In common usage, an antibiotic (from the  ??? anti , "against", and ???????? ??? bios , "life") is a substance or compound that kills bacteria or inhibits their growth.

The term "antibiotic" was coined by Selman Waksman in 1942 to describe any substance produced by a microorganism that is antagonistic to the growth of other microorganisms in high dilution. This original definition excluded naturally occurring substances that kill bacteria but are not produced by microorganisms (such as gastric juice and hydrogen peroxide) and also excluded synthetic antibacterial compounds such as the sulfonamides . Many antibiotics are relatively small molecules with a molecular weight less than 2000 atomic mass units.

With advances in medicinal chemistry, most antibiotics are now semisynthetic???modified chemically from original compounds found in nature, as is the case with beta-lactams (which include the penicillins, produced by fungi in the genus Penicillium, the cephalosporins, and the carbapenems). Some antibiotics are still produced and isolated from living organisms, such as the aminoglycosides, and others have been created through purely synthetic means: the sulfonamides, the quinolones, and the oxazolidinones. In addition to this origin-based classification into natural, semisynthetic, and synthetic, antibiotics may be divided into two broad groups according to their effect on microorganisms: Those that kill bacteria are bactericidal agents, whereas those that only impair bacterial growth are known as bacteriostatic agents.

Many treatments for infections prior to the beginning of the twentieth century were based on medicinal folklore . Treatments for infection in many ancient cultures using concoctions with antimicrobial properties were described over 2000 years ago.

Originally known as antibiosis , antibiotics were drugs which acted against bacteria. The term antibiosis , which means "against life," was introduced by the French bacteriologist Vuillemin as a descriptive name of the phenomenon exhibited by these 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.

Bacterial antagonism of Penicillium spp. were first described in England by John Tyndall in 1875. The significance to antibiotic discovery was not realized until the work of Ehrlich on synthetic antibiotic chemotherapy, which marked the birth of the antibiotic revolution. Ehrlich noted that certain dyes would bind to and color human, animal, or bacterial cells, while others did not. He then extended the idea that it might be possible to make certain dyes or chemicals that would act as a magic bullet or selective drug that would bind to and kill bacteria while not harming the human host. After much experimentation, screening hundreds of dyes against various organisms, he discovered a medicinally useful drug, the man-made antibiotic, Salvarsan. In the meantime, another synthetic antibacterial antibiotic Prontosil was developed and manufactured for commercial use by Domagk in 1932. Prontosil, the first commercially available antibacterial antibiotic, was developed by a research team led by Gerhard Domagk (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 antibiotics. In 1939, discovery by Rene Dubos of the first naturally derived antibiotic-like substance named 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. The purified antibiotic displayed antibacterial activity against a wide range of bacteria. It also had low toxicity and could be taken without causing adverse effects. Furthermore, its activity was not inhibited by biological constituents such as pus, unlike the synthetic antibiotic class available at the time, the sulfonamides. The discovery of such a powerful antibiotic was unprecedented. The development of penicillin led to renewed interest in the search for antibiotic compounds with similar capabilities.

The assessment of the activity of an antibiotic is crucial to the successful outcome of antimicrobial therapy. Non-microbiological factors such as host defense mechanisms, the location of an infection, the underlying disease as well as the intrinsic pharmacokinetic and pharmacodynamic properties of the antibiotic.

Antibiotics are commonly classified based on their mechanism of action, chemical structure, or spectrum of activity. Most antibiotics target bacterial functions or growth processes. Antibiotics that target the bacterial cell wall (penicillins, cephalosporins), or cell membrane (polymixins), or interfere with essential bacterial enzymes (quinolones, sulfonamides) are usually bactericidal in nature. Those that target protein synthesis, such as the aminoglycosides, macrolides, and tetracyclines, are usually bacteriostatic. Further categorization is based on their target specificity: "Narrow-spectrum" antibiotics target particular types of bacteria, such as Gram-negative or Gram-positive bacteria, whereas broad-spectrum antibiotics affect a wide range of bacteria. In the last few years, three new classes of antibiotics have been brought into clinical use. This follows a 40-year hiatus in discovering new classes of antibiotic compounds. These new antibiotics are of the following three classes: cyclic lipopeptides ( daptomycin), glycylcyclines ( tigecycline), and oxazolidinones ( linezolid). Tigecycline is a broad-spectrum antibiotic, whereas the two others are used for Gram-positive infections. These developments show promise as a means to counteract the bacterial resistance to existing antibiotics.

