More and more strains of rogue bacteria are turning yesterday's wonder drugs into duds, some scientists warn, because Americans have come to use antibiotics as casually as aspirin.
What started as a localized problem in a few hospitals 40 years ago has grown into a far-reaching public health issue: bacteria are becoming resistant not only to basic penicillins but also to whole classes of costlier antibiotics that have been developed as reinforcements.
In the District and many parts of the country, up to one out of five adult urinary tract infections and one out of 10 children's ear infections, for example, are complicated by the presence of organisms that have become impervious to the safest and cheapest semi-synthetic penicillins, says Clyde Thornsberry, chief of antimicrobic investigations at the federal Centers for Disease Control in Atlanta.
As a result, infections that were once easily treatable can persist for weeks, repeatedly sending the patient back to the doctor's office for more expensive, powerful and potentially toxic antibiotics. No one knows the total public health costs, but the costs of resistance in hospitals alone contributes easily "tens of millions of dollars" to the nation's $5 billion tab for hospital infections, says Thornsberry.
Experts in infectious disease are particularly concerned about the antibiotic-intensive hospital environment, where the most pernicious microbes can pick up the genetic armament to fend off a whole range of antibiotics.
In burn wards, where a day or two of unchecked infection can be fatal, Thornsberry says, immunologically impaired patients are now frequently treated with a $150-a-day, three-antibiotic combinations such as one dubbed "TNT" (tobramycin-nafcillin-ticarcillin), rather than a $6 course of penicillin or tetracycline that might have once sufficed. The reason: up to 60 percent of all hospital infections may be complicated by some resistant bacteria, says Dr. Sidney Finegold, chief of infectious disease at Los Angeles Veterans Administration Center.
"There's no question the resistance problem is getting worse," says Dr. Richard Wallace, chief of microbiology and an expert on mechanisms of resistance at the University of Texas Health Sciences Center in Tyler. "In the last 10 years, we have not only seen new organisms become suddenly resistant . . . but we have also seen an increasing number of organisms that resist several drugs at once."
So far, Wallace says, a wholesale public health crisis has been averted largely by the ability of the $7 billion antibiotic industry to produce a dozen classes of nearly 200 different antibiotics.
But the new drugs have not stopped the spread of bacterial resistance. "The problem has escalated throughout the hospital and primary-care setting to the point where it has affected treatment for almost every common infection," says Dr. Harold C. Neu, chief of infectious diseases at Columbia University College of Physicians and Surgeons.
"It's gotten to where some of the most potent new drugs are so quickly overused that they become obsolete just a few years after they are introduced," says Dr. Stuart B. Levy, professor of medicine at Tufts University Medical School in Boston and head of a National Institutes of Health task force on antibiotic resistance.
Several of the estimated 5,000 scientific papers published on bacterial resistance in the last decade have asserted that as many as 30 to 50 percent of this country's 160 million to 200 million annual antibiotic prescriptions may be unnecessary. In Third World countries, where the drugs are freely available without prescription, antibiotic abuse may be far worse.
One article in Scientific American even warned that the resistance problem may eventually return medicine to the pre-antibiotic era, when infectious disease, which even today kills roughly 125,000 Americans a year, was a bigger killer than heart disease or cancer.
In the last 15 years, a number of Third World countries, including Thailand, Guatemala and Mexico, have seen epidemics caused by antibiotic-resistant bacteria, fed by a mixture of poor hygiene and routine mass preventive antibiotic use to ward off endemic diseases like dysentery.
In one of the most tragic outbreaks, 14 young Durban, South Africa, children died in 1977 after developing systemic infections with a super-resistant strain of Streptococcus pneumoniae.
In a Johannesburg hospital, a 3-year-old boy who received several antibiotic courses as part of a heart operation suddenly became infected with a rogue strain that then got into a measles ward. Quickly, 75 out of 80 children had infections that were resistant to almost everything in the pharmacy -- penicillin, erythromycin, clindamycin, tetracycline, chloramphenicol and cotrimoxazole. One child died before an unusual, costly and sometimes toxic antibiotic called rifampin was found to be effective.
In the United States, resistance to antibiotics has shown up dramatically in gonorrhea. Since it first appeared in the mid-1970s, the U.S. incidence of penicillin-resistant gonorrhea increased from 185 cases in 1977 to at least 4,200 cases in 1984, including 5 percent of all gonorrhea in Miami.
Meanwhile, even "non-resistant" gonorrhea, a former pushover for 50,000 to 100,000 units of penicillin 30 to 40 years ago, now takes 4.8 million units to be subdued.
The problems of resistance began shortly after antibiotics were discovered. Three years after penicillin was introduced in 1945, Staphylococcus aureus -- a common culprit in surgical, respiratory, skin and bloodstream infections -- began to elude the new wonder drug. By the early 1950s, staph resistance rates in certain hospitals reached 80 percent, forcing physicians to use newer drugs, such as erythromycin, streptomycin and tetracycline. By the early 1960s, widespread resistance to those agents forced pharmaceutical companies to develop more complicated molecules -- called cephalosporins -- in addition to a new class of "knock-out" penicillins called methicillins.
Typically, resistance to a drug develops and spreads fairly quickly. While only 0.3 percent of all strains of Hemophilus influenzae showed any resistance in 1975, a University of Colorado study found that 4.2 percent did so in 1977 and 31 percent were resistant in 1981. By the same year, 42 percent of Hemophilus strains in Northern Virginia were reported to be resistant to basic penicillins.
Derived from chemicals that naturally protect fungi such as molds from bacteria, penicillins and other antibiotics prevent the normal formation of proteins that shore up cell walls found only in bacterial, but not human, cells.
Resistance to antibiotics is thought to develop through nothing more than a lucky adaptation. It is now known that once that chemical secret is out of the bag, bacteria can exchange the defense codes by switching tiny genetic packages throughout their entire colony.
If so much as a single bacterium happens to hold some antibiotic-stopping gene, that code can leap throughout an entire colony, so that a new generation (which can occur in as little as 20 minutes) can be immediately equipped with resistance to that drug. Some bacteria hold 10 or more genes for resistance at a time.
To counter the spreading resistance, an increasing number of physicians are calling for cutbacks in all unnecessary uses of antibiotics in fears that these lifesaving drugs will lose all their punch. Since 1981, one international lobbying group called the Alliance for Prudent Use of Antibiotics has grown to include members from 65 countries.
In this country, says Tufts' Levy, one fundamental perception must change. "The American public has grown up thinking that antibiotics are 'miracle drugs.' They believe they are therefore entitled to them every time they walk in the doctor's office with a sore throat or cold."
But doctors, too, often regard the agents too casually, Wallace adds. One powerful new incentive for reform may be the escalating costs of all these drugs. "With hospitals being pressured to restrain runaway costs, one of the first steps many administrators are making is to get a handle on explosive antibiotic costs," Wallace says.
That may be an effective incentive. Studies in the 1960s at Boston City Hospital and the University of Oregon showed that institutional restraints on unnecessary antibiotic use could quickly lower rates of resistance while reducing drug costs.
The other bright spot is that several drug companies are developing new types of antibiotics that actually "jam" important forms of bacterial resistance. "If these new drugs are used unwisely, some strains of bacteria may soon develop resistance to them, too," warns CDC's Thornsberry.
"Bacteria," says Wallace, "aren't dumb."