Dr. John Rex: The Drug Pipeline Is “Very, Very Thin”

Dr. John Rex is the vice president of infection clinical research at AstraZeneca, a company that is working to develop antibiotics to counter drug-resistant bacteria. This is the edited transcript of an interview conducted on May 29, 2013.

Briefly explain to me antibiotics and their discovery and their significance for modern medicine.

The first antibiotics were discovered in the early 1940s following the observation by Sir Alexander Fleming that around some colonies of mold that grew in some lab plates in his laboratory in London, that the bacteria near the mold was dying, and that led to him isolating the compound. It ended up being the compound that turned out to be the beginning of the penicillins.

And when the penicillins came out, they were magic. There is almost no other word for it. They were magic. The initial headlines talk about the miracle drugs, and the reason they were magical was that prior to that, a simple infection — bacterial pneumonia, an infected cut — could take a healthy adult and kill them in just a few days. Kill them.

These drugs allowed people to effectively get up off their deathbeds and walk away healthy.

And it also had a big impact on surgery, right?

Yes, it actually made surgery possible. The antibiotics made much of modern medicine possible along the way. It made it possible to do things like treat a cancer. It made it possible to do things that we do routinely today like replace joints, get a new cardiac valve, take care of a premature baby. Antibiotics make all of those things possible. Without them, the infections that would always occur along the way would be lethal.

So they work by exactly doing what?

Antibiotics work by killing bacteria. They are compounds that are engineered to be safe for human beings but to be lethal to bacteria.

And they must have been very important to the pharmaceutical industry. Can you describe the impact on the industry of their discovery and development?

The discovery of antibiotics in many ways drove the early pharmaceutical industry. There were companies that got engaged in the production of these new agents on a large scale because it was clear that they were going to be needed widely for populations around the world.

It was the beginning of the era when you could actually do that kind of chemistry such that you could create new kinds of molecules. You could modify them. I think it’s fair to say that it was a big part of the early stages of the pharmaceutical industry in the ’40s and ’50s.

Was there a lot of optimism that there were many more substances still to be discovered then? What was the mood about?

The mood of the ’40s and ’50s was good. We were steadily discovering new classes of antibiotics. They appeared almost every couple of years. We had the penicillins, the tetracyclines, the erythromycins, the sulfas, and it was obvious that you could work with them.

In particular, the penicillins gave an opportunity for the chemists to make a better one and a better one and yet again a better one. So it looked for a long time like we had almost an inexhaustible stream of interesting new antibiotics.

And AstraZeneca’s role in this? Can you tell me a little bit about that history?

… AstraZeneca itself, we have been in the antibiotic game with a few things along the way through the ’90s and then the first decade of this century. … We’ve had a steady stream of one-off antibiotics, but we got deeply into it around the year 2000, when the company made the decision to invest in the discovery area. …

… The ’50s and ’60s, this time of sky’s the limit. What happened?

… The thing that actually began to change, even back in the ’40s, was it was evident that bacteria could become resistant. Sir Alexander Fleming observed that right away. He says that it’s clear that the “seeds of destruction” of antibiotics are in their very use; you are going to develop resistance. So even [when] the very first one, the first penicillins, came out, resistance developed almost immediately.

But the fun thing was, the exciting thing was that it was possible to modify the penicillin to make it so that they were just no longer resistant. And what happened in the ’50s and ’60s was successive repetitions of that. The bacteria became resistant, the chemists would make a new variation, and we would have a new antibiotic.

The place where it started to turn really challenging I’d say would be in the ’80s and the ’90s, when we began to see occasional bacteria that were very hard to treat, and it became less obvious that you were able to invent new antibiotics. Looking back in retrospect now, we can see that we really didn’t discover new antibiotics beginning probably in the 1980s. We actually stopped discovering.

We had variations, but we stopped discovering brand-new things, and the brand-new things that would have been so helpful in terms of providing new tools along the way just weren’t coming at the same pace.

And then in the ’90s and the first part of this century, we began to see resistant bacteria for which we really didn’t have very much or anything at all, and we had nothing coming to treat them.

So that’s been the big change. It’s been over the last 20 years or so that we’ve gone from a sense of “We’ll always have what we need” to a sense of “We might actually not have what we need now and for sometime in the future.”

… What is this thing we’re calling resistance? What’s going on?

