The Silent War
The Killers Within: The Deadly Rise of Drug-Resistant Bacteria
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Most mornings for Glenn Morris started with his daughters. Only after he
loaded the three of them-aged fifteen, twelve, and nine-into his old Infiniti
G20 and dropped them off at the carpool did he head in to the hospital. But on
the mornings of July 2001, while the girls were on summer vacation, Morris bid
his wife goodbye and drove off alone to the front lines of a war none of his
neighbors could see or hear.
As a doctor in his late forties who was both head of epidemiology at his
hospital and chairman of the associated university department, Morris could
have graduated from going on clinical rounds. Still, he made a point of doing
it two months a year. You couldn't just teach and do research, he believed?you
had to see what new infections patients were incurring. Also, going on rounds
made him feel the same stomach-tightening anticipation of the unknown that he'd
experienced as a medical resident more than two decades before. And so he
headed in from his Tudor?style house in Roland Park?a leafy neighborhood of
large, comfortable homes built a century ago as one of Baltimore's first
suburbs?to spend his days treating half a hundred very sick patients, many of
them indigent, in the general ward of Baltimore's Veterans Affairs Medical Center.
On the fifteen-minute drive into the city, Morris liked to listen to
country-and-western music, its trucks and trains and broken hearts weaving
through his thoughts of doxycycline or ciprofloxacin for one patient,
vancomycin or Synercid for another. After parking in the hospital's underground
garage and ascending, white-jacketed, to the general ward on the third floor,
he started by checking his charts. Six new patients, he saw, had been admitted
to the ward by way of the emergency room. One's condition looked especially
bad.
Morris went from bed to bed, trailed by a note-taking team of medical
students, interns, and residents. Because this was a VA hospital, most of the
patients in the general ward were male, elderly, and afflicted with chronic
conditions. Many also had symptoms that indicated bacterial infection. A decade
ago, antibiotics would have knocked out all of these infections almost
immediately. Now on average, about 20 percent of patients on Morris's clinical
rounds had infections resistant to one, two, three, or more drugs. When he
wrote for medical journals, Morris described this multidrug resistance in dry,
clinical terms that expressed none of the emotions he felt when he witnessed
the ravages of an almost unstoppable infection. What he felt was dismay, and
alarm, and a little twitching of fear.
When Morris pointed out antibiotic-resistant infections to his interns and
residents, he didn't need to emphasize that these were bacterial
infections. They'd had it drilled into them in medical school that most
infections are either bacterial or viral, and that bacterial infections are the
ones that respond to antibiotics. Viruses, they knew, were a whole other
matter. A virus is a tiny squiggle of protein-covered DNA or RNA, so small it
isn't even a living, cellular organism: its only function is to bore into the
cells of other organisms and force those cells to produce more viruses. (AIDS
is caused by a virus; so is the common cold.) Antibiotics are useless against
viruses. Bacteria, on the other hand, are one-celled organisms: the smallest
creatures on the planet. The cell has various parts that enable the bacterium
to live and replicate. Those parts can be targets for antibiotics. Unless, that
is, the bacteria figure out how to change or deflect the drugs and make
themselves resistant.
A decade ago, Morris liked to remind his entourage, doctors had only to
reach for penicillin, or one of the third-generation cephalosporins, or the
then new, brilliantly effective fluoroquinolones. Now for empiric therapy?immediate
treatment of new patients, before a lab could determine exactly what bug they
had?doctors often found themselves in the dark, guessing which antibiotic would
work. Often there was time to correct the therapy once cultures provided a profile
of which drugs still worked against a bug. Sometimes there wasn't. Whenever a
newspaper obituary listed cause of death as “complications” following surgery,
chances were that a doctor had guessed wrong in terms of antibiotics?or that a
bug had proved resistant to all of them. This was code that all healthcare
workers, hospital staff, and HMO providers understood but few outside the
medical world knew.
