A bug in the system: the growing problem with antibiotics

Antibiotics changed the world - but some say a storm is coming, as decades of misuse and overuse have rendered many organisms resistant, while pharmaceutical companies seem unable or unwilling to create the new molecules we may need.

Examining E. coli after an outbreak in Spain in 2011. Francisco Bonilla / Reuters

When Alexander Fleming was awarded the Nobel Prize in Medicine in 1945 for his discovery of the first antibiotic, penicillin, he issued one note of warning.
"The time may come when penicillin can be bought by anyone in the shops," he said in his Nobel Lecture. "Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant."
To drive his point home, he went on to tell a fictional story of Mr and Mrs X. "Mr X has a sore throat. He buys some penicillin and gives himself [some], not enough to kill the streptococci but enough to educate them to resist penicillin."
Mrs X then contracts the sore throat and also takes penicillin, he continued, but the penicillin is no longer effective against the bacteria and Mrs X dies.
"Who is primarily responsible for Mrs X's death?" Fleming said. "Why, Mr X, whose negligent use of penicillin changed the nature of the microbe. Moral: If you use penicillin, use enough."
Almost 70 years later and Fleming's concerns about the ignorant man have proved valid. Improper use of antibiotics has caused a "serious threat to global health", according to the World Health Organisation (WHO), and the world is getting very close to a time where common illnesses and minor injuries will once again kill.
The solution, it would seem, is simple; create new antibiotics that would be effective against the mutant bacteria that have become resistant to existing medicines, and at the same time limit improper consumption to prevent further resistance.
But the golden age of antibiotic development is now a distant memory. From the 1930s to the 1970s there was a steady stream of newly designed antibiotics coming onto the market. Most importantly, they included certain types that were effective against bacteria that had already become resistant to earlier varieties.
But in the past 30 years, the pipeline for new antibiotics has been drying up and no major new types have been developed. On top of that, resistance to medicines that are used to treat HIV, influenza, malaria, tuberculosis, pneumonia and others has been growing.
"After the discovery of penicillin, there was big funding and investment towards developing antibiotics, and it just kept going," says Hosam Zowawi, a clinical microbiologist based at the University of Queensland in Brisbane, Australia. "Antibiotics were getting synthesised, developed and released to the market. Alongside that growth, pharmaceutical companies realised that bacteria are really smart and thought 'the more we develop antibiotics, the more they become resistant'. And that's why they decided to pull out from this research and development, because they didn't think it was commercially feasible."
A large report released earlier this year by the WHO detailed just how big a problem antimicrobial resistance has become. It said very high rates of resistance had been observed in bacteria that cause "common health-care-associated and community-acquired infections", such as urinary tract infections and pneumonia, all across the world.
When Antimicrobial Resistance: Global Report on Surveillance 2014 was released in April, the WHO assistant director general Dr Keiji Fukuda said a post-antibiotic era was no longer an "apocalyptic fantasy" but a real possibility for this century.
The report identified seven species of bacteria that cause common infections but have acquired very high levels of resistance. It included Escherichia coli, which causes urinary tract and bloodstream infections; Klebsiella pneumoniae, also responsible for urinary tract and bloodstream infections, and also wound infections and pneumonia; Staphylococcus aureus, the resistant form of which is known as MRSA; Streptococcus pneumoniae, which causes meningitis, bronchitis, skin infections and contagious ear infections; nontyphoidal Salmonella, causing food-borne diarrhoea and bloodstream infections; Shigella species, causing diarrhoea and dysentery; and Neisseria gonorrhoeae, causing gonorrhoea.
Zowawi points out that a third of women will suffer from a urinary tract infection - previously easy to treat with antibiotics - at some point in their lives so the consequences of not being able to treat them could be catastrophic.
If these and other bacteria continue to acquire resistance, it could wipe out the achievements of modern medicine, the WHO said.
"Ten to 20 per cent of wound bacteria are resistant to the last line of antibiotics," Zowawi says. "We still have 80 per cent that are sensitive. But by continuing to misuse them, we will keep increasing that percentage of resistant bacteria and reduce the numbers of the sensitive sort until we get a level where 100 per cent of bacteria are resistant."
