Attack of The Superbugs

By J. MADELEINE NASH CHICAGO

The advent of penicillin drugs in the early 1940s ushered in a triumphant era of medicine. With stunning speed, pharmaceutical chemists armed doctors with one antibiotic after another, giving them an arsenal of magic bullets to knock out the germs that cause everything from pneumonia to gonorrhea. It was only a matter of time, it seemed, before all infectious diseases would be conquered.

But now the invisible legions of malevolent microbes are fighting back, and medicine is no longer so confident of winning the battle. Not only have many diseases caused by viruses, such as AIDS, proved to be extraordinarily difficult to cure, but even old, easily treated bacterial ailments do not always respond to drugs as they once did. Using marvelous powers of mutation, some strains of bacteria are transforming themselves into new breeds of superbugs that are invulnerable to some or all antibiotics.

The most publicized superbugs are the strains of drug-resistant tuberculosis bacteria that have caused outbreaks of the disease in U.S. hospitals and prisons over the past few years. And in a sobering series of articles in the current Science magazine, researchers point out that the problem of drug resistance is not limited to a few germs but spans an entire spectrum of disease-causing microbes, including those responsible for gonorrhea, meningitis, streptococcal pneumonia and staphylococcus infections. "Bacteria are cleverer than men," says Dr. Harold Neu of Columbia University's medical school.

In the U.S., superbugs have not yet caused large epidemics. The total number of tuberculosis cases reported last year was 26,283, up from a low of 22,000 in 1984, but still well below the 84,000 recorded in 1953. However, scientists are worried about the future. "We forgot that microbes are restless and that they would counterattack," says Richard Krause, a senior scientific adviser to the National Institutes of Health. "That was incredible hubris on our part."

In the world's poorer countries, the fight against infectious disease is already a disaster. Malaria, tuberculosis, cholera and dysentery may claim more than 10 million lives each year. While inadequate medical care and sanitation are mainly responsible for the death toll, increasing microbial resistance to drugs is making a bad situation worse. The antimalarial drug chloroquine is no longer broadly effective, and even the newest substitute, mefloquine, is encountering resistance from some strains of the malarial parasite.

Antibiotic-proof bacteria are spreading around the globe because of the enormous increase in tourism and business travel in recent decades. Last month a woman came to a New York City emergency room with a strain of cholera picked up in Ecuador that was impervious to a variety of antibiotics. Penicillin- resistant strains of gonorrhea, originally noted in Africa around 1976, have cropped up in the Philippines, Thailand and the Washington Heights section of New York City. Public health officials are particularly concerned about potentially fatal forms of dysentery in Central and South America that are resistant to half a dozen drugs.

Quite possibly the earth's most ancient life-forms, bacteria are experts at the game of survival. Throw a bunch of them onto an ice floe or into the steaming heart of Old Faithful, and one or another of the unicellular beasties will probably turn out to possess a critical trait that enables it to live through the ordeal and pass that trait on to trillions of descendants, a rapid example of evolution through natural selection. Just as predation by lions has gradually increased the swiftness of gazelles, the use of antibiotics has spurred the emergence of bacteria that can effectively counter those potent poisons. But bacteria multiply so quickly that they evolve much faster than gazelles.

When a microbe replicates itself over many generations, mutations in the DNA that forms the organism's genetic blueprint can sometimes make it safe from an antibiotic. If, for example, the drug kills the bacterium by latching onto a specific molecule on its cell wall, a change in that molecule could make it impossible for the antibiotic to stick to its target. It's something like the protect-the-perimete r strategy used by defenders of ramparts on medieval fortresses. In other cases, says Neu, the bacteria develop enzymes capable of destroying the antibiotics and even molecular pumps that expel the drugs from the cell. The most recent example of bacterial resourcefulness came to light only two weeks ago. By deleting a single gene, an English-French research team announced, certain strains of the TB germ have protected themselves from isoniazid, currently the major weapon against this resurgent disease.

