History and Scientific Foundations
Penicillin was the first antibiotic to be mass-produced for use in treating bacterial infections. Following its introduction during World War II (1939–1945), infections that had until then been difficult to treat became easy to cure. The next 20 years was a time of great optimism; scientists heralded that most, if not all, bacterial infections would be controlled by penicillin and additional antibiotics. In 1969, the U.S. Surgeon General William Stewart proclaimed, “It is time to close the book on infectious diseases. The war against pestilence is over.”
This optimism proved to be premature. In fact, there had already been a hint of what was to come. Only three years after the introduction of penicillin, clinical infections caused by a penicillin-resistant form of the bacterium Staphylococcus aureus began to be reported. In the subsequent decades, antibiotic resistance has become a major concern in hospitals and in daily life. The problem does not have a single cause—bacteria have devised a number of ways to overcome antibiotics.
History and Scientific Foundations
By 1947, the antibiotic methicillin had been in widespread use for only two years. Nonetheless, resistance to this penicillin-related antibiotic by S. aureus was already known. This bacterium, since dubbed methicillin-resistant S. aureus, or MRSA, has become a huge problem, since it possesses resistance to a variety of other antibiotics commonly used to treat infections. As of 2007, about 50% of all infections caused by S. aureus in the United States are the result of MRSA.
Currently, there is only one antibiotic—vancomycin— that is effective against such multi-resistant bacteria. However, in 1997, a strain of S. aureus that also was resistant to vancomycin was reported in Japan. This resistant bacterium is now present in Europe and North America. While not yet as prevalent as MRSA, infection control experts warn that it is only a matter of time before the organism becomes more common.
Antibiotic resistance is present in other diseasecausing bacteria as well. Acquisition of resistance has been a consequence of the use of antibiotics in hospitals. The selective pressure on a bacterium in a hospital is to develop antibiotic resistance, since the continued survival of the bacterium depends on its ability to thwart the antibiotic.
Bacteria can also become resistant to an antibiotic purely by chance. Changes in the bacterial deoxyribonucleic acid (DNA) can occur randomly. Portions of DNA may be inserted or removed, or there may be a substitution of some of the building blocks (nucleotides) of the DNA. If the change occurs in a portion of DNA that codes for a bacterial component, the result can be resistance to an antibiotic. For example, a change in the composition of the bacterial membrane may prevent an antibiotic from passing as easily to the inside of the cell, or the enhanced activity of a bacterial enzyme may degrade a particular antibiotic. This spontaneous antibiotic resistance is thought to be responsible for the appearance of drug resistance in the bacterium that causes tuberculosis, which has led to the resurgence of this lung infection.
A second way that antibiotic resistance can be acquired is by the transfer of some of the DNA from the chromosomes of one bacterium to another. This typically occurs when the two bacteria are connected to each other by a hollow tube (a sex pilus). DNA can pass down the tube from the donor bacterium to the recipient bacterium. The process can be interrupted by breaking the tube, and so the transfer of genetic material can often be incomplete.
The third means by which antibiotic resistance develops is the most worrisome. This also involves the transfer of DNA from one bacterium to another, but instead of the transfer of DNA from the chromosomes of the donor bacterium to the recipient bacterium, the DNA found in a circular piece of DNA—known as a plasmid—is transferred from donor to recipient. Transfer of the plasmid to a new bacterium can easily occur, and the inserted plasmid may not need to be part of the recipient's genome to produce whatever factor is responsible for antibiotic resistance.
Plasmid-mediated transfer can occur at a much higher frequency than the other types of DNA transfer, and, as a result, antibiotic resistance can spread quickly. Furthermore, the DNA transfer can be promoted by selection pressure. For example, the presence of antibiotics can encourage the transfer DNA coding for anti-biotic resistance among populations of bacteria.
A plasmid may contain a number of genes that each code for resistance to a certain antibiotic, as well as the genetic information that enables all this information to be deciphered and the necessary resistance factors made. The plasmid only needs to get inside the recipient bacterium for that cell to become resistant to the antibiotics.
