Losing the Battle of the Bugs
Common bacteria are now so resistant to antibiotics that they can kill. We have no one to blame but ourselves
She could never explain why she had decided to wake him that Thursday afternoon in February. Call it mother's intuition. Susan Canterbury's 2-year-old son, Dalton, had been sleeping for hours, too long. True, the pediatrician had said he had the flu. But something about his deep, deathlike sleep scared her.
When Canterbury woke her son, he was lifeless, so weak he could not hold up his head to eat his favorite ice pop. At 3 p.m. her husband, Daniel, returned from his job at an auto body shop in York, Pa., where the family lives. They decided to take Dalton back to the doctor. A spinal tap showed cloudy fluid, a sign of bacterial meningitis.
In the ambulance on the way to York Hospital, Dalton had a seizure, caused by the infection in the membranes surrounding his brain. The boy needed 24-hour nursing in a pediatric intensive care unit. There was none in York. Dalton's best chance, the emergency physician said, was to fly him immediately to Johns Hopkins Hospital in Baltimore, 50 miles away. Susan Canterbury suddenly grasped what the doctor was trying to tell her. "You mean," she asked, "he could die?"
For over five decades, the world has conquered infectious diseases like meningitis with a vast array of wonder drugs. Faith in the power of antibiotics to cure everything from pneumonia to postnasal drip has resulted in their becoming one of the most commonly prescribed categories of drugs in the United States. More than 133 million courses of antibiotics are prescribed by doctors each year to nonhospitalized patients. Fully 190 million doses a day are administered in hospitals.
But our wonder weapons are becoming less potent: The bugs have discovered newer, more efficient ways to elude destruction. Bacteria also have more avenues of at-tack: Day-care facilities have thrown youngsters together as never before; hospitalized patients are sicker and more susceptible to infections; modern agriculture, which relies on antibiotics to boost growth and limit disease among cattle, chickens, and other animals, has led to the spread of more dangerous microbes.
But the main demon driving the rise of antibiotic-resistant pathogens is us. "People don't see a downside to antibiotic use," says Lee Harrison, an epidemiologist at the University of Pittsburgh and Johns Hopkins
University. "But there's a major downside: Antibiotic resistance is becoming a public-health nightmare." A new report by the General Accounting Office, delivered to Congress last week, indicates that antibiotic resistance is increasing worldwide--more kinds of bacteria are becoming resistant and they are resistant to multiple drugs. However, the GAO noted, it's impossible to gauge the threat because the needed data do not exist. No federal agency tracks all resistant infections or tallies their human and financial cost--a reality that Sen. Tom Harkin of Iowa, who ordered the report, calls "unacceptable." One estimate puts the financial burden at $30 billion yearly.
Young victims. Even more frightening: The victims are often children, who succumb to common microbes easy to treat just a few years ago. There's Shaunna Littlejohn, 10, now blind and in a vegetative state due to drug-resistant meningitis; Christine Girata, 3, who contracted multidrug-resistant meningitis at 2 months and was left profoundly deaf; Ariana Broadway, 4, who nearly died from a bloodstream infection and pneumonia when she was 2; and, of course, Dalton Canterbury.
The latest turn in the battle of the bugs is no surprise. Scientists have known since the dawn of the antibiotic age in the 1940s that the more an antibiotic is used, the quicker it becomes useless. That's because of natural selection: While most bacteria exposed to the drug are killed, the fittest survive and pass survival traits to their offspring. With continued use of the antibiotic, the resistant bugs proliferate. Bacteria have a broad array of tactics to combat antibiotics' toxicity, and they can give the genes that control these feats to nearby, even unrelated, bugs.
Bugs that have become resistant to one antibiotic also seem to find it easier to build resistance to others. As a result, says James Hughes, director of the National Center for Infectious Diseases at the federal Centers for Disease Control and Prevention, "We're facing a serious global problem with antimicrobial resistance now. It affects virtually all of the pathogens we previously considered easily treatable."
The evidence is everywhere: Bostonians carry resistant E. coli in their guts; a Vermont high-school wrestling team is infected with resistant Staphylococcus aureus; multidrug-resistant salmonella infects farmers and their cows; an outbreak of resistant tuberculosis sweeps through a California high school; and in some areas as many as 40 percent of the strains of Streptococcus pneumoniae, the most dangerous pathogen for children and the elderly, are drug resistant.
