On the right plate, carbapenem-resistant Enterobacteriaceae is able to grow even in the presence of antibiotics. Photo by CDC

Why so many companies have stopped trying to create new antibiotics

Editor’s note: Last night on the PBS NewsHour, science correspondent Miles O’Brien kicked off NewsHour’s special, and especially scary, series on the advent of antibiotic-resistant bacteria. This evening, in part two of the series, economics correspondent Paul Solman explores the economic impediments to creating new drugs.

One of the researchers Paul spoke with for the series is John Rex, a former executive at AstraZeneca Pharmaceuticals, in charge of developing new antibiotics. Dr. Rex talked about the growing concerns around antibacterial resistance and why so many companies, like his erstwhile employer, have stopped trying to create new drugs. Tune in to tonight’s Making Sen$e report for the full story of market failure. On Friday, we’ll continue the special series with a Making Sen$e NewsHour report on alternative ways to finance antibiotic development. And Paul and Miles will be back on the air next week to report on the antibiotic-resistance problem down on the farm.

The following conversation has been lightly edited for clarity and length.

PAUL SOLMAN: How worried are you?

JOHN REX: I am actually quite terrified by the problem of any antibacterial resistance. There are things out there even now for which we don’t really have anything. If one of those got loose, and it was a food-borne infection, we could see chaos.

PAUL SOLMAN: Really? When you say chaos, you mean hundreds of deaths?

JOHN REX: It could be. You can easily imagine the scenario in which some milk gets contaminated or a vegetable is contaminated with a bacterium that is highly resistant and difficult to get rid of, and it could spread to tens of thousands of cases. The way our food chain works these days, it’s entirely possible, and little outbreaks like that occur regularly. You may recall a few years ago there was a story about bean sprouts in Europe where there were people dying of internal hemorrhagic renal failure due to a bacterium. Imagine if that had been one for which there wasn’t a drug. So it’s that kind of thing that is really quite spooky. Then there are common bacteria like E. coli that routinely cause infections, and we expect to be able to treat them reasonably efficiently. Were we to have an outbreak of one of those, we would really be struggling.

PAUL SOLMAN: This may sound like an outlandish question, but I’m going to ask it anyway. In the next five years, what odds would you give that a truly terrible outbreak of a drug-resistant bacterium would occur?

JOHN REX: Relatively low odds of a major outbreak, but were it to occur, it would have a very significant impact. And I think you also have to put it into context with the scare factor that occurs around something like this. You may recall the anthrax episodes [15] years ago. There were far more people who were worried than were sick. But the worried also jam up the system and create a case in which people need to be taken care of or need to at least be seen. So it’s both the primary and secondary effects of the threat of infections. You know infections are spooky, because they kill you. And we’re just not used to having that sort of thing occur. Most adults today have never seen someone die from an untreatable infection. That’s a good thing. It used to be a pretty common occurrence, but we just don’t see it, and we don’t want to see it.

PAUL SOLMAN: And we panic if we do see it.

JOHN REX: I think we do.

PAUL SOLMAN: What’s happening in the pharmaceutical world with regard to developing antibiotics?

JOHN REX:The pharmaceutical industry has really gone through a long period of low productivity in this area. There are a lot of causes which we could talk about, but the net effect was that most of the companies that were really doing the large-scale development work backed away, and the amount of effort going into finding really new kinds of antibiotics really fell off dramatically. The total number of companies that were actively working in this area in 2014 and 2015 was about the same as in 1960. It went up, and then it went down.

PAUL SOLMAN: Why did it go up?

JOHN REX: Well, it went up because there was a period of time when it was possible to invent the next antibiotic reasonably efficiently. There was still chemical space to be explored. For example, Alexander Fleming discovered penicillins in the ’30s, really 1929, but in the ’30s and ’40s, and we spent 40 or 50 years mining the penicillins. There’s always the next better one to make. But you reach a point with most chemical series where it’s not that you can’t make another molecule, but the likelihood that you make one that’s meaningfully different goes down steadily.

PAUL SOLMAN: In economics, this is diminishing returns.

JOHN REX: Yeah, sort of. You’ve dug deeply, and it’s just the kinds of resistance you are seeing now don’t seem to be amenable to yet another tweak to this particular class of molecule, so it’s been hard to find new, interesting chemicals. And it’s worth emphasizing this. It’s actually pretty easy to kill bacteria. Steam, fire, bleach — they all work great.

But those aren’t drugs, right? I’m not going to treat your pneumonia with steam or fire or bleach. I have to treat your pneumonia with a very special chemical. It’s a chemical that isn’t harmful to you, that goes through your blood, it hits the lung in the right concentrations, and at that point, it succeeds in doing one thing and that is killing the bacteria without doing any damage to you. And that’s actually kind of tricky. Bacteria are living things, just like we are, and they have a lot of defenses against being killed and dying, and it’s just really tough to find a chemical that has the properties of behaving like a drug and killing bacteria and not harming you, and the ones that we do have are kind of like precious gems. I mean in some sense, it’s surprising you can do it at all.

PAUL SOLMAN: When did the disenchantment set in?

JOHN REX: It was in the ’90s that it began to really fall off. The law of diminishing returns was setting in, in terms of being able to find new and interesting things. We’ve actually got quite a good collection of drugs for most of the bacteria that are out there, so if you’re going to invent something new it’s gotta be really special in that regard, so the bar goes up. So our technical understanding of what it took to demonstrate the value of antibiotics deepened over time as with pretty much every area of pharmaceuticals. So the hurdle for bringing something onto the market, where people say, “Yes, I’d like to use that,” went up steadily as well. And it’s entirely appropriate that that occurred. You hit a point in the 2000s where it was really hard to find new drugs, and the development pathways were tough and in some senses not well-defined. Development pathways actually underwent a big review in the mid 2000s. We actually sharpened up our understanding of how you describe what a new antibiotic does. And then you layer onto that the economic problem of antibiotics, and you really had just had a situation where it didn’t really make a lot of sense to invest in the area. It’s going to be hard to find a drug, and it is going to be hard to develop it, and you weren’t going to get paid for it. So why would you do that?