Last Days of the Wonder Drugs

Years of overconfidence have made us vulnerable. Now, in the deadly arms race between people and bacteria, the bugs are winning.

By Peter Radetsky|Sunday, November 01, 1998

Wells Shoemaker is a pediatrician in a small California town. Not too long ago he saw a patient new to the area, a little boy with a runny nose. "It's the same story every time," his mother complained. "He starts out with a cold, and then his nose starts running green stuff, and then he gets an ear infection. He's only two years old, and he's already had four ear infections."

Shoemaker examined the child. He had a cold, all right, but his nasal fluid was clear, and he had no fever or bulging eardrums. No hint of an ear infection or any other bacterial attack. As Shoemaker offered his diagnosis, the mother interrupted: "The only thing that keeps him from getting an ear infection is antibiotics. My previous doctor used to give him antibiotics at the beginning of a cold. They worked great!"

"Antibiotics fight bacteria," Shoemaker explained. "Your son's cold is caused by a virus. He doesn't have an ear infection. But let's keep close tabs, and if he does begin to develop an infection, then we can turn to an antibiotic."

"But sometimes the doctor just prescribed them over the phone."

"Well, an antibiotic might prevent an infection, but it might not. It could even make way for a more aggressive germ that might cause an ear infection from hell. Then we'd have to resort to very, very powerful drugs with unpleasant side effects that have to be given by injection."

By this time the mother had heard enough. "I don't care! I know my child better than you do. I want antibiotics now!"

"I can't give them to you," Shoemaker replied. "In all good conscience, I just can't."

"Then I'm going to find another doctor, a doctor who cares about children!"

Stuart Levy would have been proud of the beleaguered pediatrician. Levy, a Tufts University School of Medicine microbiologist, is one of the world's loudest voices decrying the misuse of antibiotics. He writes books and articles about the problem, researches it in the lab, organizes conferences about it, presents it on TV. He's the founder of a worldwide network called the Alliance for the Prudent Use of Antibiotics. "We're in the midst of a crisis," he says, his baritone rising an octave. "We have to change things!"

The mother's conduct at the clinic was typical of what Levy laments: a patient demanding antibiotics for an illness that doesn't require them. What was not typical was that Shoemaker refused to give in. Many doctors do. And, like the child's previous pediatrician, many prescribe without ever being asked--even if antibiotics are not a suitable treatment. "At least half the human use of antibiotics in the United States is unnecessary or inappropriate," Levy says. "Either antibiotics are not indicated at all, or the wrong antibiotic is prescribed, or it's the wrong dosage or the wrong duration."

That leads to a lot of unneeded drugs. More than 50 million pounds of antibiotics are produced in the United States every year. Some 40 percent of that total is given to animals, mostly to promote growth rather than treat disease. Antibiotic use is also rampant in agriculture--for example, the drugs are sprayed onto fruit trees to control bacterial infections. Another little-recognized application is in antibacterial household cleaning products, soaps, toothpaste, and even plastic toys and cutting boards, which incorporate bacteria-killing substances too potent to be used in the body. The upshot of this massive exposure is the increasingly familiar predicament the world now faces: disease-causing bugs that resist the drugs that once thwarted them. We are experiencing an alarming resurgence of common but no longer curable infections from bugs that developed their resistance in our antibiotic-filled bodies, in animals, in fields, even on our antibacterial-soaked kitchen counters. It's what Levy calls "the antibiotic paradox." The miracle drugs themselves are destroying the miracle. And it may be too late to do much about it.

The magnitude of the problem is startling. At least two dozen different kinds of bacteria have developed resistance to one or more antibiotics. Some strains of three life-threatening species--the blood poisoners Enterococcus faecalis and Pseudomonas aeruginosa, and Mycobacterium tuberculosis, the TB bug--now frustrate every single antibiotic known, more than 100 different drugs. Ubiquitous pathogens such as Streptococcus, Staphylococcus, and Pneumococcus, which among them cause ear, nose, and throat infections, scarlet fever, meningitis, and pneumonia, are becoming widely resistant. The possibility that these common childhood diseases might become completely unresponsive to treatment is a physician's--and a parent's--nightmare.

