Antibiotic

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Antibiotic
Drug class
Staphylococcus aureus (AB Test).jpg
Testing the susceptibility of Staphylococcus aureus to antibiotics by the Kirby-Bauer disk diffusion method – antibiotics diffuse from antibiotic-containing disks and inhibit growth of S. aureus, resulting in a zone of inhibition.
In Wikidata

An antibiotic is a type of antimicrobial substance active against bacteria and is the most important type of antibacterial agent for fighting bacterial infections. Antibiotic medications are widely used in the treatment and prevention of such infections. [1] [2] They may either kill or inhibit the growth of bacteria. A limited number of antibiotics also possess antiprotozoal activity. [3] [4] Antibiotics are not effective against viruses such as the common cold or influenza; drugs which inhibit viruses are termed antiviral drugs or antivirals rather than antibiotics.

An antimicrobial is an agent that kills microorganisms or stops their growth. Antimicrobial medicines can be grouped according to the microorganisms they act primarily against. For example, antibiotics are used against bacteria and antifungals are used against fungi. They can also be classified according to their function. Agents that kill microbes are called microbicidal, while those that merely inhibit their growth are called biostatic. The use of antimicrobial medicines to treat infection is known as antimicrobial chemotherapy, while the use of antimicrobial medicines to prevent infection is known as antimicrobial prophylaxis.

Bacteria A domain of prokaryotes – single celled organisms without a nucleus

Bacteria are a type of biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a number of shapes, ranging from spheres to rods and spirals. Bacteria were among the first life forms to appear on Earth, and are present in most of its habitats. Bacteria inhabit soil, water, acidic hot springs, radioactive waste, and the deep portions of Earth's crust. Bacteria also live in symbiotic and parasitic relationships with plants and animals. Most bacteria have not been characterised, and only about half of the bacterial phyla have species that can be grown in the laboratory. The study of bacteria is known as bacteriology, a branch of microbiology.

Pathogenic bacteria

Pathogenic bacteria are bacteria that can cause disease. This article deals with human pathogenic bacteria. Although most bacteria are harmless or often beneficial, some are pathogenic, with the number of species estimated as fewer than a hundred that are seen to cause infectious diseases in humans. By contrast, several thousand species exist in the human digestive system.

Contents

Sometimes, the term antibiotic which means "opposing life", based on Greek roots, (ἀντι-) anti: "against" and (βίος-) biotic: "life", is broadly used to refer to any substance used against microbes, but in the usual medical usage, antibiotics (such as penicillin) are those produced naturally (by one microorganism fighting another), whereas nonantibiotic antibacterials (such as sulfonamides and antiseptics) are fully synthetic. However, both classes have the same goal of killing or preventing the growth of microorganisms, and both are included in antimicrobial chemotherapy. "Antibacterials" include antiseptic drugs, antibacterial soaps, and chemical disinfectants, whereas antibiotics are an important class of antibacterials used more specifically in medicine [5] and sometimes in livestock feed.

Greek language language spoken in Greece, Cyprus and Southern Albania

Greek is an independent branch of the Indo-European family of languages, native to Greece, Cyprus and other parts of the Eastern Mediterranean and the Black Sea. It has the longest documented history of any living Indo-European language, spanning more than 3000 years of written records. Its writing system has been the Greek alphabet for the major part of its history; other systems, such as Linear B and the Cypriot syllabary, were used previously. The alphabet arose from the Phoenician script and was in turn the basis of the Latin, Cyrillic, Armenian, Coptic, Gothic, and many other writing systems.

Penicillin group of antibiotics derived from Penicillium fungi

Penicillin is a group of antibiotics which include penicillin G, penicillin V, procaine penicillin, and benzathine penicillin. Penicillin antibiotics were among the first medications to be effective against many bacterial infections caused by staphylococci and streptococci. They are still widely used today, though many types of bacteria have developed resistance following extensive use.

Microorganism microscopic living organism

A microorganism, or microbe, is a microscopic organism, which may exist in its single-celled form or in a colony of cells.

There's evidence of antibiotic use since ancient times. Many civilizations used topical application of mouldy bread, with many references to its beneficial effects arising from ancient Egypt, China, Serbia, Greece and Rome. The first person to directly document the use of moulds to treat infections was John Parkinson (1567–1650). Antibiotics truly revolutionized medicine in the 20th century. Alexander Fleming (1881–1955) discovered modern day penicillin in 1928. After realizing the great potential there was in penicillin, Fleming pursued the challenge of how to market it and translate it to commercial use. With help from other biochemists, penicillin was finally available for widespread use. This was significantly beneficial during wartime. Unfortunately, it didn't take long for resistance to begin. [6] [7] Effectiveness and easy access have also led to their overuse [ citation needed ] and some bacteria have developed resistance. [1] [8] This has led to widespread problems, and the World Health Organization have classified antimicrobial resistance as a "serious threat [that] is no longer a prediction for the future, it is happening right now in every region of the world and has the potential to affect anyone, of any age, in any country". [9]

Antibiotic misuse

Antibiotic misuse, sometimes called antibiotic abuse or antibiotic overuse, refers to the misuse or overuse of antibiotics, with potentially serious effects on health. It is a contributing factor to the development of antibiotic resistance, including the creation of multidrug-resistant bacteria, informally called "super bugs": relatively harmless bacteria can develop resistance to multiple antibiotics and cause life-threatening infections.

World Health Organization Specialised agency of the United Nations

The World Health Organization (WHO) is a specialized agency of the United Nations that is concerned with international public health. It was established on 7 April 1948, and is headquartered in Geneva, Switzerland. The WHO is a member of the United Nations Development Group. Its predecessor, the Health Organisation, was an agency of the League of Nations.

Medical uses

Antibiotics are used to treat or prevent bacterial infections, [10] and sometimes protozoan infections. (Metronidazole is effective against a number of parasitic diseases). When an infection is suspected of being responsible for an illness but the responsible pathogen has not been identified, an empiric therapy is adopted. [11] This involves the administration of a broad-spectrum antibiotic based on the signs and symptoms presented and is initiated pending laboratory results that can take several days. [10] [11]

Protozoan infection parasitic disease caused by a protozoan

Protozoan infections are parasitic diseases caused by organisms formerly classified in the Kingdom Protozoa. They include organisms classified in Amoebozoa, Excavata, and Chromalveolata.

Metronidazole chemical compound

Metronidazole, marketed under the brand name Flagyl among others, is an antibiotic and antiprotozoal medication. It is used either alone or with other antibiotics to treat pelvic inflammatory disease, endocarditis, and bacterial vaginosis. It is effective for dracunculiasis, giardiasis, trichomoniasis, and amebiasis. It is an option for a first episode of mild-to-moderate Clostridium difficile colitis if vancomycin or fidaxomicin is unavailable. Metronidazole is available by mouth, as a cream, and by injection into a vein.

A parasitic disease, also known as parasitosis, is an infectious disease caused or transmitted by a parasite. Many parasites do not cause diseases as it may eventually lead to death of both organism and host. Parasitic diseases can affect practically all living organisms, including plants and mammals. The study of parasitic diseases is called parasitology.

When the responsible pathogenic microorganism is already known or has been identified, definitive therapy can be started. This will usually involve the use of a narrow-spectrum antibiotic. The choice of antibiotic given will also be based on its cost. Identification is critically important as it can reduce the cost and toxicity of the antibiotic therapy and also reduce the possibility of the emergence of antimicrobial resistance. [11] To avoid surgery, antibiotics may be given for non-complicated acute appendicitis. [12]

Appendicitis Inflammation of the appendix

Appendicitis is inflammation of the appendix. Symptoms commonly include right lower abdominal pain, nausea, vomiting, and decreased appetite. However, approximately 40% of people do not have these typical symptoms. Severe complications of a ruptured appendix include widespread, painful inflammation of the inner lining of the abdominal wall and sepsis.

Antibiotics may be given as a preventive measure and this is usually limited to at-risk populations such as those with a weakened immune system (particularly in HIV cases to prevent pneumonia), those taking immunosuppressive drugs, cancer patients, and those having surgery. [10] Their use in surgical procedures is to help prevent infection of incisions. They have an important role in dental antibiotic prophylaxis where their use may prevent bacteremia and consequent infective endocarditis. Antibiotics are also used to prevent infection in cases of neutropenia particularly cancer-related. [13] [14]

Preventive healthcare consists of measures taken for disease prevention, as opposed to disease treatment. Just as health comprises a variety of physical and mental states, so do disease and disability, which are affected by environmental factors, genetic predisposition, disease agents, and lifestyle choices. Health, disease, and disability are dynamic processes which begin before individuals realize they are affected. Disease prevention relies on anticipatory actions that can be categorized as primal, primary, secondary, and tertiary prevention.

