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April 5, 2011

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When drugs don't kill superbugs

DAVID Livermore is in a race against evolution. In his north London lab, he holds up an evil-smelling culture plate smeared with bacteria. This creamy-yellow growth is the enemy: a new strain of germs resistant to the most powerful antibiotics ever devised.

Out on the streets, Steve Owen is running the same race - physically pounding the pavements to draw attention to the problem of drug-resistant infections.

Owen's father Donald died four years ago of multiple organ failure. He checked in for a knee operation. But he got methicillin-resistant Staphylococcus aureus, known as MRSA, a "superbug" that all the drugs his doctors prescribed couldn't beat. After 18 months, the infection got into his blood, overpowered his vital organs and killed him.

Owen and his wife Jules have pledged to run 12 big races in 12 months to raise funds for a charity fighting MRSA.

This is a world where drugs don't work.

After Alexander Fleming's 1928 discovery of the first antibiotic, penicillin, we assumed we had the chemicals to beat bacteria. Sure, bugs evolve to develop resistance. But for decades scientists managed to develop new medicines to stay at least one step ahead of an ever-mutating enemy.

But now we are falling behind. MRSA is estimated to kill around 19,000 people every year in the United States, far more than HIV-AIDS, and a similar number in Europe.

A new wave of "super superbugs" with a mutation called NDM-1, which first emerged in India, has now turned up from Britain to New Zealand.

NDM-1 is what's growing on the plates that Livermore holds in his gloved hands. "You can't win against evolution," says the scientist, who works in a laboratory at Britain's Health Protection Agency. "All you can seek to do is to stay a jump ahead."

The reasons

That's not happening for a number of reasons. First, antibiotics are everywhere, giving bacteria countless opportunities to evolve escape routes. Drugs can be had for pennies, without prescription in countries like Thailand, India and parts of Latin America.

Even though use is controlled in the West, the system encourages doctors to shoot the bugs first and ask questions later. Perhaps most worrying, the world's top drug companies, faced with decreasing returns and ever costly and difficult science, have not only slowed efforts to develop new antibiotics but have been quitting the field in droves.

Today, only two large companies - GlaxoSmithKline Plc and AstraZeneca Plc - still have strong and active antibiotic R&D programs, according to the Infectious Diseases Society of America. Back in 1990, there were nearly 20.

That could have a profound impact on how we treat our sick. "If some of the most potent multi-resistant strains that we see now accumulate, then modern medicine potentially becomes untenable," says Livermore. "You need the ability to treat infections in vulnerable patients. Lose that and a swathe of modern medicine becomes unstable."

Are we about to go back to a pre-antibiotic era? This fear prompts the World Health Organization to devote this year's World Health Day on Thursday to antimicrobial resistance.

"Modern medicine can't function without antibiotics," says Derek Butler, chairman of the MRSA Action UK charity for which the Owens raise funds. "If we lose these magic bullets, medicine will be set back 80 years.

Rat on the ward

One aspect of the race against bugs has changed little since Fleming's time, or Florence Nightingale's before that. Hospital hygiene is the basic, unglamorous and underpaid work that's the vital first-line of defense against pathogens. It can ease the demand for drugs in the first place. Yet Steve Owen's father said he'd seen a rat in the ward - a shock in a developed world hospital.

Bugs are no respecters of age. Donald Owen was 82 when the treatment for his knee problems ended up killing him.

Susan Fallon's daughter Sammie was just 17 when she was admitted with flu-like symptoms to another British hospital in 2008. Doctors ordered blood tests and a bone marrow biopsy. She had a rare blood disorder that required chemotherapy. She also picked up a superbug. Just over a month later, before anything could work, Sammie was dead.

"I don't know who came in without washing their hands and gave this bug to Sammie," says her mother. "But if I went into hospital now I'd be saying 'Wash your hands before you come near me'."

In developed nations, a big push to improve hospital hygiene is starting to keep MRSA in check. But cheap international travel is breaking down barriers to infection. Medical progress is accelerating in places like India, China and Brazil, but often more swiftly than basic infection control in hospitals, Livermore says.

"It's sexier to do a kidney transplant than have infection-control nurses go around and berate people for not washing their hands. Yet she might save more lives."

The fact that the latest superbug - NDM-1 stands for New Delhi metallo-beta-lactamase, an enzyme that gives bacteria multi-drug resistance - first emerged in India is no surprise. Use of antibiotics is rampant and unregulated in a country with appalling sanitation and overcrowding - ideal conditions for resistance to develop. A week-long course of antibiotics can cost as little as 30 or 40 US cents.

Further, 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 is that for the first 48 hours, patients are treated blind until lab staff grow a culture to identify the bug.

In particular, Clostridium difficile has become a significant problem in hospitals because broad-spectrum antibiotics damage gut flora, allowing it to flourish.

Many strains

There are many strains of superbugs and they spread quickly around the world. Studies show that NDM-1 and its kin are not, in fact, the ultimate "super superbugs" but rather just the tip of the iceberg.

Superbug tuberculosis is a big concern. TB already kills around 5,000 people a day and multidrug resistant TB spreads fast, with about 440,000 new patients every year. "This is a public health emergency of global proportion. If we do nothing we're going to see more," says Tom Raviglione of the WHO.

No profit

This sounds like a great business opportunity. But in 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?

Thomas Lonngren of the European Medicines Agency in London argues that around US$60 billion of the US$85 billion spent globally each year on R&D is wasted on dead-end projects.

Worse, he said, drugs makers are not putting dollars into areas of unmet needs. The shortfall is glaring in antibiotics.

"We have more or less a gap of five years without research into new antibiotics," Lonngren says. "Commercial consideration doesn't really match the public health need."

Across the Atlantic, FDA Commissioner Margaret Hamburg says, "We need new and better drugs and we need them now. Yet the R&D pipeline is distressingly slow."

It wasn't always like this. For many years, making antibiotics was a bread-and-butter activity. Today it has shrunk to a neglected Cinderella business - complacent about past successes and reflecting the skewed economics that drives pharmaceutical R&D.

The industry had wrongly figured the job was done. After all, doctors had a wide choice of treatments and drugs companies just had to sell them and add up the profits.

Sums don't work

Today, it's hard to make commercial sums work. Returns on all R&D are dwindling, resulting in a wave of high-profile closures and cutbacks. Payback on antibiotics is dismal.

There are two reasons. First and foremost antibiotics, when they work, tend to cure people. Patients take small quantities for a short time - not much profit. By contrast a patient takes a cholesterol-lowering heart medicine for a lifetime - that's profitable.

Second, new antibiotics are likely to be saved for serious infections, reducing sales.

To cap it all, most existing antibiotics have are widely available as cheap generics.

Thus, while the global market for all prescription drugs grew by more than 40 percent over five years, the value of antibiotics shrank to US$14.4 billion in 2010 from US$16.1 billion in 2005. That's likely to fall to US$12.0 billion in 2015 as blockbusters lose patent protection.

The fix

Experts from science and industry argue that fixing the system will require a mixture of "push" and "pull" incentives - "push" measures to lower the cost of developing new antibiotics, and "pull" factors to increase the commercial rewards for successful products.

These boil down to easier approval and subsidies, such as tax breaks, patent extensions or government commitments to buy future drugs. Ultimately, we may simply have to accept that antibiotics should no longer be cheap, but premium priced.


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