Hospital records suggest the scope of the problem. While there are no figures on how many people enter hospitals already infected, over 2 million fall prey to microbes once they get there, in this country alone. Some 90,000 die. About 70 percent of those are infected by drug-resistant bacteria. Costs for treatment of these infections approach $5 billion a year. Overall, the yearly toll exacted by drug-resistant infections in the United States is estimated to exceed $30 billion. "The multiresistant organisms of the 1990s are a grim warning of the possibility of the post-antibiotic era," states the Centers for Disease Control and Prevention (CDC) in Atlanta.

But why? The answer involves equal parts complacency, economics, and simply the nature of nature. It's been known that bacteria can become resistant to antibiotics almost since the first one, penicillin, was discovered seven decades ago. In 1928, Alexander Fleming, a Scottish bacteriologist working in London, returned from a trip and noticed that one of his laboratory dishes containing colonies of Staphylococcus aureus was overgrown with mold. Instead of discarding the seemingly useless dish, Fleming made a historic decision: he examined it. All the staph around the mold was dead. The mold, he found, was secreting yellow drops of liquid that killed the bacteria. He had stumbled onto the first antibiotic. He called it penicillin, from Penicillium notatum, the name of the mold.

It wasn't until 1944 that penicillin could be produced in large enough quantities to make a difference, but what a difference it made: for the first time it became possible to cure deadly bacterial diseases that had plagued humans throughout history. "It was as if Prometheus had stolen fire from the gods," writes Levy in his book The Antibiotic Paradox. "The applications of this wonder drug seemed all but limitless." Soon other antibiotics followed. Medicine had entered a golden age.

Almost immediately, however, researchers noticed that previously vanquished bacteria could suddenly withstand the wonder drugs. Fleming himself observed that some bugs were beginning to evade his penicillin. Later, during the second clinical trial of the drug in 1943, one of 15 patients died from a strep infection because the microbe had become resistant to the antibiotic. And by the 1950s, epidemics of infection caused by resistant staph showed up in U.S. hospitals. But few people seemed to care.

"Geneticists certainly talked about the problem, but nobody was going to do anything about it until it slapped you in the face," recalls Rockefeller University molecular geneticist Joshua Lederberg, who has consulted for the pharmaceutical industry since the 1950s. "There were enough instances of the occurrence of resistance in this, that, and the other place, but it didn't seem that urgent."

In the mid-1970s, two dangerous bugs almost simultaneously became resistant to penicillin: Haemophilus influenzae, which induces respiratory infections, and Neisseria gonorrhoeae, the cause of the venereal disease gonorrhea. In fact, not only did they become resistant but they developed the ability to flat out destroy the drug. And both bacteria displayed the very same resistance gene--most likely it had been transferred to them from bacteria living in the gastrointestinal tract. Gonorrhea resistance was initially discovered in the Philippines in servicemen suffering from venereal disease. From there, it was traced to prostitutes in Vietnam who had been given penicillin regularly as a precautionary measure. That overexposure engendered resistance. Today every country in the world is bedeviled by drug-resistant gonorrhea.

Here was a graphic example of the power of antibiotic resistance--and its ability to spread. And still the medical and pharmaceutical communities, which were accruing enormous profits from antibiotics, were not alarmed. Says Levy, "I remember talks about resistant E. coli and Salmonella at an American Society for Microbiology meeting in the early seventies. People said, ëOh, isn't that interesting, but let me know when something serious comes along.' "

"You have to understand that a lot of these decisions were made not by scientists but by marketing-type people," says David Shlaes, vice president of infectious-disease research at American Home Products' Wyeth-Ayerst research unit. "They were looking at a marketplace they thought was saturated--there were a gazillion antibiotics--and satisfied. They didn't hear many complaints from general practitioners about resistance. It was only the scientists who were worried. When you don't get complaints from people you're selling your products to, you may not listen very hard. And they didn't."

Dramatically escalating costs of developing new drugs and more stringent regulatory requirements imposed by the U.S. Food and Drug Administration further dampened the drug industry's appetite for jumping into new antibiotic research and development.

The result was virtual paralysis in antibiotic development just when the resistance was careering out of control. "In 1991 an informal survey among pharmaceutical companies in the United States and Japan suggested that at least 50 percent of them had either diminished substantially or totally gotten out of antibacterial research," says Shlaes. "People simply sloughed off the problem of resistance."

