An antibacterial is a compound or substance that kills or slows down the growth of bacteria.[1] The term is often used synonymously with the term antibiotic(s); today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic(s) has come to denote a broader range of antimicrobial compounds, including antifungal and other compounds.[2]
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.[3] This definition excluded substances that kill bacteria, but are not produced by microorganisms (such as gastric juices and hydrogen peroxide). It also excluded synthetic antibacterial compounds such as the sulfonamides. Many antibacterial compounds are relatively small molecules with a molecular weight of less than 2000 atomic mass units.
With advances in medicinal chemistry, most of today's antibacterials chemically are semisynthetic modifications of various natural compounds.[4] 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. In accordance with this, 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.
The term antibacterial derives from Greek ἀντί (anti), "against"[5] + βακτήριον (baktērion), diminutive of βακτηρία (baktēria), "staff, cane",[6] because the first ones to be discovered were rod-shaped,[7] and the term antibiotic derives from anti + βιωτικός (biōtikos), "fil for life, lively",[8] which comes from βίωσις (biōsis), "way of life",[9] and that from βίος (bios), "life".[10]
Before the early 20th 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.[11] Many ancient cultures, including the ancient Egyptians and ancient Greeks, used specially selected mold and plant materials and extracts to treat infections.[12][13] 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, "if we could intervene in the antagonism observed between some bacteria, it would offer perhaps the greatest hopes for therapeutics".[14]
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.[15][16] 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.[17] These drugs were later renamed antibiotics by Selman Waksman, an American microbiologist, in 1942.[3][15]
John Tyndall first described antagonistic activities by fungi against bacteria in England in 1875.[14] Synthetic antibiotic chemotherapy as a science and development of antibacterials began in Germany with Paul Ehrlich in the late 1880s.[15] 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 [15][18][19] now called Arsphenamine.
In 1895, Vincenzo Tiberio, physician of the University of Naples discovered that a mold ( Penicillium ) in a water well has a antibacterial action.[20][21] After this initial chemotherapeutic compound proved effective, others pursued similar lines of inquiry but it was not until in 1928 that 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.[22][23]
The first sulfonamide and first commercially available antibacterial antibiotic, Prontosil, was developed by a research team led by Gerhard Domagk in 1932 at the Bayer Laboratories of the IG Farben conglomerate in Germany.[19] Domagk received the 1939 Nobel Prize for Medicine for his efforts. Prontosil had a relatively broad effect against Gram-positive cocci, but not against enterobacteria. Research was stimulated apace by its success. The discovery and development of this sulfonamide drug opened the era of antibacterial antibiotics. In 1939, coinciding with the start of World War II, Rene Dubos reported the discovery of the first naturally derived antibiotic, gramicidin from B. brevis. It was one of the first commercially manufactured antibiotics universally and very effectively used to treat wounds and ulcers during World War II.[24] Research results obtained during that period were not shared between the Axis and the Allied powers during the war.
Florey and Chain succeeded in purifying the first penicillin, penicillin G procaine in 1942, but it did not become widely available outside Allied military before 1945. 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.[25] 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.[24]
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.[29] A bactericidal activity of antibacterials may depend on the bacterial growth phase, and it often requires ongoing metabolic activity and division of bacterial cells.[30] These findings are based on laboratory studies, and in clinical settings have also been shown to eliminate bacterial infection.[29][31] Since the activity of antibacterials depends frequently on its concentration,[32] in vitro characterization of antibacterial activity commonly includes the determination of the minimum inhibitory concentration and minimum bactericidal concentration of an antibacterial.[29][33] To predict clinical outcome, the antimicrobial activity of an antibacterial is usually combined with its pharmacokinetic profile, and several pharmacological parameters are used as markers of drug efficacy.[34][35]
Molecular targets of antibiotics on the bacteria cell
Antibacterial antibiotics are commonly classified based on their mechanism of action, chemical structure, or spectrum of activity. Most target bacterial functions or growth processes.[15] Those that target the bacterial cell wall (penicillins and cephalosporins) or the cell membrane (polymixins), or interfere with essential bacterial enzymes (quinolones and sulfonamides) have bactericidal activities. Those that target protein synthesis (aminoglycosides, macrolides, and tetracyclines) are usually bacteriostatic.[36] Further categorization is based on their target specificity. "Narrow-spectrum" antibacterial antibiotics target specific types of bacteria, such as Gram-negative or Gram-positive bacteria, whereas broad-spectrum antibiotics affect a wide range of bacteria. Following a 40-year hiatus in discovering new classes of antibacterial compounds, three new classes of antibacterial antibiotics have been brought into clinical use: cyclic lipopeptides (such as daptomycin), glycylcyclines (such as tigecycline), and oxazolidinones (such as linezolid).[37]
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.[citation needed]
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.
