic. There are some other ways, in particular, try to entrap the antibiotic in the last part of the ilion with shark oil, and then the antibiotic is still absorbed, but it's not eliminated in the colon anymore. So the side effect of the antibiotic is prevented. So we've been at it for a little while, now asking the audience questions about antibiotics, antibiotic use, our husbandry of the antibiotic availability, questions that you have for Venki or Jean, please. Tell us who you are. I'm Jara Jackson, physician in the United States. I agree with you that antibiotics are overused, but I do have a question. Should we be looking at completely eliminating the use of prophylactic antibiotics because there are people with certain diagnoses who, when they go in for certain procedures, they need prophylaxis. I did OBGYN, and there are certain procedures that we prophylax patients for in order to prevent certain post-op complications. And again, that contributes to resistant bugs. So how do we approach those issues? Well, we need prophylaxis for several indications. That's true. This is very well demonstrated, and there are very precise guidelines to really helping people to decide if they will use prophylaxis or not. The point is that now prophylaxis is very short. So it's usually only one bolus, just before the surgical procedure, or sometimes a second one if the procedure is long enough. So then the risk of selecting resistant microorganisms is limited. But still, it's a risk, but we have to take this risk because if not, post-op infections are sometimes dramatic. Yes? I also read Johns Hopkins. You're dealing with a huge issue, and God bless. But Dr. Ramakrishnan raised an interesting issue, which I perhaps he and others can address, and that is the over-the-counter availability in developing countries. And there's some suggestions, I don't know how much proof there is, but people have suggested that in fact, a lot of the reduction in mortality in the developing world is in fact because people could get antibiotics, especially when they could get penicillins and early cephalosporins and so forth available. And that in fact did away with a lot of pneumonia that otherwise would not have been endioreal disease, it wouldn't have been. I don't know if you have any feelings about that, and how did we begin to put that into the equation? Yeah, so I really don't know anything about the statistics for whether this sort of use has had a fringe benefit. Clearly, the individual thinks there's some benefit, and that's why they're doing it. But I think there's a more rational way to do it, and it requires willpower on the part of governments to be able to treat people who are sick without having to take these sort of risky, self-prescribing measures. And I don't think this is the sort of sustainable model in the long term, I think, even if it had a benefit in the early days of antibiotics from a society that had no antibiotics to one where they could treat themselves occasionally and get better. Yes, that's probably a good thing, but it's not a sustainable model. And I think what governments need to do is have in place public health measures where people are diagnosed, and maybe diagnosis is if it can be made cheap enough, then that's perhaps the answer, and I think Sean would agree with that. Yes? Gary Cohen, BD. Are there in place any clearly articulated global guidelines, WHO, professional societies that are given the type of guidance to countries on proper use of diagnostics and proper use of antibiotics? And if there were, would they make any difference? I think that international organizations and health organizations in the West have been saying this for a very long time. But even in Europe, there isn't compliance with this prescription requirement for antibiotics. I was in Greece where I could get augmented without a prescription, and that's a relatively recent antibiotic. And so I'm a little pessimistic that without the actual participation of governments themselves and laws in place, I'm a little pessimistic that it can happen. But of course it also needs a huge social education program to have compliance. Even in India, if you could have a law, but in order to have compliance, people have to accept that the law is a good one, and so. So I'm going to interject here from the web. We'll take up some more because it's on this general topic. It's please discuss curbs on the agricultural use of antibiotics. We know that if you feed livestock antibiotics, they tend to grow bigger. We actually published an article in the New England Journal of Medicine about children in Africa who were given antibiotics when they were malnourished and they had better weight gain. So how does the use of antibiotics outside of medical therapeutics in the raising of livestock, for example, is that something that we can do? Are there examples that you know about? We know about, for example, the Danish example, making a difference in antibiotic use? I don't know what the impact has been in the Danish study that you, initiative that you mentioned. But it's interesting that this whole weight gain was actually discovered by accident during the synthesis of, I believe it was streptomycin, but it may have been one of the early antibiotics. The sort of chemical slurry was sort of fed to antibiotics, fed to cattle, and it was seen that cattle gained weight. And since then, it's been an agricultural practice, especially in the West. Now this is something that the West really bears a lot of the blame for. And what happens is that resistant bacteria in the gut of these cattle are sort of ejected in the feces of these cattle, and then from there they spread into the environment and then eventually resistance can cross over and spread. So it is a serious problem. And I think this is, again, a case where governments have to decide that this is not a good idea in the long term, because as maybe we can discuss, it takes a huge amount of money and a huge amount of time to come up with one really novel antibiotic, okay? So in order to preserve the ones that we have, it's really crucial to adopt public health measures that prevent the spread of resistance. So while we're on that topic, so here you are, you've just spent maybe half a billion dollars developing an antibiotic and you're bringing it to market and the government says, well, that's great. Don't give it to anybody. What kind of business model is that? It's a terrible business model and it's the reason why many large pharmaceutical companies have really gone away from developing new antibiotics. It's not like the 50s and early 60s where a lot of companies were developing new antibiotics and many new antibiotics came out on the market. And if you go back to how antibiotics were developed, I believe penicillin was discovered in the late 20s or it could have been the 30s, I don't remember. 