The Killers Within
by Michael Shnayerson and Mark J. Plotkin
The Silent War
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 pneumonia?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 S. pneumo, the leading bacterial cause of pneumonia. In the United States alone, S. pneumo was said to cause 500,000 cases of pneumonia, many of them pediatric, as well as 7 million ear infections, most of them pediatric, too. Only a decade ago, nearly all strains of S. pneumo had been susceptible to penicillin, the drug of choice for these infections. Now 45 percent of all S. pneumo strains were penicillin resistant. Some skeptics observed that with S. pneumo, a doctor could increase the dose of antibiotics and still hope to prevail in many cases. But that was cold comfort to parents who saw their children's lives imperiled. Gary Doern, Director of Clinical Microbiology at the University of Iowa Hospital in Iowa City, tracked S. pneumo on a national, ongoing basis and was staggered by its fast-rising rates of resistance. "Do the math," he said grimly. "Where will it be fifteen years from now?" S. pneumo claimed as many victims outside the hospital as it did because, unlike many bacterial pathogens, it was spread by droplets: coughing passed it from host to host. Enterococcus faecium and Staphylococcus aureus infected hospital patients for the most part. But with S. aureus, the most virulent of the three, there were signs that that was changing.
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 S. aureus 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 multidrug resistant S. aureus infection. "On Tuesday night, April 3 , my hand started to hurt. A lot. It was an itchy-hot-burning-searing-what the- 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, S. aureus, and S. pneumo?were now multi drug-resistant and spreading into the community. Strains of other bacteria, Acinetobacter baumannii, Pseudomonas aeruginosa, and E. faecium, remained hospital bound 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 S. aureus infection, or MRSA. Nearly all strains of S. aureus 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 Tufts University professor whose Cassandra like warnings on the subject two decades before had all come to pass, saw only worse things to come. "We are clearly in a public health crisis," he said to anyone who would listen. "In fact, we're on the road to an impending public health disaster." Joshua Lederberg, Ph.D., Nobel laureate and longtime leading expert in antibiotic resistance at New York's Rockefeller University, felt that by comparison, the Ebola virus was small potatoes. "The odds of Ebola breaking out are quite low, but the stakes are very high. With antibiotic resistance, the odds are certain and the stakes are just as high. It is happening right under our noses."
The principal cause was overuse?and misuse?of antibiotics. In 1954, 2 million pounds of antibiotics had been produced in the United States. By the end of the century, the annual figure had risen, by some estimates, to more than 50 million pounds. Yet researchers at the federal Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, judged that a full third of the 150 million outpatient prescriptions for antibiotics written each year in the United States were unnecessary: either the infection turned out to be viral or the wrong drug was prescribed. Doctors prescribed the drugs partly to placate demanding patients and partly to protect themselves legally if they failed to prescribe an antibiotic for an infection that turned out to be direly bacterial. The proliferation of antibiotics killed many bacteria but gave the hardiest few some more chances to learn how the drugs worked?and how to resist them.
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 U.S. medical institutions, 2 million patients contracted infections?bacterial, viral, and otherwise?and 90,000 died. Of those 90,000, many had drug resistant bacterial infections, mostly S. aureus. The CDC estimated that 40,000 Americans died each year of those infections. That was more than half the number of servicemen who had died during the entire Vietnam War. These deaths occurred in ones and twos, in hospital beds spread across the country, not by the scores on a single battlefield, so they tended to be noticed only by the patients' family and friends; by the hospitals, which certainly did nothing to publicize deaths caused by organisms within their institutions; and by HMOs, which quietly raised their premiums to help cover the estimated $5 billion cost of treating drug-resistant infections each year in the United States. Doctors and researchers published academic papers on drug-resistant bacteria, and, every year, their concerns grew more urgent, their prognoses more bleak. But the public remained largely oblivious to the problem, and as it did, incomprehensibly large populations of bacteria grew more and more resistant to more and more drugs.
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 Duke University had determined that only 17 percent of doctors treating patients in an intensive care unit washed their hands thoroughly and consistently. But to the bugs, every patient in an ICU presented another irresistible meal, and, with lax infection control, the bugs got fed.
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. S. aureus, the most virulent of the staphylococci, was also alarmingly widespread: between 20-40 percent of people, both healthy and sick, carried S. aureus, usually in their nose or on their skin. Once it managed to enter the bloodstream of an immunocompromised person,S. aureus 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 New York, which had become the epicenter in the United States of drug-resistant bacteria. They migrated to other places where people crowded together: prisons, military barracks, college dormitories, and, most frightening of all, daycare centers. Among the most likely carriers?or vectors, as the literature had it? were the doctors and nurses themselves. Once out, the bugs passed their resistance genes on to other bacteria, and resistance spread exponentially.
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 United States each year, nearly half was consumed by animals. At vast commercial farming operations, tens of thousands of chickens were fed antibiotics in their drinking water if even a few appeared to be sick, a practice that all but assured the spread of resistance as the bacteria of healthy birds became familiar with, and then impervious to, the drugs. Nearly all livestock in America were also fed small, daily doses of antibiotics?"sub therapeutic doses," they were called?as a time tested, if scientifically unproven, way to make the animals grow faster and fatter. If scientists had tried to devise a means of their own to foster resistance, they could not have come up with a better one than this. The tiny, sub therapeutic doses, also called "growth promoters," enabled bacteria in the animals to get familiar with the drugs but not be remotely threatened by them, and so blithely develop resistance to them. Often, resistance then passed from the livestock to the person who handled the livestock or ate undercooked meat. The agriculture industry had denied this for years, its high-paid lobbyists sounding, as they called for ever more scientific proof, eerily like tobacco lobbyists denying that cigarettes caused cancer.
The most common of the resistant food-borne infections were Salmonella and Campylobacter. Neither was as virulent as S. aureus, 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 September 11, 2001. The likelihood of any one of those people receiving an anthrax-laced envelope in the U.S. mail was very, very small. It was extremely likely, however, that many of those people would take Cipro at the first flu or cold symptom they feared might be anthrax, accelerating the spread of resistance. An entire class of drugs-the most important new class in four decades? might be compromised far sooner than anyone would have imagined five years before.
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 Africa might displace enough molecules around it to set off a series of reactions that resulted in a tornado over Kansas. With drug resistant bacteria, such a journey was fact: molecular biologists had traced the spread of earlier generations of methicillin-resistant S. aureus from a single genetic mutation in Spain, or Australia, or Brazil, clear around the world. Americans and Europeans liked to imagine that they were safe from the myriad infectious diseases that plagued developing nations, and to some extent they were right. Their water was not contaminated by cholera; their air was not abuzz with malarial mosquitoes. But agricultural products carrying resistant Salmonella were sent routinely across international borders. For that matter, resistant bacteria could travel across the world in a day by plane, and often did.
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 China and Mexico, antibiotics were sold over the counter, no prescription needed, like cough drops. More and more, they were about as effective as cough drops, too. New, more powerful antibiotics were needed. But the new drugs-unlike penicillin and its many offspring?were very, very expensive. When two or more had to be combined, the cost rose, usually far beyond what the citizens of poor nations, or their governments, could pay. Treating a single case of multidrug-resistant tuberculosis with a whole coterie of drugs over an infection period as long as twenty-four months cost as much as $180,000 in the United States. In poor nations, the cost might be somewhat less?but so would the levels of sanitation and infection control.
"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?
2002 by Michael Shnayerson and Mark J. Plotkin
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