What is drug resistance?

Causes and Symptoms

Drug resistance occurs whenever microorganisms such as bacteria, viruses, or fungi that have been exposed to a chemical agent develop the ability to resist that agent. The most clinically important form of drug resistance is the ability of bacteria to develop resistance to antibiotics.

An antibiotic attacks a bacterial cell by interfering with a vital biochemical process needed by the organism. Antibiotics generally are engineered to kill bacteria while leaving body cells unharmed. This bacteria-specific approach creates a safe way of killing pathogens while keeping the affected person safe from harm.

Bacteria can develop resistance to an antibiotic in several ways, and that resistance may be propagated through the evolutionary process of natural selection. Selection is the “weeding out” of those individuals in a population who fail to adapt to changing conditions, leaving a smaller number of “tougher” individuals. If environmental pressure (such as an antibiotic treatment) is placed on any population of organisms, the only individuals who will survive and reproduce are those resistant to that pressure.

Resistance to a particular antibiotic arises in a bacterial cell by random genetic mutation. Because a particular cell is genetically altered and survives the antibiotic treatment that destroys other bacteria of the same kind, it is able to survive, unlike its susceptible relatives. The small, resistant population that is left can perpetuate infection despite the presence of antibiotics. Nonpathogenic bacteria, too, are affected by this selective pressure, and the development of antibiotic resistance in organisms that do not ordinarily cause infection can still have a powerful impact on disease processes.

The human body contains billions of bacteria of many different kinds. These bacteria fill large and small environmental niches in the microflora that human beings carry in and on their bodies. When one or more of these susceptible bacteria types are eliminated by an antibiotic, their niches are left empty. This leaves room for the resistant bacteria that are left to multiply in greater numbers. When these surviving organisms grow to such large numbers, the mix of “normal (nonpathogenic) flora” is disturbed, and normally harmless organisms can cause disease in those circumstances. Additionally, some of these organisms may have the ability to transfer resistance genes to pathogenic bacteria.

The ability to resist a particular antibiotic is encoded as genetic information in deoxyribonucleic acid (DNA) molecules. Bacterial DNA is located in a special bacterial chromosome found in the cytoplasm of a bacterial cell. Additionally, bacterial DNA may be found on small, circular fragments of DNA called plasmids. These plasmids are separate from the bacterial chromosome and carry special information needed for the bacteria to survive under adverse environmental conditions. Plasmids carry “mating” genes, which allow the bacteria to transfer a plasmid from one bacteria to another. They also carry genes that make a bacteria resistant to a particular antibiotic. Consequently, plasmids are of particular importance because they allow antibiotic resistance to be transferred between bacteria.

Two bacterial cells may exchange plasmids by direct contact in a process known as conjugation. Not all plasmids can be exchanged in this way, but the genetic information that encodes for resistance may be transferred from a plasmid that cannot be exchanged to one that can. This occurs when a small piece of DNA known as a transposon breaks away from one plasmid and attaches itself to another. A transposon may also break away from a bacterial chromosome and attach itself elsewhere on the chromosome or onto a plasmid.

Antibiotic resistance may also be transferred between bacteria indirectly by a bacteriophage in transduction. A bacteriophage is a virus that attaches itself to a bacterial cell. The virus sometimes incorporates DNA from the invaded bacterial cell into its own DNA. The virus may then transfer this DNA to the next bacterial cell to which it attaches. In this way, it can transfer drug resistance between bacteria that are unable to undergo conjugation.

The various ways in which genetic information can be exchanged between bacteria may result in organisms with resistance to multiple drugs. Some bacteria are known to be resistant to at least ten different antibiotics. They carry a series of genes on their plasmids able to make enzymes that can degrade and destroy antibiotics. For example, bacteria able to resist penicillin treatments carry an enzyme called penicillinase that destroys penicillin, thus protecting the bacteria. Other genes may code for a change in the structure of bacterial sites to which an antibiotic binds, reducing or eliminating its effect.

