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Chapter 4
Superbugs
Not long before antibiotics entered our lives, staph in the blood-stream killed 90 percent of its victims. A man who nicked him self shaving could die from erysipelas, a strep infection. Children lost their playmates to scarlet fever, meningitis, osteomyelitis. Bacterial pneumonia, the leading cause of death, killed a third of its victims. Tuberculosis patients were advised to rest and seek clean air, because there was nothing else medicine could offer. In parts of the United States, 10 percent of women died in childbirth. Rocky Mountain spotted fever killed 20 percent of its victims. The state-of-the-art treatment for syphilis was mercury ointment. Gonorrhea had no cure. A blindfolded visitor led through a hospital could identify the surgical ward by the stench of rotting flesh.
Today, antibiotics save tens of thousands of lives yearly in the
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United States alone. Without these therapies, modern invasive medicine would come unhinged. Daily life would be an obstacle course of fear. Are we about to return to those times?
In May 2001, Mary Jane Ferraro was working at her desk when a lab supervisor stepped into her office. The woman had worked with Ferraro for 25 years, and they trusted each other’s judgment completely. “You won’t believe this,” the supervisor began. Ferraro, who directs the clinical microbiology laboratories at Boston’s Massachusetts General Hospital, listened hard. Her job is to make sure that one of the most storied medical institutions in the world—the place where patients go for help when the best outside doctors are stumped—pins down the most unexpected and difficult-to-discern agents of infection. An outgoing woman with a reddish-brown pageboy and a lyrical laugh, Ferraro soon headed down the hall to the lab, a complex of neutral-colored rooms with computers and microscopes and boxy incubation machines that warm bacterial cultures to human body temperature. The supervisor handed her a clear, round plastic plate. Growing inside were creamy yellow colonies of Staphylococcus aureus.
S. aureus is a virulent and aggressive pathogen, endemic in virtually every hospital in the world. On this May morning, the colonies of staph on the culture plate told a frightening story. In a circular arrangement on the plate were little round filter-paper disks, each saturated with a different antibiotic. If the antibiotic was effective against the staph, a wide clear ring formed around the disk, evidence that the nearby bacteria had been killed. If the bacterial colonies grew closer to the edge of the disk, it meant the drug was useless. Ferraro peered at the tiny disk containing linezolid. Barely a year earlier, to much fanfare, the Food and Drug Administration had approved the drug as the “last-resort” antibiotic for multidrug-resistant S. aureus, the most dangerous source of hospital infection. Here was the antidote doctors could supposedly turn to when every other medication failed. Ferraro couldn’t believe her eyes. The creamy colonies of bacteria grew undeterred. It was the first evidence of linezolid-resistant staph in the world. She felt an odd mix of emotions: competitive pride that her laboratory
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had caught it, and terror that the infection had already spread to other patients.
Living Pharmaceuticals
Three millennia ago, the Chinese applied spoiled soybean curd to cure carbuncles, boils, and other skin infections. Mayan Indians roasted green corn and let it rot to produce a preparation that relieved skin ulcers and intestinal infections. Renaissance-era Europeans placed loaves of bread on rafters to grow moldy; this staff of life was sliced and mixed with water to make a pasty dressing for wounds. In 1640, the apothecary of London, moonlighting as the King’s herbalist, prescribed a fungus to treat infected wounds. All were applying living pharmaceuticals, now known to be antibacterial toxins produced by fungi.
In the nineteenth century, bacteriologists shed new light on these time-tested practices. They discovered that, in the lab as in nature, the fittest microbes survived by killing other microbes. As Louis Pasteur observed, “In the inferior organisms, still more than in the great animal and vegetable species, life hinders life.” The practical implications were obvious. “If the study of the mutual antagonisms of bacteria were sufficiently far advanced,” two scientists wrote in 1885, “a disease caused by one bacterium could probably be treated by another bacterium.” At the turn of the last century, German physician and bacteriologist Paul Ehrlich likened the immune system’s antibodies to magic bullets that aimed straight for their bacterial targets while leaving everything else in their paths unscathed. Why not, Ehrlich wondered, find chemical bullets that were equally potent and benign? As a 1925 editorial in the Lancet prophetically observed, “Medicinal properties attributed by tradition to certain fungi may possibly represent an untapped source of therapeutic virtue.”
In the warm September of 1928, Scottish bacteriologist Alexander Fleming returned to his London laboratory after spending two weeks at his country home. As Fleming perused a set of glass petri dishes that he had inoculated with bacteria before embarking on his holiday, his
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eye stopped. In one, a green contaminating mold had unexpectedly taken residence. Immediately surrounding the mold, the growth medium looked clear. Only around the far edges of the dish grew the colonies of Staphylococcus aureus that Fleming had seeded in the medium. A closer look revealed what Fleming called “ghosts” of the staph bacteria—transparent remnants left when the mold “lysed,” or disintegrated, them. To Fleming, this was curious indeed. Just a few years before, he had identified the enzyme lysozyme, a component of tears and mucous fluids that kills non–disease-causing bacteria. But he knew that Staphylococcus aureus, one of the most dominant and fearsome groups of bacteria—to this day—was notoriously hard to lyse. “Obviously,” he would later write, “something extraordinary was happening.”