Resistance occurs at a biological level when the bacteria mutates. … The antibiotic attaches itself to something in the bacteria. It interferes with the bacteria in some way, and the thing to which the antibiotic wants to attach, it changes such that the antibiotic can no longer attach correctly. And that’s a way that the organism becomes resistant to the effects of the antibiotic, and that effect is it just doesn’t work anymore.

The bacteria are able to do that because there are so many of them, and they are reproducing so rapidly. The bacteria life cycle, the entire birth to death of a bacteria, can be just a couple of hours, so they have the opportunity to experiment on themselves and in successive generations very, very rapidly, and if there is a way for a bacteria to mutate so that it becomes resistant to the antibiotic, it will find it.

And those that successfully fight back against the antibiotics live, and they produce new generations.

In general, yes. Sometimes when a bacteria mutates to resistance, it actually becomes less vigorous; it becomes what we call less fit. The mutation actually has cost it something. It’s actually had to make a trade-off of some sort.

But in other cases, the bacteria, they’re just like their predecessors. They’re just as virulent. They’re just as fit, and they start to circulate in the great sea of bacteria around the globe, and they begin to spread.

The unfortunate thing is they can also teach other bacteria how to become resistant. The molecular instructions for how to become resistant can get encoded on small pieces of mobile genetic material called plasmids, and so one bacteria can bump into another one and actually teach it its tricks for being resistant.

So you’re telling me they’re like bacteria coaches that can help others fight back.

That would be a good way to describe it. …

Can you explain to me why, from a science point of view, it’s gotten more and more difficult to invent new antibiotics?

Finding something to kill bacteria from one standpoint is easy. Fire, steam, bleach — they all work great to kill bacteria. The trick is to find something that kills bacteria and doesn’t harm you at the same time.

Meaning the person, the human being.

The human being, that’s correct. And antibiotics must act very selectively. They have to get to the bacteria inside your body, and then there has to be enough of it at that site to kill the bacteria.

The bacteria are fighting back all along, so you tend to need large amounts of that chemical present locally. And it’s just challenging biologically to find chemicals that you and I can tolerate in large concentrations without side effects. It’s really as simple as that.

You can see it in one way by thinking about the size of pills. So if you think about the size of a pill for lowering cholesterol, typical dose size on those pills might be 1 or 2 or 5 milligrams.

Think about the last antibiotic you took, and what number comes to mind? One hundred, 200, 500 milligrams, 1,000 milligrams. So you need a lot more because you’ve got to put it into the blood, and then it’s got to go find the bacteria. And then the bacteria don’t want it, so they’re trying to actively get rid of it. …

Some of these medicines — I’m thinking particularly of colistin, a very old antibiotic — have side effects that are more than just inconvenient, don’t they? Can you describe what some of these trade-offs are?

The antibiotics as a whole tend to have rather a large number of side effects. Some of our older antibiotics, they are toxic to the bacteria, but they are also toxic to you. They can damage your kidneys; they can damage your liver; they can damage your bone marrow. And all of those things are trade-offs that you might be willing to accept if you had no other choices.

But in fact, killing the infection while seriously injuring yourself is not something we would like to do. We’d much prefer antibiotics that have few or no side effects.

And is it scientifically getting more difficult to find those without side effects?

Yes, it is more difficult to find things that are side effect-free. It’s actually then quite surprising that in many ways, if you look retrospectively, that it was so easy to find things that were relatively safe. The penicillins are an example of a class of drugs that is amazingly safe in human beings. We have been very fortunate to have had them.

But you get into other classes of drugs, and across the board you find that they have a variety of side effects that you have to search long and hard to find something that is safe enough at the right concentration. It’s a bit of a game of chance to find things that fit that mold.

You mentioned that AstraZeneca really got into this field in 2000. Can you describe some of what went into that?

Prior to 2000, the companies that are now collectively AstraZeneca had had small antibiotic activities going on steadily. During the ’80s and ’90s, there was a series of antibiotics that actually came out of the Zeneca laboratories, but the change that occurred was in the early 2000s, when as the result of a corporate merger, a decision was made to bring together some groups and focus in on the discovery of antibiotics for serious bacterial infections.

That effort was focused in Boston, and it was also run in parallel with an effort to develop new drugs for tuberculosis with a group in Bangalore, [India]. …

… And what happened? It led to some successes.

