The End of Antibiotics

NOTHING WORKED. FOR NINE MONTHS DR. Cynthia Gibert desperately tried one antibiotic after another on her 57-year-old kidney patient, but no matter which tablets, capsules or even IVs she gave him-from plain-vanilla ampicillin to fancy experimental teicoplanin-the man's blood was still flooded with enterococcus bacteria, which were slowly poisoning his red blood cells. "We tried six or seven different medications. Some alone. Some in combination. Some we didn't think would work. But we had nothing else to try," says Gibert, an infectious-disease specialist at the Veterans Affairs Medical Center in Washington. Sometimes her patient's blood tested clean, but within days the infection came roaring back: a few rogue bacteria, no more threatened by the antibiotics than an urban gang by a pop gun, bided their time until their more vulnerable cousins had been killed. Then they multiplied by the billions. So one morning last year, Gibert gathered her courage and walked softly into the man's room. "I guess you're coming to tell me I'm dying, he said. Nothing had worked, she explained; they had run out of options. Antibiotics, the miracle drugs of the 20th century, had been bested by bacteria, the most primitive organisms on earth. Several days later the man died of a massive bacterial infection of the blood and heart.

Ever since 1928, when Alexander Fleming serendipitously discovered penicillin oozing out of mold in a laboratory dish, "man and microbe have been in a footrace," says Dr. Richard Wenzel of the University of Iowa. It's a race in which the lead keeps changing. In 1946, just five years after penicillin came into wide use with World War II, doctors discovered staphylococcus that was invulnerable to the drug. No problem: smart pharmacologists invented or discovered (often in samples of soil they collected like souvenirs whenever they visited exotic locales) new antibiotics. The drugs pounded the microbes into submission once again. But the bacteria regrouped, and mutants capable of fending off the latest drugs appeared. New drugs, newer mutants. And so it went. Overall the drugs retained a slight lead and, slowly, scourges such as tuberculosis, bacterial pneumonia, septicemia (blood poisoning), syphilis, gonorrhea and other bacterial infections that hark back to a time of high-button shoes were vanquished. Yes, people died-and still die from these ills, but not so many, and not those who began antibiotics before the microbes wrecked some vital system. "The perception [in the 1980s] was that we had conquered almost every infectious disease," says Dr. Thomas Beam of the Buffalo, N.Y., VA Medical Center. Science was sure the real challenges would he in the conquest of cancer, heart disease and other chronic ailments. Instead, "medicine's purported triumph over infectious disease has become an illusion," writes Dr. Sherwin Nuland in his best-selling "How We Die."

Indeed, it looks like medicine declared victory and went home too soon. Every disease-causing bacterium now has versions that resist at least one of medicine's 100-plus antibiotics. Some resist all but one (chart, page 48). Drug-resistant tuberculosis now accounts for one in seven new cases; 5 percent of those patients are dying. Several resistant strains of pneumococcus, the microbe responsible for infected surgical wounds and some children's ear infections and meningitis, appeared in South Africa in the 1970s, spread to Europe and now are turning up in the United States. In January the federal Centers for Disease Control and Prevention (CDC) reported an epidemic of resistant pneumococcus in rural Kentucky and in Memphis. The bugs had spread through day-care centers like a chain letter, leaving toddlers with ear infections, pneumonia and, in six cases, meningitis. In 1992, 13,300 hospital patients died of bacterial infections that resisted the antibiotics doctors fired at them, says the CDC. It was not that they had infections immune to every single drug but rather that, by the time doctors found an antibiotic that worked, the rampaging bacteria had poisoned the patient's blood, scarred the lungs or crippled some other vital organ.

The financial toll is steep, too. Because the first antibiotic prescribed often fails, the patient has to try several; this adds some $100 million to 8200 million to the nation's health-care tab. "Right now the microorganisms are winning," says Iowa's Wenzel. They're so much older than we are. . . and wiser."

