Why antibiotics are losing the war against bacteria Dr Chan left her audience under no illusion about the consequences if a global action plan is not drawn up to deal with anti-microbial resistance (AMR). If current trends continue unabated, the future is easy to predict," she said. Some experts say we are moving back to the pre-antibiotic era. This will be a post-antibiotic era. A post-antibiotic era means, in effect, an end to modern medicine as we know it. Things as common as strep throat or a child's scratched knee could once again kill. Throughout the medical community and the pharmaceutical industry, Chan's bleak sentiments are shared. The situation is so grave that most of the experts now involved in tackling AMR turn immediately to martial analogies. 'It's an ongoing war of attrition," says David Livermore, the director of antibiotic resistance monitoring at the Health Protection Agency (HPA), the independent organisation set up by the government in 2003 to monitor infectious diseases in the UK. In the ebb and flow of man's war against the microbes, he adds, 'we certainly seem to be down now. Since Fleming opened hostilities in 1928, that war has gone through several phases, with the combatants - antibiotics and bacteria - each scoring notable victories. In the late 1950s and early 1960s, resistance began to emerge in bacteria as a result of widespread use of antibiotics as growth promoters in livestock. This led, in 1969, to the Swann Report, which culminated in the banning for use in animals of any antibiotics used in human medicine. The 1980s proved to be a 'golden age" for medicine; whole new families of antibiotics were discovered, leading to the development of a host of new drugs. But then the bugs launched the fightback, developing resistance either by preventing antibiotics reaching their targets within the bacteria cell, or by somehow defusing the drug once it struck home. To a degree, such counterpunching was an unavoidable by-product of evolution. As random mutations in bacterial genes throw up strains that are resistant to antibiotics, those strains survive and thrive while others are killed off. On top of that, bacteria also host loops of DNA known as plasmids, which carry resistance genes. Plasmids are highly mobile, and can pass from one bacterium to another, spreading resistance against antibiotics as they go. Such genes make enzymes that inactivate many antibiotics. 'When I started my PhD in 1987 there were one or two enzymes conferring resistance found in bacteria across the EU," notes David Payne, the head of antibacterial drug discovery at GlaxoSmithKline (GSK), the world's fourth largest pharmaceutical company. Now these enzymes are everywhere, all over the world - in just 20 years. That to me is absolutely remarkable. It is clear that we now need whole new classes of antibiotics. Others think that the development of new drugs is not enough. Jane Stockley is a consultant medical microbiologist at the Worcestershire Royal Hospital, and the president of the British Infection Association, which represents microbiologists in the UK. She says we must make better use of the antibiotics we have. Too often, we over-consume antibiotics. Every time we use them, we expose bacteria to the drugs, potentially allowing them to develop immunity. Patients demand them for colds, even though colds are caused by a virus (antibiotics work only against bacteria). Sometimes we take the wrong drug or too little of it, which rather than kill off the bug allows it to hone its defence mechanisms. This is why patients are always advised to complete a course of antibiotics, even if they feel better. 'Every week we are sent surveillance data from the HPA," Stockley says, 'and what we have seen is a steady increase of cases which have become resistant - often imported from abroad." Among the most notorious enzymes currently promoting resistance in bacteria is New Delhi metallo-beta-lactamase 1, or NDM-1. It confers resistance to carbapenems, a class of beta-lactam antibiotics (like penicillin) and one of the largest and most widely used families of antibiotics. NDM-1 can transform its host bacterium - such as E. coli - from nuisance to killer 'superbug. As befits its name, NDM-1 has its origins in India. But in 2008 it was discovered in a Swedish patient of Indian origin. Almost immediately after being discovered in Sweden, NDM-1 was found in the UK. In May 2010 a British man of Indian origin was hospitalised with NDM-1-enhanced E. coli. This strain was resistant to every antibiotic deployed against it. Eventually it was found to be susceptible to the antibiotic tigecycline (a drug fast-tracked on to the market in 2005 in response to AMR), and colistin, whose toxicity means it is used only as a drug of last resort. Since 2008 NDM-1 has spread around the world, from America to Japan, conferring antibiotic resistance on myriad bacterial strains. In 2010 it claimed its first life - a Belgian man involved in a car accident on the subcontinent. Repatriated to Belgium, he was given colistin, but even that could not save his life. The Belgian man had been treated in a hospital in Pakistan before being repatriated, and almost certainly picked up NDM-1 on the subcontinent. Similarly, most of the 88 British cases of NDM-1 have been contracted by patients treated in Indian hospitals, some of whom had travelled to India for elective cosmetic surgery. They unwittingly helped to unleash a potentially devastating enzyme on Europe in one 10-hour flight. Air travel is, understandably, a microbiologist's nightmare. How do you control people travelling around? It's impossible," says Jordi Vila, the scientific programme director of the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), a vast annual conference (which this year took place in London in early April), attracting 13,000 delegates from all over the world. Are you going to give everyone who arrives from India a rectal swab? For most of us, such tales of rapidly spreading superbugs are cause for morbid curiosity. But there are people in Britain, dependent on antibiotics, who know the seriousness of the problems that we could all face in