Enter the super-bug: Bacteria that cause diseases such as TB and diphtheria are developing resistance to the antibiotics we count on to fight them. Steve Connor on a medical disaster in the making

IT LIES in a state of suspended animation in the deep-freeze of a London hospital laboratory. It is a microbe that some scientists said could not possibly evolve. If it did, others warned, the world would be faced with a medical disaster. It is the super- bug of super-bugs because this deadly microbe can survive every antibiotic in existence.

Fortunately this strain of bacteria does not occur naturally - yet. It was created almost by accident in a little-publicised experiment three years ago at St Thomas's Hospital in London, where it is now stored under lock and key in its deep- frozen state. What makes it different from other strains of Staphylococcus aureus - a bacterial species that causes numerous blood infections from skin boils to food poisoning - is its resistance to the antibiotic of last resort: vancomycin.

This strain of Staphylococcus is impregnable to antibiotic attack. For hospital doctors the threat of such a microbe spreading among their patients is a nightmare prospect. Alexander Tomasz, of Rockefeller University in New York, one of the world's leading microbiologists, said last February that the appearance of a vancomycin-

resistant Staphylococcus would be 'nothing short of a medical disaster'. The experiment at St Thomas's was the final demonstration of what many medical experts are now saying openly: the era of antibiotics is coming to an end and the age-old infectious diseases are returning.

Antibiotic resistance has already become a problem with naturally occurring strains of Staphylococcus aureus. Hospitals have seen a strain that is resistant to everything but vancomycin. This multi-resistant microbe - known as Super Staph - has forced doctors to prescribe ever increasing amounts of vancomycin to control infections, which itself increases the chances of resistance to the drug.

Staphylococcus aureus has always been the microbe that hospitals fear most. It causes one in five of the infections acquired by patients during treatment because it thrives on the surface of medical devices such as heart pacemakers and catheters. Modern medical practice - such as organ transplants and cancer therapy - has increased the need for preventive treatment with antibiotics. The result, as one microbiologist puts it, is that hospitals are 'awash with antibiotics', providing the perfect environment for the evolution of bacteria that are resistant to more than one antibiotic.

The multi-resistant Staphylococcus aureus in the St Thomas's Hospital deep-freeze was born when scientists at the hospital's Institute of Dermatology mixed two species of bacteria to study how antibiotic resistance could spread from one bug to another. To their astonishment they found that relatively harmless bacteria could pass on vancomycin resistance to the deadly Staphylococcus. Before then, most microbiologists believed that no such thing could happen. 'If this strain gets out,' said Professor Bill Noble, who led the research team at St Thomas's, 'we're in trouble.' But Professor Tomasz believes it is only a matter of time before the strain occurs naturally.

The implications are terrifying. Over the past 50 years, antibiotics have all but eradicated the most dangerous diseases, such as tuberculosis, pneumonia, typhoid fever, diphtheria and meningitis. The sight of hospital beds filled with children affected by bacterial diseases - common even in the 1930s - is largely a memory.

That is already changing. Diphtheria is raging in St Petersburg and tuberculosis has struck New York. American health authorities are so worried about TB that it has imprisoned drug-addicted sufferers and forced them through a punishing schedule of drug treatment. The fear is not confined to down-and-outs. Two years ago, dealers at New York's World Trade Centre were asked to take the TB test - and wear a badge if they were negative - before they were allowed on to the exchange floor. Yet, in 1958, one expert predicted that TB would soon become a 'medical curiosity'.

THE conquest of TB, and of other infectious diseases, began with Alexander Fleming's discovery of penicillin in 1928. Fleming noticed how a fungus - penicillium notatum - growing in a laboratory dish kept the surrounding bacterial colonies at a distance. What he was seeing was the effect of an antibiotic. Secreted by the fungus into the surrounding nutrient jelly in the dish, the antibiotic prevented the growth of bacteria.

The discovery revolutionised 20th-century medicine. Bacteria are responsible for many, though not all, of the world's most deadly diseases. They are single-celled organisms, mostly living in the fluid- filled spaces between human cells. They have their own life- support systems and antibiotics are able to undermine them. (Viruses, by contrast, are fragments of genetic material that live inside human cells, making them invulnerable to antibiotics. This is largely why viral diseases - from the common cold to Aids - have proved so difficult to cure.)

Within barely 10 years of Fleming's discovery, scientists had isolated the active ingredient of the fungus he observed and so developed penicillin into the medicine that saved countless lives during the Second World War and afterwards. They developed antibiotic drugs to treat just about every bacterial illness. By 1968, the Surgeon General of the United States - America's top medical officer - was telling Congress: 'The time has come to close the book on infectious diseases.'

