杏吧原创

ANTIBIOTICS have changed what it means to be human. Few of us聽remember when bacterial infections from a wound, a bout of聽flu, sex or childbirth could kill anyone, at any time. This constant risk of death was just something we lived with. When antibiotics became common in the 1950s, that ended 鈥� and the drugs also opened a new frontier of surgery and therapy for other diseases.

But the bad old days are returning as bacteria evolve to resist antibiotics. Just last week, of two women in the UK infected with resistant, or 鈥渟uper鈥�, gonorrhoea. Thankfully they were cured, but others may not be so lucky.

You have probably heard about this problem 鈥� . After urgent alarms were sounded in 2015, governments and charities finally ploughed more money into drug discovery. These efforts are starting to bear fruit, but there is a larger problem 鈥� one of economics, not science.

The issue is that pharma firms must recoup their investment in developing drugs, but antibiotics are the antithesis of a bestseller. They are taken for days or a few weeks, whereas diabetes or heart drugs are highly profitable because patients can use them for聽life. Plus, new antibiotics can鈥檛 compete with older, cheaper drugs that still work and are no longer patented.

鈥淥nly 56 experimental antibiotics world wide have progressed as far as tests in people鈥�

By the time resistance to the old antibiotics builds up and doctors must prescribe new, expensive ones, their patented life may be almost over, leaving little time for their owner to turn a profit. Novel drugs must also be kept in reserve or used sparingly, to stop bacteria building a resistance to them, too.

As a result, says Kevin Outterson of Boston University, US sales of all antibiotics still under patent totalled just $700 million in 2017 鈥� less than what a single new cancer drug makes in聽a year. This is having a dire effect on the field. Outterson, who runs CARB-X, a global consortium that encourages the development of antibiotics, says microbiologists aren鈥檛 interested in tackling bacteria. 鈥淭he careers and money are in things like Ebola.鈥�

Firms have been abandoning work on the drugs for years. In聽2018, two more, Sanofi and Novartis, dismissed their antibiotic research teams, leaving only GlaxoSmithKline, Pfizer and Merck, and they have reduced their programmes and aren鈥檛 launching new studies. Now, most drug discovery is done by small, struggling biotech firms. Bad profit prospects meant those working on antibiotics lost some 50 to 75 per cent of their stock value in 2018, even as investment in other firms grew.

Push and pull

This market failure is creating聽a further crisis. The closures of antibiotics R&D departments had, by the start of 2018, left just some 800 experienced researchers working on antibiotics. 鈥淚n 2018 alone, we lost 200 of those. It鈥檚聽like聽losing a language,鈥� says Outterson. In five or 10 years, he聽fears, the last big firm may abandon antibiotics, and these vital researchers will be extinct.

Indeed, the pipeline for new聽drugs has been drying up. Last month, found that only聽56 experimental antibiotics worldwide have passed animal tests and are now undergoing trials in people 鈥� which, . Of those 56, only 30 per cent work in novel ways. That is a concern, because drugs that operate in the same way as existing ones may not be able to聽defeat resistance (see 鈥�New ways to kill infections鈥�).

In 2015, a commission set up by the UK government and headed by Jim O鈥橬eill, a former banker, estimated that losing antibiotics would cost society trillions of dollars. It called on governments to instead invest billions in two kinds of incentives for new antibiotic development: 鈥減ush鈥� incentives funding research to discover new kinds of drugs and 鈥減ull鈥� incentives to make it profitable to develop them.

The push part is finally happening. Last year, O鈥橬eill calculated that, if it continues, new funding should add up to the聽$2 billion over 5 years his commission called for聽鈥� and this聽money is funding new drug聽discoveries.

In contrast to the 56 older drugs聽in human trials, there are聽98 starting to be tested in animals, and nearly two-thirds attack bacteria differently from older drugs, increasing their chance of success. But 鈥渨ithout the pull incentives, this research will just accelerate into a wall鈥�, says Outterson.

O鈥橬eill estimated that government funding of between $1.6 and $3.7 billion per year could pay a firm to do the expensive tests of novel antibiotics in people. The government could then own the patent or some rights to market the new drug. The聽firm recoups its investment; the drug is used only as needed.

In May this year, the UK government will launch the first-ever such 鈥減ull鈥� project, paying two companies to bring new anti-microbial drugs to market. The price of the drug聽will be 鈥渄elinked鈥� from what the company needs to recoup its investment, so there is no pressure to market the new drugs aggressively, and they can be saved for the cases that resist all other treatments.

The newly elected US Congress also plans to discuss such 鈥渕arket entry reward鈥� schemes for new antibiotics, including an idea called 鈥減lay or pay鈥�, in which drug firms that aren鈥檛 working on antibiotics have to pay into a fund to reward companies that do. Existing legislation allowing government agencies to reward firms that develop biodefence drugs for which there is no market, such as anthrax vaccines, may also be pressed into service.

If that sounds like it will cost taxpayers a pretty penny, compare it with 聽鈥� $2.2 billion a year in the US, according to a study last March. In a patented antibiotics market worth $700聽million in the US, another $700 million might get things started, says Outterson.

鈥淭here are 98 drugs starting testing in animals, most of which attack bacteria in new ways鈥�

We might not even need to pay directly. In November, a drug called zoliflodacin passed tests showing it was safe and effective in humans against gonorrhoea, which has become so antibiotic-resistant that some infections are now almost incurable.

Many promising new drugs get this far and no further, but this one is already set to enter the big, expensive tests needed before it can be licensed. The trials will be financed by Entasis, the US company developing the drug, and also by governments and other donors organised by GARDP, a global organisation promoting antibiotic development.

If it passes, Entasis will market the drug in 34 rich countries, while GARDP gets marketing rights in 166 poor ones. Entasis makes the profit it needs, while聽the gonorrhoea epidemic in聽poor countries gets an effective drug 鈥� under tight control.

Ultimately, says Outterson, if聽these schemes don鈥檛 work fast enough, governments will have to聽take over the business of providing antibiotics. It wouldn鈥檛 be the first time they have done this kind of thing. Until the 1980s, government agencies produced the public-health vaccines that defeated diseases such as polio, measles and smallpox, as a public good, like roads and schools.

Ideology has frowned on governments messing with markets. But it may take only a few more untreatable cases of gonorrhoea or urinary tract infection to make ideologues sing聽a new song.