In a paper published the next spring, he identified the green contaminant as the fungus Penicillium notatum, from which penicillin got its name. Ultimately, it would be shown to destroy no fewer than 89 different pathogenic bacteria.
Fleming’s new germicide was unstable and difficult to produce. But the chase was on. Prontosil, first prepared by the German dye company I.G. Farbenindustrie in 1932, ushered in the sulfonamides, or sulfa drugs. These “bacteriostatic” agents didn’t actually kill microbes but rather checked their growth so that the immune system could finish them off. Ten years after Fleming’s initial find, a team of Oxford scientists purified his mold juice. In 1940, having inoculated eight mice with deadly doses of streptococci, they injected four with penicillin as well. By the next morning, only the treated animals had survived.
It took a while to produce these magic bullets in bulk. In a legendary 1941 case, an English policeman had scratched the corner of his mouth while pruning roses. He developed staphylococcal septicemia, blood poisoning that left abscesses over all his organs. Administered over five days, penicillin pulled him back from the brink of death. But the purified yellow powder was dwindling, and when the drug ran out, the patient relapsed and died.
To save the lives of Allied soldiers, the U.S. government quietly underwrote the production of larger quantities. After D-Day, penicil-
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lin was released for civilian use. It became as common as candy, mixed in over-the-counter salves, throat lozenges, nasal ointments, even cosmetic creams. The drug and its synthetic derivatives transformed the medical landscape, dramatically cutting deaths from staph infections, sepsis after childbirth, pneumococcal pneumonia, ear infections, and bacterial meningitis. As Stuart Levy writes in The Antibiotic Paradox, “It was as if Prometheus had stolen fire from the gods.”
But just as soon as antibiotics were discovered, so was antibiotic resistance. In a 1945 New York Times interview, Fleming warned about the evolutionary selection of resistant bacterial strains. He had seen it in his own lab. When he grew susceptible bacteria in ever-increasing amounts of penicillin, some flourished and took over. “There is probably no chemo-therapeutic drug to which in suitable circumstances the bacteria cannot react by in some way acquiring ‘fastness’ [resistance],” he warned. As early as 1946, a London hospital reported that 14 percent of Staphylococcus aureus strains taken from sick patients could stand up to penicillin. Three years later, that figure leaped to 59 percent. The term “hospital germ” was coined, reflecting the sense that certain microbes thrived in the dense presence of antibiotics—a far cry from the sanitarian view that dangerous infections lurked in the street or at work or on public transportation. By 1955, when most countries curbed the use of penicillin to prescription-only, it was already too late. Today, just under 100 percent of Staphylococcus aureus are penicillin-resistant. And that’s just the beginning.
As scientists began prospecting for new antibiotics, their search led them to the very ground beneath their feet. As far back as the 1880s, it had been conjectured that the reason soil wasn’t the source of perpetual epidemics—despite receiving human and animal wastes and corpses—was because of an invisible, ongoing warfare between microbes. Today, we know [1 µm]
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that each teaspoon of soil may contain thousands of different species, a more biodiverse menagerie than the earth’s entire collection of mammals. Whenever resistance emerged, researchers found a new class of drugs or chemically tweaked existing compounds. In 1944, Selman Waksman, a Ukrainian emigré to the United States and renowned soil microbiologist, systematically screened thousands of soil samples before happening upon a species named Streptomyces griseus. From this was extracted the first aminoglycoside: streptomycin, an early cure for tuberculosis. The genus of bacteria known as actinomycetes, which include the soil-loving Streptomyces, has since spun off well over half of the antibiotics used today, including the aminoglycosides, the macrolides, and the tetracyclines. The cephalosporins, refined versions of which are used today to prevent a wide range of hospital infections, were discovered in 1945; chloramphenicol, which cured typhoid fever and typhus, came in 1947; chlortetracycline, which cured pneumonia, in 1948; erythromycin, a broad-spectrum drug that stopped organisms such as Neisseria and Haemophilus, in 1950; vancomycin in 1955; methicillin in 1960; gentamicin in 1963; ciprofloxacin, a low-toxicity fluoroquinolone, in 1983.
Doctors wanted to be able to prescribe something even if they didn’t know what organism was causing a patient’s infection. So the pharmaceutical industry widened the killing swath of each new drug. As the antibiotic age unfolded, these categories would become important. Narrow-spectrum drugs such as penicillin G affect mostly Gram-positive bacteria, such as staphylococci, streptococci, and enterococci, so named because their single cell wall takes up a special stain used to differentiate microorganisms, and turns dark purple-blue. Gram-negatives, a group that includes gonococci, meningococci, and many intestinal bacteria, have a three-layer cell wall and so do not absorb the dye, showing up on a lab slide as a bright pink-red. Drugs that killed Gram-positive organisms often didn’t kill Gram-negatives. Not until researchers perfected “broad-spectrum” antibiotics and later even more widely effective “extended-spectrum” agents, were they able to treat both with the same drug. While on its face this development typified the golden
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age of therapeutics, it would have unforeseen downsides. The further antibiotics extended their reach, the wider the bacterial insurgency.
