Friday, February 02, 2007

Doctors battle to keep superbugs at bay

Doctors battle to keep superbugs at bay
By Andrew Jack and Clive Cookson
Copyright The Financial Times Limited 2007
Published: February 1 2007 21:37 | Last updated: February 1 2007 21:37

Fiona Wise, the chief executive of Ealing Hospital in west London, sighs as she describes a letter that she received from a local resident last week: “He wrote to me saying he was coming in for an operation and wanted me to guarantee that he wouldn’t get MRSA.”

It was the latest expression of public anguish about the MRSA “superbug” – and other so-called hospital-acquired infections generating concern in healthcare systems around the world – that she and her colleagues constantly encounter.

“MRSA is the main cause of anxiety for every patient who goes into hospital,” says Kathryn Murphy from the Patients’ Association, a group that campaigns for improved efforts to bring infection under control. “We’ve had people ringing us up who’ve cancelled surgery because they are too frightened to go in.”

In many ways, the situation is unsettling. The number of deaths linked to superbugs has risen sharply over the past decade, resistance to existing drugs designed to treat them has been increasing and there are few new medicines in the pipeline.

While MRSA has received most attention in the industrialised world, other bacteria such as Clostridium difficile pose related and important public health threats. In southern Africa and parts of eastern Europe, fresh concern has been sparked in recent months by extensive resistance to the already complicated and lengthy drug treatments available for tuberculosis.

Yet the periodic horror stories need to be interpreted carefully and seen against a backdrop of renewed political commitment, intensified public health measures and some signs of fresh research interest in new drugs and diagnostics.

Soon after penicillin, the first antibiotic, was manufactured on a large scale for Allied troops during the second world war, resistant forms of the common Staphylococcus aureus infection began to emerge. Within a decade of the launch of a replacement drug, methicillin, in 1961, resistant strains dubbed MRSA – methicillin-resistant Staphylococcus aureus – were identified in the UK. MRSA can cause a wide variety of symptoms depending on where it starts, ranging from skin abscesses to fatal blood poisoning.

Antibiotics transformed modern medicine but they did create a culture of greater complacency around infection. Doctors used them widely and in many countries they could be bought easily without prescription, while long-standing family advice on hand-washing faded.

Professor Peter Borriello, head of the centre for infections at the Health Protection Agency (HPA), points out that many people affected by MRSA have weakened immune systems and would not have been treatable without the medical advances of recent decades. “A few years ago you would have been attending a wake for them instead of admitting them to hospital,” he says.

The latest data issued by his agency this week showed that in England during the six months to September 2006 alone, there were 3,391 cases of MRSA infections of the bloodstream, where it is most dangerous. While probably an underestimate of the problem’s extent, the latest Office of National Statistics figures show just 360 cases where MRSA was cited as the underlying cause of death during 2004 and a further 1,168 where it was a contributory factor.

Prof Borriello stresses that such figures have to be seen against a backdrop of a substantial and continued growth in overall hospital admissions year-by-year. “The vast majority of patients do not get an infection in hospital and not all infections are preventable,” he says.

Nevertheless, the UK data reveal higher rates of infection than in many other European countries. While there are debates about the comparability of the figures and whether there may simply be a time-lag before resistance identified in the UK is found elsewhere, this suggests practical approaches adopted in other countries could have an effect in reducing infection still further.

At Ealing Hospital, Dr William Lynn, medical director, highlights posters and prominent signs on the floors urging staff and visitors to rub their hands with antiseptic gel dispensed as they enter and leave wards and at patients’ bedsides. Doctors no longer wear dangling ties and he is considering issuing uniforms that are regularly changed to even the most senior staff.

Procedures for intravenous “lines” into patients have been changed, with nurses taking over responsibility from doctors and removing them at the first sign of inflammation or if they have not been used in the previous 24 hours. Refurbished wards have more isolation units, toilets and bathrooms with fewer surfaces, and floors with lino that tapers up the walls, minimising space that is difficult to clean.

With an estimated quarter of MRSA infections brought in from outside the hospital, Dr Lynn believes the most significant improvement has come from the screening, on arrival, of nearly half of patients admitted – those judged to be most at risk. Those found to be infected are given twice-daily antiseptics for the body and nose over seven days.

The strategy seems to be paying off at Ealing and elsewhere in the UK, where the latest HPA figures show a 5 per cent decline in MRSA cases to the lowest levels since mandatory national data collection began in 2001.

But Dr Lynn also expresses longer-term concern about the need for more effective and cheap diagnostics to identify infection more rapidly than the current three days, as well as new classes of drugs to tackle particularly resistant strains. “The worry is what will happen in five or 10 years’ time,” he says.

Furthermore, while efforts to combat MRSA are improving, the HPA’s data show a 5.5 per cent rise during the first nine months of last year in Clostridium difficile, a gut infection needing a different approach to hygiene control, for which antibiotics can accentuate the risk by eliminating useful microbes.