future. Sharon Brennan, 31, from Herne Hill in south London, has cystic fibrosis (CF), an incurable genetic illness that attacks the lungs. One of the principal methods to slow the rate at which that happens is the use of antibiotics. My lungs are susceptible to infections," Brennan says. That produces scarring which reduces lung function. The aim is to stop the infections. I'm on three antibiotics a day. Improvements in treating CF have had a remarkable, transformative effect on the lives of patients with the condition. In the 1960s CF was seen as a childhood illness," Brennan says. People would die in childhood. But there have been incredible advances. Now lots of people are going to university and getting married. Brennan married last year, and acknowledges gratefully that her life 'has been a life with antibiotics. I wouldn't be here without them. She can still remember the banana flavour of the antibiotic syrup she took as a child. The problem is that, since then, those drugs have not changed much. During her regular visits to hospital, Brennan is given blood tests that detect the drugs to which the bacteria she carries are resistant. She is then presented with a 'menu" of antibiotics. But for as long as she can remember, she has always had the same menu. I have never been given a new antibiotic," she says. In recent years a lot of research has gone into gene therapies to address CF. But Sharon Brennan feels that such time and money would have been better spent on developing new antibiotics. People have taken their eye off the ball with antibiotic research," she says. It certainly seems that way. Statistics for the past quarter of a century - the same 25 years in which bacteria have staged their remarkable fightback - are revealing. According to Prof David Shlaes, a microbiologist and former vice-president at the American drug company Wyeth (now owned by Pfizer), the pharmaceutical industry has undergone extraordinary consolidation in the period. Between 1980 and 2003 the companies Aventis, Bristol-Myers Squibb, GSK, Novartis, Pfizer and Wyeth absorbed smaller research outfits and merged repeatedly. What had started in 1980 as 70 companies, each with original ideas and different ways of doing things, ended up in 2003 as only six. While consolidation brings advantages of scale, it inevitably means fewer people working on fewer ideas. Between 1983 and 1987 the Federal Drug Administration (FDA), America's drug regulator, approved 16 new antibiotics. Over the next four years, that fell to 14, and kept falling. Between 2008 and 2012 only two new antibiotics were approved, one every other year. Consolidation is just one of the problems. Large drug companies point to a host of hurdles that stand in their way when it comes to developing new antibiotics. Chief among these is the fact that the obvious candidates for drug development have already been identified. A lot of the low-hanging fruit has gone," David Livermore says. David Payne insists that GSK has a 'significant commitment" to developing antibiotics to address 'the unmet medical need." But he admits that 'the commercial parts of this are challenging" - diplomatic speak for the fact that antibiotics cost a huge amount in research and development. Bringing new drugs to market costs a fortune. And even if a drug is successful, pharma companies hold the exclusive licence for only a limited time, usually 20 years from the date of filing the patent (so the licence could be a decade old before the drug reaches the public). After that, other firms are able to produce the same drug. As competition for research funding intensifies within pharmaceutical companies, it is little wonder that boards of directors are shy of backing antibiotics. Compared with statins, or pills to control heart conditions or diabetes, many of which have to be taken for life, the profit in antibiotics, which are generally taken for a week or two, is small. Payne recognises this. In a perfect world he would like to see a whole new model of funding. Financial rewards for pharmaceutical companies should be based on the utility of the drugs they develop, he says, not the quantity of drugs that they sell. 'Antibiotics might be taken for only seven to 14 days, but might save someone's life and give them another 50 years," he says. Society has to realise the value of that. He acknowledges, however, that such a model would be revolutionary, and is 'a huge change from where we are now. No wonder that GSK is looking for funding for antibiotics from non-traditional sources. In 2010 the company published research in Nature magazine about an 'experimental antibiotic [that] kills bacteria already resistant to existing treatments. Last year it announced that it had signed a contract worth almost $40 million to develop new antibiotics. Both breakthroughs were the result of collaboration with two US government agencies, the Biomedical Advanced Research and Develop­ment Authority and the Defense Threat Reduction Agency. Bioterrorism is a word that loosens the purse strings. But drug companies must look for new strategies to combat the shortage of cash. One of these is the Innovative Medicines Initiative (IMI), a European Commission-driven public-private partnership with a €2 billion budget to stimulate pharmaceutical research and development in the EU. On a practical level, that means encouraging openness in an industry that is fiercely secretive when it comes to pooling its knowledge. Highly competitive researchers striving for Nobel Prizes in university labs and commercially driven teams at pharmaceutical companies desperate to find the next revenue-spinner are having to change their ways. Payne feels that researchers no longer have the luxury of jealously guarding every line of research. The need is too great. IMI means sharing information - and not just the successes," he says. 