back on track,starting in the United States.Thereport — called Bad Bugs, No Drugs — followed a year-long investigation into theeconomics of drug development. In theabsence of independent action by the pharma-ceutical industry, the report says, the US Congress and federal regulatory agencies muststep in with financial incentives for companiesto get back into the antimicrobial business.

Last resortThis all makes for a potential healthcarecalamity. Although the number of hospital-acquired infections has been graduallydeclining in the United States,a greater proportion of them— now about 70% — are resis-tant to at least one antibiotic.This results in a delay in effec-tive treatment, prolonging ill-ness and increasing the risk ofdeath. Two million people willpick up an infection in a US hospital thisyear, for example, and 90,000 of them willdie of it, according to estimates by the Cen-ters for Disease Control and Prevention inAtlanta, Georgia.

Because bacteria share resistance genes,antimicrobial resistance fostered in hospitalsultimately spreads to surrounding commu-nities. As a result, hard-to-treat forms of oldkillers such as tuberculosis and cholera areshowing up in many parts of the world.

In the late 1960s the battle against bacter-ial infections was considered won, in thedeveloped world at least. By the time of

Woodstock, antibiotics were curing previ-ously lethal infections in a matter of days.Infected cuts and food poisoning were nolonger life-threatening, diseases such assyphilis and gonorrhoea seemed to be onthe way to eradication, and ancient scourgessuch as plague and cholera could now becontrolled.

Now antimicrobial resistance threatensto turn back the clock. Resistance is spread-ing rapidly, particularly in hospitals, wheremany different bacterial strains can comeinto contact with each other and where anti-biotics are heavily used (see graph,page 893).The catch is that the more an antibiotic isused, the more resistance to it spreads, forc-ing doctors to try other antibiotics. Evendrugs that once served as a last resort are losing their potency.

“The cycle of resistance is inevitable,”saysChristopher Walsh, a molecular pharmacol-ogist at Harvard Medical School in Boston.“With every new drug we use, we select forresistant microbes that survive and multiplyunhampered by treatment with the sameantibiotic.”

The only solution, experts agree, is tocontinue to develop new drugs.But just as weneed them most, the antimicrobial drugpipeline is running dry. Until ten years ago,all major drug companies ran antibacterialresearch programmes. Today, these pro-grammes have been drastically pruned, andmany have been cut altogether as companiespursue more lucrative areas, such as chronicillnesses and mood disorders.

The desperate nature of the situation ledthe Infectious Diseases Society of America(IDSA) to issue a white paper in July calling fora variety of measures to get antibiotic research

Even vancomycin — still used only as alast resort because of its side effects — is losing its punch. Vancomycin-resistant gutbacteria first showed up in 1986. Then in1997, the discovery of partially resistantstrains of Staphylococcus aureus,which causesserious wound and surgical infections, shat-tered the hope of maintaining vancomycin asthe ultimate weapon against the worst hospi-tal-acquired infections. Two years ago, thefirst cases of fully vancomycin-resistant S.aureus were reported in the United States.

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

vancomycin, they will becomeresistant to everything.”

Most initiatives to deal with thesituation have concentrated ondelaying the inevitable build-up ofresistance by reducing the indis-criminate use of antibiotics inmedicine and agriculture. Several

European countries,for instance,have phasedout the use of antibiotics as growth promotersin food animals since the mid-1990s,resultingin reduced rates of resistance1.

But such measures only slow the spread ofresistance. Despite the pressing need for newantibacterials to replace those that are losingtheir effectiveness, pharmaceutical compa-nies are not beefing up their research effortsin this field.Why?

They aren’t for the very same reason that

892 NATURE | VOL 431 | 21 OCTOBER 2004 | www.nature.com/nature

A shot in the armAntibiotics are failingand drug companieshave all but stoppeddeveloping new ones. Will conquereddiseases come back tohaunt us? Martin Leebexamines one plan toavert the crisis.

“If they can becomeresistant tovancomycin, they will become resistantto everything”— Christopher Walsh

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Zero impact: bacterial growth around the white antibiotic discs spells a resistant strain.

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the problem is so intractable. Microbial resis-tance increases the demand for new productsbut at the same time it shortens their useful life,severely impairing a drug’s long-term poten-tial to return a profit. And as the best anti-biotics are often held in reserve, a newantibiotic to which there is no resistance wouldbe little used. That is not the sort of product aprofit-making company wants to develop.

Furthermore, from a marketing stand-point, antibiotics are the worst sort ofpharmaceutical because they cure the disease. Companies have more incentive to bankroll research into treatments for chronic conditions such as high choles-terol or rheumatoid arthritis, for whichpatients 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. Accord-ing to the Tufts Center for the Study of DrugDevelopment in Boston, it costs some $800million on average over 10–15 years to bringa new drug to market2. This cost, combinedwith a likely low return on investment,makes pharmaceutical companies reluctantto pursue antibiotic research.

