In November of 2015, scientists in southeastern China were combing through bacterial samples collected from hospitals in the Guangdong and Zhejiang provinces when they discovered something that would immediately grab the attention of the entire medical community.
Many of the bacteria collected were carrying a new gene called MCR-1. It’s an innocuous-sounding name for a sequence of DNA code, but it poses a potentially deadly threat to millions around the world. MCR-1 produces an enzyme that makes bacteria invincible to one of the world’s most powerful antibiotics, a drug called colistin, which is only used as a last resort when all other antibiotics have failed.
This rogue gene is making hordes of bacteria immune to colistin–and it is spreading rapidly across the globe. So far, MCR-1 has been detected in at least ten countries, including Canada, China, and the UK.
According to research published last November in The Lancet, the gene’s emergence appears to be at least partially linked to the use of colistin in agriculture. While the use of the drug in hospitals is now extremely restricted, an almost mind-boggling 12,000 metric tons (13,200 tons) of colistin were used in animal production last year. Over the next five years alone, its annual use is predicted to rise to 16,500 metric tons.
The threat to colistin is far from a one-off. Over the past few decades, our existing antibiotics have increasingly been rendered useless, one by one. But no one can say we haven’t been warned.
Drug resistance is inevitable
More than 70 years ago, Alexander Fleming was awarded the Nobel Prize for his discovery of penicillin. In his lecture at the Nobel Banquet on Dec. 11, 1945, it seemed Fleming could already see cloudy skies ahead. “The time may come when penicillin can be bought by anyone in the shops,” he told his audience.
Fleming knew that overuse of penicillin would drive microbial resistance. Prophetically, he warned that the biggest threat to the future of antibiotics was not so much the bacteria themselves, but ignorance. But few were listening. In 1950, scientists from a New York laboratory discovered that adding antibiotics to livestock feed accelerated their growth. This realization, coupled with innovations in mass production, made the drugs cheaper than conventional supplements. Data collected in 2010 and published in the journal PNAS by an international consortium of scientists revealed that more than 63,000 metric tons of antibiotics are being used in livestock production across the globe, particularly in the developing world.
But with exposure comes evolution. Over time, mutations occur, resulting in bacterial strains resistant to elimination until the development of a new chemical. The more times an antibiotic is used, the greater the likelihood of provoking a mutation.
The mortality rate rises
Today, 23,000 Americans die each year from infections caused by antibiotic-resistant bacteria, according to the US Centers for Disease Control and Prevention (CDC). Across the world, the estimated annual mortality rate is 700,000. If these trends continue, by 2050, 10 million people globally will die each year, as the potent diseases of previous centuries return to their old force, according to the Review on Antimicrobial Resistance. In 2012, the World Health Organization (WHO) reported an estimated 450,000 new cases of multidrug-resistant tuberculosis. The emergence of multiple drug-resistant pneumonia and E. coli bacteria strains are predicted to contribute significantly to increased mortalities due to their ability to spread rapidly through populations.
For doctors, surgeons, and nurses working in hospitals, it’s impossible not to notice the growing threat.
“Over the past decade we’ve seen a rapid increase in the number of infections caused by the E. coli bacteria,” says Johan Tham, an expert in treating infectious diseases at Malmo University Hospital in southern Sweden. “E. coli bacteria which produce enzymes called ESBLs are resistant to many of our most common antibiotics. It means we’re often being forced to treat fairly minor infections with intravenous antibiotics, and sometimes these bacteria are even resistant to those.”
Tham describes a recent case in which a patient in his late twenties had sustained a fever while on holiday in Thailand. After being prescribed antibiotics by a local clinic, he returned home apparently cured. But within a couple of weeks, his health changed rapidly and unexpectedly for the worse.
The source of the initial fever was a hardy strain of E. coli. Resistant to most common medicines, the infection had moved into the patent’s bloodstream. “He went into severe septic shock and had to be rushed into intensive care,” Tham says.
This particular patient was fortunate. A secondary treatment eventually cleared up the infection. But in many other patients, drugs have not worked at all, resulting in amputations or even fatalities.
Dying silently, one at a time
Swedish researchers have been particularly concerned about the rise of antibiotic-resistant bacteria. While the WHO launched a global action plan last year, researchers at Uppsala University in northern Sweden have been sounding the alarm for the past 20 years. They believe that international tourism has been a major contributing factor to the spread of antibiotic-resistant bacteria. In a 2010 survey of 105 healthy Swedish volunteers who had traveled outside of northern Europe, they found that 25% brought back antibiotic-resistant bacteria in their gut flora, mainly from countries such as India and Thailand. Bacteria thrive in these regions in particular because of poor sanitation and lax regulations on antibiotic use.