Immunodeficiency is a state in which the immune system's ability to fight infectious disease and cancer is compromised or entirely absent. Most cases of immunodeficiency are acquired ("secondary") due to extrinsic factors that affect the patient's immune system. Examples of these extrinsic factors include HIV infection, extremes of age, and environmental factors, such as nutrition. In the clinical setting, the immunosuppression by some drugs, such as steroids, can be either an adverse effect or the intended purpose of the treatment. Examples of such use is in organ transplant surgery as an anti-rejection measure and in patients suffering from an overactive immune system, as in autoimmune diseases. Some people are born with intrinsic defects in their immune system, or primary immunodeficiency. A person who has an immunodeficiency of any kind is said to be immunocompromised. An immunocompromised person may be particularly vulnerable to opportunistic infections, in addition to normal infections that could affect everyone. Immunodeficiency also decreases cancer immunosurveillance, in which the immune system scans the body's cells and kills neoplastic ones.

HIV human retrovirus, cause of AIDS

The human immunodeficiency viruses (HIV) are two species of Lentivirus that causes HIV infection and over time acquired immunodeficiency syndrome (AIDS). AIDS is a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive. Without treatment, average survival time after infection with HIV is estimated to be 9 to 11 years, depending on the HIV subtype. In most cases, HIV is a sexually transmitted infection and occurs by contact with or transfer of blood, pre-ejaculate, semen, and vaginal fluids. Non-sexual transmission can occur from an infected mother to her infant during pregnancy, during childbirth by exposure to her blood or vaginal fluid, and through breast milk. Within these bodily fluids, HIV is present as both free virus particles and virus within infected immune cells.

Administration

There are many different routes of administration for antibiotic treatment. Antibiotics are usually taken by mouth. In more severe cases, particularly deep-seated systemic infections, antibiotics can be given intravenously or by injection. [1] [11] Where the site of infection is easily accessed, antibiotics may be given topically in the form of eye drops onto the conjunctiva for conjunctivitis or ear drops for ear infections and acute cases of swimmer's ear. Topical use is also one of the treatment options for some skin conditions including acne and cellulitis. [15] Advantages of topical application include achieving high and sustained concentration of antibiotic at the site of infection; reducing the potential for systemic absorption and toxicity, and total volumes of antibiotic required are reduced, thereby also reducing the risk of antibiotic misuse. [16] Topical antibiotics applied over certain types of surgical wounds have been reported to reduce the risk of surgical site infections. [17] However, there are certain general causes for concern with topical administration of antibiotics. Some systemic absorption of the antibiotic may occur; the quantity of antibiotic applied is difficult to accurately dose, and there is also the possibility of local hypersensitivity reactions or contact dermatitis occurring. [16]

Prevalence

Antibiotic consumption varies widely between countries. The ‘WHO report on surveillance of antibiotic consumption’ published in 2018 analysed 2015 data from 65 countries. As measured in defined daily doses per 1,000 inhabitants per day. Mongolia had the highest consumption with a rate of 64.4. Burundi had the lowest at 4.4. Amoxicillin and Amoxicillin/clavulanic acid were the most frequently consumed. [18]

Side-effects

Health advocacy messages such as this one encourage patients to talk with their doctor about safety in using antibiotics. Choosing Wisely antibiotics poster small English.pdf
Health advocacy messages such as this one encourage patients to talk with their doctor about safety in using antibiotics.

Antibiotics are screened for any negative effects before their approval for clinical use, and are usually considered safe and well tolerated. However, some antibiotics have been associated with a wide extent of adverse side effects ranging from mild to very severe depending on the type of antibiotic used, the microbes targeted, and the individual patient. [19] [20] Side effects may reflect the pharmacological or toxicological properties of the antibiotic or may involve hypersensitivity or allergic reactions. [4] Adverse effects range from fever and nausea to major allergic reactions, including photodermatitis and anaphylaxis. [21] Safety profiles of newer drugs are often not as well established as for those that have a long history of use. [19]

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 . [22] Antibacterials can also affect the vaginal flora, and may lead to overgrowth of yeast species of the genus Candida in the vulvo-vaginal area. [23] Additional side-effects can result from interaction with other drugs, such as the possibility of tendon damage from the administration of a quinolone antibiotic with a systemic corticosteroid. [24]

Correlation with obesity

Exposure to antibiotics early in life is associated with increased body mass in humans and mouse models. [25] Early life is a critical period for the establishment of the intestinal microbiota and for metabolic development. [26] Mice exposed to subtherapeutic antibiotic treatment (STAT)– with either penicillin, vancomycin, or chlortetracycline had altered composition of the gut microbiota as well as its metabolic capabilities. [27] One study has reported that mice given low-dose penicillin (1 μg/g body weight) around birth and throughout the weaning process had an increased body mass and fat mass, accelerated growth, and increased hepatic expression of genes involved in adipogenesis, compared to control mice. [28] In addition, penicillin in combination with a high-fat diet increased fasting insulin levels in mice. [28] However, it is unclear whether or not antibiotics cause obesity in humans. Studies have found a correlation between early exposure of antibiotics (<6 months) and increased body mass (at 10 and 20 months). [29] Another study found that the type of antibiotic exposure was also significant with the highest risk of being overweight in those given macrolides compared to penicillin and cephalosporin. [30] Therefore, there is correlation between antibiotic exposure in early life and obesity in humans, but whether or not there is a causal relationship remains unclear. Although there is a correlation between antibiotic use in early life and obesity, the effect of antibiotics on obesity in humans needs to be weighed against the beneficial effects of clinically indicated treatment with antibiotics in infancy. [26]

Interactions

Birth control pills

There are few well-controlled studies on whether antibiotic use increases the risk of oral contraceptive failure. [31] The majority of studies indicate antibiotics do not interfere with birth control pills, [32] such as clinical studies that suggest the failure rate of contraceptive pills caused by antibiotics is very low (about 1%). [33] Situations that may increase the risk of oral contraceptive failure include non-compliance (missing taking the pill), vomiting, or diarrhea. Gastrointestinal disorders or interpatient variability in oral contraceptive absorption affecting ethinylestradiol serum levels in the blood. [31] Women with menstrual irregularities may be at higher risk of failure and should be advised to use backup contraception during antibiotic treatment and for one week after its completion. If patient-specific risk factors for reduced oral contraceptive efficacy are suspected, backup contraception is recommended. [31]

In cases where antibiotics have been suggested to affect the efficiency of birth control pills, such as for the broad-spectrum antibiotic 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. [32] 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. [34] [35] Clinicians have recommended that extra contraceptive measures be applied during therapies using antibiotics that are suspected to interact with oral contraceptives. [32] More studies on the possible interactions between antibiotics and birth control pills (oral contraceptives) are required as well as careful assessment of patient-specific risk factors for potential oral contractive pill failure prior to dismissing the need for backup contraception. [31]

Alcohol

Interactions between alcohol and certain antibiotics may occur and may cause side-effects and decreased effectiveness of antibiotic therapy. [36] [37] While moderate alcohol consumption is unlikely to interfere with many common antibiotics, there are specific types of antibiotics, with which alcohol consumption may cause serious side-effects. [38] Therefore, potential risks of side-effects and effectiveness depend on the type of antibiotic administered. [39]

Antibiotics 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. [38] In addition, the efficacy of doxycycline and erythromycin succinate may be reduced by alcohol consumption. [40] Other effects of alcohol on antibiotic activity include altered activity of the liver enzymes that break down the antibiotic compound. [41] However, red wine with a high degree of polyphenols demonstrates in-vitro antibacterial properties. [42]

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. [43] A bactericidal activity of antibacterials may depend on the bacterial growth phase, and it often requires ongoing metabolic activity and division of bacterial cells. [44] These findings are based on laboratory studies, and in clinical settings have also been shown to eliminate bacterial infection. [43] [45] Since the activity of antibacterials depends frequently on its concentration, [46] in vitro characterization of antibacterial activity commonly includes the determination of the minimum inhibitory concentration and minimum bactericidal concentration of an antibacterial. [43] [47] 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. [48]