There are different mechanisms of antibiotic resistance. Change of the target site of an antibiotic can make the antibiotic less effective or completely ineffective. For example, some Gram-negative bacteria can become resistant to a class of antibiotics called beta-lactam antibiotics by a modification to proteins called penicillin-binding proteins. The modification keeps the beta-lactam antibiotics from disrupting the construction of peptidoglycan, a component that is vital to maintaining the structure of the bacterial membrane. Other mechanisms of antibiotic resistance include the increased ability of the bacterium to pump an antibiotic back out of the cell, and the production of enzymes by the bacteria that can destroy the incoming antibiotic.
Laboratory tests can determine whether the bacteria isolated from an infection are resistant to antibiotics; which antibiotics the microbe is resistant to; and, most importantly for treatment, which antibiotics can kill the microbe. Typically, this testing involves adding the bacteria to the surface of a solid nutrient. The bacteria are spread over the surface so that they will grow as a continuous layer (often called a lawn). At about the same time, discs of a paper-like material that have been soaked in various concentrations of antibiotics are positioned on the nutrient surface. When the bacteria eventually grow, there will be circular clear zones devoid of bacteria wherever the antibiotic has been effective in killing the bacterial cells. Measurement of the diameter of these so-called inhibition zones can be used to determine how sensitive a particular type of bacteria is to the particular antibiotic. An automated version of this test also exists, but the basic design of the test is similar.
Applications and Research
Antibiotic resistance now involves a race between the development and introduction of an antibiotic and the development of bacterial resistance to the drug. Antibiotic discovery or synthesis is a long and costly process. This has hampered antibiotic research, since a pharmaceutical company needs to have a reasonable expectation of recouping the hundreds of millions of dollars spent on drug development before the drug becomes clinically less useful.
WORDS TO KNOW
BACTERIOPHAGE: A virus that infects bacteria. When a bacteriophage that carries the diphtheria toxin gene infects diphtheria bacteria, the bacteria produce diphtheria toxin.
MRSA: Methicillin-resistant Staphylococcus aureus are bacteria resistant to most penicillan-type antibiotics, including methicillin.
PLASMID: A circular piece of DNA that exists outside of the bacterial chromosome and copies itself independently. Scientists often use bacterial plasmids in genetic engineering to carry genes into other organisms.
For some antibiotics, effectiveness can be regenerated relatively easily by modifying the three-dimensional structure of the molecule. Even a slight alteration involving the replacement of one chemical group in the molecule by another can restore the potency of the drug. Unfortunately, this effectiveness tends to be short-term. Within several years, bacteria can adapt to the modified drug and once again become resistant.
Research continues to try and find new mechanisms of antibiotic resistance. By understanding how bacteria become resistant to antibiotics, researchers hope to discover or design drugs that will kill the bacteria without stimulating the development of resistance. One approach that is promising is the use of bacteriophages—viruses that specifically infect and make new copies inside of a certain type of bacteria. Different bacteriophages each infect a particular bacterium. Since bacteriophages have been around for millions of years without the development of resistance by the target bacteria, researchers have been experimenting with the use of bacteriophages to deliver a toxic payload of antibacterial compounds. As of 2007, the research seems promising.
Impacts and Issues
Antibiotic resistance is a problem that humans have created through the misuse and overuse of antibiotics. For example, it was once common practice to prescribe antibiotics for almost all illnesses, even those caused by viruses. Since viruses are not affected by antibiotics, this approach only served to exert a selection pressure favoring the development of resistance on the bacteria already present. In addition, antibiotics continue to be widely used in the poultry and cattle industries to enhance the weight gain of the birds or livestock. This practice involves giving antibiotics to healthy animals rather than using them to treat infections. It encourages the development of resistant bacteria, and this resistance can be passed to other bacterial populations.
IN CONTEXT: REAL-WORLD RISKS
Bacteria can adapt to the antibiotics used to kill them. This adaptation, which can involve structural changes or the production of enzymes that render the antibiotic useless, can make a particular bacterial species resistant to a particular antibiotic. Furthermore, a given bacterial species will usually display a spectrum of susceptibilities to antibiotics, with some antibiotics being very effective and others ineffective. For another bacterial species, the pattern of antibiotic sensitivity and resistance will be different. Thus, for diagnosis of an infection and for clinical decisions regarding the best treatment, tests of an organism's response to antibiotics are essential.
