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Paying for antibiotic addiction

BY COLMAN JONES

Just back from a stroll in the soulful confusion of the French Quarter, I reach my hotel room and find a stack of drug company brochures and invitations to free dinners stuck under my door.

The wooing has begun. For my entire stay at the 36th annual Interscience Conference On Antimicrobial Therapy And Chemotherapy, the largest scientific meeting to study bugs and drugs in the world, I will be pitched, lobbied and cajoled -- all in the service of writing favorably about this or that new drug product.

Thousands of microbiologists from all over the globe have come here, many to examine the growing problem of drug resistance, as once-effective antibiotics increasingly fail to control a whole series of often deadly bacterial infections, especially in hospitals.

WANING POWER

While the subject matter is the waning power of penicillins, the subtext is the primacy of pharmaceutical firms in defining health issues. This is a showcase to awe and overwhelm medical experts with the power of drug companies to shape the way we think of bodily well-being.

In the giant exhibit halls, I'm confronted by huge display booths, many the size of small buildings, sporting slick audio-visual presentations, interactive computer setups, even a magician entertaining passersby with card tricks.

Everywhere I turn, there is some PR flack grabbing my arm, trying to entice me with news of yet another new product. Clearly, the response of the pharmaceutical companies to this crisis of societal overdosing on antibiotics is to create new and better compounds to get around antimicrobial resistance. But some interesting minds on the margins of this gathering worry that the whole process is heading off in the wrong direction. These researchers -- many of them not invited to speak on the panels -- warn that these new formulas may, too, breed their own resistant strains and that the real solution lies in developing alternatives to antibiotics.

When antibiotics were first unveiled, these new compounds were trumpeted as a medical breakthrough, and for a while, it looked like many previously untreatable conditions were headed for medicine's history books.

But within a few years of penicillin's release, it became clear that the promise wasn't going to last. A slowly growing unease began to emerge when it was discovered that some microbes were developing resistance to the new miracle drugs.

In an all-too-familiar scenario replaying itself in hospital wards around the world, these bugs have now made a deadly comeback. These bacteria, as well as fungi and some viruses, have evolved very complex mechanisms for evading the drugs used to treat them, sometimes by producing substances that destroy them, other times by attacking cells in different ways. Paradoxically, the more antibiotics are used to fight them, the more resistant the bugs become.

"There is a tendency among doctors," says professor Jeremy Hamilton-Miller of the Royal Free Hospital in London, "to overuse antibiotics, which have been described by an eminent colleague of mine as drugs of fear -- they are used in case the patient has an infection, and the increasingly litigious nature of patients these days, in all countries, is going to make this situation worse."

Doctors are caught in an awkward bind, he concedes, trying to reconcile the immediate demands of the patient and his or her family on the one hand with contributing to the overall problem of drug resistance on the other. Although Hamilton-Miller admits these drug-resistant bugs are not normally dangerous to healthy adults, when people go to hospital these organisms can easily be spread.

Once-effective antibiotics increasingly fail to control a whole series of often deadly bacterial infections, especially in hospitals.

As a result, unlike other drugs, the effect of antibiotics taken by one person can adversely affect others. "If you take an antibiotic, the world takes an antibiotic," as Hamilton-Miller puts it. "This is where antibiotics differ from all other drugs, and I don't think this fact is appreciated enough."

Drug company scientists have had to play catch-up in order to keep one step ahead of our microbial enemies. The buzz at this conference centers around new, stronger drugs, including a class of drugs called quinolones. One such quinolone is a compound called BAY 12-8039, developed by German-based multinational drug company Bayer AG.

The obvious scientific question is this -- will this and other new products presented here eventually produce their own resistant strains as well, once introduced into human populations?

"There's no guarantee that bacteria will not become resistant to this particular quinolone, but it depends on the type of bacteria and its resistance," admits Barbara Paynter, one of Bayer's scientists.

But there are many at this gathering who say it's time to plumb alternatives to the big-money, longterm research of drugs that are likely to generate their own resistant strains. One option is the substitution of chemical compounds with plant sources.

Melissa McGuire, a New Orleans ethnobotanist who researches the historical uses of medicine by indigenous peoples, says, "There are plants all over the world that have been used for TB and leprosy." A list of these plants appears on her modest poster -- almost the only mention of natural remedies among the hundreds of presentations at the conference.

HOME REMEDIES

McGuire has uncovered a lot of these homegrown remedies by doing literature searches in electronic databases and digging through herbal guides in libraries. Test-tube studies on some of these plants have shown demonstrable activity against mycobacteria, the type of bacteria responsible for TB and leprosy.

"One of the most interesting things for us," McGuire notes, "is to find a plant that's been used for both TB and leprosy, because indigenous peoples had no way of knowing that those are both caused by mycobacteria, yet they use the same plants for similar bugs."

Infectious-diseases expert Richie Witzig of the Tulane school of public health in New Orleans observes that in using phytomedicines, as plant-based remedies are known, "You're not dealing with one compound -- it's a different philosophy. You're dealing with a multitude of compounds, at various concentrations, and nobody's really studied that."

One possible advantage of phytomedicines may lie in their tendency to not disrupt the immune system's natural function. This delicate microbial balance has been thrown out of whack by the increasing use of antibiotics over the decades, a trend that some fear may serve to alter an individual's ability to fight diseases in general.

