Zero impact: bacterial growth around the white antibiotic discs spells a resistant strain. Credit: S. ZAFEIRIS/SPL

In the late 1960s the battle against bacterial infections was considered won, in the developed world at least. By the time of Woodstock, antibiotics were curing previously lethal infections in a matter of days. Infected cuts and food poisoning were no longer life-threatening, diseases such as syphilis and gonorrhoea seemed to be on the way to eradication, and ancient scourges such as plague and cholera could now be controlled.


Now antimicrobial resistance threatens to turn back the clock. Resistance is spreading rapidly, particularly in hospitals, where many different bacterial strains can come into contact with each other and where antibiotics are heavily used (see graph, right). The catch is that the more an antibiotic is used, the more resistance to it spreads, forcing doctors to try other antibiotics. Even drugs that once served as a last resort are losing their potency.

“The cycle of resistance is inevitable,” says Christopher Walsh, a molecular pharmacologist at Harvard Medical School in Boston. “With every new drug we use, we select for resistant microbes that survive and multiply unhampered by treatment with the same antibiotic.”

The only solution, experts agree, is to continue to develop new drugs. But just as we need them most, the antimicrobial drug pipeline is running dry. Until ten years ago, all major drug companies ran antibacterial research programmes. Today, these programmes have been drastically pruned, and many have been cut altogether as companies pursue more lucrative areas, such as chronic illnesses and mood disorders.

The desperate nature of the situation led the Infectious Diseases Society of America (IDSA) to issue a white paper in July calling for a variety of measures to get antibiotic research back on track, starting in the United States. The report — called Bad Bugs, No Drugs — followed a year-long investigation into the economics of drug development. In the absence of independent action by the pharmaceutical industry, the report says, the US Congress and federal regulatory agencies must step in with financial incentives for companies to get back into the antimicrobial business.

Last resort

This all makes for a potential healthcare calamity. Although the number of hospital-acquired infections has been gradually declining in the United States, a greater proportion of them — now about 70% — are resistant to at least one antibiotic. This results in a delay in effective treatment, prolonging illness and increasing the risk of death. Two million people will pick up an infection in a US hospital this year, for example, and 90,000 of them will die of it, according to estimates by the Centers for Disease Control and Prevention in Atlanta, Georgia.

Because bacteria share resistance genes, antimicrobial resistance fostered in hospitals ultimately spreads to surrounding communities. As a result, hard-to-treat forms of old killers such as tuberculosis and cholera are showing up in many parts of the world.

Even vancomycin — still used only as a last resort because of its side effects — is losing its punch. Vancomycin-resistant gut bacteria first showed up in 1986. Then in 1997, the discovery of partially resistant strains of Staphylococcus aureus, which causes serious wound and surgical infections, shattered the hope of maintaining vancomycin as the ultimate weapon against the worst hospital-acquired infections. Two years ago, the first cases of fully vancomycin-resistant S. aureus were reported in the United States.

If they can become resistant to vancomycin, they will become resistant to everything

“This should make you very pessimistic,” says Walsh. “If they can become resistant to vancomycin, they will become resistant to everything.”

Most initiatives to deal with the situation have concentrated on delaying the inevitable build-up of resistance by reducing the indiscriminate use of antibiotics in medicine and agriculture. Several European countries, for instance, have phased out the use of antibiotics as growth promoters in food animals since the mid-1990s, resulting in reduced rates of resistance1.

But such measures only slow the spread of resistance. Despite the pressing need for new antibacterials to replace those that are losing their effectiveness, pharmaceutical companies are not beefing up their research efforts in this field. Why?

A cocktail of antibiotics is used to treat a patient with septicaemia (above, top), a bloodstream infection. Staphylococcus aureus (above) has become resistant to almost all antibiotics. Credit: G. PARKER/SPL; SPL

They aren't for the very same reason that the problem is so intractable. Microbial resistance increases the demand for new products but at the same time it shortens their useful life, severely impairing a drug's long-term potential to return a profit. And as the best antibiotics are often held in reserve, a new antibiotic to which there is no resistance would be little used. That is not the sort of product a profit-making company wants to develop.

Furthermore, from a marketing standpoint, antibiotics are the worst sort of pharmaceutical because they cure the disease. Companies have more incentive to bankroll research into treatments for chronic conditions such as high cholesterol or rheumatoid arthritis, for which patients take the drug over years or a lifetime, rather than for just a week or two.