Since 2000, the prevalence of community-associated MRSA (CA-MRSA) has been increasing. CA-MRSA infections are found in healthy people interacting normally in their community, not among those who have been hospitalized within the past year or had recent medical procedures, such as dialysis or surgery. This type of antibiotic resistance is especially challenging for health authorities, since it indicates that antibiotic resistance is capable of developing and spreading in the absence of antibiotic use. Recent outbreaks of community-associated MRSA occurred in Los Angeles county, California, and Chicago, Illinois, in 2004.
Primary Source Connection
In the following op-ed column published by the New York Times during the intense media coverage surrounding the 2001 anthrax attacks on the U.S. Postal Service, the Senate, and various media outlets, the authors Ellen K. Silbergeld and Polly Walker describe the dangers of the careless use of powerful antibiotics. At the time of publication, Ellen K. Silbergeld was professor of epidemiology at the University of Maryland School of Medicine. Polly Walker was associate director of the John Hopkins Center for a Livable Future.
What If Cipro Stopped Working?
Cipro, despite its current fame for preventing and treating anthrax, is in danger of becoming a casualty of what might be called the post-antibiotic age. Bayer, the maker of Cipro, also sells a chemically similar drug called Baytril, which is used in large-scale poultry production worldwide. The widespread use of Baytril in chickens has already been shown to decrease Cipro's effectiveness in humans for some types of infections.
Bayer recommends that Baytril be used only to treat infected poultry and says it poses no threat to public health. But the use of antibiotics in agriculture is part of a serious public health problem in the United States. According to the Union of Concerned Scientists, as much as 70 percent of all antibiotics produced in the United States are fed to healthy livestock for “growth promotion” in other words, to increase their weight for market. Not only does this reduce their effectiveness in animals; it poses a real danger to humans.
The discovery and use of antibiotics to treat human disease and save lives is one of the greatest feats of modern medicine. Many of us are alive today because of antibiotics. Just 60 years ago, the discovery of antibiotics revolutionized medicine, tipping the balance in our favor against the sea of pathogens that surrounds us. Now, with the very real threat of biological terrorism, preserving the power of antibiotics is a matter of the highest urgency.
Bacteria have always adapted to our new drugs faster and more efficiently than we can adapt to their genetic changes. Through prudent use, we can preserve the effectiveness of our drugs for use in treating human disease while we search nature and chemistry for new defenses. Yet we are now squandering this precious resource by using powerful antibiotics carelessly for livestock and poultry—mostly for nontherapeutic reasons.
Agribusiness argues that nontherapeutic use of antibiotics is essential to the continued supply of cheap food. But many countries have demonstrated that food can be safely and efficiently produced without robbing the medicine chest. In the European Union, the nontherapeutic use of antibiotics in agriculture has been banned.
The use of antibiotics in food animal production increases the risks of contracting drug-resistant infections from eating animal products. Despite a national network for testing food, every year the Centers for Disease Control and Prevention reports incidents of food poisoning by drug-resistant bacteria. In addition, using antibiotics in agriculture can result in environmental pollution by both drugs and drug-resistant bacteria.
Last month, the New England Journal of Medicine reported that drug-resistant bacteria were present in meat purchased at supermarkets in the Washington, D.C., area. An accompanying editorial recommended that the use of nontherapeutic antibiotics in farm animals be prohibited.
We need better information and more government oversight in this arena. Opinions differ on the amount of antibiotics currently used in animal production. Creating a national tracking system to measure how much of each antibiotic is used and for what purposes—as proposed by the Food and Drug Administration—is a necessary first step. Mandatory reporting of antibiotic use was discussed in January at meetings sponsored by the F.D.A., but no actual legislation or regulations have been proposed.
For Bayer, the maker of Baytril, the need for action is clear. The use of Baytril falls into a gray area between growth promotion and treatment; it is common practice in the poultry industry to add Baytril to drinking water during the last weeks of a flock's life, even if no disease has been diagnosed. Last year, the F.D.A. asked Bayer and Abbott Laboratories, the two producers of the chicken drug, to withdraw their Cipro-like antibiotics from agricultural use voluntarily. Abbott agreed. Bayer did not.
Bayer has committed itself to supporting our national efforts to protect the public health by supplying Ciproat a reduced cost to the federal government. Voluntarily withdrawing Baytril from the market would show that the company is serious about its commitment to the public health.