It was 1967 when investigators isolated the first penicillin-resistant pneumococcus, the highly invasive organism that causes middle ear infections, pneumonia, and meningitis. Found in a healthy three-year-old boy in a remote village in Papua New Guinea—and probably bred through a misguided effort to prevent such infections by injecting residents with low-level penicillin—it was seen as a fluke. Looking back, that judgment could be interpreted as myopia, wishful thinking, willful ignorance, or just plain laziness. It’s also true to form. The history of the antibiotic era is littered with blasé dismissals of newly resistant species as exceptions. Ten years later, as if on cue, drug-defying pneumococcus surged, newly equipped with biochemical weapons against several classes of drugs. Resistant strains spread to South Africa in the 1970s, to Spain and Israel in the 1980s, and to this country in the early 1990s.
In the 1970s, other common infections also began a portentous shift. Within a year after the introduction of methicillin, a semisynthetic version of penicillin, methicillin-resistant strains of staph showed up. These became epidemic in Europe before vaulting to the United States. Haemophilus influenzae, a major bacterial cause of ear infections and meningitis in children, became penicillin-resistant—a turn of events revealed when two infants who had attended the same Maryland daycare center died from ampicillin-resistant meningitis. Gonorrhea caused by penicillin-resistant strains of Neisseria gonorrhoeae radiated out from brothels in Vietnam where women received prophylactic doses of the drug, no doubt intended to protect the troops more than the women. For public health officials, all these trends were wake-up calls, signaling that common infections contracted outside of hospitals could soon become untreatable. In the early 1990s, a multidrug-resistant strain of tuberculosis killed nearly 500 people in New York City, mostly AIDS patients. Just as the outbreak seemed to diminish, TB reared up elsewhere in the world, from China to Siberia to Puerto Rico, now resistant to four of the five drugs used to treat it.
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With global travel, public health experts worry that these divergent strains will merge and become incurable.
With each passing year, what a researcher in 1957 called the “bugbear of drug resistance” shadowed every antibiotic success. By the mid1990s, the flow of replacement antibiotics slowed to less than a trickle. As infectious diseases resurged in this country, the media warned of “Andromeda strains” and “superbugs.” Those headline prophecies would soon come true.
Resistance Forces
The more we try to eliminate deadly bacteria with new drugs, the better bacteria get at dodging medicine’s magic bullets. So goes the “antibiotic paradox,” to use the succinct phrase of Stuart Levy, director for the Center for Adaptive Genetics and Drug Resistance at Tufts University School of Medicine, and for more than 20 years a cautionary voice. Every antibiotic ever used has hastened its own futility by triggering Darwinian selection. When an antibiotic attacks a group of bacteria, cells susceptible to the drug will perish. Those that can resist the drug, whether because of genetic mutations or because they have acquired protective genes from other bacteria, survive. Facing less competition for space and nutrients—antibiotics having killed off their natural competitors—these resistant cells multiply. The more they spread, the more they add to the pool of resistance genes in all bacteria, raising the odds that these genes will jump to more and more disease-causing bacteria.
In the laboratory, resistance plays out neatly and in full view. Outside the laboratory, the process is wild and sloppy and mysterious. Resistance genes flow in all directions. And though their travels cannot be tracked in real time, they can be extrapolated. Give your teenager antibiotics for acne, and you might soon develop drug-resistant staph on your own skin. Treat a toddler with cephalosporins for an earache, and soon a majority of the daycare center’s young clientele (and their parents) will be suffering resistant pneumococcal infections. Feed a flock of chickens low doses of tetracycline, and within days not only
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will their coopmates harbor intestinal bacteria highly resistant to the drug, but so will their human handlers and their human diners. Pull back the camera even further, and it becomes clear that as all the earth’s bacteria became bathed in antibiotics—millions of tons over the past half century—they have, to varying degrees, formed resistance. Resistant bacteria have even invaded U.S. waterways, from the Rio Grande to rural streams; at some sites, half of the waterborne bacteria resist ampicillin, tetracycline, and vancomycin.
Antibiotic resistance develops when two ingredients come together: resistance genes and antibiotic use. If bacteria in a community—a community being a home, a daycare center, a school, a hospital, or a city—don’t have genes that enable them to withstand an antibiotic, that drug will simply mow them down, end of story. If the bacteria do have resistance genes but are not exposed to the antibiotic, they will have no selective advantage against their competitors and will eventually dwindle in number. Or at least, that’s the theory. In reality, things get a little trickier. Bacteria exposed to one drug can sometimes develop resistance to a whole raft of unrelated agents. And long after they’ve stopped being exposed to an antibiotic, bacteria will sometimes hang on to their genetic defenses.
But the general theory holds true: antibiotic resistance requires resistance genes plus exposure to an antibiotic. The more widely an antibiotic is used, the more resistance shows up in many different bugs.
