When the drugs dont work

Owens father Donald died four years ago of multiple organ failure in a British hospital. He had checked in for a knee operation. But what he got was methicillin-resistant Staphylococcus aureus,commonly known as MRSA,a so-called superbug that all the drugs his doctors prescribed couldnt beat. After almost 18 months of severe pain,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 as many months,to raise funds for a charity that is working to fight MRSA. It was his knee thats not something he should have died from, said Jules.

Welcome to a world where the drugs dont work.

After Alexander Flemings 1928 discovery of the first antibiotic,penicillin,we quickly came to assume we had the chemicals to beat bacteria. For decades scientists did manage to develop new medicines to stay at least one step ahead of an ever-mutating enemy.

Now,though,we may be running out of road. MRSA alone is estimated to kill around 19,000 people every year in the US far more than HIV and AIDS and a similar number in Europe. Other drug-resistant superbugs are spreading. Cases of often fatal extensively drug resistant tuberculosis have mushroomed over the past few years. A new wave of super superbugs with a mutation called NDM 1,which first emerged in India,has now turned up all over the world,from Britain to New Zealand.

NDM 1 is whats growing on the plates that Livermore holds in his gloved hands. You cant win against evolution, says the scientist,who is tracking the emergence of superbugs in a national reference laboratory at Britains Health Protection Agency. All you can seek to do is to stay a jump ahead.

Thats not happening now for a number of reasons. For a start,antibiotics are everywhere,giving bacteria countless opportunities to evolve escape routes. The drugs can be picked up,without prescription,for pennies in countries like Thailand,India and parts of Latin America. Perhaps most worryingly,the worlds top drug companies,faced with decreasing returns and ever more expensive and difficult science,have not only slowed their 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 active antibiotic research programmes,according to the Infectious Diseases Society of America. Back in 1990,there were nearly 20.

Are we about to start going backwards,to a pre-antibiotic era in which things like hip replacements,chemotherapy and intensive care are simply impossible? Its a big enough fear for the World Health Organization to devote this years World Health Day on April 7 to antimicrobial resistance in a bid to safeguard these drugs for future generations.

RAT ON THE WARD

One aspect of the race against bugs has changed little since Flemings time,or Florence Nightingales before that. Hospital hygiene is the basic,unglamorous and underpaid work that forms the vital first-line of defence against pathogens. If it is done properly,it can ease the demand for drugs in the first place. Yet Steve Owen remembers his dad telling him hed seen a rat running through his ward a shock in a developed world hospital.

In developed nations,a big push to improve hospital hygiene is starting to keep MRSA in check.

At the same time,cheap international travel is breaking down the geographical 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. Its sexier to say you can do a kidney transplant,but its not so sexy that infection control nurses go around and berate people for not washing their hands. And yet it may well be that the infection control nurse would save more lives than the renal surgeon.

The fact that the latest superbug NDM 1 stands for New Delhi metallo-beta-lactamase,an enzyme that gives bacteria multidrug resistance first emerged in India comes as little surprise to many microbiologists. Use of antibiotics is rampant and unregulated in a country with appalling sanitation,high rates of diarrhoeal disease and overcrowding ideal conditions for resistance to develop.

MEET THE FAMILY

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 thats 88 per cent 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 doctors 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.

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

Whats 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 Center 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 WHOs Mario Raviglione,who is fronting its antimicrobial campaign,is particularly worried about superbug forms of tuberculosis.

TB kills around 5,000 people a day and cases of multidrug resistant TB are spreading fast,with about 440,000 new patients every year.

Were dealing here with a public health emergency of global proportion. If we dont do anything,were just going to see more and more, Raviglione says.

THE SUMS DONT 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.

There are two main reasons for this. First and foremost antibiotics,when they work,tend to cure people. Patients take small quantities for several days,a few weeks at most. Thats not a very attractive revenue flow. By contrast,a patient on a cholesterol-lowering heart medicine will keep using the pills,and contributing to drug industry profits,for the rest of his or her life. Second,even if a new antibiotic is approved for sale,its use is likely to be reserved for serious infections once again,minimizing the sales opportunity.

Faced with such economic hurdles not to mention the daunting scientific difficulties of outwitting fast-mutating superbugs a long list of big drug companies have decided to end their antibiotic research,including Roche Holding AG,Bristol-Myers Squibb Co and Eli Lilly & Co.

AstraZeneca and GlaxoSmithKline and to a lesser extent Novartis AG,Merck & Co Inc and Pfizer Inc remain in the antibiotic space.

The WHO is working on a six-point plan to target health authorities,doctors and patients. Its main message: superbugs are not just a problem for the old and the sick this affects everyone.

Steve Owen says he finds the realities of what we face difficult to grasp. He knows he lost his father because levels of hygiene in the hospital were too low. But why is the pace of drug development so slow? Ive always thought that science would keep up pace with the bugs,not that the bugs would get ahead of the scientists, he says.Kate Kelland and Ben Hirschler