Editorial: “Averting the antibiotics apocalypse now“
Antibiotic resistance poses an “apocalyptic” threat to human health. We are facing “nightmare bacteria” and a “war” against them – which we are losing. Such language, in statements from the top UK and US medical authorities – normally a very cautious bunch – reflects the enormity of the situation they feel we are now in.
In fact, our predicament is even worse than these statements suggest, with antibiotic-resistant bacteria out of control in some countries. Yet New Scientist can reveal that effective new drugs may already exist – but are stalled at the final stages of development by regulatory and market failure.
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Antibiotic resistance has been emerging for some time in the bacteria that cause tuberculosis and in “superbugs” such as methicillin-resistant Staphylococcus aureus (MRSA). Less well known are the Enterobacteriaceae, tough gut bacteria that include the common Escherichia coli, which can cause blood or bladder infections. These increasingly carry genes that disarm most antibiotics, and can be killed only by last-resort antibiotics called carbapenems.
However, carbapenem-resistant Enterobacteriaceae (CRE) are on the rise. The US Centers for Disease Control and Prevention (CDC) that 4 per cent of Enterobacteriaceae infections in the US, and a tenth of all infections caused by one member of the family, called Klebsiella, are now carbapenem resistant.
That sounds low, but worryingly, it represents a fourfold increase over the past decade. CRE are also twice as lethal as non-resistant relatives – 40 per cent of CRE blood infections lead to death – and they carry packages of genes for resisting many other kinds of antibiotics as well. Moreover, no new antibiotics that work against CREs are close to reaching the market.
On the loose
“The good news is that we still have time to stop CRE,” says Tom Frieden, head of the CDC. Infections in the US are associated with healthcare facilities, where scrupulous cleanliness can stop the bacteria’s spread. But that may not be enough: elsewhere in the world, CRE are very much on the loose.
Cases of CRE in the UK have soared – from 17 in 2008 to . This is slightly more than was reported in the US, in a population one-fifth of the size. Moreover, many cases appear to be caught outside hospital.
Meanwhile, of Klebsiella infections tested in 2011 were carbapenem resistant. Greece has also reported some cases of E. coli, the most common cause of urinary tract infections, that are resistant to carbapenem.
Greece’s situation should come as no surprise. The more antibiotics are used, the more resistant bacteria have an evolutionary advantage – and Greece has the highest rate of antibiotics use in the European Union. CRE may also be spreading there from Asia, where antibiotics are largely uncontrolled. “You can get any antibiotics easily in pharmacies [without prescription],” including carbapenems, says Danilo Lo Fo Wong of the World ÎçŇą¸ŁŔű1000ĽŻşĎ Organization, who wants to survey CRE in central Asia. of Tufts University in Boston, Massachusetts, has found Enterobacteriaceae from China with four different, novel mutations for resisting carbapenems.
Europeans who travelled to India for surgery brought home an especially noxious carbapenem-resistant bacterium called NDM-1 in 2009. Even when carbapenems are mostly confined to hospital use, gut bacteria from patients can spread in the community where sanitation is poor. In 2011, Mark Toleman of Cardiff University in the UK, who helped discover NDM-1, found it in street puddles in Delhi. It has since been found in water in Pakistan and Bangladesh.
Tighter controls
even when people take antibiotics properly, but improper use makes things worse. To slow the bacteria’s spread, Frieden and others want tighter controls on drugs and on patients in hospitals who are carrying CRE.
Similar measures have beaten back MRSA. Like MRSA, CRE are unlikely to stay in hospital, but unlike MRSA, they encompass many species and many kinds of resistance, which pass readily to other bacteria in the environment.
There the genes could thrive. Researchers that even the very low levels of antibiotics – mostly excreted by livestock – in soil and water favour the survival of antibiotic-resistant bacteria. CRE typically carry resistance genes to several kinds of antibiotic, so will thrive whenever even one is present. Once they are out there, says Toleman, it could be impossible to rein them in. They are already on the loose in Asia, and Toleman is about to look for them in British sewage and farm run-off.
We need new drugs to defeat these bacteria. Yet there is nothing imminent in the pipeline, warns Frieden. Partly, says of the University of California, Los Angeles, this is because new targets are harder to find: existing antibiotics already attack the most obvious bacterial weak points.
Still, novel antibiotics are being discovered. Levy has one that “sailed through safety tests 10 years ago”. A at the University of Genoa, Italy, found that no fewer than six novel antibiotics that work against multidrug-resistant Enterobacteriaceae have gone through early trials. Last year, the US’s Biomedical Advanced Research and Development Authority of yet another.
Costly trials
However, none has been able to attract pharmaceutical-industry funding for the expensive final trials required to establish a drug’s effectiveness, which involve several thousands of people. Spellberg was working on one until Pfizer, the pharmaceutical giant funding the work, closed its antibiotics department, then the world’s largest, in 2010. “They had a great pipeline. It’s unclear if any will ever see the light of day,” he says.
Eight major companies have abandoned antibiotics since 1990 – only three still develop them. Part of the reason is that there simply isn’t much money in it, says of the University of California, San Francisco. Unlike pills for chronic conditions like heart disease, antibiotics are taken for a week or two. What’s more, any new drug that kills resistant bacteria will deliberately be used as little as possible to slow development of resistance to it.
There is another catch-22: there aren’t yet thousands of people with similar CRE infections eligible for clinical trials. “If we wait until adequate numbers of patients can be enrolled in large trials, then the epidemic will be upon us before a therapy is ready,” warns John Rex, head of infectious disease at pharma giant AstraZeneca.
Regulatory agencies in the US and Europe are looking for ways out of the impasse. One part of the programme funded by the European Commission, which was launched this year, aims to design novel ways to get new antibiotics to market. Two novel drugs active against MRSA, although not CRE, are now starting trials under this programme.
Tax credits
The US granted stronger patent protection to new antibiotics last year, and Congress that allows new antibiotics to be approved in much smaller trials. Such a change, which the is already drafting, will in theory make new drugs riskier – but if they are used only for infections where there is no alternative, the risk is worthwhile, says Robert Guidos of the Infectious Diseases Society of America. Other measures like tax credits may also be needed to lure companies back into antibiotics, but these seem unlikely given current US budget problems.
Even if development resumes, the pipeline has been so delayed that “we are looking at the next 10 to 15 years with no drugs to treat many of these infections”, says Chambers. “It’s like going back to the pre-antibiotic era,” warns Toleman. Then, people routinely died of what we now consider minor bacterial infections. It is not an era we want to see again.
