ANTIBIOTICS

The search for antibiotics began with general acceptance of the germ (bacteria) theory of disease. The first antibiotics were developed in the late 1800s, with Louis Pasteur (1822–1895) commonly given credit for discovering that the bacterial disease anthrax could be cured in animals with an injection of soil bacteria. But it was not until Alexander Fleming (1881–1955) discovered penicillin in 1928 that the great potential of antibiotics was recognized. Especially during World War II penicillin revolutionized medical practice, but the subsequent heavy reliance on penicillin and other antibiotic agents as general technological fixes for numerous diseases has led to problems that have distinctly ethical aspects.

Historical Development

Fleming's serendipitous discovery of penicillin came when he examined an old gelatin plate he had forgotten to submerge in detergent solution. Staphylococci, common skin bacteria, were growing on the plate, along with a mold. A product of the mold had seemingly killed some bacteria. Fleming was not the first person to observe the phenomenon of bacterial destruction by mold, but he had the foresight to recognize its potential medical importance. He named the mold product penicillin after the penicillium mold that had produced it. By extracting this substance from a culture of the mold, he was able to directly show its antibacterial properties.

An event in the 1930s also helped establish that chemicals taken internally can cure infectious diseases without harming the host. This was the discovery, made by Gerhard Domagk (1895–1964), that a newly patented chemical dye, Prontosil, could cure disease caused by streptococcus bacteria when injected into diseased mice. Interestingly Prontosil only worked when used internally and could not inhibit bacterial growth in a test tube. It was later shown that it was not the dye but a chemical attached to it, the sulfonamide portion, that was responsible for killing the bacteria. The sulfonamide portion was released during metabolism and was free to fight bacterial infections. The discovery of sulfonamides and penicillin as potent antibacterial agents created a strong motivation for developing other antibiotic agents.

The twenty-five years following the introduction of penicillin in 1942 was the heyday of antibiotic development. Developed antibiotics were either natural substances isolated from an organism, or synthetic agents, exemplified by penicillin and the sulfonamides respectively. Antibiotics also typically have a limited scope of effectiveness, often restricted to either gram-positive or gram-negative bacteria. This distinction in bacteria is named after Hans Christian Gram (1853–1938) who discovered that some bacteria stained with specific dyes kept their color following washing whereas other bacteria lost their color. Those that keep their color are gram-positive and those that lose color are gram-negative. Gram-positive and gram-negative bacteria differ in the composition of their cell walls, the outermost structure of bacteria. So-called broad-spectrum agents are effective against both gram-negative and gram-positive bacteria and include the antibiotics chloramphenicol and tetracycline, first isolated from soil bacteria in the late 1940s. Cephalosporins, first introduced in 1964, were other natural, broad-spectrum agents similar to penicillin. Modification of the cephalosporins and penicillin led to a number of semisynthetic agents with properties varying in adsorption, residence time in the body, spectrum of activity, and insensitivity to degradation by bacterial enzymes. A number of synthetic antibiotics were also introduced, mainly in the 1970s, following the introduction of natural ones. While some antibiotics have been introduced since the 1990s, the pace of discovery and introduction of new antibiotics has slowed markedly from its heyday.

Antibiotic Resistance

Initially seen as miracle drugs, antibiotics, once they became widely available, were used not only for bacterial infections, but for everything from the common cold to headaches. Indeed antibiotics were a godsend, drastically improving medicine and contributing significantly to the increase in life expectancy achieved during the twentieth century. Like many technological fixes, along with the positive benefits of antibiotics came negative side effects. Antibiotics can kill the many beneficial bacteria in the human body, for instance those that promote digestion, along with invasive bacteria. Another, unexpected, consequence is the ability of bacteria to overcome the mechanisms that give antibiotics their efficacy, rendering them useless. Antibiotic resistance, first a curiosity seen in the laboratory, became common among populations of bacteria exposed to antibiotics. In a matter of years following the introduction of penicillin, penicillin-destroying staphylococci appeared in hospitals where much of the early use of penicillin had taken place.

A similar response has occurred in various strains of bacteria in response to vastly different antibiotics. Resistance traits exist for every antibiotic available in the marketplace. In addition, bacteria are often resistant to multiple antibiotic agents, leaving only expensive and potentially toxic antibiotics to fight bacterial infection, assuming a patient is fortunate enough to have access to such medicines.

Mechanisms of antibiotic resistance vary markedly but have the same effect of increasing tolerance until the bacteria are resistant. These mechanisms first appear in a few bacteria as a result of random mutations that naturally occur in the DNA that defines the genetic makeup of the bacterium. In the presence of antibiotics the bacteria having these mutations are selected for survival over those that are susceptible. With increased exposure to antibiotics, eventually only those bacteria with the resistance trait will survive. Furthering the propagation of resistances is the presence of transferable elements that readily exchange genetic material between bacteria. These elements exist either as plasmids, circular rings of DNA outside the core genetic material (chromosomes) of the bacterium, or as transposons, regions of DNA that can jump between chromosomes. Transferable elements allow susceptible bacteria to acquire resistances from other bacteria, either alive or dead. In order to limit the rise and spread of resistant bacterial strains, measures have been developed to encourage the proper use of antibiotics.

