drug resistance

(microbiology) A decreased reactivity of living organisms to the injurious actions of certain drugs and chemicals.

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Key Terms: AIDS, Antibiotic, Antiviral drug, AZT, Bacterium, CMV, Cytoxic, Gene, Gene therapy, Immune system, Pathogen.

Definition

Drug resistance refers to the ability of an organism, such as the HIV virus, the tuberculosis bacillus (TB), or cancer, to overcome the effects of a drug prescribed to destroy it. Well-known examples are the resistance of the HIV virus to AZT, or that of TB to antibiotics. Resistance has been observed to occur with every anti-HIV drug prescribed. According to the Mayo Clinic in Rochester, Minnesota, drug resistance may have played a role in the 58% rise in infectious disease deaths observed in the United States between 1980 and 1992.

Due to the immunocompromised state of cancer patients caused by the cancer treatment effect, infections with viruses and bacteria are commonplace and infectious disease treatment is paramount.

Causes

A virus like HIV becomes resistant to drugs because it has the ability to mutate. This happens because a typical virus creates billions of new viruses in the body every day—viruses that are replicas of itself. However, these replicas are not always perfect. In this daily production of billions of viruses, several small differences can occur in some of the new viruses. These differences are called mutations. When such mutations occur on that part of the virus that the drug is designed to chemically attach to, the drug's action is effectively stopped because it cannot attach. When a drug no longer works against its target, this is called drug resistance and the virus that the drug can no longer destroy is said to be resistant to the drug.

An example of drug resistance is a patient with AIDS. The patient may have a few HIV viruses that mutate in such a way that prevents AZT from working on those mutated viruses. The drug will still work against the HIV that has not mutated, eventually destroying it. However, reproduction of the mutated virus is then unchecked, and the infection keeps spreading as the mutated virus makes more copies of itself, which are also resistant to AZT. After some time, this mutated AZT-resistant HIV will be the only type of HIV left, and AZT will no longer work for that patient.

A similar scenario may occur with cancer drug resistance. Since the early 1970s, multiple drug resistance (MDR) has also been known to exist in several types of cancer cells. It now appears that certain cancers have the capacity to resist the cytotoxic (toxic to cells) effects of cancer chemotherapy, probably due to genetic abnormalities in the cancer cells. Normal tissues never develop resistance to chemotherapy. Initially, sensitive cancer cells are destroyed by chemotherapy but since mutated cancer cells are allowed to replicate (unlike normal cells that are destroyed when defective) these mutated cancer cells are no longer sensitive to some chemotherapy.

Resistance of cytomegalovirus (CMV) against anti-viral drugs is another example showing that drug resistance is becoming an increasingly serious medical problem.

Like viruses, bacteria can also become drug resistant. Every time a patient takes an antibiotic, such as penicillin, to fight a bacterial infection, the antibiotic destroys most of the bacteria. However, a few tough germs may survive—either by mutating like viruses or by obtaining resistance genes from other bacteria. These survivors can then reproduce quickly, creating new drug-resistant bacteria. As is the case with mutated viruses, the presence of these resistant bacterial strains usually means that the next infection will not be cured by the first-choice antibiotic prescribed by the doctor.

Some bacteria that have already become resistant to antibiotic attack include:

• Staphylococcus aureus: This bacterium causes the majority of infections in patients in U.S. hospitals. It spreads and infects cuts, burns, skin, as well as surgical wounds. Since 1996, at least four patients have been reported to be infected with a strain that was partially resistant to normal doses of the most powerful anti-biotic available, vancomycin.
• Streptococcus pneumoniae: This bacterium causes pneumonia, meningitis, and ear infections. According to the Mayo Clinic, it has also become partially resistant to antibiotics of the penicillin family.
• Enterococcus: This bacterium can cause everything from urinary tract to heart valve infections and it is also becoming increasingly antibiotic-resistant, including vancomycin-resistant.

If a virus or bacteria mutates at a specific location that represents the target for the drug to attach to, then modifying the drug so as to have it attach at a different place will succeed in overcoming the drug resistance. In the case of HIV, compiled databases of mutations in HIV genes that confer resistance to anti-HIV drugs are available to assist researchers in the design and production of new drugs.