Ellen K. Silbergeld
SILBERGELD, ELLEN K., AND POLLY WALKER. “WHAT IF CIPRO STOPPED WORKING?” NEW YORK TIMES (NOVEMBER 3, 2001). AVAILABLE ONLINE AT <HTTP://QUERY.NYTIMES.COM/GST/FULLPAGE.HTML?SEC=HEALTH&RES=9C0DEED91F30F930A35752C1A9679C8B63>.
See AlsoAntibacterial Drugs; MRSA.
Salyers, Abigail A., and Dixie D. Whitt. Revenge of the Microbes: How Bacterial Resistance Is Undermining the Antibiotic Miracle. Washington, DC: ASM Press, 2005.
Wickens, Hayley, and Paul Wade. “Understanding Antibiotic Resistance.” The Pharmaceutical Journal 274 (2005): 501–504.
Zoler, Mitchel L. “Long-term, Acute Care Hospitals Breed Antibiotic Resistance.” Internal Medicine News 37 (September 15, 2004): 51–52.
Antibiotics are drugs principally derived from naturally occurring fungi and microorganisms that kill bacteria and can cure patients with bacterial diseases. Before the advent of antibiotics in the 1940s, many common diseases were lethal or incurable. Tuberculosis, pneumonia, scarlet fever, staph and strep infections, typhoid fever, gonorrhea, and syphilis were all dreaded diseases until the development of penicillin and other antibiotics in the middle of the twentieth century. Yet almost as soon as antibiotics came into common use, scientists noticed that some strains of disease-causing bacteria developed resistance to the antibiotic used most often against it. People infected with an antibiotic-resistant bacteria must be treated with different antibiotics, often more potent and toxic than the commonly used drug. In some cases, bacteria may be resistant to several antibiotics. Tuberculosis, once the leading killer in the United States at the beginning of the nineteenth century, seemed defeated with the introduction of streptomycin and PAS in the 1940s and early 1950s. But tuberculosis resurged in the United States and worldwide in the 1990s as people came down with antibiotic-resistant strains of the disease. Bacteria that cause salmonella, a food-borne illness, have become increasingly resistant to antibiotics by the early twenty-first century, as have the bacteria that commonly cause early childhood ear infections. Misuse and overuse of antibiotics contribute to the rise of resistant strains.
Bacteria can become resistant to antibiotics relatively quickly. Bacteria multiply rapidly, producing a new generation in as little as a half hour. So evolutionary pressures can produce bacteria with new characteristics in very little time. When a person takes an antibiotic, the drug will typically kill almost all the bacteria it is designed to destroy, plus other beneficial bacteria. Some small percentage of the disease bacteria, maybe as little as 1%, may have a natural ability to resist the antibiotic. So a small number of resistant bacteria may survive drug treatment. When these resistant bacteria are all that are left, they are free to multiply, passing the resistance to their offspring. Physicians warn people to take the full prescribed course of antibiotics even if symptoms of the disease disappear in a day or two. This is to limit the danger of resistant bacteria flourishing. Bacteria can also develop resistance by contact with other species of bacteria that are resistant. Neighboring bacteria can pass genetic material back and forth by swapping bits of DNA called plasmids. If bacteria that normally live on the skin and bacteria that live in the intestine should come into contact with each other, they may make a plasmid exchange, and spread antibiotic resistant qualities. Antibiotic-resistant bacteria are often resistant to a whole class of antibiotics, that is, a group of antibiotics that function in a similar way. People afflicted with a resistant strain of bacteria must be treated with a different class of antibiotics.
Antibiotic resistance was evident in the 1940s, though penicillin had only become available in 1941. By 1946, one London hospital reported that 14% of patients with staph infections had penicillin-resistant strains, and that number rose precipitously over the next decade. In 1943 scientists brought out streptomycin, a new antibiotic that fought tuberculosis (penicillin was found not to work against that disease). But streptomycin-resistant strains of tuberculosis developed rapidly, and other drugs had to be found. In 1959, physicians in Japan found a virulent strain of dysentery that was resistant to four different classes of antibiotic. Some troubling cases of antibiotic resistance have been isolated incidents. But by the 1990s it was clear that antibiotic resistance was a widespread and growing problem. A few cases around the world in 1999 found deadly bacteria resistant to vancomycin, a powerful antibiotic described as a drug of last resort because it is only used when all other antibiotics fail. By this time, scientists in many countries were deeply alarmed about the growing public health threat of antibiotic resistance. A study done by the Mayo clinic and reported in 2001 claimed that deaths from infectious diseases had risen 58% between 1980 and 1992, a rising toll attributed in part to antibiotic resistance. The U.S. Centers for Disease Control and Prevention (CDC) claimed in 2001 that antibiotic resistance had spread to "virtually all important human pathogens treatable with antibiotics."
