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                                                                                MEDICINE, Page 62

Attack of the Superbugs


In the battle against old scourges, magic bullets are losing
their power, and invisible legions of drug-resistant microbes
are again on the march

By J. MADELEINE NASH CHICAGO -- With reporting by Dick
Thompson/Washington


    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-perimeter 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.