Treatments

The strategies used to overcome drug resistance depend upon the nature of the organism causing the infection but generally involve the following steps:

• Accurate and rapid diagnosis: Swift identification and treatment—the sooner the infectious organism is detected and correctly identified, the higher the chances that it will not become drug resistant since it will have less time to mutate.
• Drug combination: New combinations of drugs can be very effective. Given a mixture of mutated and unmutated pathogens, a drug "cocktail" is likely to contain a drug that may be effective against a new mutated form of the virus, thus preventing it from making billions of new copies every day. The less virus created, the less chance of further mutations occurring.
• New drugs: There is a problem facing all the strategies used to overcome drug resistance and it is that drugs have to be given at high—and sometimes toxic—doses, and also in combinations that have become quite expensive. Increasingly, they also must be taken on schedules that are difficult to follow by patients. Even then, new varieties of resistant strains still appear. There is, therefore, an urgent need to understand how drug resistance develops at the molecular level, and to use this understanding to develop more effective drugs.

Resources

Books

Kaspers, G. J. L., R. Pieters, and A. J. P. Veerman, editors. Drug Resistance in Leukemia and Lymphoma III (Advances in Experimental Medicine and Biology). New York: Plenum Press, 1999.

Periodicals

Brenner, B. G., and M. A. Wainberg. "The role of Antiretrovirals and Drug Resistance in Vertical Transmission of HIV-1 Infection." Annals of the New York Acadademy of Sciences 918 (November 2000): 9-15.

Broxterman, H. J., and N. Georgopapadakou. "Cancer Research 2000: Drug Resistance, New Targets and Drugs In Development." Drug Resistance Updates 3 (June 2000): 133-138.

Clavel, F., E. Race, and F. Mammano. "HIV Drug Resistance and Viral Fitness." Advances in Pharmacology 49 (2000): 41-66.

Durant, J., P. Clevenbergh, P. Halfon, P. Delgiudice, S. Porsin, et al. "Drug-Resistance Genotyping in HIV-1 Therapy." Lancet 353 (June 1999): 2195-2199.

Norgaard, J. M., and P. Hokland "Biology of Multiple Drug Resistance in Acute Leukemia." International Journal of Hematology 72 (October 2000): 290-297.

Teicher, B. A. "Molecular Targets and Cancer Therapeutics: Discovery, Development and Clinical Validation." Drug Resistance Updates 3 (April 2000): 67-73.

Organizations

HIV Drug Resistance Database. .

National Cancer Institute, HIV Drug Resistance Program. NCI-Frederick, Building 535, Room 109, P.O. Box B, Frederick, MD 21702-1201. Phone:(301)846-1168. .

U. S. Food and Drug Administration. 5600 Fishers Lane, Rockville, MD 20857. Phone:(888)INFO-FDA [(888)463-6332] .

Other

The AIDS Treatment Data Network. Factsheet: Trials of drugs for treating HIV. [cited July 1, 2001]. .

The AIDS Treatment Data Network. Factsheet: Understanding Drug Resistance. [cited July 1, 2001]. .

—Monique Laberge, Ph.D.

The ability of an organism to resist the action of an inhibitory molecule or compound. Examples of drug resistance include disease-causing bacteria evading the activity of antibiotics, the human immunodeficiency virus resisting antiviral agents, and human cancer cells replicating despite the presence of chemotherapy agents. There are many ways in which cells or organisms become resistant to drugs, and some organisms have developed many resistance mechanisms, each specific to a different drug. Drug resistance is best understood as it applies to bacteria, and the increasing resistance of many common disease-causing bacteria to antibiotics is a global crisis.

Genetic basis

Some organisms or cells are innately or inherently resistant to the action of specific drugs. In other cases, the development of drug resistance involves a change in the genetic makeup of the organism. This change can be either a mutation in a chromosomal gene or the acquisition of new genetic material from another cell or the environment.

Organisms may acquire deoxyribonucleic acid (DNA) that codes for drug resistance by a number of mechanisms. Transformation involves the uptake of DNA from the environment. Once DNA is taken up into the bacterial cell, it can recombine with the recipient organism's chromosomal DNA. This process plays a role in the development and spread of antibiotic resistance, which can occur both within and between species.

Transduction, another mechanism by which new DNA is acquired by bacteria, is mediated by viruses that infect bacteria (bacteriophages). Bacteriophages can integrate their DNA into the bacterial chromosome.