1928. 28, exactly. But it wasn't until the 40s that penicillin was actually produced in sufficient quantities to be put into clinical use and that took an enormous government effort. It was spearheaded at Oxford and then they collaborated with American companies to scale it up. Now, I think that the way to develop new antibiotics has got to involve both government and nonprofits working to do the fundamental groundbreaking work before commercializing it. And that's a serious issue because we cannot, I think, rely on just pharmaceutical companies alone to develop antibiotics precisely because of the business model. The patient pool for a new antibiotic is small. And moreover, the favorite drug of a pharmaceutical company is something the patient has to take for the rest of their life, a statin or what I take, a high blood pressure medication. It's not an antibiotic which you take for a week and then you're cured and you're no longer a customer. I'm being somewhat blunt about it, but this is a problem. So Tashi Yamada, you're in the audience in a pharmaceutical company person at this point in your life. How do you feel about that? Do you don't want to develop antibiotics because, gee, you're only gonna take them for a week? I think this is a very important conundrum for the industry. And there's very clear medical need, unmet medical need for new antibiotics. Yet the standards of quality and the costs for making these antibiotics are every bit as high as for any other product. As you know, some very important antibiotics were launched and then because of some toxicity, they had to be withdrawn. The biggest issue is that these antibiotics have limited patent life. So when you launch the product, if the product is not taken up quickly, it's very difficult to obtain a financial return for the investment. And nobody wants to use a brand new antibiotic for which there is no resistance for the usual infections. They want to reserve them only for the people that have failed other antibiotics and are resistant to the other antibiotics. So the conundrum is that the industry makes a big investment. The public health standard is not to use the antibiotic until absolutely necessary, and there is very little return on that investment. There have been some efforts to try to address this. A couple of professors at Duke University had written about the idea of creating some sort of incentive, a government-based incentive. Now, this has actually been applied to diseases of the developing world, whereby it's called a priority-review voucher. If you develop an antibiotic, not an antibiotic, excuse me, this is for a drug for the disease of the developing world, and you successfully register it, then you get a voucher to get a priority-review on another product that you might want to have. So let's say you have a new product for diabetes. This product can sell a billion dollars a year. If you can get that reviewed six months earlier, that voucher is worth a half a billion dollars. And for a while, there was some question as to whether these vouchers had any real value. But just recently, several companies have used these vouchers, sold these vouchers, and obtained very substantial amounts of money for the voucher. So there is a real incentive developed now for children's diseases and diseases of the developing world that has not yet been applied to antibiotics. But I think that might be an effective way to address this very complex market dynamic where a return on investment would be possible for a new antibiotic. So there are actually a number of questions that came in on social media about Techo Backton, this new antibiotic that was just described in Nature within the past month. So you want to tell us a little bit about this antibiotic? The understanding is that it was found in soil. So we're back to the days of Selman Waxman. And for those of you who don't know, he discovered streptomycin for the treatment of tuberculosis and got the Nobel Prize in 1952 for that discovery. So are we back to the future? And is this going to be the future? So it's interesting. So after Waxman discovered streptomycin from soil bacteria, streptomyces, grecius, other people, including Waxman himself, started looking at soil bacteria and large numbers of antibiotics were found from soil bacteria. So erythromycin, tetracycline, all of these came out of soil bacteria. In fact, one single genus, streptomyces, alone produced a large number of antibiotics. The problem with soil bacteria is that there are lots of bacteria in the soil which cannot be cultured in the laboratory very easily or at all. And what was done in this paper was to use a clever trick to provide sort of the environment in which these bacteria grow naturally and somehow be able to use that and still be able to isolate bacteria and to test them for potential antibacterial compounds in a large scale way. And that's how this antibiotic tachylobactin was discovered. And the other thing is that unlike many antibiotics which act on a large target, which is usually a protein or even a larger assembly like the ribosome, this actually works by binding to a precursor of the cell wall. So in some ways it's similar to vancomycin and when they tested it, it has lack of resistance developing even after many cell dilutions. So it's more vancomycin-like in its properties. I should say, coming back to the discussion we've had about funding, that this was all done by U.S. government and German government-funded fundamental research which allowed them to develop the technology, do the large-scale trials on a long shot that eventually they'd find one compound that was effective in mice. But there's a long way to go. You have to show that it's effective in humans. You have to be able to produce it cheaply. You have to be able to make sure it's absorbed correctly and all the sticks around attacks the bacteria inside humans and so on. So all of that work is for one bacterium. But I think it does open the way for looking at the vast numbers of species in soil for other types of bacteria which may be producing other compounds. So teleologically, soil bacteria are trying to destroy their other bacteria so they can take over. There's a debate about that. That is the common view, but a very famous microbiologist, Julian Davis, who's at the University of British Columbia in Vancouver, thinks that they're actually signaling molecules. And when I asked him, why does he not think that they're bacteria trying to destroy other bacteria? He says, if you look at the concentration of these compounds in soil, it's well below the minimum inhibitory concentration, which is the concentration at which it'll kill bacteria. And so he says it's absurd to