Antibiotic Resistance
Antibiotic Resistance
History and Scientific Foundations
Introduction
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
Polly Walker
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.
BIBLIOGRAPHY
Books
Salyers, Abigail A., and Dixie D. Whitt. Revenge of the Microbes: How Bacterial Resistance Is Undermining the Antibiotic Miracle. Washington, DC: ASM Press, 2005.
Periodicals
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.
Brian Hoyle