Conjugation is the most common mechanism of acquisition and spread of resistance genes among bacteria. This process, which requires cell-to-cell contact, involves direct transfer of DNA from the donor cell to a recipient cell. While conjugation can involve cell-to-cell transfer of chromosomal genes, bacterial resistance genes are more commonly transferred on nonchromosomal genetic elements known as plasmids or transposons. See also Deoxyribonucleic acid (DNA).

Mechanisms of resistance

The four most important antibiotic resistance mechanisms are alteration of the target site of the antibiotic, enzyme inactivation of the antibiotic, active transport of the antibiotic out of the bacterial cell, and decreased permeability of the bacterial cell wall to the antibiotic (see illustration).

Four common mechanisms of antibiotics resistance.

By altering the target site to which an antibiotic must bind, an organism may decrease or eliminate the activity of the antibiotic. Alteration of the target site is the mechanism for one of the most problematic antibiotic resistances worldwide, methicillin resistance among Staphylococcus aureus. See also Bacterial genetics.

The most common mechanism by which bacteria are resistant to antibiotics is by producing enzymes that inactivate the drugs. For example, β-lactam antibiotics (penicillins and cephalosporins) can be inactivated by enzymes known as β-lactamases.

Active transport systems (efflux pumps) have been described for the removal of some antibiotics (such as tetracyclines, macrolides, and quinolones) from bacterial cells. In these situations, even though the drug can enter the bacterial cell, active efflux of the agent prevents it from accumulating and interfering with bacterial metabolism or replication.

Bacteria are intrinsically resistant to many drugs based solely on the fact that the drugs cannot penetrate the bacterial cell wall or cell membrane. In addition, bacteria can acquire resistance to a drug by an alteration in the porin proteins that form channels in the cell membrane. The resistance that Pseudomonas aeruginosa exhibits to a variety of penicillins and cephalosporins is mediated by an alteration in porin proteins.

Promoters

In the hospital environment, many factors combine to promote the development of drug resistance among bacteria. Increasing use of powerful new antibiotics gives selective advantage to the most resistant bacteria. In addition, advances in medical technology allow for the survival of sicker patients who undergo frequent invasive procedures. Finally, poor infection control practices in hospitals allow for the unchecked spread of already resistant strains of bacteria.

Outside the hospital environment, other important factors promote antibiotic resistance. The overuse of antibiotics in outpatient medicine and the use of antibiotics in agriculture exert selective pressure for the emergence of resistant bacterial strains. The spread of these resistant strains is facilitated by increasing numbers of children in close contact at day care centers, and by more national and international travel.

Control

A multifaceted worldwide effort will be required to control drug resistance among disease-causing microorganisms. Ongoing programs to decrease the use of antibiotics, both in the clinics and in agriculture, will be necessary. The increased use of vaccines to prevent infection can help limit the need for antibiotics. Finally, the development of novel classes of antibiotics to fight emerging resistant bacteria will be required. See also Antibiotic; Bacteria.

The capacity of a microorganism to build a tolerance to a drug.

Drug resistance is the inability of a drug to bring about an effect on a disease-causing agent that occurred previously in the presence of that same medication. Resistance to an antibiotic, for example, occurs when bacteria that were previously killed by one antibiotic will now grow in the presence of that same antibiotic (i.e., the bacteria have developed a way to avoid or prevent cell death). In the United States, Streptococcus pneumoniae, a common cause of pneumonia, bronchitis, ear infections, and other conditions, was universally sensitive to penicillin prior to 1990. As of June 1999, however, penicillin was either no longer effective or was required in higher than previously effective doses to treat about 25–35 percent of all S. pneumoniae isolates. This decrease in the effectiveness of penicillin is attributed to an acquired drug resistance to penicillin by the bacteria.

(SEE ALSO: Antibiotics; Communicable Disease Control; Multi-Drug Resistance; Pathogenic Organisms; Penicillin)

Bibliography

Barlett, J. G.; Dowell, S. F.; Mandel, L. A. et al. (2000). "Practice Guidelines for the Management of Community-Acquired Pneumonia in Adults." Clinical Infectious Diseases 31:347–382.

— MEGANNE S. KANATANI

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