An antibacterial is a compound or substance that kills or slows down the growth of bacteria. These include, for example, the beta-lactam antibacterials, which include the penicillins (produced by fungi in the genus 'Penicillium'), the cephalosporins, and the carbapenems. Compounds that are still isolated from living organisms are the aminoglycosides, whereas other antibacterials—for example, the sulfonamides, the quinolones, and the oxazolidinones—are produced solely by chemical synthesis. Accordingly, many antibacterial compounds are classified on the basis of chemical/biosynthetic origin into natural, semisynthetic, and synthetic. Another classification system is based on biological activity; in this classification antibacterials are divided into two broad groups according to their biological effect on microorganisms: bactericidal agents kill bacteria, and bacteriostatic agents slow down or stall bacterial growth.

History

Before the early twentieth century, treatments for infections were based primarily on medicinal folklore. Mixtures with antimicrobial properties that were used in treatments of infections were described over 2000 years ago. Many ancient cultures, including the ancient Egyptians and ancient Greeks used specially selected mold and plant materials and extracts to treat infections. More recent observations made in the laboratory of antibiosis between micro-organisms led to the discovery of natural antibacterials produced by microorganisms. Louis Pasteur observed that, "if we could intervene in the antagonism observed between some bacteria, it would offer perhaps the greatest hopes for therapeutics".

The term ''antibiosis'', meaning "against life," was introduced by the French bacteriologist Vuillemin as a descriptive name of the phenomenon exhibited by these early antibacterial drugs. Antibiosis was first described in 1877 in bacteria when Louis Pasteur and Robert Koch observed that an airborne bacillus could inhibit the growth of ''Bacillus anthracis''. These drugs were later renamed antibiotics by Selman Waksman, an American microbiologist in 1942.

Antagonistic activities by fungi against bacteria were first described in England by John Tyndall in 1875. Synthetic antibiotic chemotherapy as a science and development of antibacterials began in Germany with Paul Ehrlich in the late 1880s. Ehrlich noted that certain dyes would color human, animal, or bacterial cells, while others did not. He then proposed the idea that it might be possible to create chemicals that would act as a selective drug that would bind to and kill bacteria without harming the human host. After screening hundreds of dyes against various organisms, he discovered a medicinally useful drug, the synthetic antibacterial Salvarsan. In 1928, Alexander Fleming observed antibiosis against bacteria by a fungus of the genus 'Penicillium'. Fleming postulated that the effect was mediated by an antibacterial compound named penicillin and that its antibacterial properties could be exploited for chemotherapy. He initially characterized some of its biological properties, but he did not pursue its further development. Prontosil, the first commercially available antibacterial antibiotic, was developed by a research team led by Gerhard Domagk in 1932 (who received the 1939 Nobel Prize for Medicine for his efforts) at the Bayer Laboratories of the IG Farben conglomerate in Germany. Prontosil had a relatively broad effect against Gram-positive cocci but not against enterobacteria. The discovery and development of this first sulfonamide drug opened the era of antibacterial antibiotics. In 1939, Rene Dubos reported discovery of the first naturally derived antibiotic, gramicidin from ''B. brevis''. It was one of the first commercially manufactured antibiotics in use during World War II to prove highly effective in treating wounds and ulcers.

Florey and Chain succeeded in purifying penicillin. Purified penicillin displayed potent antibacterial activity against a wide range of bacteria and had low toxicity in humans. Furthermore, its activity was not inhibited by biological constituents such as pus, unlike the synthetic sulfonamides. The discovery of such a powerful antibiotic was unprecedented, and the development of penicillin led to renewed interest in the search for antibiotic compounds with similar efficacy and safety. For their discovery and development of penicillin as a therapeutic drug, Ernst Chain, Howard Florey, and Alexander Fleming shared the 1945 Nobel Prize in Medicine. Florey credited Dubos with pioneering the approach of deliberately and systematically searching for antibacterial compounds, which had led to the discovery of gramicidin and had revived Florey's research in penicillin.

