LAST DECEMBER, a 10-year-old boy living in Louisiana developed a cough, earache and fever. By the next day his fever had risen and his breathing had deteriorated and he was taken to hospital. Less than 48 hours later, he died from pneumonia.
Three weeks after, a 14-year-old boy, also from Louisiana, was taken to hospital with flu symptoms. Two days later his breathing problems got worse and he died from severe pneumonia.
These two children were among six in Louisiana and Georgia to have died from pneumonia last winter for the same reason. The illness that claimed their lives was caused by the “hospital superbug” MRSA, aka methicillin-resistant Staphylococcus aureus. Yet none of the children had been anywhere near a hospital.
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This sinister development was highlighted by a in Atlanta, Georgia. The article warned of the rapidity with which a seemingly simple cough or cold could turn into a lethal illness, often killing its victim in just a few days.
How did the children pick up such a deadly infection? We hear a lot about antibiotic-resistant bacteria in hospitals, but the truth is that a frightening range of superbugs are lurking just about everywhere. They skulk around our homes, in schools, and at the local gym. They live in our guts, on our skin and up our noses, and within a few years of emerging, some strains have spread round the world.
The onward march of the superbugs comes at a time when drug companies are investing less in developing new antibiotics. Some doctors say it is time to start screening and isolating people whenever outbreaks occur. They fear that the increasing invulnerability of these bacteria could one day make us as defenceless to common ailments like pneumonia as we were before the advent of antibiotics. “We have the emergency room ready to respond the minute the patient hits the door,” says Robert Daum, a paediatrician at the University of Chicago Children’s Hospital, who was one of the , in 1998. “Yet we still have 50 per cent mortality.”
Antibiotic resistance may seem like a modern scourge, but in fact it has been around almost as long as antibiotics themselves. The drugs have saved countless lives since Alexander Fleming discovered penicillin in 1928, but the first recorded case of penicillin resistance was in 1947, just four years after the drug had gone into mass production.
What makes antibiotic resistance so inevitable? The drugs work either by stopping bacteria from multiplying or by interfering with crucial functions such as protein synthesis or the maintenance of their cell walls. Because of the natural genetic variation within a group of constantly mutating bacteria, a few may have the ability to withstand the antibiotic. The genes that confer this resistance could code for an enzyme that destroys the antibiotic, a pump that expels it from the bacterial cell, or a slightly altered form of the antibiotic’s target molecule, for example.
Any resistant bacteria have such an advantage that they soon outnumber their non-resistant peers, either inside the body of the person taking the drug, or in an environment where it is often used, such as a hospital. “We’re seeing survival of the fittest in action before our eyes,” says Richard Wise, a microbiologist who heads the UK government’s committee on antimicrobial resistance. “Darwin would have recognised it straight away.”
In a twist that Darwin could not have foreseen, resistance can also spread between different species of bacteria, thanks to their propensity for swapping genes in packages of DNA known as plasmids, and through viruses that infect bacteria.
Certain measures can help to combat antibiotic resistance. For the patient, it is crucial to take every dose in a course of antibiotics, and to finish it off. If bacteria are exposed to low levels of an antibiotic, then any with partial resistance to the drug will multiply faster than their non-resistant peers, increasing their chances of developing a further mutation that gives full resistance.
At the community level, the more antibiotics are used, the more resistance will grow. So doctors are heavily discouraged from using them unnecessarily, which is why they may now turn down requests for the drugs from people with coughs and colds, which are usually viral. There are also efforts to crack down on antibiotic use in farming, particularly the practice of constantly feeding them to livestock at low levels.
These steps can only slow down the inevitable, however. While there are a large number of antibiotics available, including about a dozen main classes, more and more of the drugs are ineffective. Often a single mutated gene will make bacteria resistant to an entire class of antibiotics. And once a new mutation occurs, global trade and travel mean resistant strains can quickly spread round the world. In response, doctors are increasingly turning to the antibiotics they’ve been keeping to use as a last resort.