The challenge in fighting bacteria with new drugs is that all the most promising avenues of development have been pursued, leaving today’s researchers with a much harder task. Pharmaceutical analysts love to invoke the image of “plucking the low-hanging fruit” to explain why the industry is producing fewer and fewer new drugs as it spends more and more on research.

The image is particularly apposite in antibiotic development, partly because of the field’s long history and partly because bacteria present fewer potential targets than the human biological pathways at which most other drug classes are aimed.

Many scientists hoped that the decoding of bacterial genomes during the 1990s would lead to a productive new era of antibiotic discovery. This was a false promise, as researchers at GlaxoSmithKline, the UK-based pharmaceuticals giant, admit in a bleak assessment recently published in the journal Nature Reviews Drug Discovery. They say people do not appreciate “just how difficult it is technically and how much time it takes to make a novel antibiotic”.

GSK scientists spent seven years, using the latest high-throughput screening technology, to search vast numbers of chemicals for activity against the products of 300 bacterial genes. They found only five “leads” worthy of further development, a success rate four or five times lower than similar exercises in other areas – “a disappointing and financially unsustainable outcome”, the researchers say.

Yet the medical need for new weapons against bacterial infections is so great that GSK will stick with antibiotic research – and is reverting to more traditional techniques to discover new ones – says David Pompliano, head of biology. “If you take a cold-hearted view of the financial returns, you can’t see why big pharma would be in there,” he adds, “but I think this company has its heart in the right place”.

Many other large pharmaceutical groups have given up in the face of the technical obstacles and poor market incentives. “These factors have led to the overriding view that big companies can spend their research dollars in more productive ways,” says Holger Rovini, head of infectious diseases at Datamonitor, the London-based market research company. “Ten out of the 15 largest companies have fully abandoned or cut down significantly their discovery efforts in this field since 1999.”

Datamonitor says the global antibacterial market grew at a compound annual rate of 5.1 per cent between 2001 and 2005 – slower than almost every other pharmaceutical sector – to reach $25.5bn (£13bn, €19.5bn). Projections for the next decade show the growth rate slowing to just 1 per cent a year.

Although sales of hospital antibiotics are rising more rapidly, the overall market has been held back by declining sales of the “community antibiotics” (mainly cheap generics) prescribed by family doctors as public health campaigns in the UK, France and elsewhere have had an effect.

Sir Anthony Coates, professor of microbiology at St George’s Hospital, London, points out that official restrictions on the use of antibiotics, intended to control the emergence of resistance, act as a disincentive to pharmaceutical innovation by cutting the sales of new products.

But the medical profession agrees that such restrictions are necessary, says Clive Page, professor of pharmacology, King’s College London: “It is estimated that if you introduce a new antibiotic today with a completely novel mechanism of action, resistance to it will have emerged somewhere in the world within 18 months,” he says.

Nevertheless, the antibiotic development scene is not all gloom. Last week AstraZeneca announced a $100m investment in a new research centre in Boston, which will focus on finding new treatments for infections. John Rex, the company’s head of infectious diseases, says: “We need to discover completely new classes of bacteria. We are looking for something structurally novel, for which there is no pre-existing resistance.”

Treatments for the MRSA superbug are by far the fastest growing sector of the antibiotic market. Datamonitor forecasts that their sales will rise from about $1.3bn in 2005 to $6bn in 2012. They also dominate the antibiotic development pipeline, with many smaller biotechnology companies coming up with new approaches.

Last month, for example, e-Therapeutics, a spin-out from Newcastle University, said it was planning clinical trials for three closely related drugs that kill the MRSA superbug. “We are going for a cluster-bomb effect, targeting a variety of bacterial proteins, which will make it harder for the bacteria to develop resistance,” says Malcolm Young, chief executive.

“You are going to see a lot more re-engineering of existing antibiotics – trying to get more life out of them – which is not a stupid thing to do,” says Prof Young. “But I’m more interested in wacky left-field ideas, making things that bacteria will not have seen before.”

Several other small UK biotech companies are pursuing innovative approaches to MRSA. Destiny Pharma, based in Sussex, is developing a light-activated antibiotic. Prolysis of Oxford is targeting a bacterial protein called FtsZ that is essential for cell division. Helperby Therapeutics of Yorkshire is going after bacteria in their dormant phase, which resist attack by conventional antibiotics.

The challenge is creating mechanisms that compensate for the “market failures” of small volume and low price at the core of the antibiotic field, as well as marshalling the broadest range of intellectual effort to tackle the considerable scientific challenge.

Recognising the funding gap between academics and commercial backers, the Wellcome Trust, one of the world’s largest medical charities, last month launched a new seed fund which included support to one group researching MRSA. The non-profit TB Alliance has raised funds to launch collaborative projects sharing ideas and intellectual property between pharmaceutical companies and university researchers.

That there are some signs of progress is just as well. In the fight against continuously mutating superbugs, standing still is not an option.


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