The consequences can be seen all around us. A child with an ear infection that in the early 1990s would have been instantly cured by penicillin may now need two or three or four courses of different drugs. A new mother may no longer die of “childbed fever,” but she might well contract a drug-resistant urinary tract infection that keeps her in the hospital for another day or so. In the 1990s, a Boston hospital twice had to construct a new neonatal intensive care unit (ICU) because its newborns had been colonized with highly drug-resistant staph. In 1999, a New Jersey schoolteacher who went in for surgery to remove small growths from her sinuses wound up with a staph infection that kept her out of the classroom for a year. Every day, hospital patients find themselves alone in a room with a bright
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yellow “precautions” warning on the door, declaring that visitors must don latex gloves and other protective accoutrements. What’s not explicitly stated: the patient has an incurable infection that could spread to other patients.
If the trends keep up, our most commonplace infections could turn into life-threatening illnesses. “It’s probably the biggest public health threat to the United States,” says J. Glenn Morris Jr., chairman of the department of epidemiology and preventive medicine at the University of Maryland School of Medicine. “Antibiotic resistance is something that directly affects everybody in this country, in a way that no single disease does.”
“For many common infections, we’re losing the drug of choice,” adds David Bell, who monitors antimicrobial resistance for the Centers for Disease Control and Prevention. Usually, there’s a second or third drug choice—but those medicines may be less effective or more toxic or may have to be given by injection instead of by mouth. And then there are organisms for which the rising tide of resistance has swept away medicine’s second or third choices. In those cases, says Bell, “we’re skating just along the edge.”
Sick Beds
Most resistant infections strike people in hospitals, nursing homes, and long-term-care facilities. That’s no surprise. These are places where antibiotics are used most intensively and so are the natural proving grounds for resistant infections. Because hospitals have been downsized at the same time as intensive care beds have increased, many facilities have in effect become giant intensive care units, where the sickest, most vulnerable patients are concentrated. Five percent of all U.S. hospital in-patients—about two million people annually—contract infections in hospitals. About 70 percent of those infections are caused by microbes that resist one or more antibiotics. Of those, 30 to 40 percent of the infectious organisms rebuff the drugs doctors would choose first. For the seriously ill, the immune-compromised, the very young, and the very old, any delay in curing a resistant infection raises
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the risk of death. Each year, according to the World Health Organization, drug resistance contributes to more than 14,000 U.S. hospital deaths.
If resistant pathogens could dream of paradise, their reveries would look like the inside of a hospital. Take Staphylococcus aureus. Staph homesteads in the human body, living benignly on the skin of 20 to 25 percent of us, often in our nostrils, armpits, or groin. The rise of antibiotic-resistant staph has gone hand in hand with the invasionary forces of medical progress, especially central venous catheters, those long plastic tubes that snake all the way to the heart. In intensive care units, oncology and surgical wards, and dialysis patients, these tubes are commonplace because they make it easier for nurses to give medications and blood infusions. The linezolid-resistant S. aureus that Mass General’s Mary Jane Ferraro confronted was a typical example; it had come from an 85-year-old dialysis patient who had a fixed catheter in his abdomen. Starting in the 1980s, having a “plastic” in the body became a major risk factor for resistant infections from either S. aureus or another common type known as coagulase-negative staph. Bacteria—either from the patient’s own skin or from the hands of a health care worker—cling to catheters and other prosthetic material. Patients with open wounds such as bedsores also develop staph infections. Once staph gets into the bloodstream, it can cause heart valve, blood, and bone infections, sometimes leading to septic shock and death.
In the United States, July 1997 was a turning point for public health officials who monitor hospital antibiotic resistance. That month, a 59-year-old Michigan man became infected with a strain of Staphylococcus aureus. Long ago, of course, S. aureus had stood up to penicillin. Now it defied other drugs as well. It defied methicillin, the 1960s synthetic replacement for penicillin. That act of insurrection earned the bacterium a name—MRSA, for methicillin-resistant Staphylococcus aureus. But its recalcitrance didn’t end there. MRSA had gone on to resist chloramphenicol, ciprofloxacin, clindamycin, erythromycin, gentamicin, imipenem, tetracycline, trimethoprim, and others. By the time it reached the Michigan man, MRSA—which now in effect stood for multidrug-resistant Staphylococcus aureus—reliably
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more mundane housekeeping tasks in the cell, and just happened to be ready-made for drug resistance when the drugs poured on.
Odd as it may sound, it’s the microorganisms that produce antibiotics that are also the source of resistance genes to that antibiotic. The cluster of genes that VRE uses to fend off vancomycin, for instance, is the same cluster found in the soil organism that makes vancomycin, Amycoloptosis orientalis. It is likely that bacteria need these resistance genes to help them fend off their own toxic products. The practical implication is that whenever scientists stumble on a new antibiotic, they should be able to find in the organism that churns it out genes that other bacteria will deploy to resist the drug—a preview, in other words, of how resistance will arise in humans.