Most at risk were the old and the infirm, their immune systems deteriorated,
especially in hospitals: at the dawn of the twenty-first century, roughly a
third of all people older than sixty-five were dying from infections. Nearly as
vulnerable, however, were the very young. Their immune systems were immature,
not ravaged, but the result was the same. Tough, sometimes unstoppable strains
of the usual suspects especially Streptococcus pneumoniae caused
terrible, recurrent ear infections, or meningitis, or systemic bloodstream
infections that shut down a child's vital organs. Every year, 1.2 million
children around the world were estimated to die of , the leading bacterial
cause of pneumonia. In the
In January 2001, Bryan Alexander, eighteen, was found guilty of assault and
drunken driving and sentenced to a 180-day term at a correctional boot camp in
Mansfield, Texas. On January 4, he filed a written request for medical
attention. According to his father, he filed two more requests; all three
requested treatment at the local hospital. The camp nurse chose to refuse them.
On January 9, Alexander died of pneumonia caused by a infection: an otherwise
healthy eighteen-year-old killed by microscopic organisms in just days. A few
months later, talk show host Rosie O'Donnell very nearly died after cutting her
finger with a fishing knife and incurring a multidrugresistant infection. “On
Tuesday night, April 3 [2001], my hand started to hurt. A lot. It was an
itchy-hot-burning-searing-whatthe- hell-is-happening pain,” she recalled. The
pain became unbearable; by the next day, O'Donnell was in the hospital, her
hand so swollen it looked “like a kid's bright-red baseball mitt.” Multiple
surgeries were needed to debride her finger?to cut away the dead and infected
tissue?and decontaminate the site. Neither good health nor celebrity had
protected these victims.
Strains of all three of these common bacterial infections?E. faecalis, , and
?were now multidrug-resistant and spreading into the community. Strains of
other bacteria Acinetobacter baumannii, Pseudomonas aeruginosa, and E.
faecium remained hospitalbound but had become resistant to all antibiotics.
So widely and quickly were bacteria of different species trading their
resistance genes that the vast, invisible world of bacteria could be thought of
as a single, miasmic, multicelled organism, its trillions of parts all working
together for the common goal of survival against antibiotics. What this boded
for humans, the bugs' primary source of food, was in no way good.
At the bedside of the patient whose case history worried him the most,
Morris offered greetings with a cheer he didn't feel. The patient, a man in his
seventies, had come to the hospital some time ago for a routine knee
replacement. Apparently, while his knee was cut open in surgery, he'd incurred
a methicillin-resistant infection, or MRSA. Nearly all strains of were now
resistant to penicillin; almost half the hospital strains were also resistant
to methicillin, the drug once thought to be a permanent replacement for
penicillin. The infection had manifested itself a month after the man was back
home. In he came again to the hospital for surgery to decontaminate the joint,
followed by a six-week course, also at the hospital, of vancomycin.
Vancomycin was a last resort, but that didn't make it a great drug. It often
failed to penetrate deep bone infections, and it had to be administered
intravenously, which meant using catheters, which became conduits for other
disease-causing, or pathogenic, bugs. In this case, when vancomycin failed to
stem the infection, the man's doctors removed the artificial joint altogether
and fused the joint that remained. Then they hit him with another six-week
course of vancomycin. Now he was back again, this time with a fever that almost
certainly signaled the return, yet again, of his resistant infection. He had
bedsores, a urinary catheter, a fused knee that was essentially worthless, and
deep infections that just wouldn't quit. He was almost pathologically depressed,
as well. His wife had remained a constant presence at his hospital bedside, but
she was on the verge of a breakdown herself, unsure whether the downward spiral
of complication after complication could ever be reversed.
Morris knew he had to prescribe vancomycin. He had no choice. But where to
put the IV? The man had endured so many intravenous lines he was running out of
veins. Reluctantly, Morris put him on vancomycin via a central line?a catheter
introduced into one of his large veins?and wished him luck. Privately, Morris
thought the man would be lucky to live out the year.