But even as he spoke the bugs were fighting back. One of the most significant early-warning signs came in 1967 from a remote village in Papua New Guinea, where doctors were confronted with a strain of Streptococcus pneumoniae - a lethal infectious bacterium - that was resistant to penicillin. Ten years later the strain had spread to South Africa and had become resistant to several other antibiotics along the way. By the 1990s, such multi-resistant strains of the pneumococcus were no longer oddities. They had become global killers.

'The pneumococcus,' Professor Tomasz said, 'is one of the most frequent causes of community-acquired (infectious) pneumonia worldwide. It also causes life-threatening bloodstream infections and meningitis. It is a major cause of middle ear infections in children. Globally, pneumococcal disease is estimated as having a mortality similar to the mortality of tuberculosis - in the order of two to four million per year.'

The World Health Organisation has recently declared TB a global health emergency that is expected to kill about 30 million people over the next 10 years. Hospitals in the US, especially in New York, have detected a dramatic rise in multiple-resistant strains of the tuberculosis bacterium. Of the 26,300 cases of TB in the US during 1991 - a rise of 18 per cent since 1985 - more than one in seven patients could not be treated with two or more of the most powerful antibiotics.

Professor Tomasz believes that we are on the brink of medical disaster - a bacterial disease that is resistant to all antibiotics is no longer science fiction, he says. His words are echoed by Professor Brian Spratt, an expert on the development of drug-resistant bacteria at the University of Sussex. 'The advent of antibiotics produced a truly astounding revolution in medicine, allowing essentially all bacterial diseases to be cured, and leading to the view that the battle against the bacteria had finally been won. Unfortunately, this view has turned out to be wrong . . . After 50 years of the antibiotic era, there is now a feeling that we may be heading towards a post-antibiotic era - a time when antibiotics can no longer be relied upon to cure major bacterial infections.'

WHAT has gone wrong? The simple answer is sex. In the last couple of decades scientists have realised that bacterial sex is not as straightforward as they first imagined. Microbial sex allows the free exchange of genetic material and with it the chemical instructions for developing antibiotic resistance. What has suprised scientists is just how ready bacteria are to form sexual liaisons with just about any other microbe, which makes it easy for resistance genes to pass from one microbial species to another.

But how do resistance genes come about in the first place? To answer this question, it is important to understand that antibiotics are mostly compounds that have existed in the soil for probably millions of years. The first antibiotics were created because in the Darwinian struggle for survival, some microbes gained an advantage over their cousins by killing them off with poisons. ('Antibiotic' means 'against life'.) The microbe that secreted a chemical toxin - the antibiotic - stood a better chance of survival. And it passed on the trait to future generations.

But the microbes that produced antibiotics needed some means of resisting attack from their own toxins; otherwise, they ran the risk of poisoning themselves. Thus resistance genes came about and, with them, the beginnings of an underground 'arms race' lasting billions of years. The pressure to produce new ways of killing competitors was equalled by the pressure to acquire new forms of resistance.

Humans were oblivious to all this until Fleming made his discovery in 1928. Now, drug companies look for 'new' antibiotics (actually ancient ones that remain undiscovered) by sifting through soil samples from around the world in search of 'new' microbes. This adds to the problem, Professor Spratt says. 'If you do find a new antibiotic then almost certainly there will be already in the soil a resistance gene that can destroy it.' And the free- love lifestyle of the microbe enables these resistance genes to move into the bacteria that cause disease.

Resistance to antibiotics can come in various forms. One of the simplest and most effective is for bacteria to produce an enzyme that breaks down the antibiotic molecule. This is how many bacteria become resistant to penicillin. Drug companies have responded by tinkering with the structure of the antibiotic to try to evade the enzyme, only to find about five or six years later that some bacteria have acquired enzymes that are able to destroy this new generation of antibiotics.

A second way resistance can develop is for the bacteria to change the structure of the 'target' protein that the antibiotic attacks - equivalent to a bacteria changing the locks on a door to prevent the antibiotic 'key' from working. The best example of this is resistance to methicillin, an antibiotic introduced 30 years ago to treat infections of penicillin-resistant bacteria. Within 10 years, however, bacteria had hit back, and now methicillin-resistant Staphylococcus aureus - Super Staph - is a serious problem in many hospitals throughout the world. Last April a dozen patients at Guy's Hospital in London were found to be infected with methicillin-resistant staph. One woman died.