Indications

Treatment

* Bacterial infection

* Protozoan infection, e.g. metronidazole is effective against several parasitics

Immunomodulation, e.g. tetracycline which is effective in periodontal inflammation, and dapsone which is effective in autoimmune diseases such as oral mucous membrane pemphigoid

Prevention of infection

* Surgical wound

Dental antibiotic prophylaxis

* Conditions of neutropenia, e.g. cancer-related

Pharmacodynamics

The successful outcome of antimicrobial therapy with antibacterial compounds depends on several factors. These include host defense mechanisms, the location of infection, and the pharmacokinetic and pharmacodynamic properties of the antibacterial. A bactericidal activity of antibacterials may depend on the bacterial growth phase, and it often requires ongoing metabolic activity and division of bacterial cells. These findings are based on laboratory studies, and in clinical settings have also been shown to eliminate bacterial infection. Since the activity of antibacterials depends frequently on its concentration, ''in vitro'' characterization of antibacterial activity commonly includes the determination of the minimum inhibitory concentration and minimum bactericidal concentration of an antibacterial.

Classes

Like antibiotics, antibacterials are commonly classified based on their mechanism of action, chemical structure, or spectrum of activity. Most antibacterial antibiotics target bacterial functions or growth processes. Antibiotics that target the bacterial cell wall (such as penicillins and cephalosporins), or cell membrane (for example, polymixins), or interfere with essential bacterial enzymes (such as quinolones and sulfonamides) have bactericidal activities. Those that target protein synthesis, such as the aminoglycosides, macrolides, and tetracyclines, are usually bacteriostatic.

Production

Since the first pioneering efforts of Florey and Chain in 1939, the importance of antibiotics, including antibacterials, to medicine has led to intense research into producing antibacterials at large scales. Following screening of antibacterials against a wide range of bacteria, production of the active compounds is carried out using fermentation, usually in strongly aerobic conditions.

Administration

Oral antibacterials are orally ingested, whereas intravenous administration may be used in more serious cases, such as deep-seated systemic infections. Antibiotics may also sometimes be administered topically, as with eye drops or ointments.

Side effects

Antibacterials are screened for any negative effects on humans or other mammals before approval for clinical use and are usually considered safe and most are well-tolerated. However, some antibacterials have been associated with a range of adverse effects. Side-effects range from mild to very serious depending on the antibiotics used, the microbial organisms targeted, and the individual patient. Safety profiles of newer drugs are often not as well established as for those that have a long history of use. Adverse effects range from fever and nausea to major allergic reactions including photodermatitis and anaphylaxis. Common side-effects include diarrhea, resulting from disruption of the species composition in the intestinal flora, resulting, for example, in overgrowth of pathogenic bacteria, such as ''Clostridium difficile''. Antibacterials can also affect the vaginal flora, and may lead to overgrowth of yeast species of the genus ''Candida'' in the vulvo-vaginal area. Additional side-effects can result from interaction with other drugs, such as elevated risk of tendon damage from administration of a quinolone antibiotic with a systemic corticosteroid.

Drug-drug interactions

Contraceptive pills

The majority of studies indicate that antibiotics do not interfere with contraceptive pills, such as clinical studies that suggest that the failure rate of contraceptive pills caused by antibiotics is very low (about 1%). In cases where antibacterials have been suggested to affect the efficiency of birth control pills, such as for the broad-spectrum antibacterial rifampicin, these cases may be due to an increase in the activities of hepatic liver enzymes causing increased breakdown of the pill's active ingredients. Effects on the intestinal flora, which might result in reduced absorption of estrogens in the colon, have also been suggested, but such suggestions have been inconclusive and controversial. Clinicians have recommended that extra contraceptive measures are applied during therapies using antibacterials that are suspected to interact with oral contraceptives.

Alcohol

Interactions between alcohol and certain antibacterials may occur and may cause side-effects and decreased effectiveness of antibacterial therapy. :"It is sensible to avoid drinking alcohol when taking medication. However, it is unlikely that drinking alcohol in moderation will cause problems if you are taking most common antibiotics. However, there are specific types of antibiotics with which alcohol should be avoided completely, because of serious side-effects." Therefore, potential risks of side-effects and effectiveness depend on the type of antibacterial administered. Despite the lack of a categorical counterindication, the belief that alcohol and antibacterials should never be mixed is widespread.