Combination therapy

In important infectious diseases, including tuberculosis, combination therapy (i.e., the concurrent application of two or more antibiotics) has been used to delay or prevent the emergence of resistance. In acute bacterial infections, antibiotics as part of combination therapy are prescribed for their synergistic effects to improve treatment outcome as the combined effect of both antibiotics is better than their individual effect. [49] [50] Methicillin-resistant Staphylococcus aureus infections may be treated with a combination therapy of fusidic acid and rifampicin. [49] Antibiotics used in combination may also be antagonistic and the combined effects of the two antibiotics may be less than if the individual antibiotic was given as part of a monotherapy. [49] For example, chloramphenicol and tetracyclines are antagonists to penicillins and aminoglycosides. However, this can vary depending on the species of bacteria. [51] In general, combinations of a bacteriostatic antibiotic and bactericidal antibiotic are antagonistic. [49] [50]

Classes

Molecular targets of antibiotics on the bacteria cell Antibiotics action.svg
Molecular targets of antibiotics on the bacteria cell
Protein synthesis inhibitors (antibiotics) Protein synthesis inhibitors antibiotic.png
Protein synthesis inhibitors (antibiotics)

Antibiotics are commonly classified based on their mechanism of action, chemical structure, or spectrum of activity. Most target bacterial functions or growth processes. [52] Those that target the bacterial cell wall (penicillins and cephalosporins) or the cell membrane (polymyxins), or interfere with essential bacterial enzymes (rifamycins, lipiarmycins, quinolones, and sulfonamides) have bactericidal activities. Protein synthesis inhibitors (macrolides, lincosamides, and tetracyclines) are usually bacteriostatic (with the exception of bactericidal aminoglycosides). [53] Further categorization is based on their target specificity. "Narrow-spectrum" antibiotics target specific types of bacteria, such as gram-negative or gram-positive, whereas broad-spectrum antibiotics affect a wide range of bacteria. Following a 40-year break in discovering new classes of antibacterial compounds, four new classes of antibiotics have been brought into clinical use in the late 2000s and early 2010s: cyclic lipopeptides (such as daptomycin), glycylcyclines (such as tigecycline), oxazolidinones (such as linezolid), and lipiarmycins (such as fidaxomicin). [54] [55]

Production

With advances in medicinal chemistry, most modern antibacterials are semisynthetic modifications of various natural compounds. [56] These include, for example, the beta-lactam antibiotics, 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. [56] Many antibacterial compounds are relatively small molecules with a molecular weight of less than 1000 daltons. [57]

Since the first pioneering efforts of Howard 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 ]

Resistance

Scanning electron micrograph of a human neutrophil ingesting methicillin-resistant Staphylococcus aureus (MRSA) Human neutrophil ingesting MRSA.jpg
Scanning electron micrograph of a human neutrophil ingesting methicillin-resistant Staphylococcus aureus (MRSA)

The emergence of resistance of bacteria to antibiotics is a common phenomenon. Emergence of resistance often reflects evolutionary processes that take place during antibiotic therapy. The antibiotic treatment may select for bacterial strains with physiologically or genetically enhanced capacity to survive high doses of antibiotics. Under certain conditions, it may result in preferential growth of resistant bacteria, while growth of susceptible bacteria is inhibited by the drug. [58] For example, antibacterial selection for strains having previously acquired antibacterial-resistance genes was demonstrated in 1943 by the Luria–Delbrück experiment. [59] Antibiotics such as penicillin and erythromycin, which used to have a high efficacy against many bacterial species and strains, have become less effective, due to the increased resistance of many bacterial strains. [60]

Resistance may take the form of biodegredation of pharmaceuticals, such as sulfamethazine-degrading soil bacteria introduced to sulfamethazine through medicated pig feces. [61] The survival of bacteria often results from an inheritable resistance, [62] but the growth of resistance to antibacterials also occurs through horizontal gene transfer. Horizontal transfer is more likely to happen in locations of frequent antibiotic use. [63]

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. [64]

Paleontological data show that both antibiotics and antibiotic resistance are ancient compounds and mechanisms. [65] Useful antibiotic targets are those for which mutations negatively impact bacterial reproduction or viability. [66]

Several molecular mechanisms of antibacterial resistance exist. Intrinsic antibacterial resistance may be part of the genetic makeup of bacterial strains. [67] [68] 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. [67] Antibacterial-producing bacteria have evolved resistance mechanisms that have been shown to be similar to, and may have been transferred to, antibacterial-resistant strains. [69] [70] The spread of antibacterial resistance often occurs through vertical transmission of mutations during growth and by genetic recombination of DNA by horizontal genetic exchange. [62] For instance, antibacterial resistance genes can be exchanged between different bacterial strains or species via plasmids that carry these resistance genes. [62] [71] Plasmids that carry several different resistance genes can confer resistance to multiple antibacterials. [71] 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. [71]

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 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. [72] For example, NDM-1 is a newly identified enzyme conveying bacterial resistance to a broad range of beta-lactam antibacterials. [73] The United Kingdom's Health Protection Agency has stated that "most isolates with NDM-1 enzyme are resistant to all standard intravenous antibiotics for treatment of severe infections." [74] On 26 May 2016 an E coli bacteria "superbug" was identified in the United States resistant to colistin, "the last line of defence" antibiotic. [75] [76]

Misuse

This poster from the US 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. CDC Get Smart poster healthy adult.png
This poster from the US 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.

Per The ICU Book "The first rule of antibiotics is try not to use them, and the second rule is try not to use too many of them." [77] Inappropriate antibiotic treatment and overuse of antibiotics have contributed to the emergence of antibiotic-resistant bacteria. Self-prescribing of antibiotics is an example of misuse. [78] Many antibiotics are frequently prescribed to treat symptoms or diseases that do not respond to antibiotics or that are likely to resolve without treatment. Also, incorrect or suboptimal antibiotics are prescribed for certain bacterial infections. [19] [78] The overuse of antibiotics, like penicillin and erythromycin, has been associated with emerging antibiotic resistance since the 1950s. [60] [79] Widespread usage of antibiotics in hospitals has also been associated with increases in bacterial strains and species that no longer respond to treatment with the most common antibiotics. [79]

Common forms of antibiotic misuse include excessive use of prophylactic antibiotics in travelers and failure of medical professionals to prescribe the correct dosage of antibiotics 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 antibiotic, incorrect dosage and administration, or failure to rest for sufficient recovery. Inappropriate antibiotic treatment, for example, is their prescription 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". [80] Multifactorial interventions aimed at both physicians and patients can reduce inappropriate prescription of antibiotics. [81] [82]

Several organizations concerned with antimicrobial resistance are lobbying to eliminate the unnecessary use of antibiotics. [78] The issues of misuse and overuse of antibiotics have been addressed by the formation of the US 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. [83] An NGO campaign group is Keep Antibiotics Working. [84] In France, an "Antibiotics are not automatic" government campaign started in 2002 and led to a marked reduction of unnecessary antibiotic prescriptions, especially in children. [85]

The emergence of antibiotic resistance has prompted restrictions on their use in the UK in 1970 (Swann report 1969), and the EU has banned the use of antibiotics as growth-promotional agents since 2003. [86] Moreover, several organizations (including the World Health Organization, the National Academy of Sciences, and the U.S. Food and Drug Administration) have advocated restricting the amount of antibiotic use in food animal production. [87] However, commonly there are delays in regulatory and legislative actions to limit the use of antibiotics, attributable partly to resistance against such regulation by industries using or selling antibiotics, and to the time required for research to test causal links between their use and resistance to them. Two federal bills (S.742 [88] and H.R. 2562 [89] ) aimed at phasing out nontherapeutic use of antibiotics in US food animals were proposed, but have not passed. [88] [89] 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). [90]

Despite pledges by food companies and restaurants to reduce or eliminate meat that comes from animals treated with antibiotics, the purchase of antibiotics for use on farm animals has been increasing every year. [91]

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 US Food and Drug Administration (FDA) 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. [92]

History

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 2,000 years ago. [93] Many ancient cultures, including the ancient Egyptians and ancient Greeks, used specially selected mold and plant materials and extracts to treat infections. [94] [95]

The use of antibiotics in modern medicine began with the discovery of synthetic antibiotics derived from dyes. [52] [96] [97] [98] [99]

Synthetic antibiotics derived from dyes

Arsphenamine, also known as salvarsan, discovered in 1907 by Paul Ehrlich. Salvarsan-montage.png
Arsphenamine, also known as salvarsan, discovered in 1907 by Paul Ehrlich.

