Public health: Raised resistance
A researcher works on new antibiotics to combat bacteria, which are becoming an increasingly globalised threat as international travel increases
Every morning when she arrives at Hygeia hospital in Athens, Helen Giamarellou, a senior doctor, starts her day by walking the wards, checking on hygiene and quizzing staff as she attempts to prevent a deadly infection spreading across southern Europe.
Even before the financial crisis added to the difficulties, Greece was on the frontline of what she calls “a killer strain” of the Klebsiella pneumoniae bacterium resistant to the carbapenems, a class of potent “last-line” antibiotics used to treat infections when all other drugs fail to work.
Since 2009, when it was first detected in Europe in nearly half of the dozens of hospital patients tested, the strain has spread from Greece to many other EU countries, threatening the treatment and survival of those with problems such as bloodstream and urinary tract infections.
More than half a century since the development of antibiotics led to hubristic claims that infectious diseases would soon be confined to history, health specialists are alarmed at the number of microbes that are increasingly impervious to drugs.
Many of the problems are man-made. Years of improper use of drugs – with patients not completing full courses of antibiotics or buying them unnecessarily over the counter – have made medicines ineffective. Antibiotics, and antiparasitics such as those that fight malaria, are increasingly failing, reversing mankind’s battle against diseases where victory had once seemed assured.
In a stark example, planners of the 2012 Olympic Games are considering tuberculosis: not only brought in by visitors but also contracted by them in London, which has become one of Europe’s leading centres of the disease, with a growing number of cases resisting basic treatment. Yet research into new antibiotics is limited. The science needed to outpace superbugs is complex, while the modest market means the pharmaceutical industry has instead focused on more prominent illnesses such as cancer and diabetes.
“I’m getting more and more worried,” says Otto Cars, professor of infectious disease at Uppsala university in Sweden, who chairs React, a global network that has campaigned over the past decade to fight antibiotic resistance. “We have built modern medicine on a reliance on antibiotics, but are now heading towards a world without them.”
The costs of this increased resistance are counted in loss of human lives and economic output alike. In the EU alone, researchers estimate that drug-resistant bacteria kill 25,000 patients a year, at a cost of €1.5bn to the healthcare system and to lost productivity. In the US, at least 12,000 die annually in the same way.
Weaker health systems in many poorer countries mean that even measuring the impact elsewhere is difficult. Yet, as senior figures gathered at the World Health Assembly in Geneva to discuss the issue last week, Thailand said it estimated antimicrobial resistance was costing the country $2bn a year in lost productivity, with 30,000 deaths from blood poisoning alone.
In Ghana, which co-sponsored the meeting, officials were forced to close the children’s ward in Korle Bu, the country’s leading teaching hospital, in January after identifying a number of cases of the “superbug” methicillin-resistant Staphylococcus aureus (MRSA) infection. “That whipped up serious interest,” says Alban Bagbin, the health minister.
Increasing resistance threatens a rising number of people, since antibiotics are essential for those, including the elderly, seeking an ever larger number of medical procedures that carry risks of infection, from catheters and hip replacements to pacemakers and kidney transplants.
In a world of growing international travel, bacteria respect no borders. Greatest concern is focused on the group of bacteria such as Klebsiella pneumoniae and OXA-48 known as “Gram negative”.
In 2010, Professor Timothy Walsh from Cardiff university caused a stir when he tracked infection of several UK patients with the New Delhi metallo-beta-lactamase ndm-1 drug resistant strain back to India and Pakistan, where they had sought medical care.
“You can’t help thinking the tsunami has already arrived,” he says. “The problem is getting larger and nothing is being done about it. By 2020, pan-resistant Gram negative bacteria will be commonplace in our lives.”
One factor driving antibiotic resistance is inadequate infection control. Simple soap and water or alcohol gel can kill many bacteria, preventing transmission between patients, their visitors and medical staff. Screening and isolating patients also helps.
Yet such measures often exist largely on paper, with progress hindered by cost and the inconvenience of applying such practices rigorously and regularly. A number of cases across Europe of drug resistant strains have been caused by transferring patients between hospitals, including outbreaks of Klebsiella pneumoniae in French clinics from individuals previously in Greece.
Tackling tuberculosis: A formula that strikes back at superbugs
Faced with the risk of rashes, stomach aches and even hepatitis caused by drugs they must take for six months, it is understandable that many patients with tuberculosis fail to complete their treatment.
Add disruptions to supplies and poor quality products and the recipe is perfect for fostering multi-drug resistant TB strains estimated to infect half a million new people each year and kill 150,000.
So when the World Health Organisation launched World Antimicrobial Action Day last year to raise attention to the issue, it was no surprise officials seeking a champion turned to Mario Raviglione, who runs the agency’s TB unit.
TB is an extreme example of the wider problems of antibiotic resistance. Difficult science and the lack of a voice or money of its mainly poor patients means there has been no new drug for half a century.
“Many countries don’t even test for drug-resistant TB, so the problem is even greater than we think and it’s getting worse,” says Mel Spigelman, head of the TB Alliance, a non-profit group working on new treatments. “We’re seeing just the tip of the iceberg.”