Bacteria live in a tariff-free zone. Resistance genes move freely across species—even between Gram-positives and Gram-negatives, a distance as vast in phylogenetic terms as that separating an amoeba and Albert Einstein. Staphylococcus shares resistance genes with Listeria. E. coli has traded DNA with Pseudomonas and Neisseria. MRSA became the beast that it is by steadily building its genetic stockpile. “The exchange of genes is so pervasive,” writes Stuart Levy, “that the entire bacterial world can be thought of as one huge multicellular organism.” This fluidity may enliven the social lives of these austere one-celled organisms, but it’s a disaster for public health. The history of antibiotic resistance reads like a genetic travelogue.
How do they do what they do? Let’s start with genetic mutation, the basic engine of evolution. In duplicating itself, a bacterium may accidentally alter a gene. That change may give it new armor against certain drugs, and a competitive advantage over its neighbors that lack the new gene. A single mutation helped the tuberculosis bacterium resist streptomycin; in the early 1990s, a sequence of other mutations lent it resistance to other drugs. The newfound strains of linezolid-resistant staph and enterococcus both rely on chromosomal mutations—which can be passed on to progeny—to evade the drug. But it can take many throws of the genetic dice before an organism mutates into resistance. Pneumococcus, for instance, took a quarter century to resist penicillin, and group A Streptococcus hasn’t even managed that.
Some genetic trade routes link two closely related species. In a
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process known as transduction, a bacteriophage virus infects a bacterium, incorporates that cell’s resistance genes into its own genome, then copies itself and bursts out to infect new bacterial cells, carrying along the resistance genes. Some scientists think Staphylococcus aureus acquired its methicillin resistance gene this way. In a genetic exchange program called transformation, a bacterium scavenges floating pieces of DNA released by a dead bacterial cell from a closely related species, integrating the “naked” DNA into its chromosome. Through transformation, Pneumococcus first became penicillin resistant.
The best genetic get-rich-quick scheme, however, is not to save or scrounge but to steal resistance genes right off the shelf from a donor cell. “If bacteria had a brain,” says Abigail Salyers, “this would be a no-brainer.”
The particulars of “horizontal gene transfer,” as it is called, first came to light in the 1950s. In 1959, Japanese scientists isolated a Shigella dysenteriae that resisted four different kinds of antibiotics: tetracycline, sulfonamide, streptomycin, and chloramphenicol. Then as now, Shigella was a major cause of dysentery in Asia and Central and South America. The pokey mutability of the bacterium’s own chromosome couldn’t account for this sudden wealth of resistance. In fact, Japanese scientists calculated that the microbe would have had to divide 10 million × 10 million × 10 million × 10 million times—far longer than bacteria have been on earth, or than there’s been an earth—to have pulled off this quadruple hat trick. At the same time, researchers found strains of benign E. coli resistant to the same four drugs. In what direction the gene package traveled—from the E. coli to the Shigella or the other way around—is not known. What’s important is how they rode: on circles of DNA known as plasmids which, carrying genes resistant to several drugs, enabled the consignees to quash agents they’d never seen before.
“It was an incredibly novel aspect of science,” says Julian Davies, professor emeritus of microbiology at the University of British Columbia. So novel that the first papers published in Japan were rejected in the United States, and at least one researcher lost his job over the new proposition. According to Davies, “The convention was that genes just
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don’t move around. If genes move around, how could you possibly have species? But genes do move around, and one wonders what ‘species’ really means.”
Plasmids are mobile loops of DNA separate from the bacterium’s chromosome. You can think of them as shopping carts where bacteria store genes that they only need now and then. Plasmids pack genes for all kinds of emergencies: to withstand temperature extremes and ultraviolet light, to survive a torrent of gastrointestinal juices, to degrade environmental pollutants—and to resist antibiotics. Plasmids reproduce and migrate during the tryst known as conjugation, in which two, often unrelated, bacterial cells briefly draw together and pass their genes to the other in several ways. Antibiotics such as tetracycline may act as aphrodisiacs, prompting bacteria to mate with abandon and indulge in an orgy of gene transfer. Over time, plasmids and their bacterial hosts can enter a symbiotic relationship, in which the growth of the host depends on the plasmid—one reason that the drug resistance bestowed this way is hard to reverse.
Resistance genes can also ride on mobile pieces of DNA called transposons. Known colloquially as “jumping genes,” transposons, unlike plasmids, are truly free spirits. They don’t need the host cell to survive; they can dash off whenever they like. A special kind of transposon known as a conjugative transposon plays a major role in antibiotic resistance. Conjugative transposons bearing resistance genes can jump from their seat on the donor chromosome onto a plasmid, then during mating stow away on that plasmid to another bacterium. Once they’re settled again, they can jump from the plasmid to the new host’s chromosome—a stable perch from which to do their job.