But it's no surprise that bugs should develop resistance to our efforts to wipe them out. It's only natural for an organism to do everything it can to evade its killer. By developing new drugs, we attempt to stay one step ahead of our microbial enemies, and the microbes furiously return the favor. Antibiotics actually promote resistance. For example, let's say that Shoemaker's young patient was indeed suffering from an ear infection. An antibiotic might wipe out most of those bad bugs, but a few might survive. If the child's besieged immune system were capable of mopping up, all would be well. But if it weren't, with the susceptible bacteria now dead, the resistant strains could spread like weeds through a newly harvested field. And if the child didn't take the entire prescribed course of drugs, or if they were the wrong kind, more resistant strains might propagate.

To compound the problem, antibiotics don't just kill bad bugs--like a huge scythe, they also cut down innocent bystanders. That's unfortunate, says Levy. "Non-disease-causing bacteria are essential parts of the body's natural armor against invading infectious bacteria." These benign microbes limit the spread of their dangerous brethren simply by being in the way. With them gone, the field is even more wide open for resistant bugs to proliferate.

All that may be the unintended result when antibiotics are used to cure disease. But much of antibiotic use is preventive--the penicillin given to the Vietnamese prostitutes, say, or antibiotics prescribed before surgery. Often the doses involved are comparatively low, and the drugs are given over long periods. This regime can be even more conducive for breeding resistance, as can low doses in animal feed or in agriculture--or in antibacterial products like plastics, household cleaners, soaps, and toothpaste, a more recent menace. "It's a big issue, a big issue," says Levy. "People may not understand the impact of prescription antibiotics, but show them something under the sink or in the bathroom and it really hits home." In these cases there's not nearly enough drug to kill off the hardiest bugs, while plenty is available to kill weaklings and bystanders, for the entire duration that the compounds are applied. And resistant bugs in animals and plants can readily make their way to humans or pass on their hardihood to bugs that infect us. When it comes to acquiring and spreading resistance, bacteria are superstars.

The range of microbial resistance strategies is mind-boggling. Mutation is one approach. Sometimes, by chance, bacterial genes mutate during reproduction, subtly altering the nature of the bug. Most of these alterations are useless, even detrimental, but occasionally a mutation may help the bacterium resist a particular drug. While susceptible bacteria die, this surviving microbe continues to reproduce, again and again and again, until an army of resistant bacteria squares off against the now impotent drug.

But by itself mutation might not be enough to generate widespread resistance. The microbes' ace in the hole is their ability to share resistance genes. One way they do so is by means of a kind of bacterial sex in which a bug carrying a resistance gene meets a susceptible mate, snags it with a narrow tube, reels the bug in, then transfers its gene. Bacteria aren't picky about who receives their gift. It might be another bug of the same species, it might not. When it comes time for microbial gene swapping, anything goes.

Another method involves simply vacuuming up scraps of loose DNA that have been released by dead cells in the vicinity. If the housekeeping microbe is lucky, a resistance gene may be lurking in one of these DNA snippets. And sometimes bacteria receive help in swapping genes. Viruses called bacteriophages can infect a bug and by chance whisk away its resistance gene and deposit it in another microbe.

If the methods of swapping genes are ingenious, so are the resistance mechanisms they engender. Some bacterial genes produce pumps that transport antibiotics out of the organism before they have a chance to do any harm. Others generate powerful enzymes that inactivate the drugs. Others modify the antibiotics' targets within the microbes or provide decoys that divert and disable the drugs.

Bacteria have used such survival strategies for millions of years, but now things are different. A few drops of "mold juice" have exploded into millions of pounds of bug-killing drugs. Never before have bacteria encountered such colossal evolutionary pressure. Humans are pushing microbial evolution into overdrive. It's a supercharged arms race.

Meanwhile, the world has changed in important ways. "Population has exploded," explains Levy, "creating megacities with appalling conditions that breed pathogens. People now travel like crazy. That means that a problem in one part of the world is rapidly your own problem. And all the while, resistance is mounting--and it is multidrug resistance. Resistant organisms like to accumulate resistances."

The result: Superbugs that can withstand not just one but multitudes of antibiotics. Superbugs that display resistance to the newest antibiotics even before they are formally introduced. Diseases that no longer respond to our attempts to prevent or cure them. It's a new age, all right, but no longer golden.

Is it too late to do anything? Are we spiraling back to a pre-antibiotic world in which we are reduced to trying to avoid infection and, failing that, helplessly hoping for the best?

