When Prescription Drugs Don't Work

On top of this, even in the developed world, the antibiotics used today are "broad" products, whose blunderbuss approach can kill a wide range of bugs but also trigger knock-on problems.

One reason for this is that for the first 48 hours, patients are effectively treated blind while lab staff go through the process of growing a culture sample to see just which microbe is to blame. In particular, Clostridium difficile infection has become a significant problem in hospitals because such broad-spectrum antibiotics damage gut flora, which creates an environment for it to flourish.


Antibiotic-resistant bugs like MRSA and C. difficile tend to be picked up by patients in hospitals, but the risks are far broader than a hospital stay. Take the story of the 100 or so Swedes who went travelling to different parts of the world and were tracked by scientists to see what bugs they brought home. Of the eight who went to India, seven -- that's 88% -- came back with bacteria in their guts that were resistant to a whole class of antibiotics called cephalosporins. Not one of the people in the study had been in a doctor's clinic or hospital while they were there -- indicating the superbugs they picked up were freely circulating in the community.

What makes the NDM 1 enzyme so dangerous is not only its ability to outflank carbapenems, the most powerful class of antibiotic drugs, but also the company it keeps -- in tough bacteria already resistant to many other antibiotics. Despite being identified only three years ago, it has already been detected in a wide variety of bugs, including many familiar pathogens such as Escherichia coli, or E. coli. In contrast to so-called Gram-positive bacteria, like MRSA, these microscopic enemies are Gram-negative, meaning they have tougher outer membranes which block out many antibiotics, and an unnerving ability to pump out others, making them much harder to take on and beat.

Cases of bacteria producing NDM 1 have now been found and documented in two dozen countries from North America to Europe to New Zealand to China to Kenya.

Livermore's work shows only two or three remaining antibiotics can kill these bugs -- one is toxic, so doctors use it only in extreme cases; the second can't be used to treat urinary tract infections, one of the most common infections caused by E.coli; and the third is not available in many countries and is anyway susceptible to easily developed resistance.

What's more, no new drugs active against NDM 1-producing bacteria have yet reached even the Phase II stage of the three-step pipeline process of clinical trials needed for regulatory approval. That means any new drug to tackle NDM 1 is at least five or six years away.

Even more alarmingly, NDM 1 is no lone threat -- it comes as part of a family. Similar enzymes in the same class, known as carbapenemases, have been detected worldwide. Just this month, the Eurosurveillance journal of the European Centre for Diseases Prevention and Control reported that four separate cases of a related strain had been found in Switzerland between May 2009 and November 2010. Three had come from Italy, one from Greece.

That suggests that NDM 1 and its kin are not, in fact, the ultimate "super superbugs" but rather just the tip of the iceberg. The WHO's Mario Raviglione, who is fronting its antimicrobial campaign, is particularly worried about "superbug" forms of tuberculosis -- a disease that earned the nickname of "white plague" during Victorian times in Britain because sufferers' skin tone turned so pale.

TB already kills around 5,000 people a day and cases of multidrug resistant TB are spreading fast, with about 440,000 new patients every year. Until now largely a disease of the marginalised and the poor, it's the sort of infection that mutates and could start killing more widely, regardless of its victims' wealth or home country.

"We're dealing here with a public health emergency of global proportion. If we don't do anything we're just going to see more and more," Raviglione says.

You might think all that adds up to a great business opportunity for the pharmaceuticals industry. But in the past 40 years only two new classes of antibiotics have won marketing approval, while the total number of antibacterial agents approved for sale has dived. Why are the drugs firms so quiet?


The European Medicines Agency is easy to miss among the imposing towers of London's Canary Wharf financial district. Yet alongside the U.S. Food and Drug Administration (FDA) in Washington, it is a pivotal gatekeeper to the west's flow of new drugs. Last December, outgoing Executive Director Thomas Lonngren sent invitations to a conference looking back on the watchdog's past decade of achievements, and the great and the good of the pharmaceuticals world turned out en masse.

If they had expected a celebration, they were misguided. Lonngren, a softly spoken Swedish pharmacist, berated the industry for its pitiful record of innovation, arguing that out of the estimated $85 billion spent globally each year on drug research and development, about $60 billion was effectively wasted on dead-end projects. Worse, he said, drug manufacturers were failing to put their research dollars into key areas of unmet medical need.

Nowhere was the shortfall more glaring than in antibiotics.

"We have more or less a gap of five years without research into new antibiotics," Lonngren complained. "It's an issue where commercial consideration doesn't really match the public health need." He went on to warn that, while it was not the job of regulators to tell commercial companies where to invest, they might in future need to advise politicians and the public at large about such research deficiencies.

Across the Atlantic, FDA Commissioner Margaret Hamburg shares his concerns. "We need new and better drugs- and we need them now. Yet the R&D pipeline is distressingly low," she said in a speech to the National Press Club in Washington in October.

It wasn't always like this. For many years, making antibiotics was a bread-and-butter activity for the drugs industry. Today it has shrunk to a neglected Cinderella business -- complacent about past successes and reflecting the skewed economics that can drive pharmaceutical development.

Martin Mackay, a Scottish microbiologist who has worked for many of the world's top drugmakers and now heads up research at AstraZeneca, is better-placed than most to see the big picture. Back in the late 1970s he was a researcher at Beecham Pharmaceuticals -- now part of GlaxoSmithKline -- when many in the industry were checking off the fight against bacteria in the "Job Done" column. After all, doctors had a wide choice of effective treatments and all the drug companies needed to do was go out and sell them, and let the accounts department tot up the profits.

"Back then, there was a school of thought that said we had cracked the problem of bacterial diseases," Mackay says. "It looked a pretty good picture."


Today, it's very hard to make the commercial sums work. The drugs industry has seen dwindling returns on all its R&D in recent years, resulting in a wave of high-profile laboratory closures -- cost-cutting measures that have been cheered by the stock market. The payback on antibiotics has been even more dismal than in other diseases.