Ethical Use of Antibiotics

Ironically antibiotics have become a victim of their own success. The ability of antibiotics to effectively kill bacteria has also created an environment that selects for resistant strains and allows them to propagate. Antibiotics stand alone as the only therapeutic that is detrimental to society through their usage by an individual. Aside from the individual risks of side effects and allergies, widespread use of antibiotics has a much greater societal effect. Any antibiotic use, regardless of need, will hasten the selection for and propagation of resistant bacteria. Despite this drawback, antibiotics continue to play an invaluable role in healthcare. For them to remain efficacious, the misuse and overuse of antibiotics must be curbed.

In most industrialized countries antibiotics are obtained only through prescriptions. Despite this control on availability many people acquire antibiotics by coercing doctors or hoarding leftover medicine. In some instances people will use antibiotics obtainable from pet stores without prescription. These actions may seem frivolous but in the quick-fix world of medicine many patients demand some form of treatment for every ailment. Additionally many still hold the outdated view of antibiotics as a panacea. Not only does improper use of antibiotics have the danger of side effects, anything short of a full treatment will not rid the patient's system of the entire infection. Because the surviving bacteria are often the ones with a greater tolerance to the antibiotic, the potential exists for the reemergence of an infection resistant to the antibiotic. Though potentially dire outcomes resulting from resistances occur in industrialized nations, such as the emergence of staphylococcus aureus, which is resistant to almost all antibiotics, developing countries face even greater hazards.

The overuse and misuse of antibiotics in the developing world far eclipses the abuses present in developed countries. The frequency of infections in the developing world is greater due to poor public sanitation. Infections normally treatable for patients in developed countries often prove fatal when acquired in less developed nations. The uneven distribution of wealth does not allow poorer countries to afford newer antibiotics to overcome infections resistant to the ones readily available. Even if proper medicines are available, they are often misused, encouraging the propagation of drug resistant bacteria. Where one day of treatment can equal the daily wage, many are forced to choose the savings over a full treatment. Medical usage of antibiotics is a huge concern to both developing and developed nations but is not the only use that results in antibiotic resistances.

Use of antibiotics in agriculture, aquaculture, and food animals has been a tenacious issue. Humans are not the only species affected by infectious diseases. Antibiotics can protect the food supply by limiting loss to disease and have frequently been administered as a preventive measure, though use on crops has been banned in many countries. Antibiotics have also been found to promote growth in food animals when given in low doses. The mechanism responsible for this action is not known, but it is speculated that low dose antibiotics reduce competition for nutrients from bacteria living in the guts of these animals. Antibiotics used for treating animals and crops have the same ability to select for resistance traits in bacteria. Even antibiotics not used in human medicine can help to create bacteria resistant to medicinally important antibiotics. Clearly measures for the proper use of antibiotics in food production and medicine need to be advocated.

The Future of Antibiotics

The introduction of antibiotics into medicine has improved the quality and longevity of people's lives. Infections that were once a death sentence are easily controllable in the early twenty-first century. But the misuse and overuse of antibiotics has threatened their ability to control disease. With few new antibiotics being introduced and little incentive for pharmaceutical companies to invest in their research and development, measures are being taken to protect the efficacy of already existing antibiotics. To address this problem more efforts at the local level are needed to ensure their proper use. To this end, an international group, the Alliance for the Prudent Use of Antibiotics (APUA), was established in 1981. The organization, with a presence in more than 100 countries, aims to promote the proper use of antibiotics and to protect their long-term efficacy through communication and education. Although APUA is a start, doctors, pharmaceutical companies, governments, and individual users must continue efforts to improve current usage of antibiotics in order to ensure that such drugs remain effective for future generations.

ANDREW PRICE

SEE ALSO Bioethics;Clinical Trials;Emergent Infectious Diseases;Medical Ethics; Vaccines and Vaccination.

BIBLIOGRAPHY

Ferber, Dan. (2000). "Superbugs on the Hoof?" Science 5: 792–794. Discusses findings connecting antibiotics used on livestock with outbreaks of disease caused by antibiotic-resistant bacteria.

Hadley, Caroline. (2004). "Overcoming Resistance." EMBO Reports 5(6): 550–552.

Levy, Stuart B. (2002). The Antibiotic Paradox: How the Misuse of Antibiotics Destroys Their Curative Powers. Cambridge, MA: Perseus Publishing. Classic primer on the misuse of antibiotics.

INTERNET RESOURCES

Alliance for the Prudent Use of Antibiotics (APUA). Available from http://www.antibiotic.org. Internet site of the organization.

U.S. Food and Drug Administration. Antibiotic Resistance page. Available from http://www.fda.gov/oc/opacom/hottopics/anti_resist.html. A comprehensive resource containing background articles and current news.