It has. It’s a slow process, but at this point AstraZeneca is one of the companies that has a serious discovery and development effort, and we have a series of drugs that are actually in the late phases of development or on the market that address some of those kinds of serious bacterial infections.

So I would say that it has been a success. We are one of the groups that is delivering the new tools that we will need going forward.

The antibiotic pipeline is narrowing. It’s drying up, some people say.

To say that it’s drying up is perhaps to give it more credit for having stuff in it than I actually would. I think it’s worse than drying up.

Really?

I think it is terribly close to a drought. This is one of the great catastrophes of our age, that if we don’t have new antibiotics and have a vibrant, diverse pipeline soon, we’re going to be in trouble.

What do you mean?

If you don’t have the right kind of antibiotics, you can’t do things like get your cancer treatment. You can’t take care of a premature baby. You can’t get your coronary artery surgery done. Modern medicine grinds to a halt if you do not have appropriate, effective antibacterial agents. And we are seeing now the emergence globally of some forms of bacteria that are effectively untreatable with anything that we know how to use right now. So that’s why it’s a catastrophe.

And the pipeline is very, very thin. The number of new and interesting agents is small. We’re seeing agents come through that are variations on a theme from prior examples, and that’s quite a good approach. If you take a class and where you can extend it a little bit, you can create new antibiotics. But truly new antibiotics, entirely novel mechanisms of action, are few and far between, and I’m not sure that we’re going to have very many of those coming.

So the pipeline is just very delicate. It’s not clear that we’re going to have the things that we need. We need to nurture every molecule that looks like it might be an antibiotic that needs to be taken care of.

This looming catastrophe that you’ve described, there are some economic reasons behind it, aren’t there? Can you describe what’s happened to companies that have changed the incentives? Why is this happening?

… The economics behind that kind of a model are pretty easy to understand. If you look however at antibiotics, if you need an antibiotic, you need it only briefly. Indeed that’s the correct way to use an antibiotic. And because we currently have a variety of generic antibodies for many infections, we have come to think of antibiotics as being a relatively inexpensive thing.

So you put those notions together, and you have a scenario in which a new antibiotic is expected to be relatively inexpensive.

… There’s a profit issue; there’s investors.

… So the hard thing about a new antibiotic is that it’s essentially the only therapy area in which if I invent a new antibiotic, the response is: “That’s fantastic. I’m really proud of you. That’s something we’ve been waiting for, and as a matter of fact, that’s such an important new drug that we’re not going to use it.”

Why do you say you’re not going to use it? Well, the reason you’re not going to use it right away is that we often have a generic drug that we can use for at least some patients for a given disease, and we should use those first. So the number of patients who have the highly resistant bacteria, provided we’ve not let an epidemic occur, may be relatively small. …

What that means is that the new antibiotic is greeted with great applause and cheers, and then it’s not used very much. And from the economic standpoint of a developer, that means you’re not getting the return on the investment you’ve made, because you’ve spent $600 million and $1 billion to bring that new antibiotic to market.

Wait a minute. You mean it costs up to $1 billion to bring a new drug to market?

It can easily cost up to $1 billion to bring a new drug to market. A billion dollars.

So the company must think, how do they get a return on that $1 billion? And you’re saying new antibiotics don’t bring any.

The new antibiotics, when they come out, the view is — and it’s a very appropriate view — we should be careful with them; we should limit their use; we should only use them when they are really needed. And that makes perfectly good sense. As an infectious diseases physician, that’s what I would endorse. That’s what we want to do.

But from the standpoint of somebody who has created something and now needs to repay shareholders for the investment, it’s a difficult proposition. So what we need to do are think of ways to reimburse the value of antibiotics and the innovation differently.

We need to think about models — for example, an insurance-based model — of paying for an antibiotic might be an approach that would make a great deal of sense for government to undertake. Do things to change the economics of the equation so that companies want to invest in this area.

But thinking about the companies, they have other pressures, too, don’t they? In other words, obviously Wall Street is watching their share prices. And also, aren’t there competing priorities for companies? Antibiotics aren’t the only area of drug discovery. So what are those pressures like?

Those pressures are the pressures to selectively choose where a company invests [and] are present in any kind of business activity anywhere. In the pharmaceutical industry it’s not any different.