Production

Since the first pioneering efforts of Florey and Chain in 1939, the importance of antibiotics to medicine has led to much research into discovering and producing them. The process of production usually involves the screening of wide ranges of microorganisms, and their testing and modification. Production is carried out using fermentation , usually in strongly aerobic form.

Administration

Oral antibiotics are simply ingested, while intravenous antibiotics are 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

Although antibiotics are generally considered safe and well-tolerated, they have been associated with a wide range of adverse effects.

There are various side-effects that can be very serious depending on the antibiotics used and the microbial organisms targeted. The safety profiles of newer medications may not be as well established as those that have been in use for many years. Adverse effects can range from fever and nausea to major allergic reactions including photodermatitis and anaphylaxis. One of the more common side-effects is diarrhea, resulting from the antibiotic's disrupting the normal balance of the intestinal flora. This diarrhea is sometimes caused by the anaerobic bacterium Clostridium difficile. Such overgrowth of pathogenic bacteria may be alleviated by ingesting probiotics during a course of antibiotics. The population of bacteria present in the normal vaginal flora may also be disrupted, and may lead to overgrowth of yeast species of the genus Candida in the vulvo-vaginal area. Other 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. Certain antibiotics administered by IV (e.g.aminoglycosides, vancomycin) can cause significant permanent hearing loss.

Contraceptive pills

It has been hypothesized that interference of some antibiotics with the efficiency of birth control pills is thought to occur in two ways. Modification of the intestinal flora may result in reduced absorption of estrogens. Second, induction of hepatic liver enzymes causing them to metabolize the pill's active ingredients faster may affect the pill's usefulness.

Alcohol

Interactions between alcohol and antibiotics vary depending on the specific antibiotic, and, in some cases , can cause severe side-effects and decreased effectiveness.

"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.

Because of the risks of side-effects and effectiveness, one should check the specific indications on the specific antibiotic, but there is no categorical danger in mixing alcohol and some antibiotics.

Despite the lack of a categorical counterindication, the belief that alcohol and antibiotics should never be mixed is widespread, as indicated in a survey in one British clinic.

" Patients often assume that they should avoid alcohol when taking any antibiotics. ...this belief has no foundation."

One potential source of the myth is from STD clinics in the 1950s and 1960s. Doctors gave the advice for moral reasons as they were worried that alcohol would reduce the inhibitions of sufferers and lead to further spread of diseases such as gonorrhoea.

It has been suggested, but not corroborated, that the origin of this myth centers on the fact that, during World War II, penicillin was in short supply and was recycled from urine; convalescing soldiers that drank beer produced a greater volume of urine, and, thus, were banned from drinking beer, leading to the belief that alcohol interacted poorly with antibiotics.

Specific effects

By way of side-effects, certain antibiotics, including metronidazole, tinidazole, cephamandole, latamoxef, cefoperazone, cefmenoxime, and furazolidone, cause a disulfiram-like chemical reaction with alcohol by inhibiting metabolism by acetaldehyde dehydrogenase, leading to serious side-effects , which include severe vomiting, nausea, and shortness of breath. Alcohol consumption while taking such antibiotics is, therefore, prohibited.

Other effects of alcohol involve the activity of liver enzymes, which break down the antibiotics. In addition, serum levels of doxycycline and erythromycin succinate may, in certain circumstances, be significantly reduced by alcohol consumption. This is particularly important, since these drugs are bacteriostatic and require a sustained level of the drug in the body to be effective: Increased metabolism and clearance would result in diminished pharmacotherapeutic effect.