This was a case, Morris thought, that should never have happened: a man
who'd come into the hospital in basically good health and emerged with a dire
strain of MRSA. Doctors had a phrase they used among themselves to refer to
such patients?the ones with infections resistant to one or more drugs and who
seemed too sick to respond to any antibiotics.
Train wrecks, they called them.
Not every doctor and microbiologist at the dawn of the twenty-first century
felt, as Morris did, that the golden era of antibiotics might be coming to an
end. Not all felt that bacterial resistance had become, in the words of one
physician, one of the greatest threats to the survival of the human species.
But many did. And all agreed that resistance had become an urgent global issue.
Stuart Levy, M.D., a
The principal cause was overuse?and misuse?of antibiotics. In 1954, 2
million pounds of antibiotics had been produced in the
It was a phenomenon that biologists called selective pressure. Among the
billions of bacteria in a drop of human blood, or on a pinpoint of skin, or in
a minute isolate of phlegm in the throat or stomach acid, might be a few?just a
few?with a chance mutation that enabled them to resist the antibiotic used
against them. If the antibiotic was then removed because the patient felt
better and stopped using it?or sometimes even if it wasn't?those few resistant
bugs would have an ecological niche, or clear field, in which to run wild. Because
bacteria replicated so quickly?some bugs created a whole new generation every
twenty minutes?the mutants could soon fill the niche. The pressure of the
antibiotic, rather than obliterating them, had selected them to survive.
Only a small portion of blame could be pinned on doctors in the community.
Lethally resistant bacteria now resided in every hospital and nursing home in
the world. Every year in
Often these resistant bacteria, once established by selective pressure, were
passed by contact, on the hands of doctors or nurses, from patient to patient.
Many found easy access to their victims' bloodstream through surgical incisions
or wounds or by lingering on catheters and prostheses. One study had found a
high incidence of pathogenic bacteria on computer keyboards and faucet handles
in intensive care units, or ICUs. Another had found the bugs in the cushions
and fabric of chairs in hospital common rooms, and in the acoustical tiles of
hospital ceilings?lingering there, sometimes, for years. A third had found them
on rectal thermometers, a fourth on stethoscopes.
These various reservoirs dramatized the other dimension of the problem. If
misuse of antibiotics created drug-resistant bacteria in the first place, poor
infection control in hospitals allowed the bugs to spread. Every time a doctor
or nurse failed to wash his or her hands before entering a patient's room, millions
of invisible pathogens potentially came along for the ride. Yet how feasible
was it for emergency department doctors to wash their hands before and after
treating each next desperate patient, at a rate of five or six patients an
hour? Or for doctors seeing up to two dozen patients on clinical rounds to do
the same? In fact, one recent study conducted at
The most prevalent pathogens were bacteria that people carried with them as
part of their natural “flora.” In their stomach and intestinal tract milled
billions of enterococci. In their throat resided billions more streptococci. In
their nose, and on their skin, lived the most worrisome of the big three:
staphylococci. Some of these bugs were essential to digestion; others promoted
health by staking turf that might otherwise be colonized by more virulent bugs.
But given access to a weakened host?often through a cut in the skin?certain
strains of these three species could be very bad bugs indeed. Enterococci
caused skin and bloodstream infections; under the right circumstances they
infected heart valves, too. Streptococci caused all manner of infections, from
sore throats and earaches to pneumonia to the horrific necrotizing fasciitis,
better known as flesh-eating bacteria. , the most virulent of the
staphylococci, was also alarmingly widespread: between 20-40 percent of people,
both healthy and sick, carried , usually in their nose or on their skin. Once
it managed to enter the bloodstream of an immunocompromised person, caused
surgical infections, pneumonia, heart and brain infections, and systemic
bloodstream infections that shut down vital organs one by one with an
inexorable end result.