Scare in the community
Hospital and nursing home staff have been battling superbugs for decades. Perhaps the most notorious is MRSA, which emerged in the UK in 1961, a mere two years after the antibiotic methicillin was first used. MRSA is impervious to the whole class to which methicillin belongs, the beta-lactams – which account for nearly half of all antibiotics used – as well as to several other antibiotics.
When facing MRSA doctors often turn to vancomycin, an intravenous antibiotic of last resort, although there have recently been several cases of MRSA that are partially resistant to this drug too, and seven documented cases worldwide that were totally resistant. “Vancomycin is escaping us, slowly but surely,” says Daum.
Now the archetypal hospital superbug has set up home in the community. Around a third of us probably carry the standard form of S. aureus harmlessly on our skin or inside our noses. Occasionally, it may lead to things like boils, abscesses or even pneumonia, but until now these have been easily treatable.
It is nine years since Daum drew attention to the cluster of patients at his hospital whose S. aureus turned out to be MRSA (Journal of the American Medical Association, vol 279, p 593). Puzzlingly, the patients seemed to have picked up their infection before they had reached hospital. Initially his discovery was written off as a Midwestern curiosity, says Daum, but community MRSA has gradually spread to more and more areas, and in some places it is now more common than the non-resistant form. Those who seem especially vulnerable include young people, gym-users, and those taking part in contact sports or living in close proximity, such as prisoners.
Now the strain has spread across Canada, Europe, Australia and Asia. “Everywhere it has come it has stayed, and it comes to more and more places every day,” Daum says.
Certain distinguishing features suggest community MRSA is not merely an escapee from hospitals. For one thing it is more virulent, thanks to a pair of genes that produce a toxin called PVL or Panton-Valentine leucocidin, which punches holes in immune cells, disrupting the body’s defence systems. On the plus side, community MRSA is usually susceptible to certain antibiotics that no longer work for hospital MRSA, including clindamycin and tetracycline. But this may not be the case for long, because it seems to be picking up resistance genes from its hospital-based cousin. “Once these community strains get into hospitals I would be surprised if they don’t pick up more resistance determinants,” says Robert Skov, head of the Danish National Centre for Antimicrobials and Infection Control in Copenhagen.
Although it gets the most attention, MRSA is by no means the only superbug out in the community. It is getting harder to treat patients with severe salmonella food poisoning. Resistant strains have been gaining ground since they first emerged in the 1990s, driven by the use of antibiotics in livestock farming. In May the CDC reported that in Thailand multi-drug resistant strains are passing from chickens to people and that these strains are spreading to the US and Europe via imported Thai food products.
Another important cause of bacterial infections in the community is streptococcus, which can cause respiratory illnesses ranging from sore throats and coughs to full-blown pneumonia. Growing resistance to the beta-lactams in the 1990s prompted family doctors to switch to another major class called the macrolides, but now as many as a third of all streptococcus infections are resistant to these, too.
Bacteria called enterococci, which are often present in the guts of humans and animals, can cause urinary tract infections and blood poisoning. This group are now also impervious to the beta-lactams and increasingly resistant to vancomycin and another important group called the fluoroquinolones. The UK Health Protection Agency has reported that since 2003, more patients with these infections end up in hospital and more are dying. The list goes on.
Frustratingly, coming down hard on one superbug can leave patients vulnerable to another. Doctors are increasingly having to use broad-spectrum antibiotics that kill nearly all bacteria, including the beneficial ones in our gut. This blunderbuss approach allows a bacterium called Clostridium difficile to thrive, as it is resistant to all but two antibiotics. Carried harmlessly in the bowels of around 5 per cent of healthy people, C. difficile seizes its chance when friendly gut flora are suppressed, causing severe, life-threatening diarrhoea and toxic damage to the colon.