There are different ways a company can spend its time and money. So the choice to spend time and money on antibiotics is one that requires the right situation for a company to see that that actually is an appropriate use of its funds.

I think one way to look at this is to realize that you can’t make companies do this work. You have to make them want to do this work. And one of the challenges that we’re facing as a global community right now is the need to think differently about how we should incentivize companies to work in this area.

You say incentivize, but some people have suggested that markets are actually not functioning properly here. Is capitalism failing us?

[It would] certainly be fair to say that this is an example of a market failure. If markets are supposed to pull forward the products that everybody wants, this is an example of a problem that is so tricky that the markets directly don’t actually achieve what we want.

But explain why that is. I mean, don’t markets always create a supply if there is a demand? What went wrong here?

… The market for antibiotics can be viewed as market failure, because when we have a new antibiotic, our goal with it is to use it as little as possible so that we will avoid producing resistance to it.

Every time you use an antibiotic, you have the chance of creating resistance. So from a global community standpoint, when we have a new tool, … we’d like to use it carefully for just those patients who need it.

And if you don’t use it as much, then that has an economic impact.

Correct. … And that of course makes it difficult to return the value to the shareholders who have let you invest the money to create the new drug.

And companies also are pursuing drugs for other diseases and for other conditions that will be profitable, right?

That’s always the case, that any given company has a variety of places they can invest their time, energy and money, and it’s always a tug between those things, so the choice of investing in antibiotics has to be deliberate on the part of the company.

… Aren’t antibiotics historically very cheap?

I would agree that we have long priced antibiotics in a way that doesn’t really reflect their value, so I think of a couple hundred dollars perhaps for a course of an antibiotic, that’s relative to what it does for you.

That’s really quite inexpensive, because what it might do is cure you of an infection that was going to kill you. You might get back 60 years of productive life, based on a couple of hundred dollars’ worth of an antibiotic.

I want to move on now to Gram-negative [bacteria]. … What is it about these Gram negatives that makes them so difficult?

Bacteria collectively are divided up in what are called the Gram positives and the Gram negatives. The Gram negatives are rather like the Christmas present that you got once, where when you unwrapped the first box, there was another box on the inside, and then there was another box inside that. You had to keep unwrapping the layers of the box to get to the thing on the inside.

Gram negatives are like that. They are repeatedly wrapped such that the target is hidden inside various layers of wrapping so when we design a molecule, it has to penetrate all the way through those wrappers to get to the place where it does its action.

The germ is way inside all these shells.

It would be a way to think of it. The target of the antibiotic is well wrapped up in the layers of the [bacteria]. There are two big ones, and then there are some other ones even inside that.

These are also difficult because they know how to fight back against antibodies, right, the Gram negatives? Some of them have learned how to destroy the antibiotics.

… Indeed, the Gram negatives have a whole series of very clever mechanisms that you can think of as vacuums or pumps that are actively pushing things that work their way through the first wrapper back out.

So the Gram negatives are just wired for this. They are doubly wrapped, and they have a whole series of cleanup mechanisms that keep our antibiotics from getting into them.

So it’s very difficult to develop new antibiotics that will reach the center.

That’s correct. So if you’re developing a new molecule for the Gram negatives, it has to be that you get through the first wrapper, not be thrown out by the cleanup mechanisms, get through the second wrapper, and then find its way deep into the heart of the bacteria, where it’s likely to be doing the majority of its action.

Why are these such a threat to human health?

The Gram-negative bacteria are incredibly common. You and I are carrying them at all times. Most of the contents of your colon, for example, is Gram-negative bacteria. You need them. They are actually part of normal human health.

But when they escape from their normal habitat, and you have appendicitis or you have something go wrong with your gallbladder, the Gram-negative bacteria can get in there and produce a serious infection. And because they are so relatively difficult to treat, it has been harder to find new drugs for them.

And indeed the biggest and scariest threats right now are among the Gram-negative bacteria for which we have almost no treatments.

We have almost no treatments for these Gram negatives?

There are strains of bacteria for which we have almost no treatments. It’s really kind of hard to even hear those words, isn’t it? We’re used to always having the antibiotic we need. We have always had those drugs. And to say that we actually have bacteria for which we don’t have a good drug is terrifying.

But that is actually the case. So there are strains of bacteria, there is a particular class of resistance called the metallo-beta-lactamase — that’s the fancy name. This class of resistance is something for which we have almost no good drugs.