Patent holidayThe result of these negative pressures hasbeen a 56% decline in the number of anti-biotics approved annually by the US Foodand Drug Administration (FDA) over twodecades (see the Commentary on page 899 of this issue). According to a study publishedin May this year, out of 506 drugs in late-stageclinical testing by the world’s 15 largest phar-maceutical companies, only six are newantibacterials — and all are derivatives ofknown antibiotics3. That is barely more thanthe number being developed for some lesslife-threatening ailments. Erectile dysfunctionalone accounted for four of thenew drugs being tested.

“Unless things change soon,we are going to face a majorhealth crisis,” warns Brad Spellberg, an infectious-diseaseresearcher at Harbor-UCLAMedical Center in Los Angelesand lead author on the study.

To help avert the crisis, the IDSA is rec-ommending several steps that would radi-cally alter the economic landscape for drugcompanies. First, it has proposed that Con-gress establish an independent commissionto prioritize antimicrobial discovery, whichwould identify the biggest microbial threatsand make recommendations directly to theSecretary of Health. Pharmaceutical compa-nies could then register with the Departmentof Health and Human Services to receive taxcredits if they were working on drugs to fightone of the targeted bugs.

Another carrot would be ‘wild-card’patent extensions awarded to any drug com-pany that successfully developed a newantibiotic to a targeted microbe. This wouldallow the company to extend the life of anyone of its patents — not necessarily anantibiotic — for two years. As some block-buster drugs bring in billions of dollars ayear, that amounts to quite a gift.“I think thatpatent extension will increase profits sub-stantially,” says Joseph DiMasi, director ofeconomic analysis at the Tufts Center.

At the same time, the FDA should set newdrug-approval procedures for antimicro-bials, the IDSA says. At the moment, a newantimicrobial must be proved more effectivethan an existing one against drug-sensitivebacteria.But this is nearly impossible,as cur-rent antibiotics are very effective as long asthe bacteria are not resistant.The alternative,

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testing in patients with drug-resistant infec-tions, is much more expensive, because it isdifficult to find enough patients for a com-plete trial.

The way round this is to extrapolate fromtests against drug-sensitive strains to gaininsight into how effective the antibiotic willbe against drug-resistant strains. But theFDA has no standards for allowing this,much to the disappointment of drug compa-nies says Steven Projan, director of antibac-terial research at Wyeth in Pearl River, NewJersey.“We need a roadmap for getting a drugapproved,”he says.

Additional incentives proposed by theIDSA include extending patents to make upfor time lost during FDA review,establishinga guaranteed market with federal dollars andlimiting liability for adverse effects, as hasbeen done for vaccines. All these measureswould require legislation by Congress.

Convincing Congress to act may be diffi-cult, as congressmen have a proven distastefor wealthy pharmaceutical companies com-plaining about their bottom line. “The poor

image of pharmaceutical compa-nies with Congress is a potentialobstacle,”says DiMasi.

In fact, some of the provisionswere introduced in the Senate in2001 and 2003 as part of a billknown as S. 666, written by Sena-tors Joe Lieberman (Democrat,

Connecticut) and Orrin Hatch (Republican,Utah).But S.666 never came to a vote.Instead,parts were retained in what became ProjectBioShield, the bill signed into law in July thisyear by President Bush to fund stockpiling ofvaccines and drugs against bioterror agentssuch as smallpox and anthrax.

But Project BioShield does nothing toprotect the public against the demise of anti-biotics. Now Lieberman and Hatch are plan-ning to introduce Project BioShield II laterthis year, a bill that will combine features ofboth S.666 and the IDSA recommendations.

Even if the IDSA plan is adopted,there arestill considerable scientific hurdles to clear.Nearly all the existing classes of antibioticare half a century old. Most antibiotics aremerely modifications of existing ones,whichdoes not always solve the problem of resis-tance. Since 1962, only two new classes — anoxazolidinone (linezolid) in 2000 and acyclic lipopeptide (daptomycin) in 2003 —have been approved for use.

“We have already collected the low-hang-ing fruit,” explains Projan. But in everyorchard the tastiest fruits hang the highest.The proposed incentives,say Projan and oth-ers,may provide a ladder to reach them. ■

Martin Leeb was until recently an intern in the Munich

office of Nature.1. Wegener, H. C. Curr. Opin. Microbiol. 6, 439–445 (2003).

2. DiMasi, J. A., Hansen, R. W. & Grabowski, H. G. J. Health Econ.

22, 151–185 (2003).

3. Spellberg, B., Powers, J. H., Brass, E. P., Miller, L. G. & Edwards,

J. E. Jr Clin. Infect. Dis. 38, 1279–1286 (2004).

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