When Dalton Canterbury arrived at Johns Hopkins that Thursday night, he was unconscious and suffering seizures. Doctors hooked him up to a ventilator to breathe for him, gave him drugs to control the seizures, and went to work culturing the spinal fluid sample sent from York. A complete test to identify bacterial resistance takes days. Initial results that night confirmed that Streptococcus pneumoniae, which is also called pneumococcus, was causing Dalton's meningitis.
Pneumococci are the deadliest bacteria in the United States, killing 40,000 yearly. The bug also causes an estimated 7 to 10 million middle-ear infections in children a year, 500,000 cases of pneumonia, and thousands of cases of meningitis and bloodstream infections. "This is a bug that all clinicians encounter every day in their practice," says Scott Dowell, a medical epidemiologist in the CDC's Respiratory Diseases Branch. At one time, it was easy and cheap to treat pneumococci with penicillin. But overuse of penicillin, its synthetic cousins, and other antibiotics over the years has made pneumococci multidrug resistant.
It happened fast. The first penicillin-resistant pneumococcal strain was reported in New Guinea in 1967. By 1992, about 5 percent of U.S. samples tested by the CDC were resistant to penicillin. Now, seven years later, an average of 25 percent of cases are resistant; in some areas the rate tops 40 percent.
Late that Friday, the attending infectious-disease specialist at Hopkins came to talk to the Canterburys. The doctor had bad news. Tests showed that the strain of pneumococcus infecting the fluid around Dalton's brain was resistant to penicillin. It was also partially resistant to ceftriaxone, a powerful drug used to treat penicillin-resistant meningitis. The doctors' only recourse was to give Dalton extraordinarily high doses of the drug along with vancomycin, another powerful antibiotic that kills pneumococci but does not permeate the spinal fluid well enough to be used alone.
On Monday, February 15, Bernadette Albanese, a pediatric infectious disease specialist, took over Dalton's case. Albanese tried to reassure the Canterburys that Dalton would pull through. Privately, though, she was worried. A meningitis case should show improvement within 48 hours. Dalton's seizures were continuing, and he was still unconscious. For days, the staff debated whether a pocket of infection persisted somewhere in his brain.
On Wednesday, February 18, Dalton finally regained consciousness. Albanese told Susan Canterbury she could hold him. "It felt exactly like when I first had him," Canterbury says. It was a week longer before he could sit up. He would touch her face but, his mother says, "He looked right past you." She wondered what was wrong.
On Friday, March 5, she found out. An ophthalmologist examined Dalton and found that the portion of his brain that processes visual images had been damaged. "It was devastating to me," Canterbury says, "when the doctor said he thought Dalton would be blind."
Dalton Canterbury didn't do anything special to get the bug that almost killed him. Resistant bugs can be spread to others through nasal fluid, food, and saliva. Albanese believes this is how Dalton contracted resistant meningitis--the bug was passed to him by someone else. Using antibiotics kills off many of the bacteria that normally inhabit the human body and allows resistant ones to take over. "Antibiotic use is not only an issue for the person who takes the drug," Albanese says, "but for their brother, sister, and the kids they go to day care with."
Ear infections. Dalton didn't attend day care, but children's close contact there is believed to play a major role in the dramatic increase in another pneumococcal infection--acute otitis media, or middle-ear infections. Between 1975 and 1990, physicians' diagnoses of otitis media more than doubled, and the illness is becoming resistant to treatment. The CDC studied a multidrug-resistant pneumococcal strain originating from one child at an Ohio day-care center. They found it was spread to attendees, staff, and family members, had caused recurring ear infections in 20 percent of the children at the center, and had moved into the community.
Doctors are resorting to increasingly powerful drugs to treat ear infections. In 1980, 876,000 prescriptions for cephalosporins were recorded for the treatment of acute otitis media. By 1992, the number had jumped to nearly 7 million, a 687 percent increase.