And you’re working on that, to try and cope with it with a new antibiotic. How is that going?

You bet we’re working on it. We do have a couple of different drugs, one in Phase I and one in Phase III, that look as if they would be good drugs for the treatment of the highly resistant Gram negatives.

Indeed, that’s the entire focus of the development program, is to ensure that we understand how to use them against the more difficult strains.

And this includes the NDM-1, the bacteria that came from India.

It does. So one of our products looks as if it will be active against the metallo-beta-lactamase producer called NDM-1.

… This NDM-1, this bacteria, why is it such a threat?

Bacteria that carry the NDM-1 resistance mechanism are particularly dangerous because of two things. One is the bacteria that carry them are really common. It’s the kind of bacteria that are everywhere, the kind of bacteria that are in your gut.

The other problem is that even our very best drugs fail against these bacteria. They’re our very best class of drugs, a class called the carbapenem. And NDM-1 is capable of destroying the carbapenem antibiotic.

It just chews it up or spits it out?

Chews it up, destroys it. It’s like in the game of Pac-Man. The Pac-Man comes along and chews up the bacteria. … This NDM-1 is able to gobble up the antibiotic.

And also apparently it moves itself around to different bacteria, right? It can be traded.

Absolutely. The bacteria collectively have the ability to pass the instructions around for how to become resistant. They have a way to move DNA between different bacteria and different species of bacteria so that one can teach the other how to be resistant, and it’s spread among the most common of the bacteria, the kinds of things that cause infections every day.

So if I’m a bacteria and I don’t know how to be resistant, and somebody comes along and gives me the road map, and then suddenly I can fight off antibiotics as well.

Absolutely the case. So it’s not just the case that the children of a resistant bacterium are resistant, but rather anything else that they bump into, they can —

Aunts and uncles and —

Just people they meet on the street. One bacterium can pass it to the next bacterium as they’re going past each other, so to speak, on the street.

That’s amazing.

It’s scary.

In all of these threats and difficulties, it seems like some companies have abandoned the field, and I just wonder if, thinking about it, it’s a bit of a tragedy that some companies — not AstraZeneca but others in the industry — are pulling out of antibiotic research. I am particularly thinking about Pfizer’s decision to pull out of it. What was the impact of that?

It takes a long time to learn to make any class of drug, and once you have a group in a company who have had experience with discovering, developing drugs, that experience can’t be created overnight, so when a major company leaves an area, we really do have a loss of skills, of history, in terms of understanding how to develop a new antibiotic.

So it’s very definitely the case that you have seen companies that used to work actively in this area exit the area. The Infectious Diseases Society of America [IDSA] has written about this a number of times in their monographs with a catchy title, “Bad Bugs, No Drugs.”

And you can also say bad bugs, no drugs and no drug companies. And that is a challenge for all of us, because if you decided today that you wanted to get into the business of discovering new antibiotics, probably take you about 10 years to get good at it, you being a company.

This is know-how and talent.

Know-how, talent, just kind of the getting-going steps, because it is such a complex endeavor, so when you lose a group that had that know-how, it’s a loss for us all.

… Is this a high priority for the United States government?

It has not always been a high priority, but I think it is becoming a higher priority. Is it high enough? It’s kind of hard to judge in a relative sense.

But I’d say that my sense of urgency is extraordinary at this point, because we are currently seeing bacteria for which we have almost no therapies. And I know how long it takes to create new drugs, so I actually would like to see us doing more than we collectively as a community are doing.

I can point to some things that are happening. The U.S. government is definitely investing in this area through its work through the NIAID [National Institute of Allergy and Infectious Diseases] and through BARDA [Biomedical Advanced Research and Development Authority]. …

In Europe, the European Commission has worked with a whole bunch of stakeholders to create some very exciting collaborative activities under the Innovative Medicines Initiative [IMI] that are permitting the European Commission to invest in this area.

But is it enough? Well, the pipeline is still dry, so I think that if I look at it from a pipeline standpoint, I have to say that collectively it’s not good enough.

And what about industry? … The head of the CDC [Centers for Disease Control and Prevention], Dr. Thomas Frieden, said these are “nightmare bacteria.” Is industry doing enough?

I think we need to see more industry activity in this area rather than less, but remember from our conversation about economics, you can’t make companies do this work.