As well as stimulating the antibiotic pipeline, experts say it is imperative for governments and countries to take a stronger stance on the misuse of antibiotics.
In the Middle East, for example, it is not uncommon for people to buy antibiotic medicines over the counter without a prescription, in spite of legislation making it illegal. In a recent survey of pharmacies in Abu Dhabi, all of them admitted to selling antibiotics over the counter.
The risk from this illegal practice is two-pronged. First, the customer might not even need antibiotics to begin with. Secondly, there is a high risk that self-diagnosis and self-prescribing leads to someone misusing the antibiotics by either taking them inappropriately, such as at the wrong times of day, or by not finishing the course. Misuses provide a great opportunity for bacteria to acquire resistance.
"Consequently, it is imperative that we reduce as far as possible inappropriate use of antibiotics, and stopping over-the-counter sales would certainly contribute to that aim," says Dr Alex O'Neill, a lecturer at the School of Molecular and Cellular Biology at the University of Leeds in the United Kingdom. "There are numerous things that clinicians take into account when making decisions about administering antibiotics to patients. For example, is it a bacterial infection? And if so, will it clear up on its own or is antibiotic treatment warranted? What type of bacteria are responsible and which antibiotics are such bacteria sensitive to? Which antibiotics are appropriate for treatment given the site of infection in the body?
"Given the number of considerations involved, none of which an individual standing in line at a pharmacy is able to make an informed decision on, the likelihood that an antibiotic bought over the counter will be used appropriately is, in my view, slight."
The problem of misuse is by no means limited to the Middle East. A 2009 study from the United States revealed equally worrying results. Almost half of those surveyed who had used an antibiotic within the last year admitted missing a dose (44 per cent) and the same number believed antibiotics could treat viruses. (They are, in fact, completely ineffective against viruses.)
There is also the issue of substandard drugs. Some sources say antibiotics are one of the most counterfeited products in developing countries and the WHO says most drug quality assurance systems are weak, therefore exposing patients to suboptimal levels of microbials and creating the conditions for resistance to form.
Antibiotics in agriculture is another factor that has contributed to the growing numbers of superbugs. They are used in animal husbandry not only to treat active infections but also as a preventive measure and as growth promoters.
"Since antibiotic use drives the development of antibiotic resistance, and many of the antibiotic classes used in livestock are the same as those used in human medicine, the extensive use of antibiotics in livestock for non-­therapeutic purposes acts to more rapidly render antibiotics ineffective for medical purposes," O'Neill says. "This phenomenon has been recognised since the 1960s, but we have only in recent years seen a growing will to properly regulate antibiotic use in livestock."
Earlier this month, the British prime minister David Cameron warned of the global threat of antibiotic resistance and called for global action.
He commissioned a review, led by the former Goldman Sachs economist Jim O'Neill, to look at the economic issues surrounding anti­microbial resistance. According to Cameron's office, the "full scale of the economic burden of drug-resistant infections - and the cost of failure to take concerted action to address it - is not yet fully understood".
The review will look at ways to stimulate investment in new antimicrobials and how international cooperation could be improved.
On announcing the committee, Cameron said that if the world failed to act it would be looking at an "almost unthinkable scenario where antibiotics no longer work and we are cast back into the dark ages of medicine".
The review will be hosted and funded by The Wellcome Trust, an independent charity focusing on human and animal health, and the results are expected to be released in 2016.
Producing new antibiotics is no longer an option, experts insist - it is an absolute necessity.
Figures compiled in 2009 by the European Centre for Disease Prevention and Control and the European Medicines Agency revealed a rather grim picture. A survey of antibiotic development in small and large pharmaceutical companies found that of 167 antibiotic agents under development, just 27 were assessed as having either a new target or a new mechanism of action, "thus potentially offering a benefit over existing antibiotics".