This genetic free-for-all creates problems for medicine. At Emory University, population geneticist Bruce Levin has found that resistance to an antibiotic persists long after doctors have stopped using that drug. This is a blow to researchers who hoped that bacteria resistant to over-used drugs would “evolve backward” if spared the drug. Analyzing the fragrant contents of diapers from a daycare center, Levin found that a quarter of the E. coli lurking between the folds resisted streptomycin, a drug rarely used in the past 30 years. Although in evolutionary theory
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resistant bacteria are presumed to be more genetically weighed down and therefore less fit to compete, Levin suspects that after E. coli gains drug resistance, it evolves a second compensatory mutation that keeps it from backsliding to a state of drug sensitivity.
“Resistance genes,” says Abigail Salyers, “are easy to get and hard to lose.” The mechanics of plasmid transfer leads to an exponential rise in resistance genes. And a single antibiotic to treat an infection can provoke resistance to other drugs. Take tetracycline for a chlamydia infection, say, and your gut bacteria can suddenly become resistant to half a dozen different, structurally unrelated antibiotics. One reason may be a master switch—dubbed MAR, for Multiple Antibiotic Resistance—on the cell’s chromosome. “It’s almost as if bacteria strategically anticipate the confrontation of other drugs when they resist one,” writes Stuart Levy, whose lab discovered MAR in Gram-negative organisms such as E. coli and Salmonella. Moreover, though resistant strains can drop in number if they lose out in competition with drugsensitive strains, they seldom disappear completely. That means there’s always a residue of resistant bacteria around, ready to multiply if the right antibiotic rains down on them.
Resisting Resistance
At the start of 2001, the U.S. Department of Health and Human Services announced an “action plan” to combat antibiotic resistance. But in the United States, it’s impossible to get a firm grasp on the threat. The National Nosocomial Infection Surveillance system, a CDC-sponsored voluntary reporting effort among U.S. hospitals, is not comprehensive. Indeed, no federal agency tracks all resistant infections or adds up their human and financial costs. And admittedly, statistics can play tricks. If raw data were all that counted, large teaching hospitals with very sick patients would look like they’re doing a bad job—which is why you’ll probably never find out about a hospital’s antibiotic resistance problems before you or someone you love is admitted. Even then, it’s hard to get the lowdown.
Fighting antibiotic resistance is like wrestling Kali, the many-armed
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Hindu goddess of life and death. It is not one problem but many. While some observers offer visionary solutions, and others practical nostrums, nearly everyone involved complains that deeper institutional battles are slowing progress. On one fact everyone agrees: the propensity of bacteria to alter themselves in the face of threat will never be halted, merely contained. The most that public health experts hope for is to transform antibiotic resistance from a crisis—as it is now—to a routine annoyance.
One way is to speed up the pharmaceutical production line. Today’s antibiotics belong to a surprisingly small number of structural groups, most descendants of older progenitors harvested from nature. A recent exception is linezolid, a synthetic drug and the first new antibiotic in 35 years. Because the compound is manmade—and would theoretically not encounter any preexisting resistance genes in nature— researchers expected that the drug would have a long shelf life. But dismayingly, as Mary Jane Ferraro and others have discovered, linezolid-resistant forms of both staph and enterococcus appeared almost instantly. Tomorrow’s antibiotics may be plucked from huge collections of synthetic molecules which, with new technology, can be tested in huge numbers against resistant organisms. Gene sequencing will accelerate this process by laying out complete genetic sequences of bacteria—and therefore, new biochemical pathways to target.
A second approach is to take a well-respected antibiotic that has lost its clout and give it a second life. Stuart Levy’s lab, for example, is bioengineering new tetracyclines that can block the pump in bacteria that spit it out.
A third, somewhat theoretical, approach deploys bacteriophages—the viruses that target bacteria. The inspiration for their therapeutic potential goes back to a 1917 report by Felix d’Hérelle, a young French bacteriologist, who observed that the bloody stools of soldiers struck by dysentery contained invisible agents, thought to be viruses, that could destroy the offending bacteria. D’Hérelle went on to predict that these viruses, or phages, could cure all manner of bacterial disease. Since a phage virus makes copies of itself—a single phage produces more than a billion progeny in three to five hours—it is
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potentially the only drug that could multiply itself in the body. Since the 1930s, phage work proceeded apace in the (now former) Soviet Union, with claims of success against Enterococcus and other mostly enteric and skin pathogens. More recently, researchers have completed promising experiments with mice and are embarking on human trials. Today, several American biotech companies have taken the baton, hoping to cultivate phages against VRE, MRSA, and other bugs.
Drawing on the fact that no infectious diseases have ever been eliminated by antibiotics, other experts are focusing on vaccines as the ultimate end-run around resistance. During the 1980s, Haemophilus influenzae type B (HiB) was the leading cause of meningitis in American infants and a major agent of blood poisoning and pneumonia. But since 1989, when the HiB vaccine came out, HiB meningitis has virtually disappeared in the United States. A pneumococcal vaccine approved for children in 2000 has likewise proven effective against serious complications such as bloodstream infections and pneumonia, and is expected to curtail not only kids’ ear infections but the resulting overuse of antibiotics. More challenging will be making vaccines against staph or enterococci, since these organisms are benign lodgers against which the body doesn’t mount a strong immune response— making them fuzzy targets for vaccines.
