E. coli isn't the only bug with renewed bite. Antibiotic-resistant bacteria in hospitals kill around 63,000 people in the United States each year. These include common bacteria, such as those that cause gonorrhoea; Staphylococcus, which a recent study found on nearly half of U.S. supermarket meat; and vancomycin-resistant Enterococcus (VRE), which thrives in antibiotic-treated chickens.

MRSA, an extreme form of antibiotic-resistant Staphylococcus, is on the rise and evolving. A new variant reported this month (June) is different enough to escape current DNA-based tests. Hospitals want to screen incoming patients for MRSA so they can stop it spreading, but there are fears carriers could also be denied admission.

The incidence of tuberculosis is slowly falling worldwide, but antibiotic resistance is climbing, with 25,000 cases of the XDR form that resists almost all drugs now emerging each year. Rates of TB are so high in London that health authorities have proposed reintroducing childhood vaccination, abandoned in 2005.

So-called Iraqibacter, a strain of Acinetobacter that resists virtually all antibiotics, has plagued troops in Iraq and is starting to spread further. It has prompted the U.S. military to fund studies of drugs based on natural antibacterials called defensins, which may not promote resistance.

A TIME FOR NEW WEAPONRY

In recent weeks, bacteria have killed at least 22 people in Germany and made well over 2,000 ill. There is a suspicion that they may have caught the bug from bean sprouts.

But this is no exotic invader; it is Escherichia coli, ubiquitous in our guts, our cattle and our labs. It's the most recent bug to evade normal screening methods and standard forms of treatment, and it won't be the last. So perhaps the time has come to look past antibiotics -- the wonder drugs of the 1950s -- and find new weapons in the fight against superbugs.

No commonly used method of detection would have prevented the German outbreak. The lethal strain probably came originally from cattle, and was transmitted in the manure used to grow foods, including seeds for bean sprouts. But even a recently introduced vaccine that stops cattle shedding toxic E. coli would have left it untouched, while standard tests for toxic E. coli in food would have missed it. Proposed U.S. food rules about E. coli do not, yet, apply to it.

The outbreak confirms what microbiologists have been saying for years: We need to broaden the fight against bacteria to include a better understanding of how they cause disease; the discovery of new classes of antibiotics; strategies to slow the growth of antibiotic resistance; faster diagnosis of infection and better ways to screen food.

The German strain belongs to a family of E. coli that clings to gut walls, but usually caused such mild disease -- until now -- that it's largely unstudied. It recently picked up a (STEC) gene that causes bloody diarrhea, putting it in a group known as Shiga-toxin E. coli

The hybrid was unprecedentedly lethal: Shiga toxin can cause severe kidney damage by inducing a disease called haemolytic-uraemic syndrome (HUS), but the German strain appears to be four times as likely to cause HUS as other STEC strains.

The strain also resists eight classes of antibiotic -- although this point is of little relevance, as most antibiotics can't be used on STEC strains. That's because the bacteria respond by producing more toxin, in a defense reaction called SOS.

However, two strategies used in the current outbreak point to future remedies. Some antibiotics don't elicit the SOS reaction, and doctors in Germany are now cautiously using one class, called carbapenems, against the outbreak strain.

They are lucky it doesn't resist them. In early June, the French Institute for Public Health Surveillance reported a "sharp increase" in abdominal infections that resist carbapenems, including those caused by E. coli.

This underscores our desperate need for new antibiotics, says David Hooper of Harvard Medical School, Boston, Mass. Drug companies have largely abandoned the search, he says. There's little profit in short-term treatments. New models for drug discovery are needed, such as public-private partnerships, he says.

Besides antibiotics to kill bacteria, we need anti-toxins that block their effects. Doctors in Germany are successfully using a monoclonal antibody, originally developed to treat a rare genetic disorder, to block the immune response Shiga toxin stimulates to cause HUS.

We need more therapies aimed at toxins, says Stephanie Schuller at the University of East Anglia in Norwich, UK. For example, a drug that stops a toxin moving from gut to blood would be useful, though to be used in time this would also require earlier, more accurate diagnosis than is usual.

Another possibility is to vaccinate against toxins. There are efforts to develop a vaccine for the toxin made by Clostridium difficile, says Hooper. "We could also vaccinate for Shiga, or the bacterial toxins that cause toxic shock. But those conditions are rare, so who should we vaccinate?"

Stuart Levy, of Tufts University, Boston, Mass., thinks such treatments could focus on people facing hospital bacteria, the most likely to be antibiotic-resistant. He has developed small molecules that block the bacterial MAR gene, a "master switch" that not only enables bacteria to cause disease but also activates antibiotic resistance.

"The drug will prevent disease until bacteria are dealt with by the immune system or just go through the gut," he says. Because they aren't killed, there should be no drug-resistant survivors.

Still, people are unlikely to take such drugs just so they can eat bean sprouts. A more practical option may be to vaccinate the cattle that carry E. coli. The vaccine Econiche immunizes cattle against a group of proteins called the type three secretion system (TTSS), which is used by the most common cattle-borne STEC to invade the gut wall. The vaccine cuts the quantity of bacteria shed by infected calves and could also block other TTSS-equipped bacteria, such as Salmonella. Unfortunately, the German bug doesn't use TTSS.

Policy changes could also have an effect. In the U.S., Rep. Louise Slaughter (R-N.Y.) has introduced a bill to ban antibiotic growth promoters in cattle which evoke antibiotic resistance of the same kind seen in the German E. coli. Its chances of becoming law may now have risen.

Another ploy could be to chase the bacteria off our food. Keith Warriner, of the University of Guelph in Ontario, Canada, says bacteria that live in the guts of herbivores have evolved ways to infiltrate bacterial communities on the plants herbivores eat. In some cases plant growth folds them into their tissues, so washing does not remove them.

Warriner has found that an old remedy -- phage, a virus that attacks only bacteria -- will kill Salmonella and E. coli on vegetables. A preparation claiming to do this is even on the market in the U.S. but is little used. One reason for this is that phage doesn't destroy all its hosts, and this is needed if you are to purify food.

Warriner has come close, by spraying vegetables with phage combined with harmless bacteria that displace the interlopers. But he has no funding to continue the work, and a pharmaceutical firm has lost interest. He hopes the German outbreak will change that.

The final hope is administering phage to kill bacteria in people. Work on this was abandoned in the west with the advent of antibiotics, but continued in the Soviet Union. A UK company is currently testing a phage that also packs a protein, which, like Levy's, shuts down bacterial DNA.

Levy, Hooper and others say phages are potentially useful. But we need to develop all possible antibacterial weapons far more urgently, they say. The bacteria are not waiting to attack us.

 

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