Extended Interview: Dr. Helen Boucher on Antibiotics and Resistance

For our “Stopping Superbugs” PBS NewsHour series in partnership with economics correspondent Paul Solman, we interviewed Dr. Helen Boucher, Professor of Medicine in the Division of Infectious Diseases at Tufts Medical Center. Her interview was fantastic, and we decided to provide some highlights for those who wanted to learn more about the topic of antibiotic resistance. Below is an edited version of the interview transcript.

MILES O’BRIEN: So, let’s do a quick bit of history because I think people take for granted the age of miracles in which we live. What was the world like before antibiotics?

HELEN BOUCHER: Great question. Before antibiotics, the neonatal death rate was significantly higher. We weren’t able to perform surgeries or do things like chemotherapy or transplantation because we couldn’t support patients through those things. We had problems with people dying in battle from wounds, some of which started as simple wounds that became infected.

MOB: Dr. Fleming gives us penicillin and the world changes in a dramatic way. But interestingly, he saw the potential problem, didn’t he?

Alexander Fleming, discoverer of penicillin, realized the issue of antibiotic resistance early on. Credit: Wikipedia.
Alexander Fleming, discoverer of penicillin, realized the issue of antibiotic resistance early on. Credit: Wikipedia.

HB: He did. Indeed we know that, even before, antibiotics resistance was occurring. So resistance occurs in nature–that is, bacteria show signs of being resistant to different materials. When penicillin was developed, Fleming and others noted right away that there were bacteria that were able to grow in the presence of those antibiotics. So they were showing resistance.

MOB: And even though he actually warned of it when he received his Nobel Prize, it was not anything that anybody really got a handle on for a long time. Why do you think that was? Plenty of antibiotics and no one foresaw us running out of drugs, is that what it was?

HB: I think perhaps that was part of it. I think people didn’t have any idea the pace at which this would occur. I don’t think very many people understood the risk of overusing antibiotics, which we now understand as a big reason for the rate of resistance that we’ve seen.

MOB: When did this first emerge as kind of a really important problem? Do you recall when people started talking about this?

HB: I think for many of us in this business in infectious diseases, we’ve been talking about it for 20 years. But certainly, most of us would agree with the last 10 years, it’s certainly been at the top of our agenda in the infectious diseases side of America. And other groups have been working really hard to raise awareness here in America and others around the world for certainly 10 years now.

MOB: What happened that kind of got people’s attention?

HB: Good question. I think MRSA, methicillin-resistant Staphylococcus aureus, was something that got a lot of people’s attention. The story of the Saint Louis Rams and other athletes being infected in a serious way from this pathogen, got people’s attention. The problem of Clostridium difficile causing life-threatening diarrhea also got a lot of attention.

MOB: So is there a catalogue of resistant bacteria? Do we know how many so-called superbugs are out there?

HB: There is a catalogue. The ones we know about probably number in the hundreds to the thousands. But then there are the ones we don’t know about. And so one of the many aspects of the response to this crisis is understanding more and doing surveillance to understand more about what resistant bacteria are here.

We know they come from around the world. We know that when people travel, so do the bugs. And we know that it’s more complicated even among people. So we know that our food animals carry bacteria and sometimes resistant bacteria. And we know that bacteria live in the environment, so we’re advocating an approach to make sure we honor that connection between people, animals, and the environment, and how we both look for the bacteria and treat them.

MOB: Bacteria are something that we need too, so there are good bacteria and bad bacteria, and maybe just neutral bacteria, depending on where it is. Is that right?

HB: Well, we know there are good bacteria. Bacteria are largely good. And our bodies have orders of magnitude more bacteria than any other kind of cell. So we wouldn’t be alive without bacteria. Our guts need to have good bacteria. And we’re learning more and more about this so-called microbiome that is the biology of bacteria in our bodies. So interrupting that with antibiotics and other things is not so good. And doing it with resistant bacteria is even less good.

We know that treating a cold with antibiotics and using antibiotics in other ways that are inappropriate speeds resistance. And that’s an area that we’ve been working hard to address, because that’s something we can control. We can control not overusing antibiotics.

 We’re advocating an approach to make sure we honor that connection between people, animals, and the environment, and how we both look for the bacteria and treat them.

MOB: How much of this has to do with what happens in the medical world and prescriptions and Z-Paks, etc, and how much of this is driven by what happens in the agricultural setting? What’s the balance there?

HB: That’s a very good question. And I think we have to say we don’t absolutely know the answer. We’re trying to get a handle on the answer. We know that using antibiotics for growth promotion in food animals is not a good thing. And our colleagues in Europe are ahead of us on this, they band it several years ago.

In the US, we just had a new veterinary feed directive from the FDA this year. So, we’re going to see that decrease. But the magnitude of the problem, we’re still getting our hands around it. That’s been the subject of much discussion in Washington and in other places.