Synthetic antibiotic chemotherapy as a science and development of antibacterials began in Germany with Paul Ehrlich in the late 1880s. [52] Ehrlich noted certain dyes would color human, animal, or bacterial cells, whereas 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, in 1907, he discovered a medicinally useful drug, the first synthetic antibacterial salvarsan [52] [96] [97] now called arsphenamine.

Paul Ehrlich and Sahachiro Hata Paul Ehrlich and Sahachiro Hata.jpg
Paul Ehrlich and Sahachiro Hata

The era of antibacterial treatment began with the discoveries of arsenic-derived synthetic antibiotics by Alfred Bertheim and Ehrlich in 1907. [98] [99] Ehrlich and Bertheim experimented with various chemicals derived from dyes to treat trypanosomiasis in mice and spirochaeta infection in rabbits. While their early compounds were too toxic, Ehrlich and Sahachiro Hata, a Japanese bacteriologist working with Erlich in the quest for a drug to treat syphilis, achieved success with the 606th compound in their series of experiments. In 1910 Ehrlich and Hata announced their discovery, which they called drug "606", at the Congress for Internal Medicine at Wiesbaden. [100] The Hoechst company began to market the compound toward the end of 1910 under the name Salvarsan. This drug is now known as arsphenamine. [100] The drug was used to treat syphilis in the first half of the 20th century. In 1908, Ehrlich received the Nobel Prize in Physiology or Medicine for his contributions to immunology. [101] Hata was nominated for the Nobel Prize in Chemistry in 1911 and for the Nobel Prize in Physiology or Medicine in 1912 and 1913. [102]

The first sulfonamide and the first systemically active antibacterial drug, Prontosil, was developed by a research team led by Gerhard Domagk in 1932 or 1933 at the Bayer Laboratories of the IG Farben conglomerate in Germany, [99] [103] [97] for which Domagk received the 1939 Nobel Prize in Physiology or Medicine. [104] Sulfanilamide, the active drug of Prontosil, was not patentable as it had already been in use in the dye industry for some years. [103] 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 antibacterials. [105] [106]

Penicillin and other natural antibiotics

Penicillin, discovered by Alexander Fleming in 1928 Penicillin core.svg
Penicillin, discovered by Alexander Fleming in 1928

Observations about the growth of some microorganisms inhibiting the growth of other microorganisms have been reported since the late 19th century. These observations of antibiosis between microorganisms led to the discovery of natural antibacterials. Louis Pasteur observed, "if we could intervene in the antagonism observed between some bacteria, it would offer perhaps the greatest hopes for therapeutics". [107]

In 1874, physician Sir William Roberts noted that cultures of the mold Penicillium glaucum that is used in the making of some types of blue cheese did not display bacterial contamination. [108] In 1876, physicist John Tyndall also contributed to this field. [109] Pasteur conducted research showing that Bacillus anthracis would not grow in the presence of the related mold Penicillium notatum .

In 1895 Vincenzo Tiberio, Italian physician, published a paper on the antibacterial power of some extracts of mold. [110]

In 1897, doctoral student Ernest Duchesne submitted a dissertation, "Contribution à l'étude de la concurrence vitale chez les micro-organismes: antagonisme entre les moisissures et les microbes" (Contribution to the study of vital competition in micro-organisms: antagonism between molds and microbes), [111] the first known scholarly work to consider the therapeutic capabilities of molds resulting from their anti-microbial activity. In his thesis, Duchesne proposed that bacteria and molds engage in a perpetual battle for survival. Duchesne observed that E. coli was eliminated by Penicillium glaucum when they were both grown in the same culture. He also observed that when he inoculated laboratory animals with lethal doses of typhoid bacilli together with Penicillium glaucum, the animals did not contract typhoid. Unfortunately Duchesne's army service after getting his degree prevented him from doing any further research. [112] Duchesne died of tuberculosis, a disease now treated by antibiotics. [112]

Alexander Fleming was awarded a Nobel prize for his role in the discovery of penicillin Alexander Fleming.jpg
Alexander Fleming was awarded a Nobel prize for his role in the discovery of penicillin

In 1928, Sir Alexander Fleming postulated the existence of penicillin, a molecule produced by certain molds that kills or stops the growth of certain kinds of bacteria. Fleming was working on a culture of disease-causing bacteria when he noticed the spores of a green mold, Penicillium chrysogenum , in one of his culture plates. He observed that the presence of the mold killed or prevented the growth of the bacteria. [113] Fleming postulated that the mold must secrete an antibacterial substance, which he named penicillin in 1928. Fleming believed that its antibacterial properties could be exploited for chemotherapy. He initially characterized some of its biological properties, and attempted to use a crude preparation to treat some infections, but he was unable to pursue its further development without the aid of trained chemists. [114] [115]

Ernst Chain, Howard Florey and Edward Abraham succeeded in purifying the first penicillin, penicillin G, in 1942, but it did not become widely available outside the Allied military before 1945. Later, Norman Heatley developed the back extraction technique for efficiently purifying penicillin in bulk. The chemical structure of penicillin was first proposed by Abraham in 1942 [116] and then later confirmed by Dorothy Crowfoot Hodgkin in 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. (see below) The development of penicillin led to renewed interest in the search for antibiotic compounds with similar efficacy and safety. [117] For their successful development of penicillin, which Fleming had accidentally discovered but could not develop himself, as a therapeutic drug, Chain and Florey shared the 1945 Nobel Prize in Medicine with Fleming. [118]

Florey credited Rene 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. [119] In 1939, coinciding with the start of World War II, Dubos had reported the discovery of the first naturally derived antibiotic, tyrothricin, a compound of 20% gramicidin and 80% tyrocidine, from B. brevis. It was one of the first commercially manufactured antibiotics and was very effective in treating wounds and ulcers during World War II. [119] Gramicidin, however, could not be used systemically because of toxicity. Tyrocidine also proved too toxic for systemic usage. Research results obtained during that period were not shared between the Axis and the Allied powers during World War II and limited access during the Cold War. [120]

Etymology

The term 'antibiosis', meaning "against life", was introduced by the French bacteriologist Jean Paul Vuillemin as a descriptive name of the phenomenon exhibited by these early antibacterial drugs. [52] [121] [122] 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 . [121] [123] These drugs were later renamed antibiotics by Selman Waksman, an American microbiologist, in 1942. [52] [121] [124]

The term antibiotic was first used in 1942 by Selman Waksman and his collaborators in journal articles to describe any substance produced by a microorganism that is antagonistic to the growth of other microorganisms in high dilution. [121] [124] This definition excluded substances that kill bacteria but that are not produced by microorganisms (such as gastric juices and hydrogen peroxide). It also excluded synthetic antibacterial compounds such as the sulfonamides. In current usage, the term "antibiotic" is applied to any medication that kills bacteria or inhibits their growth, regardless of whether that medication is produced by a microorganism or not. [125] [126]

The term "antibiotic" derives from anti + βιωτικός (biōtikos), "fit for life, lively", [127] which comes from βίωσις (biōsis), "way of life", [128] and that from βίος (bios), "life". [41] [129] The term "antibacterial" derives from Greek ἀντί (anti), "against" [130] + βακτήριον (baktērion), diminutive of βακτηρία (baktēria), "staff, cane", [131] because the first bacteria to be discovered were rod-shaped. [132]

Research

Alternatives

The increase in bacterial strains that are resistant to conventional antibacterial therapies together with decreasing number of new antibiotics currently being developed in the drug pipeline has prompted the development of bacterial disease treatment strategies that are alternatives to conventional antibacterials. [133] [134] Non-compound approaches (that is, products other than classical antibacterial agents) that target bacteria or approaches that target the host including phage therapy and vaccines are also being investigated to combat the problem. [135]

Resistance and modifying agents

One strategy to address bacterial drug resistance is the discovery and application of compounds that modify resistance to common antibacterials. Resistance modifying agents are capable of partly or completely suppressing bacterial resistance mechanisms. [136] 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. [136] [137] Targets include:

Metabolic stimuli such as sugar can help eradicate a certain type of antibiotic-tolerant bacteria by keeping their metabolism active. [139]