Once a bacterium has a protective combination of genes, they are duplicated every time the bacterium reproduces itself. Moreover, the microbe can pass its genetic shield to a different strain of bacteria through a process called conjugation, the bacterial equivalent of sex. In addition to exchanging DNA in the form of chromosomes, conjugating bacteria can swap smaller snippets of DNA called plasmids. Like viruses, plasmids make exceedingly effective shuttles for carrying drug-resistant traits from one bacterium to another.

Overuse of antibiotics has accelerated the evolution of superbugs, and hospitals, in particular, are major breeding grounds. For decades, surgeons and internists have fought infections in some extremely ill patients with massive doses of antibiotics, and when one drug didn't work, they tried another and another. From the standpoint of their individual patients, the physicians could do no better. The consequences for society as a whole, however, are troubling. Stubborn strains of bacteria resistant to many different antibiotics have taken up permanent residence in hospitals around the world. Experts predict that the effectiveness of widely active antibiotic agents such as the cephalosporins, which entered clinical use in 1964, will soon be dramatically reduced.

Day-care centers provide another setting that amplifies microbial mischief. & In 1989, for instance, eight children in a center near Cleveland, Ohio, came down with chronic middle-ear infections caused by the same antibiotic- resistant strain of pneumococcus. Subsequent throat swabs revealed that 50 of the 250 children enrolled at the center had been infected but had not yet shown symptoms. Such outbreaks could have serious consequences: recurrent middle-ear infections can impair hearing, and pneumococcus can also cause meningitis and bacteremia, an infection of the blood that may spread to the joints, heart and even the brain. In the Third World, pneumococcus is a leading cause of pneumonia.

One reason bacteria acquire resistance to several antibiotics is that many drugs are derivative of one another. For example, when bacteria developed an enzyme to chew up penicillin, drug designers retaliated with larger antibiotic molecules that did not fit into the site that serves as that enzyme's "mouth." In short order, says Dr. Mitchell Cohen, an epidemiologist at the U.S. Centers for Disease Control, "the bacteria responded to the challenge by developing an enzyme with a bigger mouth."

More imaginative approaches to drug development are essential. "What we need to do," says Dr. Fred Cohen, a biophysicist at the University of California at San Francisco, "is start selecting new targets based on our understanding of the biology of the organism." Already scientists are thinking up strategies for attacking the malarial parasite based on the knowledge that it lives off human red blood cells. Cohen is exploring ways of making hemoglobin appear unappetizing to the parasite, thereby causing it to starve to death.

Effective new drugs will probably be developed, but a decade may pass before they are ready for use. In the meantime, several measures could prolong the usefulness of antibiotics currently on the shelf. To counter the rise of resistant strains of salmonella, the practice of dosing farm animals with large quantities of antibiotics could be curtailed. Hospitals could do a better job of using late-model antibiotics more sparingly, thereby preserving their effectiveness. Public health departments in major cities could return to the old practice of strictly monitoring the drug therapy of TB patients who haven't been following their regimens carefully. Fortunately, resistant strains of this highly contagious disease can still be killed with a combination of antibiotics -- if they are taken on schedule for a sustained period of time.

AIDS patients and many other extremely ill people have a special problem: their immune systems are too impaired to fight disease efficiently. As a result, they often require repeated courses of antibiotic therapy to hold infections at bay. But the longer the treatment lasts, the greater the likelihood that resistant strains will arise. By using antibiotics in combination with drugs that enhance immune response, however, physicians may be able to reduce treatment time.

Fewer antibiotics would be needed if drug companies and university laboratories revived the neglected art of vaccine development. Vaccines use inactivated forms of germs to spur the body to build up antibodies -- and thus prevent infection from ever taking hold. But poorly made vaccines can occasionally cause severe reactions. As a result, the threat of product- liability suits has thrown up an obstacle to vaccine development -- at just the wrong time.

Researchers who once thought they had won the war with microbes now know better. "Disease," observes chemist Irwin Kuntz of the University of California at San Francisco, "is an ongoing battle between one species and another." Homo sapiens cannot expect a decisive victory in this struggle. Instead, they must heed the recurring reminders of the need to develop newer and more clever defenses.

With reporting by Dick Thompson/Washington