You have to make them want to do this work so the companies are responding to what they perceive to be appropriate places to invest. And we need to change that math so that companies are working in this area, so that we actually have more companies doing it.

What I really want us to have globally is a diverse, vibrant pipeline. We need to have derivative antibiotics, entirely new classes of antibiotics, entirely new approaches to treating bacterial infections. All those things are going to be needed if we’re going to maintain the quality of life that we’re used to maintaining, and we need to collectively as a community get behind causing that to happen.

Why does the company do it if there are all these economic problems of doing it? Is it just out of the good of their heart?

Companies are always like you or me with our checkbook. Ultimately you have to balance your checkbook at the end of the day. Can a company do this entirely out of the good of its heart? I think not.

Ultimately a company has to be able to pay the way, and given the cost of this, we’re not getting hundreds of millions of dollars to develop a new drug.

It’s not free.

It’s not free to develop a new antibiotic, and if we want to have companies invest in this area, we have to make it rational for them to do so.

But do you think that AstraZeneca sees a bigger profit on the horizon than other companies do, an opportunity here?

… AstraZeneca’s investment in this began at a time when there weren’t a lot of companies in here. We could see the problem of resistance coming, and we felt like it should be possible with a focused activity to bring forward new antibiotics that would have at least a reasonable amount of reward, that would pay us back for the investment that we were going to make to bring those antibiotics forward.

So that’s where we are now, and we don’t have dozens of drugs. We have a few. Those few are chosen carefully to be things that we think will create great medical value and for which we think we can produce an appropriate return for our shareholders.

… Do you think that our society values these antibiotics highly enough, and is there any worry about the seeming complacency about the problem of resistance? Do you worry about it?

I worry a lot about how antibiotics are viewed and how they are valued, because I think you are correct that we do not really understand the value in an antibiotic.

What do you mean we don’t understand?

Let me try it with an example. When I was a medical student, I once took care of a young man, was about 19 or 20 at the time, who a couple of hours before he came to me had suddenly developed a cough, started bringing up bloody sputum. He had spiked a fever, and he felt terrible. What he had was classic bacterial pneumonia. …

If that young man had not gotten an antibiotic from me, what would have happened to him? Well, we know historically that people like that are incredibly sick for the next 10 days or so, and then about 15 to 20 percent of young men die. An older person, somebody who is over 50, two out of three people in the over-50 group would die from that infection. Here we are with a healthy young man who two hours ago was just fine, and now he has an infection that might kill him.

It was an extraordinary thing for me as a medical student, because I gave him an antibiotic, and that evening he said, “You know, I just feel so much better.” And he was gone the next day. He can finish his course of antibiotics at home.

Magic what we did for that young man, an otherwise lethal infection turned around. And of course in 24 hours, he was back on his way, doing his deal, and he’s had the rest of his life now to be a productive citizen.

That value is really hard to measure, and it’s easy to overlook, because we don’t see people die of bacterial infections anymore. Just doesn’t happen, because we always have the drugs.

Your six-year-old develops an ear infection. An ear infection in a six-year-old could kill a six-year-old. It could give you meningitis. It could give you bone infections. You don’t die from that anymore, at least as long as we have good antibiotics.

So do I think they’re undervalued? Yeah, I do think they’re undervalued. People do not see the consequences anymore because it’s been generations since we have seen people dying from infections.

A hundred years ago, to see somebody die from an infection [would] be a pretty common event in somebody’s life. Would have occurred regularly.

People died from infections regularly, every day.

Several hundred years ago, absolutely. You’ll find it in the novels of the 18th and 19th century. Somebody gets dreadfully ill and lays down in the bed, and then there’s the vigil at the bedside. Will they get better? Will they not? There’s not a lot you can do without an antibiotic. You need that tool. …

This looming catastrophe you talked about, and these infections that we do see, more and more of them, especially the Gram-negative ones, is there any way to quantify this problem? Are thousands and thousands of people dying from these new, tougher, nastier bacteria?

You can measure it. An example of a recent effort to measure that was the European Commission, their report that they published in 2009 that estimated that approximately 25,000 people a year died in Europe that shouldn’t have because of a resistant bacterial infection. The cost to Europe for those infections, the direct cost was about 1.5 billion Euros, so you can measure it.