Not if pharmaceutical companies have anything to say about it. Finally, belatedly, the industry is scrambling to avert such a catastrophe.

"The turnaround occurred in the mid-nineties," says Shlaes. "The major event was the epidemic of resistant Enterococcus--that really made an impact on people. And there was the continuing spread of multiresistant staph around the world.

"In the next five to ten years we're going to see new and novel kinds of antibiotics coming out of drug companies," Shlaes predicts. "I'm optimistic. But it's not going to be soon."

So even if these new drugs prove to be effective--and there's no assurance of that--what are we going to do in the meantime? Stuart Levy suggests an approach he calls prudent use. His hope is that if we can get antibiotic use under control, with physicians prescribing appropriately, according to more precise diagnoses; if animal and agricultural use is pared down to the bare essentials; and if household disinfectants are no longer spiked with lingering bug killers, then we might be able to turn back the clock. The good bugs might supplant the bad, and our existing drugs might once more be able to shoulder the load.

Levy's hope rests on a basic tenet of evolution: if you get something, you generally have to give up something. In acquiring antibiotic-fighting capabilities, it seems, bacteria have to divert energy from other needs. Some resistant bugs just don't reproduce well, for example--they have a tough time making the necessary protein building blocks for their offspring. It's evolution's quid pro quo. If this enormous pressure on bugs to develop resistance were curbed, the hope is, the remaining susceptible microbes might outstrip their more muscular, but relatively barren, brethren. And back we'd go to the golden age.

Don't count on it, advises population and evolutionary biologist Bruce Levin. He points to a T-shirt hanging in his office at Emory University in Atlanta. Printed on the back is the statement you Can't Go Back Again. Recent experiments have led him to that bleak assessment.

Two years ago Levin and his student Bassam Tomeh sampled bacteria from the diapers of 25 toddlers at a nearby day-care center. When they isolated samples of the common gut bacteria Escherichia coli, they found that a quarter were resistant to the antibiotic streptomycin. At first glance the find is disturbing but not remarkable--after all, drug-resistant E. coli has become an ominous fact of today's life. But a closer look raises red flags. "Doctors have almost never used streptomycin in the last 30 years," Levin exclaims. For some reason, these bacteria are holding on to hard-to-maintain defenses that are no longer needed.

Why? That's what Levin and colleagues Stephanie Schrag and VÈronique Perrot set out to discover. First they raised 160 generations (18 days' worth) of E. coli that had become resistant to streptomycin because of a lucky mutation in a chromosome. Then the researchers pitted the bugs against a batch of susceptible strains, dumping both onto lab dishes to see which would reproduce more effectively. Based on past experience, they expected that the resistant bugs, saddled with deficient protein-making capabilities, would lose out or revert back to sensitivity. The result was a surprise--the bugs kept their resistance and were almost as fit as their prolific kin. These resistant bugs were no longer poor protein manufacturers. Something had happened to them--most likely a compensatory mutation that made up for their weakness, the researchers thought.

To find out if their guess was right, Levin, Schrag, and Perrot made some of the drug-resistant bugs susceptible again by replacing their resistance gene with a gene that conferred sensitivity. When they set these modified microbes against their resistant mates in another reproduction competition, the genetically altered microbes failed miserably. Whatever this compensatory mutation was, it needed to be paired with the initial resistance gene. Deprived of that partnership, the bacteria were helpless. No wonder, then, that the bugs in the children's diapers remained resistant. To revert to susceptibility would have meant curtains. Once they had compensated for the downside of their defensive strategy in this way, they had to remain resistant or die. Can't go back again, indeed.

One part of the story remained: discovering how the compensatory mechanism works its magic. The Emory team recently found that at least three genes modify the bacteria's protein-making factory, the ribosome--which is also streptomycin's target. The drug works by binding to the factory and disabling it. The resistance gene, however, by changing the shape of the ribosome, succeeds in blocking the drug--but at the cost of slowing down protein output. Says Levin, "The initial resistance gene screws up the ribosome. That reduces the bug's fitness but also blocks action by the streptomycin. These other mutations pull the ribosome back into pretty good shape. But when we put this restored ribosome into the original sensitive bugs, they get even more screwed up." It's as though a mechanic reworks an automobile's fuel system to compensate for a faulty carburetor. But when the carburetor is replaced with the original functioning part, the two systems cancel each other out and the car can't start.