In the last decade, the bugs had acquired intricate mechanisms of resistance
more quickly, as if the bacterial world was mirroring humanity's own ever
quickening pace of development. Some succeeded in making their cell walls
impermeable to antibiotics. Others created tiny pumps that actually vomited
them out of the cell. Many antibiotics targeted one enzyme or another of the
cell wall itself, attaching to it just as the bacterium was making more cell
wall enzymes in order to replicate; yet many bugs had figured out how to change
or replace those enzymes so that the drug failed to attach. Still other bugs'
enzymes attacked the drug itself, slicing its chemical rings. The
broad-spectrum antibiotics that most doctors reached for first were the ones
likeliest to provoke these mechanisms. They killed a wide range of bugs, as the
term implied, but used frequently they also gave that wide range of bugs more
chances to develop successful mutations or import resistance genes from other
bacteria. As microbiologist Barry Kreiswirth of New York City's Public Health
Research Institute put it, “The bugs are getting stronger?and they're getting
stronger faster.”
Stuart Levy, a puckish fellow given to bow ties and elegant suits, often
observed in his lectures, and in his classic book The Antibiotic Paradox,
that the answer had caused the problem. Or rather, the answer to one problem
had led to the next problem. Antibiotics had changed the world, eradicating the
horror of pervasive infections that killed young and old alike. They had
transformed surgery from a butchery in which most patients died of infections into
a modern medical science. Yet the development of novel invasive therapies like
organ transplants, prosthetic implants, dialysis machines for kidney failure,
and chemotherapy for cancer had resulted in more and more immunosuppressed
patients, which in turn provided additional fodder for the microbes. And the
better that modern medicine enabled patients to overcome once-lethal conditions
like faulty hearts or cancer, the longer it enabled them to live, the more
likely they were to decline gently into the clutches of invisible microbial
pathogens. “We can close the books on infectious diseases,” U.S. Surgeon
General William Stewart had declared in 1969, suggesting, in a breathtaking
show of hubris, that humans had beaten the bugs once and for all. But the bacteria
were fighting back?and gaining on us.
In the early 1990s, only doctors and nurses in hospitals had worried about
drug-resistant bacteria. Now, like so many microscopic prisoners, the bacteria
were breaking out. They caught their rides on the skin or in the intestinal
tract of recovering patients in home care. They clung to aging patients
shuttled back and forth between hospitals and long-term care facilities or
nursing homes, especially in crowded cities like
What rule, after all, had ever restricted resistant bugs to hospitals? No
rule they knew of.
Resistance flowed from hospitals, it radiated out from antibiotic misuse by
doctors in outpatient settings, and it welled up, too, from a third, ubiquitous
source in the community: the agriculture industry. Of those 50 million pounds
of antibiotics used in the
The most common of the resistant food-borne infections were Salmonella
and Campylobacter. Neither was as virulent as , the most worrisome bug
of all. But both affected so many people that deaths did occur. Each year, Salmonella
infected 1.4 million Americans and killed 500; Campylobacter infected
2.4 million Americans and killed 100. To epidemiologists like Morris looking at
the big picture, the more alarming fact was that strains of Salmonella
and Campylobacter were now resistant to as many as five drugs. A
relatively new, synthetic class of antibiotics was very effective against both Salmonella
and Campylobacter. Unfortunately, that class was the quinolones, which
included drugs being used in livestock. Animal use of the quinolones was
provoking resistance in the animals' own Salmonella and Campylobacter,
which were then passing to people who ate that meat. The quinolones included
ciprofloxacin, the drug that untold tens of thousands of Americans had
persuaded their doctors to prescribe for them as an antidote to anthrax in the
aftermath of
The social fabric on which drug-resistant bacteria spread did not flutter to
an end at the far edge of town or stop at the city limits. It passed from state
to state, country to country, continent to continent. Chaos theory held,
famously, that a butterfly flapping its wings in
Throughout poor and developing countries, the list of other microbes on the
march was abysmally long. Either no antibiotics for them were available or,
ironically, too many were available, leading to rampant overuse. In
“We are seeing a global resurgence of infectious diseases,” U.S. Surgeon
General David Satcher warned the U.S. Congress on the eve of the twenty-first
century, a dramatic reversal of his office's stance a generation ago.