They are indeed wise, especially in the ways of evolution. Bacteria develop resistance to antibiotics for the same Darwinian reason that gazelles evolved speed in response to lions. When a colony of bacteria is dosed with, say penicillin. most die. But a few lucky microbes, by chance, harbor mutant genes that make them immune to the drug. They survive, just as speedy gazelles lived to romp another day, while their slower-footed herd mates became dinner. The mutants pass on their resistance genes to their progeny-one bacterium can leave 16,777,220 offspring within 24 hours. Even more insidious, the mutants gladly share their resistance gene with unrelated microbes. In one version, a microbe exudes a come-hither chemical, attracting another bacterium; when the two touch, they open pores and exchange a loop of DNA called a plasmid in a process that can only be called unsafe bacteria] sex (diagram, page 49). Through this sort of coupling, cholera bacteria picked up resistance to tetracycline from plain old E. coli in the human intestine. So while antibiotics did not create resistance genes, the drugs fast-forwarded their spread. "Antibiotic usage has stimulated evolutionary changes unparalleled in recorded biologic history," writes Dr. Stuart Levy of Tufts University in his 1992 book "The Antibiotic Paradox."

Even more ominous, there are signs that bacteria are "clever little devils," as microbiologist Stanley Falkow of Stanford University puts it, in ways scientists never suspected. It turns out that the germs can become resistant to antibiotics they never even met. In women receiving tetracycline for a urinary-tract infection, for instance, E. coli developed resistance not only to tetracycline but to other antibiotics, too. "It is almost as if bacteria strategically anticipate the confrontation of other drugs when they resist one," says Levy.

How did we get into this bind? In their eagerness to finish off the old diseases, doctors and patients have, paradoxically, given them new life. Patients demand antibiotics for viral infections, like colds, that antibiotics cannot touch; every dose of antibiotics makes it that much easier for resistance to spread. Also, doctors sometimes dispense antibiotics without knowing whether the sore throat, or even the pneumonia, is indeed caused by bacteria (page 50).

For sheer overprescription, no doctor can touch the American farmer. Farm animals receive 30 times more antibiotics (mostly penicillins and tetracyclines) than people do. The drugs treat and prevent infections. But the main reason farmers like them is that they also make cows, hogs and chickens grow faster from each pound of feed. Resistant strains emerge just as they do in humans taking antibiotics-and remain in the animal's flesh even after it winds up in the meat case. Many salmonella strains in turkey, for instance, are resistant to several common antibiotics. Although high heat kills them, the superbugs spread from animals to people through raw or undercooked meat. (People on antibiotics are particularly vulnerable the drugs kill off susceptible strains in the intestinal tract, leaving the field wide open for infection by resistant strains.) At least 500 people in the United States die annually from microbes present in meat and poultry; among them were the three children who ate E. coli-infested hamburger at Jack-in-the-Box restaurants last year. An additional 6.5 million people fall ill.

The threat could be even greater to those who down a milkshake with their burger. Milk is allowed to contain a certain concentration of 80 different antibiotics-all used on dairy cows to prevent udder infections. With every glassful, people swallow a minute amount of several antibiotics. The U.S. Food and Drug Administration sets limits on how much of the 80 antibiotics milk can contain, and insists that the less than 1 percent of milk that violates these limits is dumped. But a 1992 study by Congress's General Accounting Office found that states test for only four of the federally regulated antibiotics. The GAO's own tests discovered traces of 64 antibiotics at levels "that raise health concerns": they could produce resistant germs in milk drinkers. That may be understating the case. In a recent study at Rutgers University, antibiotics at levels deemed safe by the FDA increased the rate at which resistant bacteria emerged by 600 to 2,700 percent.

The drug residues are likely to increase now that genetic engineering has taken hold on the back 40. The FDA recently approved bovine growth hormone (rBGH), which is produced through gene splicing and increases milk production. But BGH also raises the incidence of udder infection and, with it, the need to give the cows antibiotics. And the FDA is about to hold hearings on whether the biotech company Calgene may market a tomato containing a gene that confers resistance to the antibiotic kanamycin. The announced benefit: a tomato that will stay fresh longer. But environmental groups warn that the resistance gene will be taken up by bacteria in people's stomachs and intestines. breeding still more invulnerable bugs.