Vaccines

Vaccines rely on immune modulation or augmentation. Vaccination either excites or reinforces the immune competence 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. [140] 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. [141]

Phage therapy

Phage injecting its genome into bacterial cell Phage injecting its genome into bacteria.svg
Phage injecting its genome into bacterial cell

Phage therapy is another method for treating antibiotic-resistant strains of bacteria. Phage therapy infects pathogenic bacteria with their own viruses. Bacteriophages and their host ranges are extremely specific for certain bacteria, thus they do not disturb the host organism and intestinal microflora unlike antibiotics. [142] Bacteriophages, also known simply as phages, infect and can kill bacteria and affect bacterial growth primarily during lytic cycles. [142] [143] Phages insert their DNA into the bacterium, where it is transcribed and used to make new phages, after which the cell will lyse, releasing new phage able to infect and destroy further bacteria of the same strain. [143] The high specificity of phage protects "good" bacteria from destruction. However, some disadvantages to use of bacteriophages also exist. Bacteriophages may harbour virulence factors or toxic genes in their genomes and identification of genes with similarity to known virulence factors or toxins by genomic sequencing may be prudent prior to use. In addition, the oral and IV administration of phages for the eradication of bacterial infections poses a much higher safety risk than topical application, and there is the additional concern of uncertain immune responses to these large antigenic cocktails. There are considerable regulatory hurdles that must be cleared for such therapies. [142] The use of bacteriophages as a replacement for antimicrobial agents against MDR pathogens no longer respond to conventional antibiotics remains an attractive option despite numerous challenges. [142] [144]

Phytochemicals

Plants are an important source of antimicrobial compounds and traditional healers have long used plants to prevent or cure infectious diseases. [145] [146] There is a recent renewed interest into the use of natural products for the identification of new members of the 'antibiotic-ome' (defined as natural products with antibiotic activity), and their application in antibacterial drug discovery in the genomics era. [133] [147] Phytochemicals are the active biological component of plants and some phytochemicals including tannins, alkaloids, terpenoids, and flavonoids possess antimicrobial activity. [145] [148] [149] Some antioxidant dietary supplements also contain phytochemicals (polyphenols), such as grape seed extract, and demonstrate in vitro anti-bacterial properties. [150] [151] [152] Phytochemicals are able to inhibit peptidoglycan synthesis, damage microbial membrane structures, modify bacterial membrane surface hydrophobicity and also modulate quorum sensing. [148] With increasing antibiotic resistance in recent years, the potential of new plant-derived antibiotics is under investigation. [147]

New antibiotics development

Both the WHO and the Infectious Disease Society of America (IDSA) reported that the weak antibiotic pipeline does not match bacteria's increasing ability to develop resistance. [153] [154] The IDSA report noted that the number of new antibiotics approved for marketing per year had been declining and identified seven antibiotics against the Gram-negative bacilli (GNB) currently in phase 2 or phase 3 clinical trials. These drugs however, did not address the entire spectrum of resistance of GNB. [155] [156] According to the WHO fifty one new therapeutic entities (NTEs) - antibiotics (including combinations), are in phase 1-3 clinical trials as of May 2017. [153] Recent entries in the clinical pipeline targeting multidrug-resistant Gram-positive pathogens has improved the treatment options due to marketing approval of new antibiotic classes, the oxazolidinones and cyclic lipopeptides. However, resistance to these antibiotics is certainly likely to occur, the need for the development new antibiotics against those pathogens still remains a high priority. [157] [153] Recent drugs in development that target Gram-negative bacteria have focused on re-working existing drugs to target specific microorganisms or specific types of resistance. [153]

A few antibiotics have received marketing authorization in the last seven years. The cephalosporin ceftaroline and the lipoglycopeptides oritavancin and telavancin for the treatment of acute bacterial skin and skin structure infection and community-acquired bacterial pneumonia. [158] The lipoglycopeptide dalbavancin and the oxazolidinone tedizolid has also been approved for use for the treatment of acute bacterial skin and skin structure infection. The first in a new class of narrow spectrum macrocyclic antibiotics, fidaxomicin, has been approved for the treatment of C. difficile colitis. [158] New cephalosporin-lactamase inhibitor combinations also approved include ceftazidime-avibactam and ceftolozane-avibactam for complicated urinary tract infection and intra-abdominal infection. [158]

Streptomyces research is expected to provide new antibiotics, including treatment against MRSA and infections resistant to commonly used medication. Efforts of John Innes Centre and universities in the UK, supported by BBSRC, resulted in the creation of spin-out companies, for example Novacta Biosystems, which has designed the type-b lantibiotic-based compound NVB302 (in phase 1) to treat Clostridium difficile infections. [160]

Possible improvements include clarification of clinical trial regulations by FDA. Furthermore, appropriate economic incentives could persuade pharmaceutical companies to invest in this endeavor. [156] In the US, the Antibiotic Development to Advance Patient Treatment (ADAPT) Act was introduced with the aim of fast tracking the drug development of antibiotics to combat the growing threat of 'superbugs'. Under this Act, FDA can approve antibiotics and antifungals treating life-threatening infections based on smaller clinical trials. The CDC will monitor the use of antibiotics and the emerging resistance, and publish the data. The FDA antibiotics labeling process, 'Susceptibility Test Interpretive Criteria for Microbial Organisms' or 'breakpoints', will provide accurate data to healthcare professionals. [161] According to Allan Coukell, senior director for health programs at The Pew Charitable Trusts, "By allowing drug developers to rely on smaller datasets, and clarifying FDA's authority to tolerate a higher level of uncertainty for these drugs when making a risk/benefit calculation, ADAPT would make the clinical trials more feasible." [162]

See also

Related Research Articles

Antimicrobial resistance ability of a microbe to resist the effects of medication

Antimicrobial resistance is the ability of a microbe to resist the effects of medication that once could successfully treat the microbe. The term antibiotic resistance is a subset of AMR, as it applies only to bacteria becoming resistant to antibiotics. Resistant microbes are more difficult to treat, requiring alternative medications or higher doses of antimicrobials. These approaches may be more expensive, more toxic or both. Microbes resistant to multiple antimicrobials are called multidrug resistant (MDR). Those considered extensively drug resistant (XDR) or totally drug resistant (TDR) are sometimes called "superbugs".

Macrolide A group of often glycosylated macrocyclic compounds formed by chain extension of multiple PROPIONATES cyclized into a large (typically 12, 14, or 16)-membered lactone

The macrolides are a class of natural products that consist of a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered. Macrolides belong to the polyketide class of natural products. Some macrolides have antibiotic or antifungal activity and are used as pharmaceutical drugs.

Drug resistance is the reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition. The term is used in the context of resistance that pathogens or cancers have "acquired", that is, resistance has evolved. Antimicrobial resistance and antineoplastic resistance challenge clinical care and drive research. When an organism is resistant to more than one drug, it is said to be multidrug-resistant. The immune system of an organism is in essence a drug delivery system.

Linezolid chemical compound

Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics. Linezolid is active against most Gram-positive bacteria that cause disease, including streptococci, vancomycin-resistant enterococci (VRE), and methicillin-resistant Staphylococcus aureus (MRSA). The main uses are infections of the skin and pneumonia although it may be used for a variety of other infections including drug resistant tuberculosis. It is used either by injection into a vein or by mouth.

Broad-spectrum antibiotic type of antibiotic

The term broad-spectrum antibiotic can refer to an antibiotic that acts on the two major bacterial groups, gram-positive and gram-negative, or any antibiotic that acts against a wide range of disease-causing bacteria. These medications are used when a bacterial infection is suspected but the group of bacteria is unknown or when infection with multiple groups of bacteria is suspected. This is in contrast to a narrow-spectrum antibiotic, which is effective against only a specific group of bacteria. Although powerful, broad-spectrum antibiotics pose specific risks, particularly the disruption of native, normal bacteria and the development of antimicrobial resistance. An example of a commonly used broad-spectrum antibiotic is ampicillin.

Multiple drug resistance (MDR), multidrug resistance or multiresistance is antimicrobial resistance shown by a species of microorganism to multiple antimicrobial drugs. The types most threatening to public health are MDR bacteria that resist multiple antibiotics; other types include MDR viruses, parasites. Recognizing different degrees of MDR, the terms extensively drug resistant (XDR) and pandrug-resistant (PDR) have been introduced. The definitions were published in 2011 in the journal Clinical Microbiology and Infection and are openly accessible.

