Drug resistance

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 antiviral 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 antibiotic 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.

See Also AIDS-related cancers

Resources

BOOKS

Huemer R. P., and J. Challem. The Natural Health Guide to Beating the Supergerms: and Other Infections, Including Colds, Flus, Ear Infections and Even HIV New York: Pocket Books, 1997.

Kaspers, G. J. L., R. Pieters, and A. J. P. Veerman, eds. Drug Resistance in Leukemia and Lymphoma III (Advances in Experimental Medicine and Biology) 457 New York: Plenum Press, 1999.

Kellen, J. A. Alternative Mechanisms of Multidrug Resistance in Cancer New York: Springer Verlag, 1995.

Levy, S. B. The Antibiotic Paradox: How Miracle Drugs Are Destroying the Miracle Boulder, CO: Perseus Press, 1992.

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.

Emery, V. C. "Cytomegalovirus Drug Resistance." Antiviral Therapy 3 (1998): 239-242.

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

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. <http://www.ncifcrf.gov/hivdrp>

U. S. Food and Drug Administration. 5600 Fishers Lane, Rockville, MD 20857. Phone:(888)INFO-FDA [(888)463-6332] <http://www.fda.gov/default.htm>

HIV Drug Resistance Database. <http://204.121.6.64:581/Resist_DB/default.htm>

OTHER

The AIDS Treatment Data Network. Factsheet: Understanding Drug Resistance. 1 July 2001 <http://www.aidsinfonyc.org/network/simple/resistance.html>

The AIDS Treatment Data Network. Factsheet: Trials of drugs for treating HIV. 1 July 2001 <http://www.aidsinfonyc.org/network/trials/hiv.html>

Monique Laberge, Ph.D.

KEY TERMS

AIDS (Acquired Immunodeficiency Syndrome)

—A state of severe immune suppression caused by the HIV virus. A diagnosis of AIDS is given to a patient infected with HIV and who also experiences at least one condition from a list compiled by the Center for Disease Control and Prevention (CDC), as for example an infection with cytomegalovirus (CMV) or a cancer such as Kaposi's sarcoma.

Antibiotic

—A drug that slows bacterial growth or kills bacteria.

Antiviral drug

—A drug that slows viral growth or kills viruses.

AZT (Retrovir, zidovudine, ZDV)

—The first drug licensed to treat HIV. It is almost always used in combination with other anti-HIV drugs. AZT is also used to prevent transmission of HIV from mother to fetus.

Bacterium

—A tiny microorganism that reproduces by cell division. It can be shaped like a rod, sphere, or spiral and is found virtually everywhere. Many types of bacteria cause infection and disease.

CMV (Cytomegalovirus)

—A virus that belongs to the herpes virus family and is present as a silent infection in almost everyone. CMV often becomes activated in people with AIDS.

Cytoxic

—A substance toxic (poisonous) to cells.

Gene

—The part of DNA responsible for determining a person's characteristics. It also transfers information from old cells to new cells.

Gene therapy

—The use of genes to treat cancer and other diseases.

Immune system

—The system within the body, consisting of many organs and cells, that recognizes and fights foreign cells and disease.

Pathogen

—Anything capable of causing disease, usually a virus or bacterium, but it also refers to chemical substances, such as asbestos.

Tuberculosis

—An infectious disease of the lungs caused by a type of bacterium called amycobacterium. Symptoms include weight loss, fever, and cough, often with blood-streaked mucus. Tuberculosis is highly contagious.

DRUG RESISTANCE

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.

Meganne S. Kanatani

(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.