In people, we know that overuse of antibiotics is a bad thing and we’ve known this for years.  And we know that giving antibiotics for a cold is not a good thing. And giving antibiotics for too long is not a good thing. So, we’ve done a lot to address that. The CDC and other groups had to educate doctors like, for example, pediatricians to not give antibiotics for colds and respiratory infections in children. That takes a lot of persuasion, right, persuading moms.

MOB: Is it conceivable to imagine the end of the antibiotics era? Do you envision that? Do you see it down the road?

HB: I certainly hope not. I think a lot of us are working hard at our day jobs, in our volunteer jobs to make sure that doesn’t happen. And I think now, you have political will both nationally and internationally to see to it that we don’t have that happen. I think having this problem, antibiotic resistance, on the G20 agenda for example has elevated it to the level of a national security issue and a global security issue. We can’t afford to have this happen.

MOB: Tell me about the national security and global security issues.

Dr. Boucher speaks to Miles about antibiotic resistance.
Dr. Boucher speaks to Miles about antibiotic resistance.

HB: So, if one were to project having antibiotic resistance really take off to the point where we had to worry about people entering our country because they had multidrug-resistant infections that could slow down trade, it could slow down travel, tourism, a lot of things that keep our economies going.

MOB: So, the typical American response to this would be, “Well, let’s just go out and get some new drugs! We’ll get it fixed, right?” It’s not as simple as that. Walk us through the problems.

HB: So, first of all, we know that the problem is beyond drugs. It comes back to that One Health approach that has to do with our environment, our food supply, and other things. But if we even focused on drugs, what a lot of us have been working on for the past ten years is the fact that we don’t have drugs, right?

So we know that Big Pharma has largely left this area because for a variety of reasons, including the fact that it’s not economically attractive. Most drugs that are developed are taken for someone’s lifetime or are extremely expensive and used for something like cancer. Antibiotics are meant to be used for a very short period of time. They’re traditionally very cheap and we, infectious disease doctors and others, encourage good stewardship.

We’re asking a company to develop a new special medicine and then save it on the shelf, so it’s not economically attractive. If you take that plus the scientific challenge, plus the regulatory difficulties of developing antibiotics, there are a number of obstacles that have gotten us to a place where we have a… shall we say, dryer antibiotic pipeline.

MOB: The business model just doesn’t work for antibiotics as it stands right now. The pharmaceutical industry can’t make it. The bottom line, it just isn’t there, right?

HB: Well, that’s what we certainly heard a lot of and that was cited as one of the main reasons for Big Pharma getting out of the space.

What’s happened is the innovation is largely moved to small companies who have different economic models and groups like IDSA and others have worked on generating incentives.  So, we had GAIN Act which gave a little bit of extra patent protection for certain antibiotics that need a particular unmet need. And there’s a lot of work being done by BARDA and other groups to simulate other incentives. And there’s discussion in Washington about things like transferable patents and tax credits and other so-called pull incentives. But what we believe is that a variety of push incentives and pull incentives are needed to sort of reinvigorate the economic piece of antibiotic development.

MOB: So it requires a little bit of government intervention to make this work you think, whether it’s patents or tax credits, etc?

HB: Potentially. I think public-private partnership has been cited as a potentially better way to do this. And so, we have an example of that with BARDA, which is a government agency that contracts with industry, and we have a new public-private partnership that was started within the last year called CARB-X, which has many million dollars potentially, and they’ve already funded 11 small companies with early stage products in the pipeline to help push them into development.

MOB: Is it too long a wait for these new drugs potentially?

HB: So, it does take time. It takes on average up to ten years. And so, one of the things we advocate is for robust and renewable pipeline so that we’re not waiting, so that there’s always things moving through the pipeline. And I think that work has been done on ways to streamline development and to ensure that the most promising drugs can get through in a timely fashion. The FDA has been a great partner in this, working on ways to allow for streamlining development, especially for medicines that meet the biggest needs that we see.

We’re asking a company to develop a new special medicine and then save it on the shelf, so it’s not economically attractive.

MOB: I suppose if you are true, hardcore laissez-faire free market person, you say, “Why don’t they just charge more for the antibiotics?” Wouldn’t that solve the business model and maybe reduce the amount of overprescription? Or, is that a bad idea?

HB: Well, it’s a very good question, and it’s something that’s gotten a lot of attention–the whole discussion of the value of antibiotics. I think that there is a school of thought and a camp who believes that we should charge commensurate with the value that antibiotics bring. They’re life-saving medicines, they allow us to do very important therapies.

That discussion continues. I think there have been some other kind of parallel discussions that are very interesting that have to do with changing the structure a little bit of how antibiotics are paid for, so taking it away from a “you get paid for how much you sell” model towards something that’s been termed “de-linkage,” that is de-linking the sales from the revenue of antibiotics.