Our global interconnectivity means that resistant strains can emerge in developing countries and easily spread across the world. But contrary to popular belief, the migration of bacteria isn’t entirely a recent issue. In the centuries following 1000 BCE, the movement of Indo-European tribes spread pulmonary tuberculosis across the world. The difference now is simply the speed at which it happens. Take a strain of mutant bacteria carrying a gene called NDM-1. First detected in India in 2007, by 2012 NDM-1 had spread to 29 countries including Canada, the UK and China.
And, yet, while the threat is obvious to many within the health care profession, much of the world remains oblivious. The approximately 11,300 total fatalities inflicted by the Ebola crisis received blanket media coverage throughout 2014, and news reports are currently consumed by the latest on the Zika virus. But deaths from antibiotic-resistant bacteria go largely unreported. As such, the situation has been dubbed the “silent tsunami” by Otto Cars, founder of an organization called ReAct that campaigns for action on antimicrobial resistance.
“The reason why these deaths slip under the radar is because these people are dying silently one at a time in different hospitals or homes,” notes Cars, who is also professor of infectious diseases at Uppsala University.
“Because they’re often already ill from another disease, the actual cause of death—a lack of effective antibiotics or a delay in prescribing the right treatment for a bacterial infection—gets forgotten,” Cars says. “And instead doctors tell the relatives, ‘There was an underlying disease, your mother was very ill, and we’re sorry we couldn’t save her.’ This is very different from saying, ‘Unfortunately we didn’t have the treatment,’ so I think a lot of doctors are protecting themselves from the reality here.”
The animal-to-human pipeline
Cars and like-minded advocates believe that governments are guilty of simply ignoring the problems of antibiotic resistance and not introducing stricter regulations sooner–particularly when it comes to the controversial use of antibiotics in the food production industry. Indeed, conventional antibiotics were used in animal feed in the European Union for decades before being officially banned in 2006. (European farmers can still use antibiotics to prevent animal infections.) Antibiotics use remains commonplace in feed throughout Asia. This is particularly troubling since so many of the deadliest diseases in human history have originated in animals and then spread to humans.
This is, again, not a particularly new concern. As the CDC notes:
Antibiotics must be used judiciously in humans and animals because both uses contribute to the emergence, persistence, and spread of resistant bacteria. Resistant bacteria in food-producing animals are of particular concern. Food animals serve as a reservoir of resistant pathogens and resistance mechanisms that can directly or indirectly result in antibiotic resistant infections in humans. For example, resistant bacteria may be transmitted to humans through the foods we eat.
Unfortunately, tightening regulations on animal feed remains relatively unpopular, especially in the business community. “Your average farmer isn’t concerned about global antibiotic resistance,” says Suwit Wibulpolprasert, senior advisor at Thailand’s ministry of public health. “He’s simply concerned about profits. And the only way you can dissuade him from using the drugs he has now, is to come up with a cheaper replacement to antibiotics.”
A team of scientists at University College London are trying to solve this problem by replacing antibiotics in poultry production with a chemical taken from Indian medicinal plants. But the financial challenges are considerable. Chickens are mass-produced at a very low cost—around 50 cents per bird, meaning that any replacement has to cost even less. “It’s a tall order,” says Simon Gibbons, of University College London’s school of pharmacy, who leads the project. “You not only have to find a compound which works, but it also has to be non-toxic to humans, can be produced in large amounts, doesn’t affect the flavor or shape of the meat, and is so cheap.”
Short-term benefits, long-term risk
Nonetheless, the overuse of antibiotics across the world is not merely a problem associated with the food production industry. Antibiotics are also chronically overprescribed (pdf). This problem is particularly acute in less developed countries where diagnostic technologies are inefficient and doctors may feel compelled to treat patients immediately with wide-ranging antibiotics. More often than not, such prescriptions are only partially useful or sometimes wholly ineffective; this type of unnecessary exposure only drives bacterial resistance.
“Imagine you’re a doctor in rural India faced with a mother and a feverish child,” Cars says. “The infection is probably caused by a virus but you can’t be 100% sure. What do you do? They may have been walking five hours to get to the clinic and you can’t tell them to come back tomorrow. You have to give them a really broad spectrum antibiotic but you’re groping around in the dark and that’s why so many of these drugs have rapidly become useless in these countries.”