Of these 27, just 15 could be systemically administered (as opposed to topical medicines that are applied locally), meaning they are delivered to the circulatory system and the whole body is affected. Of these 15, only a third of the agents had progressed to clinical trials at the time when the survey was carried out.
Zowawi, who specialises in antimicrobial resistance and novel diagnostic tools, says that while the pharmaceutical companies have indeed failed to invest in antibiotic development, the blame must be shared.
"We should blame ourselves as scientists and experts in this area because we haven't been communicating well to the general public about this issue. If we had done this earlier we might have avoided this," he says. "Now this issue is huge. This is absolutely threatening mankind from now."
Antimicrobial resistance is not a new subject and the dangers of improper use of antibiotics were identified long ago. There have been scores of research papers released in the past 30 years warning of an impending threat.
A 1979 article in the journal Clinical Infectious Diseases examined the emergence of antibiotic resistance in hospitals from 1935 to 1975 and said: "The dominant factor in the emergence and spread of antibiotic-resistant bacterial pathogens, whether in hospital wards or in the community, is clearly the intensive use of the antibiotic agents to which resistance emerges then spreads."
So even while the threat was known, it seems little progress was made in terms of developing new antibiotics. The expense of doing this may go some way to explaining why.
Recent estimates put the cost of producing a new antibiotic at between US$800 million and US$1.7 billion (Dh2.938-6.244bn), and suggest it would take more than a decade of work. The concern that pharmaceutical companies do not consider it a worthwhile investment seems feasible given how little has been produced in recent decades.
Pharmaceutical companies are for-profit businesses and therefore focus their efforts on the most lucrative products. The global pharmaceutical market is worth an estimated US$300bn a year, according to the WHO, and is likely to reach US$400bn within a couple of years.
The 10 largest drug companies, which control more than a third of the whole market, have profit margins of around 30 per cent.
Somewhat tellingly, the WHO reports, pharmaceutical companies spend a third of their sales revenue on marketing their products - twice as much as they spend researching and developing new medicines.
Antibiotics are routinely identified in research papers as being poorly performing drugs when it comes to pharmaceutical companies' balance sheets.
One reason for this is they are only prescribed for short periods of time, maybe a couple of days to a few weeks at most.
A 2013 paper in Globalization and Health on the economics of antibiotics calls the current situation in new antibiotic development an "impending global crisis". "As a class of drugs" it says, "antibiotics have several unique properties which make them less profitable and therefore less attractive to corporate investment."
For starters, by their nature, antibacterial drugs should indeed be prescribed for as short a time as possible to limit the chances of improper and over use. Drugs that are prescribed in much larger quantities and for longer times - such as those used to treat chronic diseases such as diabetes or cardiovascular disease - are obviously more profitable in the long run.
Even the WHO admits that "the profit imperative ensures that the drugs chosen for development are those most likely to provide a high return on the company's investment".
There are also the costs associated with putting a drug through clinical trials. Antibiotics specifically require different trials for each new indication in varying organ systems, making them more costly to test than other sorts of medicines, according to David Brogan and Elias Mossialos in The Incentives for New Antibiotics: the Options Market for Antibiotics (OMA) Model, an article in Globalization and Health.
Without some sort of intervention, the development of new antibiotics may come too late. "A critical market demand large enough to spur development may not exist until a crisis has emerged," the report says.
O'Neill tells The National that the past couple of years have brought some signs of improvement but they have yet to translate into "tangible benefits" in terms of patient treatment. One of the most serious problems, he says, is simply that it is incredibly difficult to identify potential antibiotic compounds with the right properties to develop as drugs.
They must be highly toxic to bacteria but non-toxic to the human body and not exhibit the potential to become rapidly compromised by the development of antibiotic resistance.
O'Neill refers to a 2013 Clinical Microbiology Reviews report by MJ Pucci and K Bush, which said that a "surprising number of new agents" were currently in the corporate pipeline, particularly in phase 3 of clinical development where their effectiveness is assessed. "But these compounds still have some way to go before they could reach the clinic, some may of course not make it, and meanwhile the resistance crisis builds," he says. "So while these signs of improvement are most welcome, they have yet to translate into tangible benefits in terms of patient treatment."