Afraid to crawl. When they brought Dalton home from the hospital in March, he was a different child. He could no longer run wildly through the house. He stayed in whatever room Susan Canterbury put him in, afraid to walk or crawl off the rugs onto the wood floors, as though he would fall off the sides of the Earth.
But the Canterburys were hopeful that Dalton would regain some of his vision. On his last day in the hospital, he had reached out and picked up a big pink block without first groping for it. Now at home, he played with musical toys that lighted up. Maybe, Susan Canterbury thought, he could see them. But there were other times, she says, where "he would lie there like in space, and you could tell he couldn't see anything."
Not so long ago, doctors wouldn't have worried about finding a drug to treat Dalton. With more than 25,000 antibiotic products available by the mid-'60s, the medical community became complacent, and the pharmaceutical industry shifted priorities. "There was a tendency to feel the problem was solved," says Martin Rosenberg, senior vice president for infectious diseases at the SmithKline Beecham pharmaceutical company.
There were still bright young scientists interested in bacterial diseases--but the money had moved on to genetics and biotechnology. "For years, young investigators have completed their training in my laboratory," says Stuart Levy, a professor of microbiology at Tufts University, "only to find no jobs in the field."
Now that the pharmaceutical industry is scrambling to find new and better antibiotics, there aren't enough researchers available. "We've been left with a void in people who understand bacteria and bacterial disease," Rosenberg adds.
The brain drain in bacterial research has been compounded by the crumbling of the United States' once mighty public-health-surveillance system. State and county health departments, set up at the end of the 19th century to control epidemics like smallpox and typhoid, were left, says Jeffrey Koplan, director of the CDC, "to benign neglect." Until 1992, only $55,000 a year was spent on antibiotic-resistance surveillance nationwide. "It's not quite that pathetic today," says the CDC's David Bell, assistant director of the National Center for Infectious Diseases, who is in charge of antimicrobial resistance. The CDC is spending over $2 million this year on surveillance. Next year the agency has requested $14 million for antimicrobial-resistance efforts.
Still, only a handful of local public-health labs can test for bacterial drug resistance, because they lack the proper equipment. Fewer than half of the states require reporting resistant infections, unlike mandatory reporting of tuberculosis, AIDS, and sexually transmitted diseases. According to a February General Accounting Office report, state and local health officials lack basic office equipment such as computers and faxes. Half of local health departments aren't even hooked up to the Internet. "While the kids are zipping through Web sites to order zirconium earrings," says the CDC's Koplan, "we've got epidemiologists trying to track resistant pneumococcal infections with paper and pencils."
The week that Dalton Canterbury left Johns Hopkins Hospital, Bernadette Albanese visited the office of Maryland Primary Care Associates in Arnold, Md., 27 miles south of the hospital. Albanese was wearing her other hat--research associate at the Johns Hopkins University School of Hygiene and Public Health and the director of a CDC- and state-funded pilot project called Use Antibiotics Wisely.
The goal of the project, which Albanese hopes will be replicated nationally, is to educate doctors and the public about the spread of antibiotic resistance and to limit unnecessary use of antibiotics. Maryland is one of nine sites in the CDC's Emerging Infections Program, in which local scientists such as Albanese track the spread of resistant bacteria, foodborne illnesses, and other pathogens.
Doctors like those at Maryland Primary Care Associates are on the front lines of the antibiotic-resistance problem. Their patients are suburban families with kids, the nation's heaviest consumers of antibiotics. The rate of antibiotic use among children has jumped more than 48 percent since 1980, according to the CDC. Forty-four percent of kids are prescribed antibiotics for colds and 46 percent for upper- respiratory infections--both conditions usually caused by viruses, against which antibiotics are useless. "In the past we may have gotten away with this," Albanese told the clinic staff. "It didn't seem to cause any harm. But now, in 1999, the risk is high and the scales are tipping. When we start using antibiotics for things like colds, we've exposed the patient to a risk and there is no benefit."
Thomas Walsh, a family practitioner who is MPCA's medical director, raised his hand. "A big thing missing in this discussion is the role of capitated health care," he said. Under a capitated health plan, doctors serving the plan are paid a fixed amount per patient per month for all their office visits and care. Costs above that come out of the doctors' pockets. "Essentially," Walsh said, "you're being paid not to see people." The incentive is to just prescribe antibiotics, even over the phone.