Antibacterials such as metronidazole, tinidazole, cephamandole, latamoxef, cefoperazone, cefmenoxime, and furazolidone, cause a disulfiram-like chemical reaction with alcohol by inhibiting its breakdown by acetaldehyde dehydrogenase, which may result in vomiting, nausea, and shortness of breath.

Other effects of alcohol on antibacterial activity include altered activity of the liver enzymes that break down the antibacterial compound. In addition, serum levels of doxycycline and erythromycin succinate two bacteriostatic antibacterials (see above) may be reduced by alcohol consumption resulting in reduced efficacy and diminished pharmacotherapeutic effect.

Resistance

The emergence of resistance of bacteria to antibacterial drugs is a common phenomenon. Emergence of resistance often reflects evolutionary processes that take place during antibacterial drug therapy. The antibacterial treatment may select for bacterial strains with physiologically or genetically enhanced capacity to survive high doses of antibacterials. Under certain conditions, it may result in preferential growth of resistant bacteria while growth of susceptible bacteria is inhibited by the drug. For example, antibacterial selection within whole bacterial populations for strains having previously acquired antibacterial-resistance genes was demonstrated in 1943 by the Luria–Delbrück experiment. Survival of bacteria often results from an inheritable resistance. Resistance to antibacterials also occurs through horizontal gene transfer. Horizontal transfer is more likely to happen in locations of frequent antibiotic use. Antibacterials like penicillin and erythromycin, which used to have high efficacy against many bacterial species and strains, have become less effective, because of increased resistance of many bacterial strains. Antibacterial resistance may impose a biological cost thereby reducing fitness of resistant strains, which can limit the spread of antibacterial-resistant bacteria, for example, in the absence of antibacterial compounds. Additional mutations, however, may compensate for this fitness cost and can aid the survival of these bacteria. For example, NDM-1 is a newly identified enzyme conveying bacterial resistance to a broad range of beta-lactam antibacterials.

In agriculture, antibacterials are often used to promote weight gain in livestock animals. More than 70% of the antibacterials used in U.S. are given to livestock animals in the absence of infectious diseases. This practice has been associated with the emergence of antibacterial-resistant strains of bacteria including ''Salmonella'' spp., ''Campylobacter'' spp., ''Escherichia coli'', and ''Enterococcus'' spp. The emergence of antibacterial resistance has prompted restrictions on antibacterial use in the UK in 1970 (Swann report 1969), and the EU has banned the use of antibacterials as growth-promotional agents since 2003. Moreover, several organizations (e.g., The American Society for Microbiology (ASM), American Public Health Association (APHA) and the American Medical Association (AMA)) have called for restrictions on antibiotic use in food animal production and an end to all non-therapeutic uses. However, commonly there are delays in regulatory and legislative actions to limit the use of antibacterials, partly attributable to resistance against such regulation by industries using or selling antibacterials, and to the time required for research to test causal links between antibacterial use and resistance. Two federal bills (S.742 and H.R. 2562) aimed at phasing out non-therapeutic use of antibacterials in US food animals were proposed but have not passed. These bills were endorsed by public health and medical organizations, including the American Holistic Nurses’ Association, the American Medical Association, and the American Public Health Association (APHA).

Alternatives

The increase in bacterial strains that are resistant to conventional antibacterial therapies has prompted the development of alternative strategies to treat bacterial diseases.

Resistance-modifying agents

One strategy to address bacterial drug resistance is the discovery and application of compounds that modify resistance to common antibacterials. For example, some resistance-modifying agents may inhibit multi-drug resistance mechanisms, such as drug efflux from the cell, thus increasing the susceptibility of bacteria to a antibacterial. Targets include: The efflux inhibitor Phe-Arg-β-naphthylamide.

Beta-lactamase inhibitors, such as clavulanic acid and sulbactam.

Phage therapy

Phage therapy is the use of viruses (called phages) that infect bacteria for the treatment of bacterial infections. Phages are common in bacterial populations and control the growth of bacteria in many environments, including in the intestine, the ocean, and the soil.

Biotherapy

Biotherapy may employ organisms, such as protozoa,

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External links

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Category:Antibiotics Category:Greek loanwords

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