Chantal Morel, a research officer and economist at the London School of Economics (LSE) in the UK, suggests that changing the way pharmaceutical companies are rewarded for their products might help stimulate growth in the necessary areas.
"If we are seeking a longer-term solution to this problem we should ensure that we remove the incentive for high unit sales," she tells The National. "We need to effectively decouple sales from the reward that companies receive for developing a new antibiotic. [We] need a business model to drive antibiotic development."
Pharmaceutical companies use a "net present value" (NPV) calculation to identify which therapeutic areas are worth investing in. It includes projected costs and returns. For antibiotics, due to the time and cost of research and development and the quantity issues, they do not produce a favourable NPV figure.
Patrick Vallance, the president of research and development at Glaxo­SmithKline, told the BBC recently that his firm had spent around US$1bn in the last decade on antibiotic research and development. "I am not going to stand here and say we have a great pipeline coming through which is going to solve this problem because we haven't, and nobody has, and there needs to be more effort here," he said. He also acknowledged a "disparity" in the way society viewed antibiotics - for which people are prepared to pay very little - and cancer drugs, for example, which are very expensive, despite the former having "equally big effects".
There is also the problem of generic medicines, which sell at much lower prices because the generic manufacturers have not had to invest in the initial research, development and clinical trials.
This means pharmaceutical companies have difficulty competing against generic manufacturers, according to a 2010 WHO report co-authored by Morel.
"We need arrangements that better spread risk between the public sector entities and industry," she says. "[We] need some push funding to steer research in the desired direction as well as some strong pull incentives to encourage full product development.
"Companies have been investing where they know they will make much more money - for example, cancer, cardiovascular [disease] etc - even when they develop drugs that offer only minor therapeutic gains compared to the life-saving nature of antibiotics."
Morel has researched and written extensively on why pharmaceutical companies and governments have not invested more in creating new antibiotics, despite the obvious and pressing need.
"Supposedly the pipeline is in slightly better shape than it was a few years ago," she says. "However, that said, I think that this estimate of 27 new antibiotic agents was in fact an overestimate."
In 2010, Morel co-authored a paper with Elias Mossialos, a professor of health policy at the LSE, on the subject of stoking the antibiotic pipeline with financial incentives. The report cited 2004 figures that revealed that only 1.6 per cent of the drugs in development by the world's 15 largest pharmaceutical companies were antibiotics.
Despite the low figures, some organisations are determined to get things moving. The Infectious Diseases Society of America (IDSA), representing doctors, scientists and other medical professionals specialising in infectious diseases, is running the 10 x '20 campaign to push for a commitment from pharmaceutical companies, governments and other stakeholders to create 10 new antibiotics by 2020. Launched in 2010 and now with just six years remaining, it is unlikely to succeed.
"As a global society, we have a moral obligation to ensure, in perpetuity, that the treasure of antibiotics is never lost and that no infant, child, or adult dies unnecessarily of a bacterial infection caused by the lack of effective and safe antibiotic therapies," the IDSA says.
The British government is also pushing for more to be done. This year sees the return of the Longitude Prize, which was first offered 300 years ago to encourage the discovery of a reliable way to measure longitude at sea; this year's challenge is to "create a cheap, accurate, rapid and easy-to-use point-of-care test kit for bacterial infections".
The subject matter was chosen from a list of six - which included finding a way to fly without damaging the environment, and restoring movement to those with paralysis - via a three-day public vote. Entrants have up to five years to solve the challenge and could win £10m (Dh63m) if they succeed.
"Point-of-care test kits will allow more targeted use of antibiotics, and an overall reduction in misdiagnosis and prescription," the Longitude website says.
Zowawi, of the University of Queensland, says initiatives like this, that spark interest and debate in the field, could be the solution to the problem of antibiotic resistance. "It can't be done alone," he says. "This is an issue not just for scientists or physicians or nurses or the general public. This is an issue for the globe."
Mitya Underwood is a senior features writer for The National.
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