A lot of discussions in Europe, but also now in the U.S. we’re having the so called firehouse analogy. John Rex, who’s a big leader in this area, coined this term and said, “You know, think of it like the fire department. We all rely on the fire department. But if you took a room of a hundred people and said ‘how many of you called it in the last year?’ maybe only one or two did, but we need it to be there.”

We need to know that the antibiotics are there if we’re the one who gets the resistant infection next year. So ideas like a market entry reward, if you develop an antibiotic that treats a certain resistant infection, you’ll get paid X to manufacture it every year. If you sell more than X, you’ll make a little more, but there’ll be some limits on that. So, it would assure the innovator a return but one that was reasonable and that wouldn’t get out of control.

MOB: Is there much traction for that idea here at this country right now?

HB: There’s more. I’ll say two years ago, we all thought we’d get laughed out of the room.

Overprescription of antibiotics is driving resistance in bacteria.
Overprescription of antibiotics is driving resistance in bacteria.

MOB: Everybody today at one time or another has said, “You know what? Europe is so far ahead of us.” Why are they smarter than we are on this?

HB: That’s an excellent question and it’s something that has bothered a lot of us who spend our time thinking about this. I don’t know, is the total answer.

I think, clearly, they were much more progressive on the link between using antibiotics in animals and resistance in people. They have more national health systems and better surveillance. So, they had a better handle on how much resistance was present down to the city level. You can click on a map of Europe and go down to the country and down to the city to see what’s going on in terms of resistance. So, I think they had perhaps a little lead in that direction. But I think part of it is structural and that, with national healthcare, it’s a little bit easier to navigate some of these things that took us a little bit longer.

MOB: Antibiotic stewardship is really hard to do, right? You have to wait a couple of days now to culture a bacteria, to figure out what might be the appropriate antibiotic. In the meantime, you’ve got to get the patient something, right? So, what can be done about that particular problem?

HB: I think that the first question is always, “Do we need to use an antibiotic?” And I think changing our dogma from “I have to give them something,” to, “Do I need to give them something?” is really important. That is at every level for us: in the ICU, here in the hospital, but also at the doctor’s office, at the student health center, at the employee health center. So changing that perspective is really important.

And then thinking about diagnostics, we now do have some diagnostics that are rapid.  So, this winter, if you came into my office or the hospital, I could do a swab, a little nose swab and find out in an hour if you had influenza, if you had another virus, or if you had a Legionella bacterial infection. That’s quick, and that has enabled us to use fewer antibiotics in respiratory infections for example.

MOB: So the next step in the stewardship is what?

HB: Well, the next step is thinking about not overusing antibiotics. So, not treating for too long if we treat and focusing on educating and making changes at all levels, from the hospital all the way down to the community, and measuring the impact of those changes.

I think having this problem, antibiotic resistance, on the G20 agenda for example has elevated it to the level of a national security issue and a global security issue.

MOB: You know, we’re always told, “Finish the course, finish the course.” That’s not so much the truth anymore. Explain why that’s important.

HB: Yeah, it’s very important.

I think the first fact is we don’t always know whether or not you need to take the whole course. So, we finally began to study it. For skin infections, we’ve learned that six days is as good as ten. Some very good studies done a few years ago showed us that.

We don’t know that three days is as good as six. I think that’s the next study that needs to be done. Unfortunately, those studies are not sexy.

Dr. Boucher’s lab is vigilant in tracking superbugs at Tufts Medical Center.
Dr. Boucher’s lab is vigilant in tracking superbugs at Tufts Medical Center.

We’ve learned for a very few infections, like ear infections in two-year-olds, you need to treat for the whole course. But for many others, we’re learning that shorter is fine. So, I think if you’re a patient at a doctor you should ask, “Do I need to take it all or not?” And, oftentimes, the answer will be, “No.”

MOB: So, when you look at the big picture, the overall days of antibiotic use in aggregate are very important, right? Because that’s when you’re training bugs to get super?

HB: Absolutely, more exposure is not a good thing. So the longer that the bacteria sees the antibiotic, the more chances it has just numerically to become resistant.

My decision to treat you with an antibiotic affects you, which is very important–you’re my patient. But it also affects everybody else. And so, I do think we have an obligation to think in those terms. So, that’s where the stewardship principle of using the best antibiotic comes in. We want to use the most narrow antibiotic. If I know what’s causing your infection, if I know you have an E. coli urinary tract infection, I want to treat that bug only and not with an antibiotic that kills everything else in its path that could cause more resistance down the road.

MOB: Perhaps doctors kind of forgot some of those risks with antibiotics and thought there was no downside?

HB: I think we did. I think everybody gets busy and sometimes, does forget. But I think that’s our job, in infectious diseases and in stewardship, to sort of bring those things back to the floor and help make those decisions more balanced.

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