Understanding the Apocalypse
MacKenzie, D. (2013). THE BACTERIAL APOCALYPSE. (Cover story). New Scientist, 217(2908), 6-7.
NEWSFOCUS / ANTIBIOTIC RESISTANCE
Why are new antibiotics locked away when superbugs are on the loose, asks Debora MacKenzie
ANTIBIOTIC resistance poses an "apocalyptic" threat to human health. We are facing "nightmare bacteria" and are losing a "war" against them. Such language, in statements made over the past week by the top UK and US medical authorities -- normally a very cautious breed -- reflects the enormity of the situation they feel we must now confront.
In fact, our predicament is even worse than these words suggest, with antibiotic-resistant bacteria out of control in some areas. What's more, New Scientist can reveal that effective new drugs may already exist -- but are stuck in the final stages of development because they cannot overcome economic and regulatory hurdles.
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 severe infections. Increasingly, they carry genes that disarm most antibiotics -- little else but antibiotics called carbapenems will now kill them.
However, carbapenem-resistant Enterobacteriaceae (CRE) are on the rise. The US Centers for Disease Control and Prevention (CDC) reported last week that 4 per cent of all Enterobacteriaceae infections in the US -- and a tenth of all infections caused by one family member, Klebsiella -- are now carbapenem-resistant.
Worryingly, this 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 are deadly -- and they carry genes for resisting many other kinds of antibiotics as well. Worst of all, no new antibiotics that work against CREs are close to reaching the market.
"The good news is that we still have time to stop CRE," says Tom Frieden, head of the CDC. Rigorous cleanliness can stop the bacteria spreading in hospitals, where most infections occur in the US. But that situation may not last; it hasn't elsewhere (see "On the loose and out of control").
Cases of CRE infection in the UK have soared from 17 in 2008 to 799 last year -- slightly more than in the US, and in a population one-fifth the size. Moreover, some cases are appearing outside hospitals.
In Greece, 68 per cent of Klebsiella infections tested in 2011 were carbapenem-resistant. The country has also reported some cases of E. coli, which causes many bladder infections, that are carbapenem-resistant.
Greece's situation is no accident. It has the highest rate of antibiotic use in the European Union -- and the more antibiotics are used, the more resistant bacteria have an evolutionary advantage. 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 Health Organization, who wants to survey CRE in central Asia. Stuart Levy of Tufts University in Boston, Massachusetts, has found a strain from China with four novel mutations for resisting carbapenems.
We need new drugs to defeat these bacteria. Yet there is nothing imminent, Frieden warns. This is partly because existing antibiotics already attack the most obvious bacterial weak points, says Brad Spellberg of the University of California, Los Angeles.
Still, novel antibiotics are being discovered. Levy has one that "sailed through safety tests 10 years ago". A 2011 survey by researchers at the University of Genoa, Italy, found that six new antibiotics effective against multidrug-resistant Enterobacteriaceae have been through early trials. Last year, the US's Biomedical Advanced Research and Development Authority funded development of yet another.
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 2010, when the US-based drug company Pfizer that had been funding the work simply closed its antibiotics department -- then the world's largest. "They had a great [drug] 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. There simply isn't much money in it, says Chip Chambers of the University of California, San Francisco. Unlike pills for chronic conditions like heart disease, antibiotics are taken for a limited time. 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: we lack enough people with similar CRE infections who are eligible for clinical trials. "If we wait until adequate numbers of patients can be enrolled, then the epidemic will be upon us before a therapy is ready," warns John Rex, head of infectious disease at the UK pharma giant AstraZeneca.
Regulatory agencies in the US and Europe are looking for ways out of the impasse. One part of the "New Drugs for Bad Bugs" programme funded by the European Commission, launched this year, aims to create novel ways of getting antibiotics to market. Two drugs active against MRSA are now starting trials under this programme.
The US Congress may shortly consider a measure that allows new antibiotics to be approved after much smaller trials. Such a change, which the European Medicines Agency is already drafting, will in theory make new drugs riskier -- but it's a risk worth taking if they are used only where there is no alternative, says Robert Guidos of the Infectious Diseases Society of America.
Even if development resumes, "we are looking at 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 Mark Toleman of Cardiff University, UK. Then, people routinely died of what we now consider minor bacterial infections. It is not an era we want to see again.
Pretty deadly: a sign of bacteria that can resist carbapenems, our last-ditch antibiotic
ON THE LOOSE AND OUT OF CONTROL
Bacteria that can resist last-resort antibiotics called carbapenems are on the rise in the US, although epidemiologists hope to contain the bugs by isolating carriers. But containment is no longer an option elsewhere.
Carbapenem-resistant Enterobacteriaceae (CRE) -- disease-causing gut bacteria -- are already loose in Asia. Europeans who travelled to India for surgery brought home a CRE called NDM-1 in 2009. In countries with poor sanitation, resistant gut bacteria bred in hospitals can spread widely. In 2011, Mark Toleman of Cardiff University, UK, found CRE in street puddles in Delhi, India. It has since been found in water samples in Pakistan and Bangladesh.
Toleman is about to look for CRE in sewage in the UK. He fears that once CRE gets into the environment, it could persist there. Even low levels of antibiotics -- excreted by humans and animals -- favour the survival of resistant bacteria in soil and water where the drugs end up.
Resistant bugs can die out if the antibiotic they resist is not present to give them a competitive advantage. Carbapenems are seldom found in the environment, but CRE resist other antibiotics, too, so could thrive where any one of these is present, says Toleman. Once they escape, it could be impossible to rein them in.
Campaigners want US farmers to divulge how much antibiotic they are using in livestock, but a bid to enforce this failed in the US last week.
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By Debora MacKenzie
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