Antibiotic resistance makes treatment of infected patients difficult. The sexually transmitted disease gonorrhea was easily cured with a single dose of penicillin in the middle of the twentieth century. By the 1970s, penicillin-resistant strains of the disease had become prevalent in Asia, and migrated from there to the rest of the world. Penicillin was no longer used to treat gonorrhea in the United States after 1987. Standard treatment was then a dose of either of two classes of antibiotics, fluoroquinolones, or cephalosporins. By the late 1990s, strains of gonorrhea resistant to fluoroquinolones had been detected in Asia. The resistant strains showed up in California in 2001. The California CDC soon recommended not using fluoroquinolones to treat gonorrhea, fearing that use of these drugs would actually strengthen the antibiotic resistance. If patients were only partially cured by fluoroquinolones, yet some infection lingered, they could pass the resistant strain to others. And the resistance could become stronger as only the most resistant bacteria survived exposure to the drug. So public health officials and doctors were left with cephalosporins to treat gonorrhea, more costly drugs with more risk of side effects.
Overuse of antibiotics contributes to antibiotic resistance. The number of antibiotic prescriptions for children rose almost 50% in the United States between 1980 and 1992. Children and the elderly are the most likely to receive antibiotic prescriptions. By 1998 the CDC estimated that approximately half the 100 million prescriptions for antibiotics issued by doctor's offices in the United States annually were unnecessary. Antibiotics work only against bacterial diseases, and are useless against viral infections. Yet physicians frequently prescribe antibiotics for coughs and colds. An article on the problem in American Family Physician found that most doctors understood the inappropriateness of their prescriptions, yet feared that patients were unsatisfied with their care unless they received a drug. The CDC launched various state and national initiatives to educate both doctors and their patients about overuse of antibiotics. Other groups took on specific diseases. For example, an association of pediatricians publicized the danger of over prescribing for childhood ear infections in 2001. The common ailment was known to be treatable without antibiotics, but many doctors continued to give antibiotics anyway. By 2001, almost one-third of children in daycare who had ear infections had an antibiotic-resistant form, according to a survey conducted by the National Association of Child Care Professionals (NACCP). The NACCP hoped to convince both pediatricians and parents to use antibiotics only when necessary. The president of the American Medical Association spoke out in 2001 about the number of prescriptions for ciprofloxacin (Cipro) given out in the wake of the mail attacks of inhalation anthrax . Tens of thousands of people received prescriptions for Cipro in October 2001, putting them at risk for developing pools of Cipro-resistant bacteria in their bodies. Most bacteria live in the body without causing harm, but can make people ill if they build up to certain levels, or if a person's immune system is weakened. People carrying Cipro-resistant bacteria could potentially come down with a resistant form of pneumonia or some other bacterial illness later in life.
People are also exposed to antibiotics through meat and other food. About half the antibiotics used in the United States go to farm animals, and some are also sprayed on fruits and vegetables. Some farm animals are given antibiotics to cure a specific disease. But other antibiotics are given as preventives, and to promote growth. Animals living in crowded and dirty conditions are more susceptible to disease, and the preventive use of antibiotics keeps such animals healthier than they would otherwise be. The antibiotics prescribed by veterinarians are similar or the same as drugs used in humans. Farm animals in the United States are routinely fed penicillin, amoxicillin, tetracycline, ampicillin, erythromycin, and neomycin, among others, and studies have shown that antibiotic resistance is common in contaminated meat and eggs. One study conducted by the Food and Drug Administration (FDA) and the University of Maryland and reported in 2001 found 20% of ground meat samples taken from several urban supermarkets contained salmonella bacteria. Over 80% of the salmonella bacteria sampled was resistant to at least one antibiotic and over half was resistant to at least three antibiotics. Salmonella bacteria is killed when meat is cooked properly, and most cases of salmonella disease get better without treatment. But for the small percent of cases of more serious infection, multiple antibiotic resistance could make treatment very difficult. A food-borne E. coli bacteria was found in 2001 to be causing urinary tract infections which were resistant to the standard antibiotic treatment. Twenty percent of the urinary tract infections studied were resistant to Bactrim, meaning that in most cases physicians would be advised to treat with a stronger antibiotic with more side effects.