Carbapenem group of β-lactam antibiotics

Carbapenems are a class of highly effective antibiotic agents commonly used for the treatment of severe or high-risk bacterial infections. This class of antibiotics is usually reserved for known or suspected multidrug-resistant (MDR) bacterial infections. Similar to penicillins and cephalosporins, carbapenems are members of the beta lactam class of antibiotics, which kill bacteria by binding to penicillin-binding proteins, thus inhibiting bacterial cell wall synthesis. However, these agents individually exhibit a broader spectrum of activity compared to most cephalosporins and penicillins. Furthermore, carbapenems are typically unaffected by emerging antibiotic resistance, even to other beta-lactams.

Ampicillin/sulbactam is a combination of the common penicillin-derived antibiotic ampicillin and sulbactam, an inhibitor of bacterial beta-lactamase. Two different forms of the drug exist. The first, developed in 1987 and marketed in the United States under the tradename Unasyn, generic only outside the United States, is an intravenous antibiotic. The second, an oral form called sultamicillin, is marketed under the trade name Ampictam outside the United States. And generic only in the United States, ampicillin/sulbactam is used to treat infections caused by bacteria resistant to beta-lactam antibiotics. Sulbactam blocks the enzyme which breaks down ampicillin and thereby allows ampicillin to attack and kill the bacteria.

Lincosamides group of chemical compounds

Lincosamides are a class of antibiotics, which include lincomycin, clindamycin, and pirlimycin.

Dicloxacillin chemical compound

Dicloxacillin is a narrow-spectrum β-lactam antibiotic of the penicillin class. It is used to treat infections caused by susceptible (non-resistant) Gram-positive bacteria. It is active against beta-lactamase-producing organisms such as Staphylococcus aureus, which would otherwise be resistant to most penicillins. Dicloxacillin is available under a variety of trade names including Diclocil (BMS).

Tetracycline antibiotics type of broad-spectrum antibiotic

Tetracyclines are a group of broad-spectrum antibiotic compounds that have a common basic structure and are either isolated directly from several species of Streptomyces bacteria or produced semi-synthetically from those isolated compounds. Tetracycline molecules comprise a linear fused tetracyclic nucleus to which a variety of functional groups are attached. Tetracyclines are named for their four ("tetra-") hydrocarbon rings ("-cycl-") derivation ("-ine"). They are defined as a subclass of polyketides, having an octahydrotetracene-2-carboxamide skeleton and are known as derivatives of polycyclic naphthacene carboxamide. While all tetracyclines have a common structure, they differ from each other by the presence of chloride, methyl, and hydroxyl groups. These modifications do not change their broad antibacterial activity, but do affect pharmacological properties such as half-life and binding to proteins in serum.

In microbiology, the minimum inhibitory concentration (MIC) is the lowest concentration of a chemical, usually a drug, which prevents visible growth of bacterium. MIC depends on the microorganism, the affected human being, and the antibiotic itself.

Fosfomycin chemical compound

Fosfomycin is a broad-spectrum antibiotic produced by certain Streptomyces species, although it can now be made by chemical synthesis.

β-Lactamase inhibitor Endogenous substances and drugs that inhibit or block the activity of beta-lactamases

Beta-lactamases are a family of enzymes involved in bacterial resistance to beta-lactam antibiotics. They act by breaking the beta-lactam ring that allows penicillin-like antibiotics to work. Strategies for combating this form of resistance have included the development of new beta-lactam antibiotics that are more resistant to cleavage and the development of the class of enzyme inhibitors called beta-lactamase inhibitors. Although β-lactamase inhibitors have little antibiotic activity of their own, they prevent bacterial degradation of beta-lactam antibiotics and thus extend the range of bacteria the drugs are effective against.

Multidrug tolerance or antibiotic tolerance is the ability of a disease-causing microorganism to resist being killed by antibiotics or other antimicrobials. It is mechanistically distinct from multidrug resistance: It is not caused by mutant microbes, but rather by microbial cells that exist in a transient, dormant, non-dividing state. Microorganisms that display multidrug tolerance can be bacteria, fungi or parasites.

Quinolone antibiotic class of pharmaceutical drugs, subgroup of quinolones

A quinolone antibiotic is a member of a large group of broad-spectrum bactericides that share a bicyclic core structure related to the compound 4-quinolone. They are used in human and veterinary medicine to treat bacterial infections, as well as in animal husbandry.

Cephalosporins are a broad class of bactericidal antibiotics that include the β-lactam ring and share a structural similarity and mechanism of action with other β-lactam antibiotics. The cephalosporins have the ability to kill bacteria by inhibiting essential steps in the bacterial cell wall synthesis which in the end results in osmotic lysis and death of the bacterial cell. Cephalosporins are widely used antibiotics because of their clinical efficiency and desirable safety profile.

The Eagle effect, Eagle phenomenon, or paradoxical zone phenomenon, named after Harry Eagle who first described it, originally referred to the paradoxically reduced antibacterial effect of penicillin at high doses, though recent usage generally refers to the relative lack of efficacy of beta lactam antibacterial drugs on infections having large numbers of bacteria. The former effect is paradoxical because the effectiveness of an antibiotic generally rises with increasing drug concentration.

Antibiotic synergy is one of three responses possible when two or more antibiotics are used simultaneously to treat an infection. In the synergistic response, the applied antibiotics work together to produce an effect more potent than if each antibiotic were applied singly. Compare to the additive effect, where the potency of an antibiotic combination is roughly equal to the combined potencies of each antibiotic singly, and antagonistic effect, where the potency of the combination is less than the combined potencies of each antibiotic.

