Superbugs are here. Microbes vanquished for decades are slowly mutating to resist our pharmaceutical defenses. In U.S. hospitals, bacterial infections sicken almost 2 million people a year and kill 90,000. In more than 70 percent of afflicted patients, the bacteria have become resistant to one or more antibiotics. More ominously, drug-resistant strains that were formerly found only in hospitals have cropped up in community settings, such as schools, jails, and Army training centers.

A more recent threat, HIV, continues to mutate toward drug resistance. Some studies suggest that 10 to 20 percent of newly infected patients in the United States are resistant to at least one HIV drug, and a rare, multidrug-resistant strain cropped up in an infected man in New York City in 2005. Strains of drug-resistant tuberculosis are on the rise in Eastern Europe and Central Asia, and malaria has roared back as one drug after another has become ineffective against the parasite. The World Health Organization General Assembly recently named drug resistance in microbes as one of the top three threats to global health.

Resistance is not confined to human pathogens. The new strain of avian flu that has infected more than 100 people in Asia, and killed more than half of them, may become the next great pandemic. One way to slow its spread is to treat infected birds with amantadine, an antiviral drug meant for humans. But Chinese farmers seem to have used the drug so widely and indiscriminately that a drug-resistant flu strain has developed in some birds, rendering the treatment useless in certain regions.

So far, this avian virus cannot easily infect humans and is contracted only through close exposure to infected birds. But without an effective drug to combat avian infections, more flu-infected birds will come into contact with people, adding to the risk of a mutation that will allow a human-to-human transmission of the flu.

In the developing world, nonprofit organizations working in collaboration with the Bill and Melinda Gates Foundation and other groups take aim at a variety of infectious scourges, supporting dozens of efforts to develop new and improved vaccines and antibiotics as well as to improve methods for preventing the spread of disease. A couple of small, recently funded projects take a completely novel approach toward combating drug resistance. One researcher in China is hoping to devise a drug that targets parts of human cells that infectious organisms such as those that cause tuberculosis and hepatitis B depend on but that are not essential for humans.

 The goal is a treatment that would render the patient’s body completely inhospitable to the bug. Another project is developing medication that boosts overall immunity, decreasing susceptibility to any infection.

Despite these efforts, the short-term solution to drug-resistant microbes is more drugs. Just as chemotherapy often requires several drugs to combat resistance in cancerous cells, successful antimicrobial therapy against some pathogens requires a combination of drugs. The idea is to target microbes at different points in their life cycle, thus minimizing their ability to evolve a defense against a drug and become resistant. Pharmaceutical companies have been slow to develop new antibiotics, mostly relying instead on subtle chemical modifications to older existing antibiotics.

The pipeline for treating drug resistance in HIV, however, holds some interesting prospects. The new drug Fuzeon targets where HIV binds to the cell membrane, blocking its entry, but it must be injected twice a day. An oral drug in development, PA-457 from Panacos Pharmaceuticals, so disrupts the virus’s maturation within a cell that a newly released viral particle cannot successfully infect a cell.

As for malaria, the parasite has become resistant to virtually all treatments. An effective plant-based remedy, artemisinin, exists, but it is too expensive for poor regions such as sub-Saharan Africa. Scientists in India and Thailand are testing a synthetic version, which would be cheaper and easier to produce. Optimism about combination therapy with artemisinin-related drugs is tempered by a recent study finding that the malaria parasite may be only one simple mutation away from becoming resistant to artemisinin.

The war against infections is eons old, but the arms race has escalated over the past few decades. “We are trying to stay one step ahead,” says Barry Bloom, a dean at the Harvard School of Public Health.

Barry Bloom is dean of faculty at the HarvardSchool of Public Health.

What is the greatest infectious disease threat we face these days? B:

The possibility of a bird flu outbreak. The frightening thing is that we have no immunity to bird flu. We get flu outbreaks every year, but these are viruses we have developed an immunity to. In 1918 the flu killed between 20 million and 40 million worldwide because we had no immunity to that flu [the original source of the pandemic].

How can we prepare? B:

We don’t know what the virus is—the human one—because it hasn’t yet occurred, so it’s difficult to prepare for it. We know the bird version of the virus. We have several [genetic] sequences, and we’re making vaccines for these bird viruses. But think about spending millions to make a vaccine for a virus that hasn’t appeared yet.

Can a virus that is likely to emerge in Asia

be contained? B:

This is the vexing thing: If it happens, how are we going to know about it? There are no little CDCs [Centers for Disease Control] in the region. The World Health Organization has some programs, and the governments, too, but there’s nobody home in terms of pulling the information together to rapidly respond to an outbreak.

Is there any treatment for avian flu? B:

A drug called Tamiflu slows down the virus; it doesn’t prevent it. If there is an outbreak, we will need it, but it’s still on patent [with Roche Laboratories], and it’s expensive. There is enough stockpiled in the United States for about a quarter of the population. We need more. There is none in Asia.

What is the state of technology when it comes to treating viral infections? B:

We don’t have a lot of drugs for viruses. A virus works with the cell machinery, so it’s hard to come up with a drug that doesn’t interfere with the cell’s normal function. We should have a bigger research effort for this. Bacteria are easier because you can shut down mechanisms in the cell.

How big a problem is drug resistance? B:

It’s a huge, emerging, threatening problem. We used to think that if we had a vaccine or a drug, then that was that, but we now know that bugs mutate. If you apply a pressure to kill off the normal variants, you allow the mutants to survive. We are causing resistance by putting antibiotics into pigs that we eat. In hospitals, staph infections are becoming resistant to vancomycin, and resistance is already there for penicillin and methicillin. If we lose vancomycin, we’re in trouble.

Can our technology get better? B:

I think we’ll keep up. There will be a lag of two to three years with each case of resistance.

Is bioterrorism a real threat? B:

We are more aware of the threats since September 11, 2001, and the following month, when anthrax was released in the mail. The National Institutes of Health and the Centers for Disease Control have stepped up efforts on research on pathogens that could be used for bioterrorism. I am optimistic. But what company will invest millions of dollars against a pathogen that does not yet exist? One solution would be a guarantee of purchase by governments and foundations.