Why Antibiotic Dreams Don't Come True

Wonks need to learn that just because you can describe something doesn’t mean it’s possible.
Photographer: Tannen Maury/Bloomberg News

Just because you can describe something doesn't mean it's possible.

This is the hardest lesson for wonks of all sorts to learn. There's a wonderful Robert F. Kennedy quote that is very popular at commencements: "There are those that look at things the way they are, and ask why? I dream of things that never were, and ask why not?" This is just the sort of thing to send your heart soaring as you embark on life's great journey. But as practical advice for living, it's terrible. The world is filled with people dreaming of things that never were, asking "Why not?" Unfortunately, few of them wait for an answer before they start demanding multibillion-dollar programs to turn their dreams into reality.

A case in point is from the field of antibiotics. Antibiotic resistance is a terrible, horrible, no good, very bad problem. Everyone knows exactly what we need to fix this problem: more antibiotics. Unfortunately, many people seem to think that, having identified this daring solution, we can now turn it over to the government or pharmaceutical companies and demand that they make it happen.

Some cold water from Derek Lowe, who doesn't need to ask "Why not?" because he knows. Here he is talking about an interview on "The Daily Show" between Jon Stewart and Dr. Martin Blaser of New York University:

So finding a Streoptococcus-only drug is a very tall order. You'd have to find some target-based difference between those bacteria and all their close relatives, and I can tell you that we don't know enough about bacterial biochemistry to sort things out quite that well. Stewart brings up genomic efforts, and points to him for it, because that's a completely reasonable suggestion. Unfortunately, it's a reasonable suggestion from about 1996. The first complete bacterial genomes became available in the late 1990s, and have singularly failed to produce any new targeted antibiotics whatsoever. The best reference I can send people to is the GSK "Drugs For Bad Bugs" paper, which shows just what happened (and not just at GSK) to the new frontier of new bacterial targets. Update: see also this excellent overview. A lot of companies tried this, and got nowhere. It did indeed seem possible that sequencing bacteria would give us all sorts of new ways to target them, but that's not how it's worked out in practice. Blaser's interview gives the impression that none of this has happened yet, but believe me, it has.

The market for a narrow-spectrum agent would necessarily be smaller, by design, but the cost of finding it would (as mentioned above) be greater, so the final drug would have to cost a great deal per dose -- more than health insurance would want to pay, given the availability of broad-spectrum agents at far lower prices. It could not be prescribed without positively identifying the infectious agent -- which adds to the cost of treatment, too. Without faster and more accurate ways to do this (which Blaser rightly notes as something we don't have), the barriers to developing such a drug are even higher.

And the development of resistance would surely take such a drug out of usefulness even faster, since the resistance plasmids would only have to spread between very closely related bacteria, who are swapping genes at great speed. I understand why Blaser (and others) would like to have more targeted agents, so as not to plow up the beneficial microbiome every time a patient is treated, but we'd need a lot of them, and we'd need new ones all the time. This in a world where we can't even seem to discover the standard type of antibiotic.

And not for lack of trying, either. There's a persistent explanation for the state of antibiotic therapy that blames drug companies for supposedly walking away from the field. This has the cause and effect turned around. It's true that some of them have given up working in the area (along with quite a few other areas), but they left because nothing was working. The companies that stayed the course have explored, in great detail and at great expense, the problem that nothing much is working. If there ever was a field of drug discovery where the low-hanging fruit has been picked clean, it is antibiotic research. You have to use binoculars to convince yourself that there's any more fruit up there at all. I wish that weren't so, very much. But it is. Bacteria are hard to kill.

Antibiotic resistance is one of the few policy areas where everyone agrees that something should be done. Well, maybe except for some nutcases in the Voluntary Human Extinction Movement. Even more rarely, it is an area where we all agree on what we would like to see done. Unfortunately, the folks who actually have to do it seem to have no idea how to make it happen.

And you know what? That's not an accident. If we knew how to find lots of great new antibiotics, this wouldn't be a policy argument; we'd have lots of great new antibiotics, and we wouldn't need to worry about resistance. The very existence of a policy issue tells you that it is difficult to solve, either politically or technically.

This is worth remembering the next time you ask "Why not?" It's fine to ask the question -- but you should be prepared for the fact that most of the time, the answer is that we don't know how to make it happen.

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