think that these things are some sort of biological warfare. He thinks they're either byproducts of metabolism that are being sort of excreted or they're signaling molecules that act at a much lower concentration. So they're dirt and dirt? Yes, could be. Another problem with this antibiotic is that it's active only against part of the bacteria, only gram-positive. And now we have mostly, really we need antibiotics for gram-negatives, mostly, and we have very few. We have a lot of antibiotics to treat gram-positive. Not a lot, but enough, I mean. So it's an issue. So we have a new antibiotic and go back to Selman Waxman. He discovers streptomycin, realizes that this is something active against tuberculosis, can't make it in his basement. So he has to partner with a drug company and he partners with Merck so they can make enough of it and they're able to show that this can actually help treat tuberculosis. So with the new antibiotic that's just been discovered, how do we decide who gets the right? Is it high as bitter? It's the one that claims they're going to bring it to the marketplace for the least amount of money. Because as you pointed out, there's a lot of work left to go. As Tachi Yamada said, we might develop as antibiotics, it looks terrific and when you give it to 10,000 or 100,000 people, you'll discover some terrible side effect that would make it very hard to use. So how do we move something like this forward, something that we all know we need? This is the world economic forum. Should it be just based on money or is it something where governments really should be taking the role and since this is an international problem, what's the international government to take the role? Well, I can only tell you my experience with licensing the use of our structures to develop new antibiotics. So it's a much earlier stage than this case where there actually is some compound that might be very promising. There, the Medical Research Council licenses it, but it's not based on the highest bidder. It's based on some combination of their feeling that this is a company with the expertise and, importantly, the will to actually use the licensing and go forward with it. And of course, licensing can be non-exclusive. I think many people would favor non-exclusive licensing where lots of companies can license it and decide, you know, how to proceed with it. Often companies don't want to do a non-exclusive license because they feel if they do all this work they don't want to have to compete with other companies in the market. I think this is a difficult problem, but I would be in favor, not of just giving it to the highest bidder, but looking at the expertise, the infrastructure and the intent of the company before granting a license. But in this case, I believe they're already working with a company to exploit it. So it brings up the question of antibiotic research. Are we at the end of the line? Or in fact, is this such a rich field that the best and brightest ought to be going into it because there are going to be thousands of new compounds that can be developed, things that'll make a difference in the lives of hundreds of millions of people? I think that we are not at the stage of the pre-antibiotic era because we know so much more about microbiology, molecular biology. We have all these tools in biotech and so on. So it's not the same as going back. Let's say we run out of working antibiotics. It's not like going back to the 1920s or 30s. But what I hope is that people are aware enough that there is an impending problem and start working on it proactively before there's a crisis. So we don't want to have to respond constantly to a crisis where there are epidemics and people are dying, things have stopped working. What I would rather have happen is that people realize that there's an impending problem treated in a variety of ways, including preventing abuse of antibiotics, improving public health and hygiene, but also improving diagnostics, improving our understanding of how bacteria cause disease. That's very different for each bacterium and we don't really understand exactly what is it that makes one strain virulent and the other not. And so the biology of infection needs to be studied. That'll provide us with more targets. And then also improving better, finding better compounds that will inhibit the bacterium once you get the disease. So I think it's a multi-pronged approach. There are countries, by the way, who have been clever enough to do that. Scandinavian countries, for example, they have a very low consumption. They have a very low resistance. And they have been clever enough for many years in their way to use antibiotics and also for hygienic purposes they are very good. So it works. I mean it works. One last question from the floor. Yes. What does the use of cortisone and steroids do to the body's ability to subsequent use of antibiotics and resistance to them? Well, I'm not a clinician. Would you like to answer that? No, I don't really know. No, I cannot really tell you the answer of that. A very long-term use of steroids will cause immunosuppression. Yeah, this is different. You mean acute effect on antibiotic absorption? Well, it's a mixed bag. We know in certain infections, such as meningitis, especially tuberculosis meningitis, that the inflammatory response is worse than the infection. In that case, treatment with steroids to dampen the inflammatory response actually improves outcomes. But there are lots of infections where that's probably not the case. And what we need to do is to study them on a case-by-case basis to try to be able to make things work. So to sum up, we've learned that antibiotics are a precious resource that we're not about to run out of them, but the only way to use them wisely is to use them when we really need them and not to use them frivolously. Because even though we're not about to run out, we realize that the supply is somewhat limited. And then we need to think of other ways to limit infection, ways that make a difference without using antibiotics. My brief observation in this forum, for example, is that hand-washing after using the lavatory is a single very important public health measure and very few people employ it. And so I actually implore the people that run this conference center to put hot water in the lavatories so that we can encourage people to use them. Because it's a reason not to use it. I'm freezing! I don't want to have to do this. But there are lots of things that we can do that will make a difference so that we won't have to worry about the end of antibiotics, but rather that they'll be an adequate supply. So I want to thank Venki, Ramakishnan, and Jean-Carlay, and all of you for your participation. Let's keep antibiotics on the shelf and working. Thank you.