There are also ecologic approaches to defusing resistance. Researchers talk of biodegradable antibiotics that would lose their resistance-breeding potency once released into the environment. Another proposal would harness the evolutionary forces that foster resistance and turn them to our favor. Picture a bacterial reclamation project, in which resistant flora are replaced with friendly—i.e., drug-sensitive— microbial species. In Stuart Levy’s mind, that requires first stopping the use of certain antibiotics so that the selective pressure is off, and then literally restocking the environment with susceptible bacteria— say, by spraying drug-sensitive enterococci in intensive care units. Other scientists, however, worry that these newly added bacteria will also become resistant.
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But technological fixes take time. At the CDC, researchers estimate that a third of the 150 million annual outpatient prescriptions for antibiotics are unnecessary, either because the illness is not bacterial or because the bacteria aren’t sensitive to the antibiotics. According to a 1998 study, antibiotics were prescribed 66 percent of the time during office visits for coughs, even though most coughs—and sore throats and runny noses—are caused by viruses, which antibiotics can’t touch.
In response, the American College of Physicians in 2001 issued new recommendations urging doctors to use antibiotics for common respiratory illnesses only when they strongly suspect a bacterial cause. Respiratory infections account for three-quarters of all antibiotic prescriptions. “We were all taught in medical school that anybody who was coughing up something green had a bacterial infection. But now we know that this is just the natural evolution of a viral infection,” says internist Vincenza Snow, who coauthored the ACP guidelines. “As physicians, we have to unlearn some of the things we’ve been taught. And we have to reeducate our patients.” In 2000, the federal Agency for Healthcare Research and Quality found that the vast majority of children with middle ear infections recover without antibiotics—so waiting for a few days won’t put kids at risk, even when they require treatment later for their illness. Patients who do take antibiotic drugs are being reminded to take all their pills, so as not to promote resistant bacteria.
Doctors and patients may finally be getting the message. A CDC survey found that between 1989 and 1998, antibiotic prescriptions for children under 15 dropped by 30 percent. Unpublished data show that, among adults, antibiotic prescriptions fell by 10 to 15 percent between 1995 and 1999. But according to experts, these declines must double before the upward trend in antibiotic resistance reverses.
To curtail antibiotics, doctors need to know precisely what’s ailing their patients. That’s not always easy. Today, there are no tests to instantly pin down what bug is causing an infection and what drugs it resists. Besides, managed care groups are trying to save money by cutting back on tests, including microbiologic cultures, because it’s cheaper to prescribe broad-spectrum drugs and wait to see if patients
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get better. If new gene-based tests were around tomorrow, would doctors use them? More to the point, would health maintenance organizations pay for them?
Meanwhile, the Food and Drug Administration has focused on cutting agricultural antibiotics crucial in human medicine—playing a long-delayed game of catch-up. In 1977, when the agency first proposed removing penicillin and tetracycline from growth promoters, Congress blocked the move. “That set back the national agenda for 20 years,” says the CDC’s Fred Angulo. By 2005 or so, the agency intends to establish regulations that will automatically remove an antibiotic from farm use if it’s proven to cause high levels of drug-resistant infections in people. The focus will be on preserving drugs crucial for human medical therapy. For their part, consumers may think twice about buying household products that trumpet their “germ-fighting” prowess.
Many public health experts are betting on an up-to-the-minute information system that could tell doctors what resistant organisms are in their community and therefore what drugs to steer away from. But there are times when all the information in the world won’t help a doctor make a tough call—times, in fact, when a doctor’s drive to deliver the best clinical care seems at odds with public health campaigns against resistance. Doctors, after all, are advocates for their patients— not for all patients, not for global ecology. “It gets into some extremely difficult philosophical questions,” says the University of Maryland’s Glenn Morris. “I’m the bad guy. I wear the black hat. Because I tell doctors they can’t use drugs that they think they need for their patients.” The tension between what’s right for the individual and what’s right for public health becomes especially poignant at the end of life. Should a doctor give last-resort antibiotics to a patient who is sure to die soon anyway—even if it means raising the risk of drug resistance in another patient five feet away?
“When you’re looking a patient in the eye, or when you’re looking a farmer in the eye who’s got a flock of sick chickens, it’s very difficult to say, ‘I’m not sure you need that antibiotic,’” says Morris. “If it’s your grandmother sitting in the hospital with a bad infection, would you
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prefer that the doctor gave her three antibiotics to make sure he’s covered whatever’s causing the infection, or that he said, ‘Let’s just give her one and wait for the culture to come back’? The answer is, of course, ‘Do everything you can, Doc!’ Multiply that by hundreds of thousands of cases, and you have overuse in hospitals.”
The daunting challenge of antibiotic resistance owes itself to institutional complacency as well. Few researchers today have been trained in the basic biology of bacteria—because few university laboratories are left to specialize in the problem of drug resistance. Discouraged by the dearth of funding for the field, young investigators have chosen other disciplines.