All of which paints a grim picture. If Levin's findings mirror what is happening in the outside world, we may be stuck with what we have sown. "It's not clear to me that we can even slow down this process of evolving resistance," he says. "Maybe Bruce is right," concedes Levy. "Maybe you can't go back again in terms of converting resistant bacteria back to susceptible ones. But that's not the point. The point is that it's a numbers game."

The numbers he's talking about involve the ratio between resistant and susceptible bacteria. If resistant bugs predominate, then yes, their inability to revert to susceptibility is important. But if susceptibles outnumber resistants, then the more vulnerable bugs may carry the day despite the intransigence of the others. Levy is fond of citing a French study showing that when people whose guts were plagued by resistant E. coli ate only sterilized food, the nature of the prevailing microbes changed. Susceptible bugs once more outnumbered resistants. Either the resistant bacteria had been strengthened by reinforcements entering with commercial foods, or the food contained antibiotics that induced the microbes to propagate while destroying their competition. Bugless, drugless, sterilized food reversed the trend.

Three U.S. hospitalñbased studies showing that resistant bugs disappear with the withdrawal of antibiotics drive home the point. At the Veterans Affairs Medical Center in Minneapolis, when the antibiotic gentamicin was no longer given for infections by a variety of resistant gut bacteria, including E. coli, the levels of resistance dropped accordingly. Studies at the Veterans Affairs Medical Centers in Tucson and Richmond, Virginia, chronicle similar results with the antibiotic clindamycin and resistant diarrhea-causing bacteria called Clostridium difficile. Get rid of clindamycin and you get rid of resistant bugs--within months.

"That's pretty dramatic data," Levy says. "It tells us that there's a flux of bacteria coming and going. Some stay and some go. We want the susceptibles to stay."

One way to accomplish that may be to seed our bodies with benign, drug-susceptible bugs. It's an approach that Madrid-based microbiologist Fernando Baquero calls ecological intervention. "This should be envisaged as an ecological problem--ecology for our gut," he explains. "Resistant bugs are modifying our normal flora. Our flora has evolved with us from the beginning of the human species. We don't know about the long-term consequences of the alteration of this normal ecology. What we should have are reserves of susceptible bacteria to recolonize us. We should make susceptible-bacteria banks."

Levy agrees. "Let's just bring in the susceptibles and get rid of the resistants. For example, bring in susceptible E. coli. Drink it, day in and day out. What do you think is going to happen? Resistant strains are going to stay there? No! They're going to be shed and the susceptibles take over."

This very approach is being used in animal husbandry. In March the FDA approved a spray containing 29 types of bacteria isolated from the guts of mature chickens. These are the bugs that chicks would normally receive from their mothers but that hatchery-born chicks lack. Once sprayed with the mix, the chicks ingest the bacteria while preening themselves.

So far the results have been promising (and in Japan, where the spray has been available for more than a year, it has been highly successful). Not only does the spray of good bugs protect the chicks from pathogenic bacteria--in particular Salmonella--simply by occupying the niches where the bad bugs would otherwise lodge, but it discourages antibiotic use. Because why would anyone want to give these animals antibiotics that would kill off the very bugs that are protecting them?

Levy considers this approach a model of what can be done in humans. But the list of changes that must accompany such an approach is daunting: education and more accurate diagnoses leading to fewer, and more appropriate, prescriptions of antibiotics; restrained use of antibiotics in animal husbandry and agriculture; reduced use of antibacterials in household disinfectants. And all this not only in the United States but in countries worldwide, some of which are even more profligate with antibiotics.

"There's a lot of ingrained social behavior associated with antibiotic use," observes Levin. To wit, Shoemaker's unhappy encounter and Levin's own experience at the day-care center. "The majority of the kids were on antibiotics during the six months we did the study. At least one kid was on five different antibiotics. Another was on triple antibiotic therapy--prophylactically! She wasn't even sick." He shrugs his shoulders. "And the parents of these kids were from Emory and the CDC. So it wasn't exactly an unenlightened group. How are you going to change most people's minds if you can't change theirs?"

And what if, after all is said and done, prudent use can be implemented--what if it just doesn't make a difference? The years to come may be grim, indeed, seared by a hard reality the more fortunate parts of the world have not had to face for the last half-century. The bugs are reminding us who's boss.

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