Antibiotics in preventive doses or for growth promotion of farm animals were banned by the European Union in 1998. Many groups in the United States concerned with antibiotic resistance recommend the United States follow suit. The plan released by the CDC, the Food and Drug Administration (FDA) and the National Institutes of Health (NIH) in 2001 to combat antibiotic resistance called for increased monitoring of antibiotic use in agriculture and in human health. The plan also called for public education on the risks of overuse and improper use of antibiotics, and for more research in combating drug-resistant diseases. The FDA continued to investigate links between agricultural use of antibiotics and human health.
[Angela Woodward ]
Moore, Peter. Killer Germs. London: Carlton Books, 2001.
"Antibiotic Resistance: Appropriate Use, Not "Magic Bullet" Best Bet to Ward Off Dangers." TB and Outbreaks Week (June 6, 2000): 24–25.
Barlam, Tamar. "Antibiotics in Jeopardy." Nutrition Action Health Letter 29, no. 2 (March 2002): 9.
Brody, Jane E. "Studies Find Resistant Bacteria in Meats." New York Times (October 18, 2001): A12.
Colgan, Richard, and Powers, John H. "Appropriate Antimicrobial Prescribing: Approaches that Limit Antibiotic Resistance." American Family Physician 64, no. 6 (September 15, 2001): 999.
Cunha, Burke A. "Effective Antibiotic-Resistance Control Strategies." Lancet 357, no. 9265 (April 28, 2001): 1307.
"Drug Resistance: Anthrax-Fighting Drugs Apt to Spur Resistance to Common Bugs." Medical Letter on the CDC and FDA (November 25, 2001 December 2, 2001): 18.
"Higher Rates of Repeat Infections Occur Among Children in Group Child Care." Medical Letter on the CDC and FDA (December 30, 2001 January 6, 2002): 15.
Kirby, David. "New Resistant Gonorrhea Migrating to Mainland U.S." New York Times (May 7, 2002): D5.
Monroe, Judy. "Antibiotics Vs. the Superbugs." Current Health 2 28, no. 2 (October 2001): 24.
Alliance for the Prudent Use of Antibiotics, 75 Kneeland Street, Boston, MA USA 02111 (617) 636-0966, Fax: (617) 636-3999, , <http://www.healthsci.tufts.edu/apua>
Antibiotic resistance is the ability of a bacterium or other microorganism to survive and reproduce in the presence of antibiotic doses that were previously thought effective against them. Examples of microbe resistance to antibiotics dot the countryside, plaguing humankind. For instance, in February 1994 dozens of students at La Quinta High School in southern California were exposed to the pathogenic (disease-causing) agent, Mycobacterium tuberculosis, and eleven were diagnosed with active tuberculosis. Many strains of this bacterium are multi-drug resistant (MDR). As for the sexually transmitted pathogen Neisseria gonorrhea, which causes gonorrhea, the antibiotics penicillin and tetracycline that were used against it in the 1980s can no longer be the first lines of defense, again because of antibiotic resistance. If only 2 percent of a N. gonorrhea population is antibiotic resistant, a community-wide infection of this persistent strain can occur.
Mechanisms of Resistance
Antibiotics, whether made in the laboratory or in nature by other microbes, are designed to hinder metabolic processes such as cell wall synthesis, protein synthesis, or transcription, among others. If humans are to prosper against microbial disease, it is necessary to understand how and why bacteria are able to mount their clever defenses. Aided with the knowledge of the genetics and mechanisms of resistance, scientists can discover new ways to combat the resistant bacteria.