Alcohol can interfere with the activity or metabolization of antibiotics

The emergence of antibiotic resistance is an evolutionary process that is based on selection for organisms that have enhanced ability to survive doses of antibiotics that would have previously been lethal.

The underlying molecular mechanisms leading to antibiotic resistance can vary. Intrinsic resistance may naturally occur as a result of the bacteria's genetic makeup.

Antibiotic-resistant microorganisms, sometimes referred to as "superbugs", may contribute to the re-emergence of diseases which are currently well-controlled. For example, cases of tuberculosis (TB) that are resistant to traditionally effective treatments remain a cause of great concern to health professionals. Every year, nearly half a million new cases of multidrug-resistant tuberculosis (MDR-TB) are estimated to occur worldwide. NDM-1 is a newly-identified enzyme that makes bacteria resistant to a broad range of beta-lactam antibiotics.

Antibiotic misuse

Inappropriate antibiotic treatment and overuse of antibiotics have been a contributing factor to the emergence of resistant bacteria. The problem is further exacerbated by self-prescribing of antibiotics by individuals without the guidelines of a qualified clinician and the non-therapeutic use of antibiotics as growth promoters in agriculture.

Common forms of antibiotic misuse include excessive use of prophylactic antibiotics in travelers, failure to take into account the patient's weight and history of prior antibiotic use when prescribing, since both can strongly affect the efficacy of an antibiotic prescription, failure to take the entire prescribed course of the antibiotic, failure to prescribe or take the course of treatment at fairly precise correct daily intervals (e.g., "every 8 hours" rather than merely "3x per day"), or failure to rest for sufficient recovery to allow clearance of the infecting organism. These practices may facilitate the development of bacterial populations with antibiotic resistance . Inappropriate antibiotic treatment is another common form of antibiotic misuse. A common example is the prescription and use of antibiotics to treat viral infections such as the common cold that have no effect. One study on respiratory tract infections found "physicians were more likely to prescribe antibiotics to patients who they believed expected them, although they correctly identified only about 1 in 4 of those patients". Multifactorial interventions aimed at both physicians and patients can reduce inappropriate prescribing of antibiotics. Delaying antibiotics for 48 hours while observing for spontaneous resolution of respiratory tract infections may reduce antibiotic usage; however, this strategy may reduce patient satisfaction.

Several organizations concerned with antimicrobial resistance are lobbying to improve the regulatory climate. In France, an "Antibiotics are not automatic" government campaign starting in 2002 led to a marked reduction of unnecessary antibiotic prescriptions, especially in children. In the United Kingdom, there are NHS posters in many doctors' surgeries indicating that 'no amount of antibiotics will get rid of your cold', with many patients specifically requesting antibiotics from their doctor inappropriately, believing they treat viral infections.

In agriculture, associated antibiotic resistance with the non-therapeutic use of antibiotics as growth promoters in animals resulted in their restricted use in the UK in the 1970 (Swann report 1969). At the current time, there is a EU-wide ban on the non-therapeutic use of antibiotics as growth promoters. It is estimated that greater than 70% of the antibiotics used in U.S. are given to feed animals (e.g., chickens, pigs, and cattle) in the absence of disease. Antibiotic use in food animal production has been associated with the emergence of antibiotic-resistant strains of bacteria including Salmonella spp., Campylobacter spp., Escherichia coli , and Enterococcus spp. Evidence from some US and European studies suggest that these resistant bacteria cause infections in humans that do not respond to commonly prescribed antibiotics. In response to these practices and attendant problems, 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, delays in regulatory and legislative actions to limit the use of antibiotics are common, and may include resistance to these changes by industries using or selling antibiotics, as well as time spent on research to establish causal links between antibiotic use and emergence of untreatable bacterial diseases. Two federal bills (S.742 and H.R. 2562) aimed at phasing out non-therapeutic antibiotics in US food animal production were proposed but 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). The EU has banned the use of antibiotics as growth promotional agents since 2003.