The cost of drug development adds to the pressure for high-return products. According to the Tufts Center for the Study of Drug Development in Boston, it costs some $800 million on average over 10–15 years to bring a new drug to market2. This cost, combined with a likely low return on investment, makes pharmaceutical companies reluctant to pursue antibiotic research.

Patent holiday

The result of these negative pressures has been a 56% decline in the number of antibiotics approved annually by the US Food and Drug Administration (FDA) over two decades (see the Commentary on page 899 of this issue). According to a study published in May this year, out of 506 drugs in late-stage clinical testing by the world's 15 largest pharmaceutical companies, only six are new antibacterials — and all are derivatives of known antibiotics3. That is barely more than the number being developed for some less life-threatening ailments. Erectile dysfunction alone accounted for four of the new drugs being tested.

If things don't change soon, we are going to face a major health crisis

“Unless things change soon, we are going to face a major health crisis,” warns Brad Spellberg, an infectious-disease researcher at Harbor-UCLA Medical Center in Los Angeles and lead author on the study.

To help avert the crisis, the IDSA is recommending several steps that would radically alter the economic landscape for drug companies. First, it has proposed that Congress establish an independent commission to prioritize antimicrobial discovery, which would identify the biggest microbial threats and make recommendations directly to the Secretary of Health. Pharmaceutical companies could then register with the Department of Health and Human Services to receive tax credits if they were working on drugs to fight one of the targeted bugs.

Another carrot would be ‘wild-card’ patent extensions awarded to any drug company that successfully developed a new antibiotic to a targeted microbe. This would allow the company to extend the life of any one of its patents — not necessarily an antibiotic — for two years. As some blockbuster drugs bring in billions of dollars a year, that amounts to quite a gift. “I think that patent extension will increase profits substantially,” says Joseph DiMasi, director of economic analysis at the Tufts Center.

At the same time, the FDA should set new drug-approval procedures for antimicrobials, the IDSA says. At the moment, a new antimicrobial must be proved more effective than an existing one against drug-sensitive bacteria. But this is nearly impossible, as current antibiotics are very effective as long as the bacteria are not resistant. The alternative, testing in patients with drug-resistant infections, is much more expensive, because it is difficult to find enough patients for a complete trial.

The way round this is to extrapolate from tests against drug-sensitive strains to gain insight into how effective the antibiotic will be against drug-resistant strains. But the FDA has no standards for allowing this, much to the disappointment of drug companies says Steven Projan, director of antibacterial research at Wyeth in Pearl River, New Jersey. “We need a roadmap for getting a drug approved,” he says.

Additional incentives proposed by the IDSA include extending patents to make up for time lost during FDA review, establishing a guaranteed market with federal dollars and limiting liability for adverse effects, as has been done for vaccines. All these measures would require legislation by Congress.

Convincing Congress to act may be difficult, as congressmen have a proven distaste for wealthy pharmaceutical companies complaining about their bottom line. “The poor image of pharmaceutical companies with Congress is a potential obstacle,” says DiMasi.

In fact, some of the provisions were introduced in the Senate in 2001 and 2003 as part of a bill known as S. 666, written by Senators Joe Lieberman (Democrat, Connecticut) and Orrin Hatch (Republican, Utah). But S. 666 never came to a vote. Instead, parts were retained in what became Project BioShield, the bill signed into law in July this year by President Bush to fund stockpiling of vaccines and drugs against bioterror agents such as smallpox and anthrax.

But Project BioShield does nothing to protect the public against the demise of antibiotics. Now Lieberman and Hatch are planning to introduce Project BioShield II later this year, a bill that will combine features of both S. 666 and the IDSA recommendations.

Even if the IDSA plan is adopted, there are still considerable scientific hurdles to clear. Nearly all the existing classes of antibiotic are half a century old. Most antibiotics are merely modifications of existing ones, which does not always solve the problem of resistance. Since 1962, only two new classes — an oxazolidinone (linezolid) in 2000 and a cyclic lipopeptide(daptomycin) in 2003 — have been approved for use.

“We have already collected the low-hanging fruit,” explains Projan. But in every orchard the tastiest fruits hang the highest. The proposed incentives, say Projan and others, may provide a ladder to reach them.