Why are so few antibiotics available for clinical use?

There are three reasons behind our present lack of new antibiotics. Firstly, it’s scientifically hard to find new antibiotics. The low-hanging fruit of tetracyclines, penicillin, streptomycin, was gathered long ago. Secondly, there were regulatory challenges. It’s hard to get your new antibiotic through the Food and Drug Administration in the United States, through the European Medicines Agency, here in the EU. It’s rightly hard - we demand medicines that are safe and effective but the challenge is so huge as, in some cases, to make development unattractive. And that really leads to a third challenge, which is that antibiotics are unattractive to the pharmaceutical industry compared with many other types of medicine. They’re taken for short periods.

People like me speak with forked tongues, on the one hand we say, this is a great new drug, on the other hand we say, use it very carefully for reasons of antibiotic stewardship. So, developing a new antibiotic that somebody takes for a week or two is less attractive than a heart medicine that somebody may take for several years.

If you go back to the 1940s to the 1960s what pharmaceutical companies used to do was get soil samples, from more or less exotic places, see what filamentous bacteria streptomyces and fungi they could grow from them, and see if these produced antibiotics, and for long while that worked. It’s how we got the penicillin, streptomycin, other amino glycosides, chloramphenicol or tetracycline, but gradually the law of diminishing returns was hit. You re-found tetracycline a hundred times for each new antibiotic you found, and the companies moved to taking older antibiotic, tweaking it to improve its activity. That too became hard. Then in the 90s, we had a genomics revolution.

We found the whole genomic sequences of different bacteria, and companies began to think well, we know the whole the whole genome, we can identify lots of new potential targets for antibiotics, and then we can tailor a new antibiotic to attack those targets. Beautiful, elegant, scientific in principle. It failed completely. So, by the early part of this century, companies like GlaxoSmithKline were describing themselves as target-rich, compound poor. They could find a target. They might even find a drug that would bind to it or a molecule that would bind to it. Trouble was that molecule, that potential antibiotic they’d then find couldn’t get into bacteria, or it got in and it was efluxxed - it was pumped back out again.

So a long string of development disappointments, particularly from this genomic strategy around the turn of the century, gradually companies are moving back to older, more trusted ways to discover antibiotics but fewer of them have stayed in the field.

We all, absolutely rightly, demand that drugs are safe and effective. That means any new antibiotic, or indeed any new medicine, has to go through a long series of trials. In total, these take about seven years. For an antibiotic - first its tested against bacteria in the laboratory, then it’s tested in animal models, then it goes into humans ,through a phase one trial, to look at what its pharmacokinetics are. If those look satisfactory, it moves into Phase two, which is to treat a small number of patients with real infections to see if, in principle, it works. If it passes phase two, it goes to Phase three, which is a comparative double-blinded trial against best available ,or standard therapy.

If it passes all that, it then gets a license from the regulator. By the time you reach this point, you’ve spent something like 700 million to a billion dollars on developing your antibiotic - a large amount of money. And the regulations around the clinical trials are extremely tight, so it’s difficult to recruit the patients to the clinical trials and companies tend to do trials in those indications, skin and skin structure infections for anti gram-positive drugs, and intra-abdominal infections and complicated urinary tract infections for anti gram-negative drugs, which aren’t necessarily the settings in which clinicians want to use the antibiotics as they’re developed.

So there’s often a mismatch between what a drug gets a license for, at very considerable cost, and actually where physicians wish to use it.

If a company develops a new antibiotic, a patient may take it for a week or two. At the end, their infections cured, or it’s not cured ,and if it’s not cured they’re changed to a different antibiotic, or they die. If you develop a new heart drug, on the other hand, then a patient is likely to take it for years, so your income stream from the new heart drug is much better than from the new antibiotic.

Secondly, people like me, as I say, speak with forked tongues - on the one hand we say, this is a marvelous new antibiotic, it overcomes this or that type of resistance, which is causing a great public health concern - on the other hand we say, look, this is a very valuable drug, all our past experience teaches us that, if we use, or overuse, antibiotics we select resistance for them. Therefore, you must keep it on the shelf and only use it in the more difficult cases where patients have got rather resistant bacteria. Otherwise, you must conserve it. This is bad for the company’s income stream. So you can argue that the whole business model for antibiotic development is no longer working.

The drugs are difficult to find. They’re difficult and expensive to get through the regulatory process, and once they’ve got through that regulatory process then we encourage physicians to keep them in reserve and on the shelf. This isn’t a good business model for the developer.