Bacterial resistance threatens to disable our health-care system, but it still brings a glint of wonderment to J. Glenn Morris' eyes. "From a scientific standpoint, it is fascinating to
watch," says Dr. Morris, chief epidemiologist at the University
of Maryland Medical Center. "As a physician, it's scary as
hell."
Across the United States, and the world, bacteria and other
microorganisms are challenging medical arsenals. A half
century of antibiotic overuse -- in doctors' offices and hospitals,
but also in livestock feed and antibacterial hand creams -- has
provoked the opposite of its intent. Instead of a world safe from
infectious bugs, we have a world where the most stubborn bugs
survive. Already, drug-resistant bacteria are killing thousands
of people each year. It's not too simplistic to say that we're
racing the bugs to save such endeavors as neonatology, organ
transplants and cancer chemotherapy, none of which could exist
without effective antibiotics. "You don't know how the race is
going to go," says Christopher Walsh, a Harvard Medical School
professor of pharmacology and biochemistry. "You could be a
strategic optimist and say the basic science is bound to save us
in the nick of time. Or you could be a defensive pessimist and say
we're going to be in a post-antibiotic era for a while."
At the 750-bed downtown Baltimore hospital monitored by Morris, a bearded man with gentle blue eyes, the post-antibiotic
era has, in a limited sense, already arrived. In 1992 the medical
center had the dubious honor of becoming one of the first
hospitals in America to detect colonies of vancomycin-resistant
bacteria called enterococci. Vancomycin -- a drug known in
intensive care units as "the Big Gun," or "The Mighty Vanc"--
is a powerful antibiotic. Doctors began flooding surgical
patients with vancomycin in the 1980s when Staphylococcus aureus,
the cause of "staph" infections, developed widespread resistance
to an earlier miracle drug, methicillin. Today, methicillin-resistant staphylococcus and vancomycin-resistant enterococcus
are endemic to Morris' hospital. Carriers are isolated in
separate rooms where staff and visitors are ordered to wear
gloves and gowns. But despite efforts to control their spread
from patient to patient, the bugs "are here to stay," says
Morris.
Random samples show vancomycin-resistant enterococci in up to 25
percent of all patients at the hospital, Morris says. What this
means is that vancomycin resistance isn't just in the hospital --
it's walking the red-brick streets of the city spread below
Morris' ninth-floor window. And it kills, although Morris can't
say how often. (At most hospitals, infection control officers
won't even talk to reporters.) "No hospital will admit that
people are dying of resistant bacteria they acquired in that
hospital," says Morris. But they are dying. In 1997, 90,000
people died in U.S. hospitals while infected with hospital-acquired bacteria -- 70 percent of which were antibiotic-resistant
strains, according to Dr. Stuart Levy of Tufts University in
Massachusetts (although infection was not necessarily the major cause of
all or even a majority of those deaths).
Luckily for most of us, enterococci are dangerous only to
patients with compromised immune systems. But enterococci will seem like mother's
milk if and when vancomycin resistance becomes a factor in staph
infections. Staphylococcus aureus "can cause havoc and death to even otherwise
healthy people," says Levy.
Staphylococcus, a bacteria that colonizes the noses
of one in five people, has proven over the years to be among the most
adaptable bacteria. Targeted with penicillin in 1942, by 1948
staph was largely resistant. Erythromycin was introduced in 1952
and quickly lost its bite, leading to raging hospital infections.
Methicillin, introduced in 1960, was effective for longer -- until
the mid-1980s. Now vancomycin is the magic bullet.
It's not that bugs are "outsmarting" us; they're as dumb as they
seem. As a class, though, they are certainly less individualistic
than we are. Bacteria are indifferent to how they get their
genes. They'll mutate, have sex with cousins and strange species
or gobble up free-floating DNA. Sworn to the
Hippocratic oath, doctors will throw everything in their arsenal at bacteria to save
one patient. "A million bacteria get their heads blown off for
every one that survives" an antibiotic, says Dr. Abigail Salyers
of the University of Illinois. But a few do survive -- and each resistant survivor and its progenitors gain Lebensraum in the body each time the antibiotic is used again, killing off the bacteria that lack genes to adapt.