But growing concern in recent years – and the emergence of drug resistance in richer countries – means TB researchers have been forced to innovate in ways that provide a potential model for tackling antibiotic resistance more generally.
They have developed pioneering partnerships between academics, doctors and drug companies, worked with regulators to find better ways to run clinical trials and built strong links to local communities to help ensure drugs are taken as prescribed.
As a result, the pipeline of new drugs looks more promising than for many years, with Johnson & Johnson, Otsuka and Pfizer among companies with experimental treatments.
That still leaves the question of pricing and ensuring usage is tightly controlled. Patrizia Carlevaro from Otsuka says: “We must learn the lessons of the past and ensure that new TB drugs are used rationally and delivered to market in a responsible manner.”
Mr Raviglione says the lessons from TB for other diseases threatened by drug resistance include the need for a global network of surveillance, quality assurance, suitable regulations and infection control techniques.
Ultimately, despite this month’s fresh calls at the World Health Assembly to tackle resistance, he says “it requires commitment, accountability and money” to ensure rhetoric is converted into practice.
Asecond issue is animal husbandry. Antibiotics have long had a common secondary application: treating and preventing disease in livestock. While boosting yields, they have also helped foster the development of drug-resistant animal strains of bacteria that threaten humans.
Dominique Monnet, responsible for antimicrobial resistance at the European Centre for Disease Control (ECDC), an EU-funded body, stresses there is not always a direct crossover. But he cites high levels of resistance to drugs such as ciprofloxacin from humans infected with campylobacter, salmonella and E. coli from fowl and cattle. “There is more and more evidence of a link between resistance and food animals,” he says.
More fundamentally, there are deep-rooted cultural attitudes towards the liberal use of antibiotics in many parts of the world. Long taken for granted, they have been substantially overused, allowing bacteria to evolve and adapt to undermine their value.
Figures released last year by ECDC showed the highest European volumes were consumed by patients in Greece, one of several EU countries that, as in much of the developing world, sells some antibiotics “over the counter” to paying patients without a doctor’s prescription.
That raises a danger of inappropriate self-diagnosis. For instance, an EU-wide survey in 2009 suggested that half of Europeans erroneously believed that antibiotics could kill viruses and were effective against colds and flu.
But Prof Giamarellou argues pharmacists and doctors also give antibiotics unnecessarily, either because their own training or ability to diagnose suitable infections is limited or because of perverse financial incentives. “If patients don’t get a prescription, they will just go to another doctor who will give them one,” she says.
Another concern is that even patients who are correctly diagnosed do not take their complete course of treatment. “No one likes to take medicine, especially if they are feeling well,” says Mel Spigelman, head of the TB Alliance, a non-profit group developing new drugs for a disease where even the basic treatment at present requires six months.
Substantial sales of counterfeit medicines and poorly manufactured “substandard” ones with the wrong strength or quality also foster resistance.
A final difficulty has been the absence of new antibiotics to replace existing ones, partly reflecting the complicated science that has helped drive a number of companies to abandon their work. Patrick Vallance, president of pharmaceuticals research and development at GlaxoSmithKline, says: “It’s a real concern. Bacteria live to overcome everything that biology throws at them.”
While stressing his group’s continued commitment, he says there are limited financial incentives for drug companies to remain involved. “There’s a very fundamental problem. The more you use an antibiotic, the more you will get resistance. So [as a doctor] you want a very good new one that you keep on the shelf and don’t need to use.”
Despite the concerns, there have been signs of progress. France has reduced antibiotic use through public awareness campaigns. Mr Monnet says MRSA appears on the decline in some European countries and animal drug resistant strains are stable, although cases involving carbapenem-resistant bacteria continue to rise.
Last week, the Innovative Medicines Initiative, jointly funded by the European Commission and pharmaceutical industry, unveiled a €224m research programme, NewDrugs4BadBugs, involving five companies committed to working with public bodies and academics to develop new treatments.
Industry has also recently proposed patent life extensions and ways to “de-link” any financial reward for developing a new antibiotic from the level of sales, as a way to discourage overuse. Executives remain nervous that the failure to tightly control distribution could still quickly jeopardise any new products developed.
Specialist meetings and political initiatives – including a European Commission plan adopted last year and publication of a report from the Transatlantic Taskforce on Antimicrobial Resistance launched jointly by the EU and the US – have also drawn up recommendations.
These include enhanced disease surveillance; improved infection control; joint efforts with regulators to ease the burdens on the development of new drugs; and campaigns to promote more responsible and limited antibiotic use. Others call for tougher penalties and inspections to tackle counterfeits and improve drug quality.
Yet such proposals have long been around, while progress remains modest. Prof Giamarellou argues simple measures including hiring more nurses to enhance infection control in hospitals, and the free distribution of cheap diagnostic tests to general practitioners in Greece to better identify infections requiring antibiotics, would easily pay for themselves. But like her counterparts worldwide, she is battling a reluctance to spend any money during intense budget cuts.
“I’m scared,” says Prof Cars. “We need to attack this issue on many fronts but there is no new political commitment. Resistance should be picked up by the G8 or the G20. We are soon arriving at a tipping point.”
For now, there is at least as much hand-wringing as hand-washing.