If there is a lurking Andromeda Strain in all this, it is Staphylococcus aureus, the bacterium responsible for some pneumonias and, most worrisome, for blood poisoning in surgical wounds. Some 40 percent of staph in hospitals are resistant to every antibiotic but one, vancomycin. "We know at some point vancomycin will succumb and the bacteria will grow and proliferate unrestrained," worries the VA's Beam. "It will be like the 1950s and 1960s, when we had nothing to treat this infection, and the mortality rates were as high as 80 percent." In those decades, thousands of people each year died of staph infections.

Researchers even have a good hunch how that supermicrobe will be created. The culprit will likely be enterococcus, the blood-poisoning microbe that killed Gibert's patient. About 20 percent of enterococcal infections in hospitals are resistant to vancomycin, says Barry Kreiswirth of New York's Public Health Research Institute. The number is rising: in 1989, only one hospital in New York reported vancomycin-resistant enteroccocus; in 1991, 38 did. The following year, a British researcher showed that the gene for this resistance can travel from enterococcus to S. aureus. The finding was so terrifying that the researcher immediately destroyed all his stocks of vancomycin-resistant staph-but microbiologists have no doubt that the transfer of vancomycin resistance will happen in some hospital, somewhere, soon. "Bacteria have their own Internet." says Stanford's Falkow, swapping plasmids the way humans exchange E-mail. Once staph gets the gene for vancomycin resistance, warns Dr. Richard Roberts of Cornell Medical School, "we will really. really have a problem. Vancomycin is the last line."

Won't the next miracle drug save us? Until the mid-1980s, pharmaceutical companies always had another antibiotic in the wings. But then it began to look as if most bacterial infections were fading away with the millennium. The domestic antibiotic market was saturated and the only emerging market seemed to be in the developing world, with its cholera and dysentery and other ills that modern sanitation had banished elsewhere. Comparatively few Third World citizens can lay out $100 for the latest pill. Many of the big pharmaceutical firms stopped looking for the next penicillin Even the government got complacent: federal funds for antibiotics research dwindled. "There hasn't been any support of [basic antibiotic research] by the government in the last 20 years," says Dr. George Miller, head of infectious-disease research at Schering-Plough. As a result, in 1990, the FDA approved one new antibiotic; in 1991, five; in 1992, three; last year ... one.

Some companies, at least, are scrambling to catch up with a race of microbes that has sprinted at least five years ahead of the ability to control them. One strategy is to better understand how bacteria fight off antibiotics. The microbes defend themselves in several ways (diagram). They can secrete an enzyme that dismembers the drug, as staph does to neutralize penicillins. They can change their cell walls so antibiotics cannot get in, or alter some other site that the drug attacks. Enterococcus does this to foil erythromycin. Or, the microbes simply pump out the drug, which is how E. coli resist tetracycline. The first oral antibiotic to foil a superbug is Smith-Kline Beecham's Augmentin. Along with a form of penicillin, it contains a chemical that knocks out the enzyme that resistant bacteria deploy to neutralize the drug. But three years ago a strain of E. cob learned to make a new penicillin-slaying enzyme. This left Augmentin ineffective against those E. coli (though it still kills other bacteria) and raised the specter that E. coli might transfer its resistance to other bacteria. That's why trying to cripple bacteria's defenses, says Miller, "will not do much more than buy us five to 10 years."

In the past, pharmaceutical companies typically found new antibiotics by chance. Employees traveling to exotic climes were asked to bring back samples of dirt, which chemists back at headquarters would screen for antibiotics churned out by the soil microbes. In the 1980s, the companies adopted a new approach: with "rational drug design," they would build antibiotics from the bottom up, molecule by molecule. But now it's back to nature. The companies are searching everywhere from the bottom of the sea to the jungles of Borneo for the next bacteria-killing compound.