It was the antibiotic of last resort - vancomycin - that medical scientists felt confident would hold the line against drug-resistant microbes like Super Staph. Vancomycin works differently from other antibiotics. It actually binds to the cell walls of the bacteria, causing them to burst like a balloon. Professor Spratt said that to get vancomycin resistance 'you would have to change the structure of the cell wall . . . and it was thought that bacteria would have no way of doing that'.

Then, in the past few years, bacteria emerged in hospitals that were resistant to vancomycin. 'The mechanism is incredible. You have this set of genes which allow the bacteria to produce a completely different cell wall,' Professor Spratt said. 'They arrived from nowhere. What's amazing is that it is another example of something that is totally unexpected. Everyone thought you can't get resistance. But once people started using vancomycin a lot, suddenly resistance appeared.'

From Paris, however, there came reassuring news. An eminent microbiologist at the Pasteur Institute had tried and failed to transfer the vancomycin genes from the bacteria where they were found - relatively harmless microbes that live in the gut - to the deadly Staphylococcu. But then Professor Noble and his team at St Thomas's began their experiment using the simple procedure of mixing the two kinds of bacteria on the surface of the skin. He covered the microbes with a plaster and allowed them several hours in the warmth and sweat to get to know one another. The fruit of this union

was the strain of vancomycin- resistant Staphylococcus now stored in Professor Noble's deep freeze. He keeps it like any scientist keeps a record of an interesting experiment and is adamant it is safe and secure. 'Things don't walk on their own,' he says.

But, Professor Spratt says, the events in the experiment are bound to occur naturally before long. 'It's actually quite surprising it hasn't happened already, because generally we think anything you can do in the laboratory, nature can do.'

With hospitals in the US relying increasingly on vancomycin to clear up troublesome infections, the perfect conditions exist for resistant strains to evolve. And since bacteria can produce millions of offspring in a day, just one mutant carrying the vancomycin-resistant genes would be enough to trigger a global pandemic.

IT IS the overuse - and misuse - of antibiotics that has been blamed for the dramatic increase in all types of resistant bacteria. Treatment with antibiotics has got to be given regularly and over several days or weeks - sometimes months - to ensure that all partially resistant strains are effectively wiped out. Stopping treatment mid-way through a course - even if the symptoms have disappeared - would allow the partially resistant bacteria that may have survived to repopulate. This is why doctors always insist patients must finish a course of antibiotics.

The growth of TB in New York is a prime example of how antibiotic use can go wrong. 'If you want to cure TB you've got to have a combination of drugs for six months to a year,' Professor Spratt explained. 'It's very hard to get anybody to remember to take their drugs three times a day for six months to a year. To get somebody on the streets, on crack cocaine with TB, to take their drugs is impossible. So you have this population who take their drugs for the first couple of weeks, forget, and then take them again for a while. That's exactly the sort of conditions you need for resistance to develop.'

The appearance of resistant TB in New York does not surprise him. 'TB is a disease of poverty. The situation in parts of New York is like the Third World and incidence of TB in parts of the Bronx is like the incidence in the Third World.' To make matters worse, because doctors in America fear being sued by patients who fail to be cured of an apparently routine infection, they are ll too ready to prescribe antibiotics.

What happens in the US - indeed anywhere in the world - in terms of antibiotic resistance affects everyone. A prime example is the multi-resistant strains of Streptococcus pneumoniae. This bacterium began acquiring resistance to the older antibiotics - such as penicillin - in Spain. Over the past 10 years it moved to the US, where it quickly acquired resistance to the most modern antibiotics, the third generation cephalosporins.

Children with bacterial meningitis (distinct from viral meningitis, which is usually less serious) caused by this strain of Streptococcus can only be treated by injecting vancomycin directly into the spine. If this strain becomes resistant to vancomycin, we could see bacterial meningitis regaining its notoriety as a large-scale killer of the young.

The ease with which bacteria acquire antibiotic resistance combined with the dearth of new antibiotics coming out of the drug companies' research labs point to a bleak future. 'Perhaps 10 years ago there looked as if there were enough antibiotics around for us to cope,' Professor Noble explained. 'I'm not certain whether we are getting smarter at detecting what's going on, or whether the bugs are getting smarter at doing things.'

History tells us that whenever a new antibiotic is introduced, it takes only five or six years before resistance develops. Like Professor Noble, Professor Spratt is pessimistic, because not enough is being done now to counteract the overuse of antibiotics. At the same time, drug companies are showing little interest in the problem. 'It's always been this battle between the bacteria and the chemists and my worry is that the bacteria will not give up, but the chemists might.'

(Photograph omitted)

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