References

  1. 1 2 3 "Antibiotics". NHS. 5 June 2014. Retrieved 17 January 2015.
  2. "Factsheet for experts". European Centre for Disease Prevention and Control. Retrieved 21 December 2014.
  3. For example, metronidazole: "Metronidazole". The American Society of Health-System Pharmacists. Retrieved 31 July 2015.
  4. 1 2 Chemical Analysis of Antibiotic Residues in Food (PDF). John Wiley & Sons, Inc. 2012. pp. 1–60. ISBN   978-1-4496-1459-1.
  5. "General Background: Antibiotic Agents". Alliance for the Prudent Use of Antibiotics. Retrieved 21 December 2014.
  6. Gould, K (2016). "Antibiotics: From prehistory to the present day". Journal of Antimicrobial Chemotherapy. 71 (3): 572–575. doi:10.1093/jac/dkv484.
  7. Gualerzi CO, Brandi L, Fabbretti A, Pon CL (4 December 2013). Antibiotics: Targets, Mechanisms and Resistance. John Wiley & Sons. p. 1. ISBN   978-3-527-33305-9.
  8. Brooks M (16 November 2015). "Public Confused About Antibiotic Resistance, WHO Says". Medscape Multispeciality. Retrieved 21 November 2015.
  9. Antimicrobial resistance: global report on surveillance (PDF). The World Health Organization. April 2014. ISBN   978-92-4-156474-8 . Retrieved 13 June 2016.
  10. 1 2 3 Antibiotics Simplified. Jones & Bartlett Publishers. 2011. pp. 15–17. ISBN   978-1-4496-1459-1.
  11. 1 2 3 4 Leekha S, Terrell CL, Edson RS (February 2011). "General principles of antimicrobial therapy". Mayo Clinic Proceedings. 86 (2): 156–67. doi:10.4065/mcp.2010.0639. PMC   3031442 . PMID   21282489.
  12. Rollins KE, Varadhan KK, Neal KR, Lobo DN (October 2016). "Antibiotics Versus Appendicectomy for the Treatment of Uncomplicated Acute Appendicitis: An Updated Meta-Analysis of Randomised Controlled Trials". World Journal of Surgery. 40 (10): 2305–18. doi:10.1007/s00268-016-3561-7. PMID   27199000.
  13. Flowers CR, Seidenfeld J, Bow EJ, Karten C, Gleason C, Hawley DK, Kuderer NM, Langston AA, Marr KA, Rolston KV, Ramsey SD (February 2013). "Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline". Journal of Clinical Oncology. 31 (6): 794–810. doi:10.1200/JCO.2012.45.8661. PMID   23319691.
  14. Bow EJ (July 2013). "Infection in neutropenic patients with cancer". Critical Care Clinics. 29 (3): 411–41. doi:10.1016/j.ccc.2013.03.002. PMID   23830647.
  15. Pangilinan R, Tice A, Tillotson G (October 2009). "Topical antibiotic treatment for uncomplicated skin and skin structure infections: review of the literature". Expert Review of Anti-Infective Therapy. 7 (8): 957–65. doi:10.1586/eri.09.74. PMID   19803705.
  16. 1 2 Lipsky BA, Hoey C (November 2009). "Topical antimicrobial therapy for treating chronic wounds". Clinical Infectious Diseases. 49 (10): 1541–9. doi:10.1086/644732. PMID   19842981.
  17. Heal CF, Banks JL, Lepper PD, Kontopantelis E, van Driel ML (November 2016). "Topical antibiotics for preventing surgical site infection in wounds healing by primary intention" (PDF). The Cochrane Database of Systematic Reviews. 11 (11): CD011426. doi:10.1002/14651858.CD011426.pub2. PMID   27819748.
  18. "UK antibiotic consumption twice that of the Netherlands, WHO report finds". Pharmaceutical Journal. 14 November 2018. Retrieved 22 December 2018.
  19. 1 2 3 Slama TG, Amin A, Brunton SA, File TM, Milkovich G, Rodvold KA, Sahm DF, Varon J, Weiland D (July 2005). "A clinician's guide to the appropriate and accurate use of antibiotics: the Council for Appropriate and Rational Antibiotic Therapy (CARAT) criteria". The American Journal of Medicine. 118 Suppl 7A (7): 1S–6S. doi:10.1016/j.amjmed.2005.05.007. PMID   15993671.
  20. Slama, T. G.; Amin, A.; Brunton, S. A.; File Jr, T. M.; Milkovich, G.; Rodvold, K. A.; Sahm, D. F.; Varon, J.; Weiland Jr, D.; Council for Appropriate Rational Antibiotic Therapy (CARAT) (2005). "A clinician's guide to the appropriate and accurate use of antibiotics: The Council for Appropriate and Rational Antibiotic Therapy (CARAT) criteria". The American Journal of Medicine. 118 Suppl 7A (7): 1S–6S. doi:10.1016/j.amjmed.2005.05.007. PMID   15993671.
  21. "Antibiotics – Side effects". NHS Choices. National Health Service (NHS), UK. 6 May 2014. Retrieved 6 February 2016.
  22. "Antibiotic-Associated Diarrhea – All you should know" . Retrieved 28 December 2014.
  23. Pirotta MV, Garland SM (September 2006). "Genital Candida species detected in samples from women in Melbourne, Australia, before and after treatment with antibiotics". Journal of Clinical Microbiology. 44 (9): 3213–7. doi:10.1128/JCM.00218-06. PMC   1594690 . PMID   16954250.
  24. Lewis T, Cook J (1 January 2014). "Fluoroquinolones and tendinopathy: a guide for athletes and sports clinicians and a systematic review of the literature". Journal of Athletic Training. 49 (3): 422–7. doi:10.4085/1062-6050-49.2.09. PMC   4080593 . PMID   24762232.
  25. Ray K (November 2012). "Gut microbiota: adding weight to the microbiota's role in obesity--exposure to antibiotics early in life can lead to increased adiposity". Nature Reviews. Endocrinology. 8 (11): 623. doi:10.1038/nrendo.2012.173. PMID   22965166.
  26. 1 2 Jess T (December 2014). "Microbiota, antibiotics, and obesity". The New England Journal of Medicine. 371 (26): 2526–8. doi:10.1056/NEJMcibr1409799. PMID   25539109.
  27. Cho I, Yamanishi S, Cox L, Methé BA, Zavadil J, Li K, Gao Z, Mahana D, Raju K, Teitler I, Li H, Alekseyenko AV, Blaser MJ (August 2012). "Antibiotics in early life alter the murine colonic microbiome and adiposity". Nature. 488 (7413): 621–6. Bibcode:2012Natur.488..621C. doi:10.1038/nature11400. PMC   3553221 . PMID   22914093.
  28. 1 2 Cox LM, Yamanishi S, Sohn J, Alekseyenko AV, Leung JM, Cho I, Kim SG, Li H, Gao Z, Mahana D, Zárate Rodriguez JG, Rogers AB, Robine N, Loke P, Blaser MJ (August 2014). "Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences". Cell. 158 (4): 705–721. doi:10.1016/j.cell.2014.05.052. PMC   4134513 . PMID   25126780.
  29. Trasande L, Blustein J, Liu M, Corwin E, Cox LM, Blaser MJ (January 2013). "Infant antibiotic exposures and early-life body mass". International Journal of Obesity. 37 (1): 16–23. doi:10.1038/ijo.2012.132. PMC   3798029 . PMID   22907693.
  30. Thorpe K, Staton S, Sawyer E, Pattinson C, Haden C, Smith S (July 2015). "Napping, development and health from 0 to 5 years: a systematic review". Archives of Disease in Childhood. 100 (7): 615–22. doi:10.1136/archdischild-2014-307241. PMID   25691291.
  31. 1 2 3 4 Anderson KC, Schwartz MD, Lieu SO (January 2013). "Antibiotics and OC effectiveness". Jaapa. 26 (1): 11. doi:10.1097/01720610-201301000-00002. PMID   23355994.
  32. 1 2 3 Weaver K, Glasier A (February 1999). "Interaction between broad-spectrum antibiotics and the combined oral contraceptive pill. A literature review". Contraception. 59 (2): 71–8. doi:10.1016/S0010-7824(99)00009-8. PMID   10361620.
  33. Weisberg E (May 1999). "Interactions between oral contraceptives and antifungals/antibacterials. Is contraceptive failure the result?". Clinical Pharmacokinetics. 36 (5): 309–13. doi:10.2165/00003088-199936050-00001. PMID   10384856.
  34. Hassan T (March 1987). "Pharmacologic considerations for patients taking oral contraceptives". Connecticut Dental Student Journal. 7: 7–8. PMID   3155374.
  35. Orme ML, Back DJ (December 1990). "Factors affecting the enterohepatic circulation of oral contraceptive steroids". American Journal of Obstetrics and Gynecology. 163 (6 Pt 2): 2146–52. doi:10.1016/0002-9378(90)90555-L. PMID   2256523. Archived from the original on 18 November 2010.
  36. Lwanga J, Mears, Bingham JS, Bradbeer CS (2008). "Do antibiotics and alcohol mix? The beliefs of genitourinary clinic attendees". BMJ. 337: a2885. doi:10.1136/bmj.a2885.
  37. "antibiotics-and-alcohol". Archived from the original on 18 November 2010., Mayo Clinic
  38. 1 2 "Can I drink alcohol while taking antibiotics?". NHS Direct (UK electronic health service). Archived from the original on 18 November 2010. Retrieved 17 February 2008.