Joanne Flynn, an assistant professor at the University of Pittsburgh school of medicine, says it's hard to tell what effect antibiotics have on longterm immunity to other infections. "Obviously, it changes your normal bacterial flora," she says. "The most common example is with penicillin derivatives given for bacterial infection and the threat of a candida (yeast) infection, because you're disturbing your natural microbial balance."

LOOMING THREAT

Indeed, recurrent yeast infections are on the rise, even after appropriate therapy has been given. This looming threat is being studied by Jaime Hernandez, assistant professor of medicine at West Virginia Hospital in Charleston, who notes that "It may be difficult, if not impossible, to eradicate yeast infection from the gut, at least with the drugs we have now."

Hernandez feels that while treatment with antifungal agents in acute infections is obviously necessary, efforts should be concentrated on trying to identify resistance mechanisms that can be modified to prevent yeast infections from recurring. This includes possibly boosting the immune system through the use of immunostimulants known as cytokines, small molecules naturally produced by the body to control the responses of various cells.

However, Flynn warns, "Cytokines have a vast array of effects on different cells and can cause a lot of different things to happen, and until we completely understand how those molecules work, there can also be problems with side effects we didn't anticipate."

IMMUNE RESPONSE

Understanding the fundamental basis of immunity to infection is key to sorting out these problems, notes Flynn, who works on the immune response to tuberculosis. "You cannot understand an infectious disease and the organism that causes it unless you understand the host," she insists, pointing to tuberculosis, whose immune effects are still little known.

Yet the prime focus at this conference is not on ways to help the body's response to infection, but on new -- mostly synthetic -- drugs.

"If we can identify immunotherapies -- or vaccines - that might be useful against TB, for example, the problem of drug-resistant TB should be much less," Flynn notes, "because you don't run into the problems of people not following their drug regimens or becoming infected with drug-resistant organisms."

Hamilton-Miller, however, points out that vaccinations have so far proved impossible for a number of diseases, including urinary tract infections. "We don't know what particular factor is important enough, that causes the infection, that we should protect against. A lot more research is needed on what precisely in the bacterium causes the symptoms of the disease, so we can target that particular factor."

Another alternative Hamilton-Miller and others have looked at is probiotics, which have been successfully used to treat various intestinal infections. Unlike antibiotics, which are designed to kill bacteria, probiotics are considered friendly bacteria, increasingly marketed in foods like yogurt and fermented milk.

Unfortunately, these products don't always contain what they claim to, as Hamilton-Miller discovered after he went to health-food stores, buying preparations containing probiotic bacteria and analyzing them in his lab.

"The numbers are often nothing like as great as they are said to be, but more seriously, I found some organisms that shouldn't be there, the most significant of which is Enterococcus faecium, a potentially dangerous organism that can cause serious infections, especially for liver transplant patients" -- and one of several that are rapidly developing resistance to the available arsenal of drugs used to treat it.

As a result, people who've never taken antibiotics or gone to hospital can still get antibiotic-resistant bugs, simply from the food they eat. Exposure through food is only one way of acquiring these potentially dangerous drug-resistant organisms. The most common way of transmitting these various infections often lies in everyday contact, which is why there is a big push at this conference for a return to basic hygiene.

Gail Cassell, past president of the American Society of Microbiology (organizers of this conference) notes, "One of the most effective means of preventing the spread of many types of infectious diseases, including some respiratory infections, is simply by washing your hands, particularly when you've come in contact with a large number of individuals."

Meanwhile, conspicuously absent at this meeting is significant new drug development for age-old diseases affecting mainly poor, Third World nations, such as tuberculosis, which infects one-third of the world's population, killing 3 million people a year.

This sobering reality is not lost on Scott Franzblau, chief of the pharmacology research department at the GWL Hansen's disease center at Louisiana State University, where he looks for new drugs to treat leprosy and tuberculosis.

"Because the drug companies, by and large, feel that they cannot make the size of profit they need to make on a drug just for TB, it has made me feel that we really have to be out there looking at everything we can, because they are not," he says.

Instead, what we have is a scientific-industrial complex almost exclusively concerned with developing products it can market to rich, western nations. Companies have concentrated their efforts on drugs likely to yield a return on their investment -- those used to treat diseases in developed countries, leaving it up to government and university scientists like Franzblau to do research on the diseases of the poor and marginalized, like TB.

The mild-mannered PhD scientist notes cynically, "If (pharmaceutical firms) develop a drug for an infection that's going to make them money -- you know, for pneumonia, strep throat -- and the drug is also good for TB, great, but no drug company is going to go out and develop a drug just for TB, with maybe one or two exceptions."

SCREEN ANYTHING

Franzblau's group has a large National Institutes of Health contract to test whatever compounds they can get their hands on for anti-TB activity, including synthetic preparations, plant extracts from drylands in Argentina, Chile and Mexico, and marine microbes.

"We'll screen anything - -anything on the planet that anyone will send. That's our role in this -- to pick up the slack where a lot of companies have been hesitant.

"For my own part, I feel it's best to develop capability in the developing countries themselves to do as much of the science as possible." To that end, he has people come over and train in his lab, to learn how to go back and test their own natural products for possible anti-TB drugs.

"TB is a good disease on which to take this type of approach, because it is so ancient. We should spend time on these plants that people have used for centuries -- they probably deserve that type of attention."



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