Infectious diseases included viral killers?among them AIDS. But resistant
bacterial pathogens were a growing subset, and each threat exacerbated the
other. Roughly a third of the world's population, for example, was infected
with tuberculosis, the result of early childhood exposure to the bug. Most of
those carriers lived their whole lives without having the walled-off tubercles
in their lungs break out and cause disease; most remained unaware they even had
tuberculosis. But as AIDS spread, ravaging the immune systems of everyone it
infected, many of its victims then developed active tuberculosis.
The more widely TB spread, the more widely, and indiscriminately, a host of
drugs were used against it. The more that happened, the more resistant TB
became to those drugs. At the end of a particularly wrenching day on clinical
rounds, even Reba McEntire did nothing to soothe Morris as he drove home from
the hospital to his tree-lined neighborhood. He would glance at the handsome
houses of Roland Park and think, They have no idea. Cosseted in their
plush living rooms, most of his neighbors simply had no clue how many
disease-causing bacteria were growing resistant to antibiotics, how in the
silent, invisible war of bugs against drugs, the bugs were beginning to win.
The first thing Morris did when he walked into his big house was go to the
kitchen and wash his hands?once more, with soap, just to be sure. Then he went
in to hug his wife, a physician herself, and his daughters. Sometimes he
marveled at how his daughters took their perfect health-and everything else?for
granted. Like most children, they took limited interest in the details of their
father's day. Perhaps that was just as well. Morris didn't want to scare them
with details of his latest cases. Nor did he want to say that he doubted their
children would have antibiotics for every need. More and more infections, he
felt sure, would be unstoppable killers, just as they had before the age of
antibiotics began.
Could it be only a decade ago that most doctors and drug company scientists
had believed the antibiotics they had on hand would work forever? In that
whisker of time, the entire medical establishment had been forced to swallow a
very bitter pill. No antibiotic would work forever. Eventually, every
bacterial pathogen would learn how to become resistant to every drug used
against it. Given how quickly bacteria were adapting now, Glenn Morris was only
echoing the fears of most colleagues when he predicted that many bacterial
pathogens would likely be resistant to all existing antibiotics in another
human generation or two. In a decade, after all, while some modest fraction of
humanity reproduced itself, bacteria reproduced 50,000 times, trying each time,
in some soulless but utterly determined, Darwinian way, to adapt in order to
prevail.
How, Morris wondered, could our species have made such a monumental blunder? Sixty years ago, scientists had discovered the first of the natural antibiotics and seen how brilliantly they worked against various bacteria: the biggest medical find of the century. In their excitement, they had failed to remember that bacteria had existed for billions of years, probably before any other life on the planet. Their ancestors, trillions of microbial generations ago, had seen the appearance of brontosauruses, tyrannosauruses, woolly mammoths, and saber-toothed tigers. And they had feasted on their carcasses. After surviving unimaginable extremes of fire and ice, were those bugs really going to let themselves be vanquished by a brand-new arrival in geologic time, using weapons they themselves had devised?
END OF EXTRACTS
About the Author
For much of the past 20 years, Dr. Mark J. Plotkin has worked with and
learned from the ancient shamans of Central and
The Killers Within: The Deadly Rise of Drug-Resistant Bacteria
A battle is taking place on the frontiers of medicine between
rapidly evolving bacteria that threaten our health and the doctors who are
struggling to outwit them. These bacteria are everywhere: in and on our bodies,
in homes, schools, hospitals, crowded
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