'The industry can't afford multiple companies to have the same failures. The other imperative, all agree, is for regulatory reform, particularly in America, where the FDA stands accused of regularly raising the bar that antibiotics must cross to get approved. The result is, as David Livermore says, 'a number of extremely complicated failures in clinical trials. Such hurdles mean that if new antibiotics do eventually reach the market, they may have cost between $500 million and $1 billion to develop. That is not counting all the failures that never make it out of the lab. Still, there have been success stories. Over the past decade the staphylococcus aureus (SA) bacterium has become the focus for enormous public concern. That is because it became 'multidrug resistant" - leading to its more widely known acronym, MRSA. Staphylo­coccus aureus lies behind a range of ailments, from spots and boils to sepsis and toxic shock syndrome. MRSA became a hot issue in the mid-2000s. Reports of the NHS being swept by indomitable 'killer bugs" gripped the nation. Infections reached their peak in 2003/4 with more than 7,500 cases reported to the HPA. Last year that fell to 1,185 - a reduction of more than 80 per cent. It turned out that tackling MRSA was a question of getting back to basics. Infection control in the UK was poor," says Dr Tim Boswell, the chairman of the Healthcare Infection Society, which advises infection control officers in hospitals. But the government reacted. Hygiene and cleaning improved. Every time there is an MRSA infection there is a root cause analysis," Stockley says. The cause can be as simple as not washing hands. For now at least, MRSA is 'yesterday's problem," according to Laura Piddock, a professor of microbiology at Birmingham University's School of Immunity and Infection. That is partly because bacteria fall into two categories, gram-negative and gram-positive. The latter group, which includes MRSA, have thick cell walls which, perversely, are more easily permeable by antibiotics. Gram-negative, Livermore says, have defences that are 'thinner but significantly trickier. Piddock, who is also the director of Antibiotic Action, a strictly independent initiative set up to raise awareness of the threat posed by AMR and stimulate funding for antibiotic discovery, is also working with her team on ways of bypassing the defences of gram-negative bacteria. Their structure is more complex than something like MRSA," she says. 'They're really clever, really sophisticated. If an antibiotic gets in, they promptly pump it out again. For that reason most of the drugs that have been developed don't work against gram-negative bacteria. Some researchers, like Piddock, are trying to find the off switch for bacteria's super-smart pumping mechanism. But such ideas can take more than a decade to win approval and reach patients; and then there is no guarantee that the bugs won't simply find a new way of stopping the drugs working. That prompts a healthy respect for bacteria among those trying to destroy them, for they are remarkable organisms. The problem is that bacteria are older and wiser than human beings," Piddock says. So how to defeat such super-organisms? At the ECCMID conference, it was clear that progress is being made in one crucial area: better diagnosis. When a patient arrives at a hospital with a serious infection, the first 48 hours are critical to survival. The problem is that it takes at least 48 hours for a swab from that patient to reach a lab and return to the hospital with the precise identity of the bacterial strain which is causing the infection. Once the bacterium has been identified it can be targeted with exactly the right antibiotics. But in those first, crucial 48 hours, the temptation, as Livermore puts it, 'is to treat the patient with everything you have. If we can get those 48 hours down to a few hours, we can tailor the treatment to the bacteria. At ECCMID firms big and small run stands to promote their wares to the doctors at the conference. This year a large number of those stands were promoting diagnostic aids - from sophisticated kit to equip a world-class laboratory, to so-called 'labs on a chip" - tiny boxes that could be used in GPs" surgeries or hospital wards to offer rapid diagnoses on the spot. Once you have the diagnostics you have the tool to develop targeted therapies," Piddock says. 'Then you don't have to keep using the big, broad-spectrum blockbuster drugs in treatment. Diagnostics in the next five years are going to revolutionise what we do. But it is not only the medical establishment that must change its ways. Success in dealing with MRSA has shown the power of a coordinated government response to public outcry. Yet there is little public outcry about AMR, despite the severity of the threat. I am trying to get everyone to understand the size of the problem," Piddock says. If people become aware that they could get an infection and that there might not be many options to treat them, I hope that will mobilise activity. It is not rare, exotic infections that should be worrying the public, it seems, but common bugs much closer to home. The two that keep Livermore awake at night are Klebsiella, one of the most common hospital bacteria, and E. coli - both gram-negative. E. coli is so frequently found that it causes up to 80 per cent of urinary tract infections in the UK, and more than 30 per cent of all UK cases of blood poisoning. What alarms Livermore is that these bacteria are quickly developing resistance to antibiotics. Ten years ago only four per cent of E. coli infections were drug-resistant; that figure is now 17 per cent. If Klebsiella and E. coli continue to accumulate resistance then a lot of modern medicine is going to become a lot harder than it is today - from gut surgery to chemotherapy," Livermore says. The storm clouds are gathering. So should we panic? Not yet, Livermore says. The individual patient going into hospital today should be OK. And if by some mischance they pick up an infection, it should be treatable. For the moment. But for the strategic planner working out how we're going to maintain our advances in two decades" times - there is real reason for concern." Piddock puts it more emotively: 'I'll be honest with you, a lot of people are scared, including some of my colleagues. I'm a mother of two children. If their children could die of an infection that was treatable in the 1990s, that's a scary scenario.