The Rise of Antibiotic-Resistant Infections by Ricki Lewis, Ph.D. When penicillin became widely available during the second world war, it was a medical miracle, rapidly vanquishing the biggest wartime killer--infected wounds. Discovered initially by a French medical student, Ernest Duchesne, in 1896, and then rediscovered by Scottish physician Alexander Fleming in 1928, the product of the soil mold Penicillium crippled many types of disease-causing bacteria. But just four years after drug companies began mass-producing penicillin in 1943, microbes began appearing that could resist it. The first bug to battle penicillin was Staphylococcus aureus. This bacterium is often a harmless passenger in the human body, but it can cause illness, such as pneumonia or toxic shock syndrome, when it overgrows or produces a toxin. In 1967, another type of penicillin-resistant pneumonia, caused by Streptococcus pneumoniae and called pneumococcus, surfaced in a remote village in Papua New Guinea. At about the same time, American military personnel in southeast Asia were acquiring penicillin-resistant gonorrhea from prostitutes. By 1976, when the soldiers had come home, they brought the new strain of gonorrhea with them, and physicians had to find new drugs to treat it. In 1983, a hospital-acquired intestinal infection caused by the bacterium Enterococcus faecium joined the list of bugs that outwit penicillin. Antibiotic resistance spreads fast. Between 1979 and 1987, for example, only 0.02 percent of pneumococcus strains infecting a large number of patients surveyed by the national Centers for Disease Control and Prevention were penicillin- resistant. CDC's survey included 13 hospitals in 12 states. Today, 6.6 percent of pneumococcus strains are resistant, according to a report in the June 15, 1994, Journal of the American Medical Association by Robert F. Breiman, M.D., and colleagues at CDC. The agency also reports that in 1992, 13,300 hospital patients died of bacterial infections that were resistant to antibiotic treatment. Why has this happened? "There was complacency in the 1980s. The perception was that we had licked the bacterial infection problem. Drug companies weren't working on new agents. They were concentrating on other areas, such as viral infections," says Michael Blum, M.D., medical officer in the Food and Drug Administration's division of anti-infective drug products. "In the meantime, resistance increased to a number of commonly used antibiotics, possibly related to overuse of antibiotics. In the 1990s, we've come to a point for certain infections that we don't have agents available." According to a report in the April 28, 1994, New England Journal of Medicine, researchers have identified bacteria in patient samples that resist all currently available antibiotic drugs. Survival of the Fittest The increased prevalence of antibiotic resistance is an outcome of evolution. Any population of organisms, bacteria included, naturally includes variants with unusual traits--in this case, the ability to withstand an antibiotic's attack on a microbe. When a person takes an antibiotic, the drug kills the defenseless bacteria, leaving behind--or "selecting," in biological terms--those that can resist it. These renegade bacteria then multiply, increasing their numbers a millionfold in a day, becoming the predominant microorganism. The antibiotic does not technically cause the resistance, but allows it to happen by creating a situation where an already existing variant can flourish. "Whenever antibiotics are used, there is selective pressure for resistance to occur. It builds upon itself. More and more organisms develop resistance to more and more drugs," says Joe Cranston, Ph.D., director of the department of drug policy and standards at the American Medical Association in Chicago. A patient can develop a drug-resistant infection either by contracting a resistant bug to begin with, or by having a resistant microbe emerge in the body once antibiotic treatment begins. Drug-resistant infections increase risk of death, and are often associated with prolonged hospital stays, and sometimes complications. These might necessitate removing part of a ravaged lung, or replacing a damaged heart valve. Bacterial Weaponry Disease-causing microbes thwart antibiotics by interfering with their mechanism of action. For example, penicillin kills bacteria by attaching to their cell walls, then destroying a key part of the wall. The wall falls apart, and the bacterium dies. Resistant microbes, however, either alter their cell walls so penicillin can't bind or produce enzymes that dismantle the antibiotic. In another scenario, erythromycin attacks ribosomes, structures within a cell that enable it to make proteins. Resistant bacteria have slightly altered ribosomes to which the drug cannot bind. The ribosomal route is also how bacteria become resistant to the antibiotics tetracycline, streptomycin and gentamicin. How Antibiotic Resistance Happens Antibiotic resistance results from gene action. Bacteria acquire genes conferring resistance in any of three ways.
In spontaneous DNA mutation, bacterial DNA (genetic material) may mutate (change) spontaneously (indicated by starburst). Drug-resistant tuberculosis arises this way.
In a form of microbial sex called transformation, one bacterium may take up DNA from another bacterium. Pencillin-resistant gonorrhea results from transformation.
Most frightening, however, is resistance acquired from a small circle of DNA called a plasmid, that can flit from one type of bacterium to another. A single plasmid can provide a slew of different resistances. In 1968, 12,500 people in Guatemala died in an epidemic of Shigella diarrhea. The microbe harbored a plasmid carrying resistances to four antibiotics!
The Greatest Fear--Vancomycin Resistance When microbes began resisting penicillin, medical researchers fought back with chemical cousins, such as methicillin and oxacillin. By 1953, the antibiotic armamentarium included chloramphenicol, neomycin, terramycin, tetracycline, and cephalosporins. But today, researchers fear that we may be nearing an end to the seemingly endless flow of antimicrobial drugs. At the center of current concern is the antibiotic vancomycin, which for many infections is literally the drug of "last resort," says Michael Blum, M.D., medical officer in FDA's division of anti-infective drug products. Some hospital- acquired staph infections are resistant to all antibiotics except vancomycin. Now vancomycin resistance has turned up in another common hospital bug, enterococcus. And since bacteria swap resistance genes like teenagers swap T-shirts, it is only a matter of time, many microbiologists believe, until vancomycin- resistant staph infections appear. "Staph aureus may pick up vancomycin resistance from enterococci, which are found in the normal human gut," says Madden. And the speed with which vancomycin resistance has spread through enterococci has prompted researchers to use the word "crisis" when discussing the possibility of vancomycin-resistant staph. Vancomycin-resistant enterococci were first reported in England and France in 1987, and appeared in one New York City hospital in 1989. By 1991, 38 hospitals in the United States reported the bug. By 1993, 14 percent of patients with enterococcus in intensive-care units in some hospitals had vancomycin-resistant strains, a 20-fold increase from 1987. A frightening report came in 1992, when a British researcher observed a transfer of a vancomycin-resistant gene from enterococcus to Staph aureus in the laboratory. Alarmed, the researcher immediately destroyed the bacteria. Ricki Lewis is a geneticist and textbook author. Answer the following reading questions in complete sentences on a separate sheet of paper:
1. When did we first see bacteria that were resistant to penicillin? 2. Do antibiotics actually cause bacteria to become resistant? Explain your answer. 3. List three ways that antibiotic resistant bacteria evade the action of antibiotics. 4. Explain how antibiotic resistance of certain bacteria illustrates the 5 principles of natural selection. 5. Why is vancomycin resistance in bacteria such a serious concern for society?
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