It’s indirect, because how do you value the life that you get back because you’ve had an infection treated promptly? But people, when they estimate it, they come up with rather extraordinarily large numbers.

And in the United States, do you think we have a similar [number]?

We would certainly have similar numbers. I can’t quote any for you right now in terms of the size of the measured value, but the number of resistant bacterial infections is substantial.

You used the word “catastrophe” [to describe what] we’re facing. Do you mean the pipeline? And do you also think that the problem of resistance is a little catastrophe as well?

When I say that the dwindling antibiotic pipeline is a catastrophe, it’s the collection of those things. It’s a catastrophe because resistance is spreading. The bacteria that we’re seeing emerge as a problem in one part of the world can be on the airplane to the other part of the world the next day, and you have an outbreak of it downstream. Bacteria do not respect any boundary.

They and the resistant bacteria can move around the globe quite freely, so where we have a resistance problem now is just going to get bigger over time, and not having antibiotics for that is a catastrophe because modern medicine isn’t possible without good antibiotics.

Do you think that high levels of government are doing enough?

I think it would be great if we saw really high-level government push on this. If the most senior leaders in the country were to say this is a problem that threatens us all, a problem that we need to solve, I think that would be a very powerful statement.

Is it true that in the last two decades or so, there are fewer and fewer companies?

It is the case that the number of companies actually working in this area has overall gone down, and it’s gone down because it became harder to discover new antibiotics. It also became harder to develop new antibiotics, and then finally there is the economic challenge of antibiotics.

But in terms of discovery and development, it just became more difficult to find interesting things to bring forward. And I’d say that the development challenge is one that is easily misunderstood.

The challenge with developing a new antibiotic can be can be thought of as fairly simply. When you’re developing a drug, any drug, not just an antibiotic, when you are developing any drug at all, the typical way you do it is through what are called Phase III stages, big trials, trials of several thousand.

Testing it on people, thousands of people.

Several thousand people get put into Phase III trial, and that’s the last step in the development of any drug.

Let’s pretend now that you want to develop a new drug for resistant bacterial infections. If you say, “All right, what I now need are several thousand people with infections due to resistant bacteria,” that actually means that you’ve had to wait until there’s an epidemic of that infection ongoing and people are getting really sick from it.

And that, of course, is the last thing we want to do. We actually need ways to develop antibiotics before the epidemic occurs. So we have needed to adapt our development mechanisms and our regulatory paradigms so that we could bring antibiotics forward before the epidemic occurred, and that’s been something we’ve needed to spend time on.

We’ve really only made that change in the last couple of years. So people got out of this area because it was hard to find new drugs; it was hard to develop them; and it also has been historically difficult to get the value out of them.

And that’s a regulatory problem, too, right? How does the government approve a drug if you don’t have thousands of people to test?

That’s correct. … The orphan drug laws allow us to develop drugs for populations as small as a few hundred people. There are very rare diseases, where there are only a few hundred people in the world, and we have a pathway for developing a drug for them.

What we’ve needed to do was to adapt those ideas in a way that was fit for antibiotics. It’s not quite a one-to-one relationship, but there are similarities that can be applied, and that’s what we’ve done. …

Are you suggesting a paradigm shift or a change in the big way we think about antibiotics?

Absolutely. I think there are a number of paradigm shifts that you could point out simultaneously here. The paradigm shift in how we develop new drugs. We have developed new ways, and we have sort of invented ways that we can bring a drug to market based on a smaller number of people. It’s a different regulatory paradigm.

We need to think differently about what antibiotic stewardship means. What is the good use of an antibiotic? How do we measure that? And that’s a conversation we need to have globally, because what’s the correct use of an antibiotic? It isn’t zero. It’s going to be some amount, and we need to collectively define how that will work for the global community.

The other paradigm shift is value. What is an antibiotic worth? How do we measure the possible value or values of an antibiotic? How do we reflect the fact that a short course of an antibiotic gives you back 60 years of productive life? How do we correctly reward the innovator of an antibiotic for the effort that has gone into that?

So there’s a possibility that … we could go back to a pre-antibiotic era?

Without a doubt. We are looking at the possibility of returning to a stage where you might have an infection and there’s not a good drug, or the drug itself is almost as toxic as the infection. So that’s actually the kind of thing that we’re facing now. We actually have examples of that now, infections that really can’t be treated short of something very toxic, if it can be treated at all.

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