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.[38] Side-effects range from mild to very serious depending on the antibiotics used, the microbial organisms targeted, and the individual patient.[citation needed] Safety profiles of newer drugs are often not as well established as for those that have a long history of use.[38] Adverse effects range from fever and nausea to major allergic reactions, including photodermatitis and anaphylaxis.[citation needed] 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.[39] Antibacterials can also affect the vaginal flora, and may lead to overgrowth of yeast species of the genus Candida in the vulvo-vaginal area.[40] 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.
The majority of studies indicate antibiotics do not interfere with contraceptive pills,[41] such as clinical studies that suggest the failure rate of contraceptive pills caused by antibiotics is very low (about 1%).[42] 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.[41] 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.[43][44] Clinicians have recommended that extra contraceptive measures be applied during therapies using antibacterials that are suspected to interact with oral contraceptives.[41]
Interactions between alcohol and certain antibacterials may occur and may cause side-effects and decreased effectiveness of antibacterial therapy.[45][46]
- "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."[47]
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.[47]
Other effects of alcohol on antibacterial activity include altered activity of the liver enzymes that break down the antibacterial compound.[48] In addition, serum levels of doxycycline and erythromycin succinate[clarification needed] two bacteriostatic antibacterials (see above) may be reduced by alcohol consumption, resulting in reduced efficacy and diminished pharmacotherapeutic effect.[49]
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.[50] 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.[51] Survival of bacteria often results from an inheritable resistance.[52] Resistance to antibacterials also occurs through horizontal gene transfer. Horizontal transfer is more likely to happen in locations of frequent antibiotic use.[53] Antibacterials such as 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.[54] 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.[55]
Several molecular mechanisms of antibacterial resistance exist. Intrinsic antibacterial resistance may be part of the genetic makeup of bacterial strains.[56] For example, an antibiotic target may be absent from the bacterial genome. Acquired resistance results from a mutation in the bacterial chromosome or the acquisition of extra-chromosomal DNA.[56] Antibacterial-producing bacteria have evolved resistance mechanisms that have been shown to be similar to, and may have been transferred to, antibacterial-resistant strains.[57][58] The spread of antibacterial resistance often occurs through vertical transmission of mutations during growth and by genetic recombination of DNA by horizontal genetic exchange.[52] For instance, antibacterial resistance genes can be exchanged between different bacterial strains or species via plasmids that carry these resistance genes.[52][59] Plasmids that carry several different resistance genes can confer resistance to multiple antibacterials.[59] Cross-resistance to several antibacterials may also occur when a resistance mechanism encoded by a single gene conveys resistance to more than one antibacterial compound.[59]
Antibacterial-resistant strains and species, sometimes referred to as "superbugs", now contribute to the emergence of diseases that were for a while well-controlled. For example, emergent bacterial strains causing tuberculosis (TB) that are resistant to previously effective antibacterial treatments pose many therapeutic challenges. Every year, nearly half a million new cases of multidrug-resistant tuberculosis (MDR-TB) are estimated to occur worldwide.[60] For example, NDM-1 is a newly identified enzyme conveying bacterial resistance to a broad range of beta-lactam antibacterials.[61] United Kingdom Health Protection Agency has stated that "most isolates with NDM-1 enzyme are resistant to all standard intravenous antibiotics for treatment of severe infections."[62]
This poster from the U.S. Centers for Disease Control and Prevention "Get Smart" campaign, intended for use in doctors' offices and other healthcare facilities, warns that antibiotics do not work for viral illnesses such as the common cold.
The first rule of antibiotics is try not to use them, and the second rule is try not to use too many of them.
[63]—Paul L. Marino, The ICU Book
Inappropriate antibacterial treatment and overuse of antibiotics have contributed to the emergence of antibacterial-resistant bacteria. Self prescription of antibacterials is an example of misuse.[64] Many antibacterials are frequently prescribed to treat symptoms or diseases that do not respond to antibacterial therapy or are likely to resolve without treatment, or incorrect or suboptimal antibacterials are prescribed for certain bacterial infections.[38][64] The overuse of antibacterials, like penicillin and erythromycin, have been associated with emerging antibacterial resistance since the 1950s.[54][65] Widespread usage of antibacterial drugs in hospitals has also been associated with increases in bacterial strains and species that no longer respond to treatment with the most common antibacterials.[65]
Common forms of antibacterial misuse include excessive use of prophylactic antibiotics in travelers and failure of medical professionals to prescribe the correct dosage of antibacterials on the basis of the patient's weight and history of prior use. Other forms of misuse include failure to take the entire prescribed course of the antibacterial, incorrect dosage and administration, or failure to rest for sufficient recovery. Inappropriate antibacterial treatment, for example, is the prescription of antibacterials to treat viral infections such as the common cold. One study on respiratory tract infections found "physicians were more likely to prescribe antibiotics to patients who appeared to expect them".[66] Multifactorial interventions aimed at both physicians and patients can reduce inappropriate prescription of antibiotics.[67]
Several organizations concerned with antimicrobial resistance are lobbying to eliminate the unnecessary use of antibacterials.[64] The issues of misuse and overuse of antibiotics have been addressed by the formation of the U.S. Interagency Task Force on Antimicrobial Resistance. This task force aims to actively address antimicrobial resistance, and is coordinated by the US Centers for Disease Control and Prevention, the Food and Drug Administration (FDA), and the National Institutes of Health (NIH), as well as other US agencies.[68] An NGO campaign group is Keep Antibiotics Working.[69] In France, an "Antibiotics are not automatic" government campaign started in 2002 and led to a marked reduction of unnecessary antibacterial prescriptions, especially in children.[70]
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.[71] 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 nontherapeutic uses.[citation needed] However, commonly there are delays in regulatory and legislative actions to limit the use of antibacterials, attributable partly 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[72] and H.R. 2562[73]) aimed at phasing out nontherapeutic use of antibacterials in US food animals were proposed, but have not passed.[72][73] 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).[74]
There has been extensive use of antibiotics in animal husbandry. In the United States the question of emergence of antibiotic-resistant bacterial strains due to use of antibiotics in livestock was raised by the United States Food and Drug Administration in 1977. In March, 2012 the United States District Court for the Southern District of New York, ruling in an action brought by the Natural Resources Defense Council and others, ordered the FDA to revoke approvals for the use of antibiotics in livestock which violated FDA regulations.[75]
The increase in bacterial strains that are resistant to conventional antibacterial therapies has prompted the development of alternative strategies to treat bacterial diseases.