Like MRSA, C. difficile has long been seen as a hospital superbug, but a recent were increasing faster than those in hospitals (vol 334, p 708). One reason could be the growing use of anti-ulcer drugs that suppress stomach acid production, thus allowing the bacterium to establish infection.
There was a time when C. difficile mainly afflicted the elderly, but younger people are now falling prey to it and the disease has become more severe. A highly virulent strain known as ribotype 027, which produces 10 times as much toxin, has become widespread in Canada and the US and was responsible for a major outbreak in the UK in 2004/2005.
What we desperately need are more antibiotics. Unfortunately, the supply of new drugs isn’t keeping pace with the demise of older ones (see Bar chart). Drug companies are loath to invest millions in developing drugs that doctors initially only use as a last resort, may become redundant within a few years and are taken for only brief periods compared with drugs for lifelong conditions such as diabetes.
Retapamulin, an example of the first new antibiotic class to be developed in nearly 20 years, was approved in the US and Europe this year, and a few others are on the horizon. But if the trickle is to become a torrent, we need more publicly funded research, says Daum. “There needs to be a research call to arms.”
In the meantime, we can try to reduce the spread of superbugs. Some hospitals are screening patients for MRSA and isolating carriers while the bacteria are cleared from their skin and nose with antiseptic. Earlier this year, hospitals in England and Wales were sent for people scheduled to undergo certain types of surgery.
Some doctors want all patients to be screened, however, even those admitted as an emergency or visiting an emergency room. That would mean using rapid – and costly – genetic tests, and most hospitals would need more isolation beds. According to Richard James, director of the Centre for Healthcare Associated Infections in Nottingham, UK, it would save hospitals money in the long term. He cites figures from the US that suggest treating a patient with MRSA costs between $30,000 and $40,000. And if community MRSA became as widespread in the UK as it is in the US the economy would feel the pinch in terms of loss of earnings, he points out. “The cost to the UK economy would dwarf the extra costs to the National Health Service.”
In Scandinavia they have taken the battle against MRSA into the community. “Every case of MRSA, regardless of whether it causes infection or is just colonisation, is a transmission possibility,” says Skov. “That means we should fight MRSA in the community too. If you don’t then you will have a silent pool who are continuously spreading it to other people.”
“If we don’t fight MRSA in the community, a silent pool will be constantly spreading it”
This strategy seems to have worked in the county of Jutland in Denmark, where an outbreak of community MRSA was contained by sending nurses to people’s homes to treat carriers and educate them and their families about hygiene. Simple measures like hand washing and not sharing towels, razor blades or gym equipment were effective. “Just by instructing people in hygiene you can get quite far,” says Skov. Similar measures in Finland and Sweden have led to a decrease in the rates of community MRSA.
Strategies like these may well hold antibiotic-resistant bacteria at bay in countries where they are not yet dominant outside hospitals. In the US, however, the MRSA genie escaped the bottle a long time ago. Daum believes the problem is now too widespread in his own country for screening to have much impact. “We’re seeing these infections in the general population more than we ever have before,” he says. “And there’s potential for those strains becoming even more resistant. That’s real bad.”
Double whammy
What do you get if you cross MRSA with bird flu? A “nightmare scenario”, says Paul Williams of the Staphylococci Research Group at the University of Nottingham, UK.
MRSA is usually seen as a hospital superbug, but in the US it is increasingly causing infections such as pneumonia in people who have been nowhere near a hospital, and the signs are such “community” MRSA is spreading round the world.
Most flu experts say it is only a matter of time before the next global pandemic occurs, possibly stemming from the current H5N1 bird flu outbreak, or perhaps triggered by a different viral strain. In previous pandemics it was not the flu virus itself that killed most people but pneumonia caused by streptococcus or staphylococcus bacteria.
“If these community strains with their broad antibiotic resistance were to get in on the back of an influenza outbreak that could create a huge public health problem,” Williams says. The 1918 flu pandemic, which occurred before the development of antibiotics, led to the death of between 50 and 100 million people. We could see similar numbers this time round.