Multi-drug-resistant organisms (MDRO), in general, refer to bacteria that are not affected by the clinical doses of classical antibiotics, in particular, the antibiotics used to treat them until recently. The rise of these organisms has created a need for alternative antibacterial therapies.

Resistance-modifying agents

One solution to combat resistance currently being researched is the development of pharmaceutical compounds that would revert multiple antibiotic resistance. These so-called resistance-modifying agents may target and inhibit MDR mechanisms, rendering the bacteria susceptible to antibiotics to which they were previously resistant. These compounds' targets include among others

• Efflux inhibition (Phe-Arg-??-naphthylamide)

• Beta-Lactamase inhibitors - Including clavulanic acid and sulbactam

Phage Therapy

Phage therapy, the use of a particular group of viruses capable of invading bacteria known as phages to treat bacterial infections.

Bacteriocins

Bacteriocins are also a growing alternative to the classic small-molecule antibiotics. Different classes of bacteriocins have different potential as therapeutic agents. Small molecule bacteriocins ( microcins, for example, and lantibiotics) may be similar to the classic antibiotics; colicin-like bacteriocins are more likely to be narrow-spectrum, demanding new molecular diagnostics prior to therapy but also not raising the spectre of resistance to the same degree. One drawback to the large-molecule antibiotics is that they have relative difficulty crossing membranes and travelling systemically throughout the body. For this reason, they are most often proposed for application topically or gastrointestinally. Because bacteriocins are peptides, they are more readily engineered than small molecules. This may permit the generation of cocktails and dynamically improved antibiotics that are modified to overcome resistance.

Nutrient withdrawal

Nutrient withdrawal is a potential strategy for replacing or supplementing antibiotics. The restriction of iron availability is one way the human body limits bacterial proliferation. and parasitic ). This is distinct from chelation therapy for conditions other than bacterial infections - including successful treatment for iron overload.

Vaccines

Vaccines are a commonly suggested method for combating MDRO infections. They actually fit within a larger class of therapies that rely on immune modulation or augmentation. These therapies either excite or reinforce the natural immune competency of the infected or susceptible host, leading to the activity of macrophages, the production of antibodies , inflammation, or other classic immune reactions.

Just as the macrophage engulfs and consumes bacteria, various forms of biotherapy have been suggested that employ organisms to consume the pathogens. This includes the employment of protozoa and maggot therapy.

Probiotics

Probiotics are another alternative that goes beyond traditional antibiotics by employing a live culture, which may, in theory, establish itself as a symbiont???competing, inhibiting, or simply interfering with colonization by pathogens.

The comparative ease of identifying compounds that safely cured bacterial infections was more difficult to duplicate in treatments of fungal and viral infections. Antibiotic research led to great strides in the knowledge of biochemistry, establishing large differences between the cellular and molecular physiology of the bacterial cell and that of the mammalian cell. This explained the observation that many compounds that are toxic to bacteria are non-toxic to human cells. In contrast, the basic biochemistries of the fungal cell and the mammalian cell are much more similar. Most antifungal drugs have targeted steps in the synthesis of the fungal cell membrane (e.g., imidazole, triazole, and allylamine antifungals) or target components of the formed cell wall (e.g., polyene antifungals). However, toxicity is not fully avoided in the case of polyene antifungals since they can target human membrane cholesterol, mistaking it for fungal ergosterol.

This restricts the development and use of therapeutic compounds that attack a fungal cell, while not harming mammalian cells. Similar problems exist in antibiotic treatments of viral diseases. Human viral metabolic biochemistry is very closely similar to human biochemistry, and the possible targets of antiviral compounds are restricted to very few components unique to a mammalian virus.

For related articles, see fungicide, antifungal drug, and antiviral drug.