Frequent exposure to antibiotics increases the evolutionary pressure in bacterial populations and increases the likelihood that resistance will develop. An important factor in the emergence of antibiotic resistance is the misuse of antibiotics. For example, antibiotics have no effect on viruses but are often used against viral illnesses. A study published in 1997 revealed that at least half of all patients in the United States who visited doctors’ offices with colds, upper respiratory tract infections, and bronchitis received antibiotics, even though 90 percent of these illnesses are caused by viruses. The same study showed that almost one-third of all antibiotic prescriptions were used for these kinds of illnesses. It is also important to remember that misuse can include underutilizing prescribed drugs, such as may stem from poor patient compliance with medical directions. Failure to take as directed, typically until the whole course of antibiotics has been consumed, may encourage the development of drug resistance, as the antibiotics will not have the opportunity to exert their full effect on the bacteria causing the problem. The bacteria that survive
the partial course may be more likely to be resistant to that drug, making future administrations less effective.

This misuse of antibiotics has been one of the strongest forces pushing the selection of antibiotic-resistant bacteria—but this is not only because of its use in humans. Specifically, even if doctors stop overprescribing antibiotics, other factors are at work. In 2000, an estimated fifty million pounds of antibiotics were used in the United States; half that amount was used for veterinary and agricultural purposes. Antibiotics are administered in huge doses to farm animals to keep them healthy and allow them to grow larger. These drugs are even being used in the petroleum industry for cleaning pipelines. The World Health Organization (WHO) noted a sharp decrease in the incidence of antibiotic-resistant bacterial strains in Denmark after antibiotic use in livestock was all but eliminated in 1998.

A final factor in the increase in antibiotic resistance is the use and overuse of substandard and counterfeit antimicrobial agents in developing countries. In Nigeria, for example, WHO has estimated that there are twenty thousand unlicensed medical stands scattered throughout the country. These street vendors do not require prescriptions to dose patients. Additionally, the common use of antibiotics in developing nations to “sterilize” households risks the development of cross-resistant bacterial strains.

Several public health concerns have arisen as a result of drug resistance. Since the mid-twentieth century, multiple antibiotic resistance has emerged in bacteria, causing pneumonia, gonorrhea, meningitis, and other serious illnesses.

In the 1980s, drug-resistant tuberculosis emerged as a public health concern. In 1991, in New York City, for example, 33 percent of all tuberculosis infections were resistant to at least one drug, and 19 percent were resistant to both of the most effective drugs used to treat the disease. Because of resistance, many tuberculosis patients require treatment with four drugs for several months. Some patients are required to be directly observed by a health care worker every time they take a dose of medication to ensure compliance. The use of multiple drugs and the need for increased numbers of health care workers greatly increase the cost of treating tuberculosis.

A new challenge appeared in 1997, when patients in Japan and the United States developed infections caused by a highly resistant strain of the bacteria known as Staphylococcus aureus. This bacteria is an organism often found on human skin, and it can cause potentially fatal infections when it enters the bloodstream. Shortly after the development of penicillin in the 1940s, it was reported that some strains of this organism, initially highly susceptible to penicillin, had developed resistance to it by producing an enzyme that inactivated it (penicillinase). In response, scientists developed a new generation of penicillins (including methicillin) that could withstand penicillinase. Within a few years, many strains of
staphylococci
developed resistance to methicillin and to all classes of penicillins and related drugs through a different mechanism, an alteration in the bacterial cell wall component to which these drugs bind. Few drugs remained active against these strains of methicillin-resistant S. aureus (MRSA); the most reliable and the mainstay of treatment for these infections was vancomycin. In 1997, vancomycin-resistant Staphylococcus aureus (VRSA) emerged, threatening to cause major public health problems. Fortunately, in part owing to strict practices of isolation and to heightened awareness of the potential for life-threatening, untreatable infections, VRSA has not become a frequent cause of infection. MRSA, however, once found primarily in hospitals and nursing homes, is now frequently found to cause community-acquired infections, including some fatal infections in high school athletes (infected through minor traumatic wounds) and in children with complications of influenza.

Another problem bacteria is pneumococcus. This bacterial species was once completely sensitive to penicillin, but then, according to bacteriologist Perry Dickinson, up to 55 percent of the pneumococcal strains became penicillin-resistant. The group most at risk for infection with the drug-resistant Streptococcus pneumoniae (DRSP) is children age six or younger. The resistant strains are a serious threat among children, but pneumococcus is still vancomycin-sensitive, and some derivatives of penicillin remain effective.