The phenomenon of antibiotic resistance in some cases is innate to the microbe. For instance, penicillin directly interferes with the synthesis of bacterial cell walls. Therefore, it is useless against many other microbes such as fungi, viruses, wall-less bacteria like Mycoplasma (which causes "walking pneumonia"), and even many Gram negative bacteria whose outer membrane prevents penicillin from penetrating them. Other bacteria change their "genetic programs," which allows them to circumvent the antibiotic effect. These changes in the genetic programs can be in the form of chromosomal mutations, acquisition of R (resistance) plasmids , or through transposition of "pathogenicity islands."
An example of a chromosomal mutation is the increasing number of cases of penicillin-resistant Neisseria gonorrhae. This bacterium mutated the gene coding for a porin protein in its outer membrane, thereby halting the transport of penicillin into the cell. This is also termed "vertical evolution," meaning that the spread occurs through bacterial population growth. The most common method by which antibiotic resistance is acquired is through the conjugation transfer of R plasmids, also termed "horizontal evolution." In this method the bacteria need not multiply to spread their plasmid. Instead the plasmid is moved during conjugation. These plasmids often code for resistance to several antibiotics at once.
The third method is transfer due to transposable elements on either side of a "pathogenicity island," which is group of genes that appear on the DNA and carry the codes for several factors which make the infection more successful. These transposable elements allow the genes to jump from bacteria to bacteria or simply from chromosome to plasmid within the organism.
The "road blocks" that bacteria have evolved which result in antibiotic resistance employ several mechanisms. One strategy is simply to destroy or limit the activity of the antibiotic. The beta-lactamases are enzymes which render the penicillin-like antibiotics dysfunctional by cleaving a vital part of the molecule. Some bacteria can deactivate antibiotics by adding chemical groups to them; for instance, by changing the electrical charge of the antibiotic through the addition of a phosphate group. Other bacteria accomplish a similar effect by bulking themselves up with the addition of an acetyl group.
Still other bacteria acquire resistance by simply not allowing the antibiotic to enter the cell. The bacterium mentioned above, Neisseria gonorrhea, has altered porin proteins, thereby stopping uptake of the antibiotic. Some bacteria acquire intricate pumping mechanisms to expel the drug when it gains entry to their cell.
Finally, bacteria may mutate the gene for the target macromolecule with which the antibiotic is supposed to bind. For example, tetracycline binds to and inhibits ribosomes, so a mutation in the ribosomal genes may cause conformational alterations in the ribosomal proteins that prevent tetracycline from binding but still allow the ribosome to function.
Resistance and Public Health
The effects of antibiotic resistance are reflected in the agriculture, food, medical, and pharmaceutical industries. Livestock are fed about half of the antibiotics manufactured in the United States as a preventative measure, rather than in the treatment of specific diseases. Such usage has resulted in hamburger meat that contains drug-resistant and difficult-to-treat Salmonella Newport, which has led to seventeen cases of gastroenteritis including one death. Some MDR-tuberculoid strains arise because patients are reluctant to follow the six-months or more of treatment needed to effectively cure tuberculosis. If the drug regimen is not followed, less sensitive bacteria have the chance to multiply and gradually emerge into resistant strains. In other cases the "shotgun" method of indiscriminately prescribing/taking several antibiotics runs the risk of creating "super MDR-germs." Moreover, millions of antibiotic prescriptions are written by physicians each year for viral infections, against which antibiotics are useless. The patient insists on a prescription, and many doctors willingly go along with the request.
Because global travel is common, the potential of creating pandemics is looming. In many Third World countries, diluted antibiotics are sold on the black market. The dosage taken is often too low to be effective, or the patient takes the drug for a very short time. All these behaviors contribute to the development of resistant strains of infectious organisms. If humans are to gain the upper hand against MDR bacteria, it is the responsibility of these industries and the public to educate themselves and to engage in careful practices and therapy.
see also Conjugation; Eubacteria; Mutagen; Plasmid; Transposable Genetic Elements.
Paul K. Small
Garrett, Laurie. The Coming Plague. New York: Farrar, Strauss, Giroux, 1996.
Ingraham, John, and Caroline Ingraham. Introduction to Microbiology, 2nd ed. Pacific Grove, CA: Brooks/Cole, 2000.
Nester, Eugene W., et al. Microbiology: A Human Perspective, 3rd ed. Boston: McGraw Hill, 2001.
Schaechter, Moselio, et al. Mechanisms of Microbial Disease, 3rd ed. Baltimore: Williams and Wilkins, 1998.