In December 1996, epidemiologists at the Centers for Disease Control and Prevention got a long-anticipated but still chilling report. A child in Japan had
contracted a staph aureus infection that appeared to thumb its
nose at vancomycin. CDC officials have since confirmed four U.S.
cases of near-resistant Staphylococcus -- in Michigan, New Jersey
and New York, and last month in an undisclosed Midwestern
hospital. The appearance of the bug in scattered hospitals
suggests that, like a series of supercomputers seeking answers to
a complicated equation, staphylococci around the world are on the
verge of cracking the vancomycin code. "It's evolution in
parallel," says Morris. "There are all sorts of fairly nasty
scenarios that you could dream up." The mutant bugs could be
controlled if surveillance was vigorous enough. But many managed-care companies now limit expensive lab cultures, and there is no
national reporting requirement for staph infections. The CDC is relying
on a fairly new network of monitoring sites to detect and study the
organisms.
To control vancomycin resistance, the worst thing hospitals can
do is to throw more vancomycin at staph. But they often have no
alternative. Morris and his colleagues spend a certain amount of
time balancing their commitment to patients and the tragedy of
the commons -- the idea that pursuing individual benefit can ruin
collective resources. And although vancomycin use is being
reined in, what's best for the individual is always the last
word. "The clinician says, 'I've got a patient who is dying and
I think I can keep them alive and, well, to hell with the guy in
the corner who's saying don't use vancomycin,'" says Morris.
"You can get into some pretty heavy philosophy -- to put it
mildly."
Perhaps the spookiest aspect of this looming threat is that, as
in a Gabriel Garcma Marquez story, it has been foretold. "Public
officials have become complacent about the staph problem. Young
doctors have never witnessed babies dying of staph pneumonia,"
wrote a Kentucky pediatrician named Warren Wheeler upon his
retirement in 1972. "It would amaze me if in the future some new
strains don't develop which will smoulder without recognition for
a while, passing from one human to another, juicing up their
virulence as they do until they add the property of methicillin
resistance and explode." Within a decade, as Wheeler anticipated,
methicillin-resistant staph was widespread. Vancomycin, isolated
from organisms that a missionary gathered on a jungle path in
Borneo, stepped into the breech. Should vancomycin fail there is
no new magic bullet to replace it -- for now, at least.
The FDA is poised to approve a new drug, Synercid, that can kill
staphylococcus and a range of other bacteria. It is said to have
serious side affects, though, and even more troubling news
emerged at a conference of microbiologists in Chicago last week.
There, it was revealed that 1 percent of human enterococci are
already resistant to Synercid. How did this happen? A similar
antibiotic has been fed to livestock since 1974, creating
resistant enterococci in chickens. Scientists hypothesize that
the chicken bacteria passed their resistance genes to human
enterococci after their hosts became food. "Bacteria from
livestock and hospitals communicate," says the German
microbiologist Wolfgang Witte. "They communicate via meat."
Several drug companies are working on new antibiotics; Pharmacia
& Upjohn says that Zyvox, from a new class of antibiotics called
oxazolidinones, should be on hospital pharmacy shelves next year.
Many bacteria have been genetically decoded, giving scientists
plentiful targets for new drugs -- although identifying gene
targets is only the first step in a process that takes a decade
or more. In addition, "resistance to new drugs is a cyclical process,"
says Harvard's Walsh. "Every time we introduce a drug and use it
widely we guarantee resistance. It's only a question of how long.
There is no one-time solution, but continual cycles of discovery."
Most promising, in the long run, are vaccines, which prepare our
immune systems to deactivate bugs without the help of
antibiotics. Vaccines have worked wonders in the recent past. In
the 1970s and early 1980s, drug-resistant Haemophilus influenza
type B bacteria killed or disabled thousands of children every
year. The so-called Hib vaccine was introduced in 1985; in
1997 there were fewer than 300 serious Hib-related cases. The most
promising new vaccine target is Streptococcus pneumoniae, which
leads to nearly 40,000 deaths, 500,000 cases of pneumonia and 7 million ear infections every year. Over-prescription of antibiotics has created nasty new strains of pneumococcus, but it's hoped that a childhood pneumococcus vaccine, which has
performed well in large trials, could work as well as the Hib shots have.
An experimental vaccine against Staphylococcus aureus showed
promise in mice, according to research published in Science last
month. But vaccines take even longer than drugs to develop, and
"the reason we don't have a staphylococcus vaccine has nothing
to do with people not having tried," says Paul H. Axelsen, a
professor of pharmacy at the University of Pennsylvania. In any
case, antimicrobial resistance is a moving target -- no one knows
which bugs will be the biggest threats in 15 years, when the
current crop of new drugs and vaccines hits the market. Pessimism
is the default setting in the field. "I doubt we'll get a crisis
or a plague," says Salyers. "More like the gradual erosion of
our ability to control human diseases." Adds Morris, "We're
starting to see the closing of the window, of the antibiotic era.
The question is how fast it closes."
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