As might be expected, hospitals and nursing homes, where antibiotic usage is highest, are the sites where antibiotic resistance is most common and most complex. The last few decades of the twentieth century saw the development of high levels of resistance among gram-negative bacilli in addition to the gram-positive organisms previously discussed. These organisms frequently cause nosocomial (hospital-acquired) pneumonia, urinary tract infections, surgical wound infections, and other complications. MRSA continues to be a problem in hospitals as well as in the community. It is a major cause of surgical wound infections and infections related to intravenous devices, including hemodialysis accesses. Although VRSA has not yet emerged as a common pathogen, another gram-positive organism, the enterococcus, has acquired resistance to penicillins and vancomycin; vancomycin-resistant enterococci (VRE) are an important cause of nosocomial infections. These bacteria often give rise to infections in the urinary tracts of patients, but they are also the cause of meningitis, septicemia, and endocarditis. Most frequently, Enterococcus is found in children, the elderly, HIV-infected individuals, or the immunologically compromised, whose immune systems are not fully functioning.

Treatment and Therapy

In the context of emerging drug resistance, treatment of most infections requires a culture of the pathogen as well as laboratory testing to establish the antibiotics to which the cultured strain is susceptible, a process that lasts several days. A physician may prescribe an antibiotic in the meantime, using knowledge of prevalent antibiotic susceptibility patterns. Laboratory results may subsequently confirm the effectiveness of that choice or guide the selection of a replacement.

The rapidity with which microorganisms develop resistance to antibiotics has been a challenge to pharmaceutical companies, which are working to create a widening array of safe and effective new therapies. Some efforts aim at expanding previously developed lines of antibiotics. For example, a number of drug classes have been derived from penicillins. These “beta-lacatam” antibiotics have a common mechanism of action on bacterial cell walls; modifications have extended their spectrum of activity against an ever-widening variety of organisms and have stabilized them against the activity of penicillinase-like inactivating enzymes. Some of these newer agents include carbapenems and monobactams.

The expanding classes of previously developed drugs include the quinolone antibiotics, derived from nalidixic acid, an early drug for urinary tract infections. Likewise, teicoplanin is chemically related to the glycopeptide vancomycin.

A number of entirely new antibiotics have been developed since the late twentieth century. One of the most promising superdrugs, linezolid, developed to combat antibiotic resistance, falls into a category of antibiotics called oxazolidinones. These drugs act at an early stage in the synthesis of protein by bacteria. Without protein production, bacteria cannot multiply, and they die. The antibiotic linezolid is effective against many gram-positive bacteria, including MRSA, VRSA, VRE, and penicillin-resistant pneumococci. In hospital trials involving patients with MRSA infections, linezolid produced clinical success in more than 83 percent of the patients. The drug can be taken orally or injected, making it quite versatile. Robert Moellering of Harvard University Medical School suggested that this versatility is convenient for patients because they can complete their therapy at home. This drug has also been shown to have few side effects. The streptogramins (qunupristin/dalfopristin) and lipopeptides (daptomycin) are other newly developed classes active against gram-positive bacteria.

While much of the experience and knowledge of drug resistance centers on bacteria, similar problems occur in viruses, fungi, and parasites. Human immunodeficiency virus (HIV) rapidly developed resistance to the early antiretroviral drugs. Despite enormous research and development efforts, drug resistance continues to pose challenges in the treatment of HIV infection. Likewise, malaria and tuberculosis are two highly adaptable organisms responsible for a huge proportion of deaths worldwide. Both have developed resistance to many of the available drugs, compounding the difficulties in treating and preventing these infections, particularly in underdeveloped countries with limited resources.

Perspective and Prospects

Several different strategies have been suggested for handling the problem of drug resistance. In general, these strategies involve educating the public and health care workers; monitoring antibiotic, antiviral, and antifungal use; and promoting research into methods to deal with resistant pathogens.

The general public should be aware of the proper use of these medicines as well. Many patients expect to be given antibiotics for illnesses that do not respond to them, such as viral infections. Similarly, they may pressure physicians into prescribing antiviral or antifungal medications even when physicians are aware that these drugs are useless. Patients must learn to understand the difference between a bacterial and a viral infection and how each is treated. Patients must also be educated not to use another person’s medicines or an old supply of medicines that they have saved from previous illnesses. Finally, patients must learn to take the entire course of medicines. Often, patients who begin to feel better may fail to take the entire amount prescribed. This leads to an increased risk of drug-resistant infection if they do not completely eliminate the original infection.