A better strategy might be to abandon antibiotics altogether in favor of different kinds of drugs. Resistance can affect a bacterium's ability to make a living, rendering it more vulnerable to temperature extremes or to acidity, for instance. "A drug-resistant bacterium is always at a competitive disadvantage," says Dr. Lee Green, a family practitioner at the University of Michigan. Maybe researchers can hit some bugs where they hurt through a drug that, say, increases the acidity in the intestine. Researchers are also looking for chemicals that can prevent the multiplication of plasmids, those E-mail messages of the microbial world, and for decoy molecules that can lure away the bacteria's killer enzyme and so allow the antibiotic to sneak in. Alternatively, vaccines might work against bacteria-there is already a vaccine against pneumococcus. But research on vaccines against strep and staph is nearly nonexistent. Why? "My gut feeling is vaccines aren't really big revenue generators," says Thomas Salzmann, vice president of chemical research at Merck.

Or maybe what we need is not more technological fixes but some plain common sense. Like not tossing the hand grenade of powerful antibiotics at the mosquito of a minor infection. Like rotating antibiotics to roll back resistance by allowing weaker germs to re-establish themselves. Like limiting the use of antibiotics in agriculture. Like insisting that doctors and nurses and even orderlies use antiseptic on their hands before treating or touching a patient, a sheet, a gurney. Like giving some antibiotics a well-deserved rest: "If we do, we know we'll see a re-emergence of vulnerable strains," says Dr. Richard Duma, head of the National Foundation for Infectious Diseases.

Antibiotics, more than anything else cooked up in biomedical labs, have led 20th-century medicine out of an era when women died during childbirth because of blood poisoning, when children's ear infections metamorphosed into fatal meningitis, when simple wounds turned lethally septic. Modern sanitation and better understanding of disease ensure that we will not return to those days. But already patients are suffering and dying from illnesses that science predicted 40 years ago would be wiped off the face of the earth. The scientists were wrong. Before science catches up with the microbes, many more people will die.

Only a few years after penicillin came into wide use with World War II, strains of staph had emerged that were immune to the drug. Since then, resistance has spread.


The following reads as follows:

MICROBE; DISEASES CAUSED; ANTIBIOTICS THAT NO LONGER WORK

Blood poisoning, surgical infections; Aminoglycosides, cephalosporins, erythromycin, penicillins, tetracycline, vancomycin

Meningitis, ear infections, pneumonia, sinusitis; Chloramphenicol, penicillins, tetracycline, trimethoprim/sulfamethoxazole

Tuberculosis; Aminoglycosides, ethambutol, isoniazid, pyrazinamide, rifampin

Gonorrhea; Penicillins, spectinomycin, tetracycline

Malaria; Chloroquine

Severe diarrhea; Ampicillin, chloramphenicol, tetracycline, trimethoprim/sulfamethoxazole

Blood poisoning, pneumonia, surgical infections; All but vancomycin

Meningitis pneumonia; Aminoglycosides, cephalosporins, chloramphenicol, erythromycin, penicillins, tetracycline, trimethoprim/sulfamethoxazole

Antibiotics attack bacteria in several ways, such as dissolving cell walls. But sometimes, by chance, a bacterium acquires a trait that fights back against the antibiotic, making the microbe resistant to the drug.

When it works, the drug can destroy the germ's cell wall, or wreck its ability to produce life-sustaining proteins.

If a bacterium develops a genetic mutation, it can strengthen its cell wall to keep the antibiotic out, break apart the drug or protect its genes and protein-making machinery.

The resistant bacterium sends out a filament to another bacterium, pulling it in.

The resistant microbe makes a copy of the loop of DNA that contains the gene for resistance,

When the two bacteria touch, the resistant one transfers the extra loop of DNA through its cell wall, into the other microbe.

The second bacterium is now resistant to the antibiotic, and can transfer that resistance to its own progeny and to other bacteria.

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