Data has shown that even in the West, too many clinicians still prescribe antibiotics more regularly than we can afford, often due to pressure from patients. For example, an analysis of sore throat treatment in the US between 1997 and 2010 concluded doctors prescribed antibiotics for a sore throat about 60% of the time, when they should really only be prescribed around 10% of the time. “Research has shown that GPs are more likely to prescribe antibiotics when they think a patient wants them,” says Mark Ebell, a professor of epidemiology at the University of Georgia. “Part of the problem is that many patients expect their chest cold to be better in a week, when it typically takes two weeks or even longer to resolve, with or without an antibiotic.”
The era of easy antibiotic discovery is over
While bacterial resistance has always been present, for many years it seemed a relatively mild threat due to the flourishing pipeline of new antibiotics. It didn’t matter if an antibiotic became useless, as new drugs were being discovered by the dozen. When the hospital superbug MRSA became resistant to penicillin in the 1950s, the drugs methicillin and flucloxacillin were produced. Indeed, the first signs of MRSA resistance were documented almost as methicillin was being clinically introduced. The alarm was slow to sound because more new drugs were already on their way. At the time chemicals with the capability of killing harmful bacteria seemed so easy to find, and we harvested them at will for decades.
Inevitably, the easily discoverable antibiotics–the “low hanging fruit” in the soil, in plants and in water–have now been found. In 2016, it’s been almost 30 years since the last new class of antibiotics made it into doctors’ hands in 1987. Finding new chemicals that can work with the potency of medicines like penicillin has become progressively harder. Modern medicine remains reliant on old drugs, the fading relics of a bygone era. Remember, colistin—the drug of last resort now compromised by MCR-1—was discovered back in the early 1940s.
It’s not all bad news. Predicted mortality rates over the next three decades coupled with the projected impact on healthcare systems across the world may have finally spurred some politicians into action. Antibiotic resistance was one of the main topics in last June’s G7 Summit. Also in June, the World Health Organization announced a deadline of 2019 to develop the next new class of antibiotics, drugs capable of dealing with antibiotic resistant bacteria.
Chemical needles in haystacks
But the challenges are considerable. Not only does a new antibiotic have to be capable of killing these bacteria, it needs to be able to be produced relatively cheaply, and to destroy dangerous microbes without eliminating human cells at the same time.
Scientists are increasingly turning back to nature in the hope of finding new chemicals. Micro-organisms living in relatively unexplored terrain ranging from rainforests to the depths of the ocean are being scrutinized in the hope of utilizing their weapons for our own good. But with no guarantee of success, such forays often lack funding.
“For antibiotic discovery we need projects which are purely about the chemistry, screening plants, fungi and insects which produce novel chemical extracts, and isolating the antibiotic compounds,” says Gibbons. “But we don’t know what’s out there. There’s no guarantee of finding a successful medicine and the research councils who supply the grants don’t like that.”
Finding the chemicals is just one part of the problem. The giants of the pharmaceutical world—and their resources—have largely left the stage, frustrated by the technical difficulties and costs of developing novel antibiotics. Infection research divisions have slowly closed down over the past decade. AstraZeneca recently spun off its antibacterial research into a smaller company, dramatically cutting its staff. Many smaller companies have simply disappeared after failing to attract funding from risk-averse venture capitalists. After all, no one has successfully taken a new drug from academic research to the clinic in many years.
Big Pharma has to come back to the table
Now it is time for political leaders to step up and bring the pharmaceutical companies back to the table. But the business model surrounding antibiotics must first change. Over the past half-century, antibiotics have been at the forefront of marketing campaigns driven by profit. This emphasis on high-volume sales has led to overuse. Sweden, Thailand, and many other countries are starting to set targets for clinicians and hospitals to reduce antibiotic use. With the revenue stream from any future drugs likely to be limited, Big Pharma must be persuaded to accept a different return on investment.
“It’s corporate social responsibility,” Cars says. “The public sector needs to intervene with other incentives like milestone payments for stepwise development of the product and maybe a buyout at the end. But it needs to be non-profit otherwise medical needs can never go hand in hand with bureaucracy.”
There are few straightforward solutions, but Cars believes the world may yet wake up to the impending crisis. Pragmatists would note that this isn’t just about mortality rates. If little changes, the healthcare burden from antibiotic resistant bacteria could reduce global GDP by 3.5% by 2050, according to the Review on Antimicrobial Resistance.
“It’s a scary situation now as treatment options are running out,” he says. “But the momentum is building. Ten years ago I was speaking about this, and nobody fully grasped what I was saying, but the urgency of the situation has now become clear. If the world’s leaders can come together and push through a new global structure of innovation, we can make changes relatively quickly. Because at the end of the day if we don’t fix this, it will affect us all.”