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 multidrug resistance mechanisms, such as drug efflux from the cell, thus increasing the susceptibility of bacteria to an antibacterial. Targets include:
Metabolic stimuli such as sugar can help eradicate a certain type of antibiotic tolerant bacteria by keeping their metabolism active.[77]
Phage therapy is the use of viruses that infect bacteria (i.e. phages) for the treatment of bacterial infections.[78][79] Phages are common in bacterial populations and control the growth of bacteria in many environments, including in the intestine, the ocean, and the soil.[80] Phage therapy was in use in the 1920s and 1930s in the US, Western Europe, and Eastern Europe. However, success rates of this therapy have not been firmly established, because only a limited number of clinical trials testing the efficacy of phage therapy have been conducted.[79] These studies were performed mainly in the former Soviet Union, at the Eliava Institute of Bacteriophage, Microbiology and Virology, Republic of Georgia.[81] The development of antibacterial-resistant bacteria has sparked renewed interest in phage therapy in Western medicine.[82] Several companies (e.g., Intralytix, Novolytics, and Gangagen), universities, and foundations across the world now focus on phage therapies.[82][83][84][85] One concern with this therapeutic strategy is the use of genetically engineered viruses, which limits certain aspects of phage therapy.[79][86][87]
Bacteriocins are peptides that can be more readily engineered than small molecules,[88] and are possible alternatives to conventional antibacterial compounds.[89] Different classes of bacteriocins have different potential as therapeutic agents. Small-molecule bacteriocins (microcins and lantibiotics) are similar to the classic antibiotics; colicin-like bacteriocins possess a narrow spectrum, and require molecular diagnostics prior to therapy.[citation needed] Limitations of large-molecule antibacterials include reduced transport across membranes and within the human body. For this reason, they are usually applied topically or gastrointestinally.[90]
Chelation of micronutrients that are essential for bacterial growth to restrict pathogen spread in vivo might supplement some antibacterials. For example, limiting the iron availability in the human body restricts bacterial proliferation.[91][92] Many bacteria, however, possess mechanisms (such as siderophores) for scavenging iron within environmental niches in the human body, and experimental developments of iron chelators, therefore, aim to reduce iron availability specifically to bacterial pathogens.[93]
Vaccines rely on immune modulation or augmentation. Vaccination either excites or reinforces the immune competency of a host to ward off infection, leading to the activation of macrophages, the production of antibodies, inflammation, and other classic immune reactions. Antibacterial vaccines have been responsible for a drastic reduction in global bacterial diseases.[citation needed] Vaccines made from attenuated whole cells or lysates have been replaced largely by less reactogenic, cell-free vaccines consisting of purified components, including capsular polysaccharides and their conjugates, to protein carriers, as well as inactivated toxins (toxoids) and proteins.[94]
Biotherapy may employ organisms, such as protozoa,[95] to consume the bacterial pathogens. Another such approach is maggot therapy.
Probiotics consist of a live culture of bacteria, which may become established as competing symbionts, and inhibit or interfere with colonization by microbial pathogens.[96]
An additional therapeutic agent is the enhancement of the multifunctional properties of natural anti-infectives, such as cationic host defense (antimicrobial) peptides (HDPs).[94]
Functionalization of antimicrobial surfaces can be used for sterilization, self-cleaning, and surface protection.
Copper-alloy surfaces have natural intrinsic properties to effectively and quickly destroy bacteria. The United States Environmental Protection Agency has approved the registration of 355 different antibacterial copper alloys that kill E. coli O157:H7, methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus, Enterobacter aerogenes, and Pseudomonas aeruginosa in less than 2 hours of contact. As a public hygienic measure in addition to regular cleaning, antimicrobial copper alloys are being installed in healthcare facilities and in a subway transit system.[97][98][99]
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