"How does that play out?" Albanese asked.
"When I have a mother on the phone with a kid with a recurrent ear infection," he said, "and it's a capitated patient and I have the opportunity to see another patient who is fee for service, if I can treat the child with the ear infection over the phone, then I might do that. There is a tendency to keep the volume up so things that might require a little added time, physicians don't do."
Ground zero. Albanese agreed but told Walsh that the problem remains. "It's white suburban dwellers--your patients--who are the people getting these resistant infections. This county has among the highest rates of invasive pneumococcal infections of any we're studying." In Anne Arundel County, where the practice is located, 27 percent of patients with invasive pneumococcal disease--pneumonia, meningitis, or bloodstream infections--were infected with penicillin-resistant strains in 1998. By comparison, downtown Baltimore, with a lower-income population that sees doctors less often, had more invasive infections, but only 12 percent were resistant.
It may be that higher socioeconomic levels and greater access to health care are a mixed blessing in dealing with the microbial world. "Patients who have been exposed to antibiotics for whatever reason are more likely in one to three months to acquire a resistant pneumococcal infection," explains the CDC's Dowell.
Although many doctors admit that they are part of the problem, they say that educating the public, particularly parents, to the perils of overuse of antibiotics is the only answer. "Around here," says MPCA's Walsh, "we have both parents working and they want antibiotics for their kids because they think they can be in day care then. We try hard, but we get a lot of pressure." Those views were borne out by a recent study of over 600 pediatricians in Pediatrics, in which 96 percent of doctors surveyed reported that parents had recently requested antibiotics for their children when they were not indicated. Nearly one fourth of parents asked for a specific drug. One third of the doctors admitted they had complied with the parents' demands.
"Doctors need to do two things," says Albanese. "They need to stand their ground when an antibiotic is not needed. But they also have a responsibility to explain to the patient why an antibiotic isn't necessary and to give them some tips on how to take care of their symptoms."
New drugs and vaccines may ease the crisis somewhat. Within the next year, a new pneumococcal vaccine to protect children under 2 from invasive infections should reach the market. Several new drugs are in the pipeline for treating resistant pneumococcal and similar infections. One of these, Zyvox, or linezolid, now being tested by Pharmacia & Upjohn, represents a new class of antibiotics that may be available next year. Genetic mapping of microbes, and of humans, may make it easier to devise drugs tailored to bacterial survival mechanisms. "This is the first time in 50 years that there has been tremendous excitement and a new set of strategies," says SmithKline Beecham's Rosenberg.
New vaccines, however, will not be available for every bacterium, and new drugs will have to be used parsimoniously, the way today's antibiotics have not been. Even with new "wonder" drugs, the solution will be the same: Use fewer antibiotics in smarter ways. "You can't blow this off like in the past," Albanese told the doctors. "How do we fix it? Tighten your belts and if you have to, say to the patient, 'Sorry.'"
On a Sunday in late March, a small miracle took place. Dalton Canterbury stood up and, for the first time since he'd been home, walked right up to Susan Canterbury and looked at her. Soon he was able to run through the house. By mid-April, he had regained a great deal of his eyesight. Dalton may have some vision and learning problems or continuing seizures. But none of that seems important right now, because he is alive.
"You know," says Susan Canterbury, "you hear about people using antibiotics too often, but I don't think I ever realized the seriousness of this until Dalton got sick. I didn't know that we have overmedicated ourselves to the point that we've put ourselves in jeopardy."
Eluding the enemy
Some genes enable bacteria to "learn" new tactics for evading and inhibiting antibiotics. Here are three of the basics.
1 Expelling. Genetically developed pumps catch antibiotics as they enter the cell membrane and expel them from the bacterium.
2 Degrading. Some genes produce enzymes that degrade the antibiotics, rendering them useless against disease.
3 Deactivating. Other genes make enzymes that chemically deactivate the antibiotics.
[Illustration labels]: Cell membrane; Antibiotic-resistant genes; Antibiotic; Pump; Degrading enzyme; Deactivating enzyme
This story appears in the May 10, 1999 print edition of U.S. News & World Report.