All health care workers should be aware of the importance of avoiding the spread of resistant pathogens from one patient to another. In the late 1990s, about two million Americans per year acquired nosocomial infections. These infections were responsible for about eighty thousand deaths per year. The most important factors in reducing the rate of nosocomial infections are frequent and thorough hand washing, glove changes, and disinfectant applications.

Children should be immunized at a young age against pneumococcal infections. Children who are immunized do not get the infections; hence, no antibiotics are needed, and no extra antibiotics enter into the general population. Additionally, children who are ill should be kept home from day care centers. Day care centers are potentially dangerous incubators, where disease may run rampant. In these places, children spread bacterial infections among themselves, often amplifying pathogenicity and drug resistance. This can be avoided by isolating sick children at home.

Physicians need to be aware of the proper ways to use antibiotics. Microbiologists have suggested better instruction in antibiotic use in medical schools, more continuing education on the subject for practicing physicians, and the development of computer programs to aid physicians in selecting antibiotics. Some have suggested that all physicians prescribing antibiotics in hospitals be required to consult with physicians who specialize in infectious diseases. Standardized order forms that include guidelines for the proper use of each antibiotic have also been proposed. Additionally, doctors who have been thoroughly educated must learn not to accede to patient demands for antibiotics, and they must defer antibiotic use in self-limiting infections that will heal on their own. They must also avoid prescribing antibiotics over the phone.

Researchers agree that monitoring antibiotic use is critical in fighting drug resistance. A study published in 1997 demonstrated the effectiveness of education and monitoring in reducing resistance. Physicians in Finland were educated in the proper use of the antibiotic erythromycin, and use of the drug was monitored. In 1992, 16.5 percent of bacteria known as group A Streptococci were resistant to erythromycin. In 1996, only 8.6 percent were resistant. Some experts have proposed using computers to share information about antibiotic use and resistance among as many health care facilities as possible.

Faster development of new antibiotics for use on multiply resistant bacteria is another improvement. Researchers stress, however, that these new antibiotics must be used only when necessary, in order to avoid promoting resistance to them. Consequently, new antibiotics are used sparingly.

Other methods have been proposed for minimizing antibiotic resistance. Because patients often expect or demand prescriptions when they visit physicians, some experts have suggested that the physician write a lifestyle prescription when drug use is not appropriate. Such a prescription would explain why antibiotics should not be used in a particular situation and would give the patient specific instructions on how to treat the illness without them.

Eliminating the routine use of antibiotics in farm animals would be of great help. As the Danish study suggests, the risk of resistant bacterial strains in livestock could be reduced, making human lives safer as well.

International concerns over antibiotic resistance have been at such a height that in 2000, eight international medical societies gathered to spend a full day discussing the problem. They called this event Global Resistance Day, and the medical professionals discussed the dilemma and solutions for global antibiotic resistance.

Bibliography

"Antibiotics." MedlinePlus, 23 July 2013.

"Antimicrobial (Drug) Resistance." National Institute of Allergy and Infectious Diseases, 3 Apr. 2012.

"Antimicrobial Resistance." World Health Organization, May 2013.

Brooks, G. F., et al., eds. Jawetz, Melnick, and Adelberg’s Medical Microbiology. 25th ed. New York: McGraw-Hill, 2010.

Fischback, M. A., and C. T. Walsh. “Antibiotics for Emerging Pathogens.” Science 325, no. 5944 (August 28, 2009): 1089–93.

Levy, Stuart B. The Antibiotic Paradox: How the Misuse of Antibiotics Destroys Their Curative Powers. 2d ed. Cambridge, Mass.: Perseus, 2002.

Mayo Clinic Staff. "Antibiotics: Misuse Puts You and Others at Risk." Mayo Clinic, 4 Feb. 2012.

Shnayerson, Michael, and Mark J. Plotkin. The Killers Within: The Deadly Rise of Drug Resistant Bacteria. Boston: Little, Brown, 2003.

Walsh, Christopher. Antibiotics: Actions, Origins, Resistance. Washington, D.C.: ASM Press, 2003.