Nor has the pharmaceutical industry been keen to tackle drug resistance. The biological paradox that antibiotics sow the seeds of their own failure is matched by an economic paradox: if a new antibiotic is good, regulators will ask doctors to use it sparingly and the drug won’t quickly recoup its investment. Despite the development of linezolidresistant staph and enterococcus, will its manufacturer push the new drug? “The pneumonia market is many orders of magnitude larger than the enterococcus market,” says John Quinn, a physician at the University of Illinois at Chicago, who first published evidence of linezolid-resistant VRE. “And if you’re sales manager for a new agent, and your compensation is linked to the number of doses of that drug being administered, it’s got to be awfully tempting to promote the use of the drug in respiratory infections. I’m not making a specific accusation that the company is doing that. But certainly the history of antibiotics is one of enthusiastic use followed by overuse followed by resistance.”
Making matters worse, most of the easy drug targets have already been discovered, so that it’s even more costly to find chinks in bacterial armor. This dilemma could discourage drug companies from investing in what typically takes at least seven years and costs $350 million to bring a new antibiotic to market. At the end of that road, what companies want is a blockbuster like Viagra or Prozac, something that will stand out from its competitors and make an immediate $2 billion to $4 billion. “In most companies, antibacterial discovery and development
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is a Cinderella field,” says David Shlaes, vice president of infectious disease research at Wyeth-Ayerst Research. “In the 1980s, drug companies started getting out of this business in droves, and that hasn’t stopped. It remains for the pharmaceutical companies a tight market and a competitive market.” To offset the economic losses of a rationed drug, companies might need to be compensated with longer patents, fast-track approval, or other marketing incentives for drug development, as orphan drugs for rare diseases now receive. “When we find a drug effective against VRE,” says Glenn Morris, “we should use it only against VRE, even if we’re only talking ten thousand to twenty thousand cases a year.”
Controlling hospital infections would also help cut down drug resistance. In the last two decades, the rate of hospital-acquired infections has risen in part because today’s patients are sicker and more vulnerable. Yet there are few incentives for hospitals to monitor infection rates. A head-in-the-sand attitude prevails in this country: If hospitals don’t look for resistant infections, they won’t find them and they won’t have to fret about them. Besides, the thinking goes, why should one institution pay a public relations price for a problem entrenched in every hospital? In our competitive and cost-cutting times, infection control departments are perceived as nests of unbillable activities. “If I’ve got to make a choice between adding an infection control nurse or a hospital epidemiologist versus a cardiac surgeon,” explains the CDC’s William Jarvis, “I’m choosing the cardiac surgeon, who can bring me several million dollars a week.”
Yet a mathematical model developed by Emory University’s Bruce Levin and Harvard School of Public Health’s Marc Lipsitch underscores the need for infection control. It says that the influx of fresh, drug-sensitive bacteria carried by newly admitted patients should be able to outcompete resistant strains in hospitals—as long as those hospitals vigorously try to prevent antibiotic resistance. Judging from the few documented interventions attempted in this country—controlling VRE rates by segregating colonized patients, reducing resistant bloodstream infections among cancer patients through infection control, and
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others—prevention can save money in the long run. But that will happen only if every hospital and doctor shoulders the task equally.
Hospital administrators claim that outside pressures force doctors to err on the side of prescribing antibiotics, even when unnecessary. Four floors above the emergency room of Boston’s Beth Israel Deaconess Medical Center, ambulance sirens repeatedly pierce the air. From that perch, Robert Moellering Jr., chair of the Department of Medicine, must grapple with the legal repercussions of pressured medical decisions. “We’re in this position of trying to get physicians not to overuse antibiotics,” he says. “But I have never yet seen a physician sued for giving antibiotics inappropriately. I’ve seen all kinds of them sued for not giving antibiotics.” This fear of malpractice suits, Moellering says, also stokes antibiotic resistance.
We’re not yet on the brink of a post-antibiotic age. Compared to the last turn of the century, we have better hygiene, sanitation, and nutrition, safeguards that have always prevented disease from starting and spreading. And even though 70 percent of the bugs that cause hospital infections defy at least one antibiotic, there are usually four or five others to try.
But like love, drug resistance is here to stay. “We have squandered an immense resource, much of it a true natural resource, by using it frivolously, inappropriately, and ineptly. . . . Above all, we polluted our hospitals, and in doing so we set up a truly global laboratory: a colossal Darwinian experiment in enhanced evolution,” writes the physician Imre J. P. Loefler, in the Lancet. “We wasted resources that, if husbanded, would have helped us treat infections perhaps for hundreds of years. We squandered because of ignorance, consumerism, mercantilism, cynicism, and carelessness.”
Tracking the relentless rise of resistance at the University of Maryland Medical Center, which had the dubious honor of being one of the first to report VRE in this country, Glenn Morris feels a sense of dread. “This is the gradual, inexorable movement of a glacier headed directly toward your town. It’s slow, silent, unexciting. But every year you look at the ‘Percent Resistant’ isolates in your hospital. At times it feels like we’re hanging on by our fingernails.”
Representative terms from entire chapter:
antibiotic resistance