  39. Moore AA, Whiteman EJ, Ward KT (March 2007). "Risks of combined alcohol/medication use in older adults". The American Journal of Geriatric Pharmacotherapy. 5 (1): 64–74. doi:10.1016/j.amjopharm.2007.03.006. PMC   4063202 . PMID   17608249.
  40. Stockley, IH (2002). Stockley's Drug Interactions (6th ed.). London: Pharmaceutical Press.[ page needed ]
  41. 1 2 "Antibiotics FAQ". McGill University, Canada. Archived from the original on 16 February 2008. Retrieved 17 February 2008.
  42. Arianna Di Lorenzo (2016). "Effect of Winemaking on the Composition of Red Wine as a Source of Polyphenols for Anti-Infective Biomaterials". Materials (Basel). 9 (5): 316. Bibcode:2016Mate....9..316D. doi:10.3390/ma9050316. PMC   5503068 . PMID   28773444.
  43. 1 2 3 Pankey GA, Sabath LD (March 2004). "Clinical relevance of bacteriostatic versus bactericidal mechanisms of action in the treatment of Gram-positive bacterial infections". Clinical Infectious Diseases. 38 (6): 864–70. doi:10.1086/381972. PMID   14999632.
  44. Mascio CT, Alder JD, Silverman JA (December 2007). "Bactericidal action of daptomycin against stationary-phase and nondividing Staphylococcus aureus cells". Antimicrobial Agents and Chemotherapy. 51 (12): 4255–60. doi:10.1128/AAC.00824-07. PMC   2167999 . PMID   17923487.
  45. Pelczar MJ, Chan EC, Krieg NR (2010). "Host-Parasite Interaction; Nonspecific Host Resistance". Microbiology Concepts and Applications (6th ed.). New York: McGraw-Hill. pp. 478–479.
  46. Rhee KY, Gardiner DF (September 2004). "Clinical relevance of bacteriostatic versus bactericidal activity in the treatment of gram-positive bacterial infections". Clinical Infectious Diseases. 39 (5): 755–6. doi:10.1086/422881. PMID   15356797.
  47. Wiegand I, Hilpert K, Hancock RE (January 2008). "Agar and broth dilution methods to determine the minimal inhibitory concentration (MIC) of antimicrobial substances". Nature Protocols. 3 (2): 163–75. doi:10.1038/nprot.2007.521. PMID   18274517.
  48. Dalhoff A, Ambrose PG, Mouton JW (August 2009). "A long journey from minimum inhibitory concentration testing to clinically predictive breakpoints: deterministic and probabilistic approaches in deriving breakpoints". Infection. 37 (4): 296–305. doi:10.1007/s15010-009-7108-9. PMID   19629383.
  49. 1 2 3 4 Ocampo PS, Lázár V, Papp B, Arnoldini M, Abel zur Wiesch P, Busa-Fekete R, Fekete G, Pál C, Ackermann M, Bonhoeffer S (August 2014). "Antagonism between bacteriostatic and bactericidal antibiotics is prevalent". Antimicrobial Agents and Chemotherapy. 58 (8): 4573–82. doi:10.1128/AAC.02463-14. PMC   4135978 . PMID   24867991.
  50. 1 2 Bollenbach T (October 2015). "Antimicrobial interactions: mechanisms and implications for drug discovery and resistance evolution". Current Opinion in Microbiology. 27: 1–9. doi:10.1016/j.mib.2015.05.008. PMID   26042389.
  51. "antagonism" . Retrieved 25 August 2014.
  52. 1 2 3 4 5 6 Calderon CB, Sabundayo BP (2007). Antimicrobial Classifications: Drugs for Bugs. In Schwalbe R, Steele-Moore L, Goodwin AC. Antimicrobial Susceptibility Testing Protocols. CRC Press. Taylor & Frances group. ISBN   978-0-8247-4100-6
  53. Finberg RW, Moellering RC, Tally FP, Craig WA, Pankey GA, Dellinger EP, West MA, Joshi M, Linden PK, Rolston KV, Rotschafer JC, Rybak MJ (November 2004). "The importance of bactericidal drugs: future directions in infectious disease". Clinical Infectious Diseases. 39 (9): 1314–20. doi:10.1086/425009. PMID   15494908.
  54. Cunha BA (2009). Antibiotic Essentials. Jones & Bartlett Learning. p. 180. ISBN   978-0-7637-7219-2.
  55. Srivastava A, Talaue M, Liu S, Degen D, Ebright RY, Sineva E, Chakraborty A, Druzhinin SY, Chatterjee S, Mukhopadhyay J, Ebright YW, Zozula A, Shen J, Sengupta S, Niedfeldt RR, Xin C, Kaneko T, Irschik H, Jansen R, Donadio S, Connell N, Ebright RH (October 2011). "New target for inhibition of bacterial RNA polymerase: 'switch region'". Current Opinion in Microbiology. 14 (5): 532–43. doi:10.1016/j.mib.2011.07.030. PMC   3196380 . PMID   21862392.
  56. 1 2 von Nussbaum F, Brands M, Hinzen B, Weigand S, Häbich D (August 2006). "Antibacterial natural products in medicinal chemistry--exodus or revival?". Angewandte Chemie. 45 (31): 5072–129. doi:10.1002/anie.200600350. PMID   16881035.
  57. Dougherty TJ, Pucci MJ (2011). Antibiotic Discovery and Development. Springer. p. 800. ISBN   978-1-4614-1400-1.
  58. Levy SB (October 1994). "Balancing the drug-resistance equation". Trends in Microbiology. 2 (10): 341–2. doi:10.1016/0966-842X(94)90607-6. PMID   7850197.
  59. Luria SE, Delbrück M (November 1943). "Mutations of Bacteria from Virus Sensitivity to Virus Resistance". Genetics. 28 (6): 491–511. PMC   1209226 . PMID   17247100. Archived from the original on 18 November 2010.
  60. 1 2 Pearson, Carol (28 February 2007). "Antibiotic Resistance Fast-Growing Problem Worldwide". Voice of America. Archived from the original on 2 December 2008. Retrieved 29 December 2008.
  61. Topp E, Chapman R, Devers-Lamrani M, Hartmann A, Marti R, Martin-Laurent F, Sabourin L, Scott A, Sumarah M (2013). "Accelerated Biodegradation of Veterinary Antibiotics in Agricultural Soil following Long-Term Exposure, and Isolation of a Sulfamethazine-degrading sp". Journal of Environmental Quality. 42 (1): 173–8. doi:10.2134/jeq2012.0162. PMID   23673752.
  62. 1 2 3 Witte W (September 2004). "International dissemination of antibiotic resistant strains of bacterial pathogens". Infection, Genetics and Evolution. 4 (3): 187–91. doi:10.1016/j.meegid.2003.12.005. PMID   15450197.
  63. Dyer, Betsey Dexter (2003). "Chapter 9, Pathogens". A Field Guide To Bacteria. Cornell University Press. ISBN   978-0-8014-8854-2.
  64. Andersson DI (October 2006). "The biological cost of mutational antibiotic resistance: any practical conclusions?". Current Opinion in Microbiology. 9 (5): 461–5. doi:10.1016/j.mib.2006.07.002. PMID   16890008.
  65. D'Costa VM, King CE, Kalan L, Morar M, Sung WW, Schwarz C, Froese D, Zazula G, Calmels F, Debruyne R, Golding GB, Poinar HN, Wright GD (August 2011). "Antibiotic resistance is ancient". Nature. 477 (7365): 457–61. Bibcode:2011Natur.477..457D. doi:10.1038/nature10388. PMID   21881561.
  66. Gladki A, Kaczanowski S, Szczesny P, Zielenkiewicz P (February 2013). "The evolutionary rate of antibacterial drug targets". BMC Bioinformatics. 14 (1): 36. doi:10.1186/1471-2105-14-36. PMC   3598507 . PMID   23374913.
  67. 1 2 Alekshun MN, Levy SB (March 2007). "Molecular mechanisms of antibacterial multidrug resistance". Cell. 128 (6): 1037–50. doi:10.1016/j.cell.2007.03.004. PMID   17382878.
  68. Pawlowski AC, Wang W, Koteva K, Barton HA, McArthur AG, Wright GD (December 2016). "A diverse intrinsic antibiotic resistome from a cave bacterium". Nature Communications. 7: 13803. Bibcode:2016NatCo...713803P. doi:10.1038/ncomms13803. PMC   5155152 . PMID   27929110.
  69. Marshall CG, Lessard IA, Park I, Wright GD (September 1998). "Glycopeptide antibiotic resistance genes in glycopeptide-producing organisms". Antimicrobial Agents and Chemotherapy. 42 (9): 2215–20. doi:10.1128/AAC.42.9.2215. PMC   105782 . PMID   9736537. Archived from the original on 18 November 2010.
  70. Nikaido H (February 2009). "Multidrug resistance in bacteria". Annual Review of Biochemistry. 78 (1): 119–46. doi:10.1146/annurev.biochem.78.082907.145923. PMC   2839888 . PMID   19231985.
  71. 1 2 3 Baker-Austin C, Wright MS, Stepanauskas R, McArthur JV (April 2006). "Co-selection of antibiotic and metal resistance". Trends in Microbiology. 14 (4): 176–82. doi:10.1016/j.tim.2006.02.006. PMID   16537105.
  72. "Health ministers to accelerate efforts against drug-resistant TB". World Health Organization (WHO).
  73. Boseley, Sarah (12 August 2010). "Are you ready for a world without antibiotics?". The Guardian. London. Archived from the original on 18 November 2010.
  74. "Health Protection Report". Health Protection Agency. 3 July 2009. Archived from the original on 18 November 2010.
  75. McGann P, Snesrud E, Maybank R, Corey B, Ong AC, Clifford R, Hinkle M, Whitman T, Lesho E, Schaecher KE (July 2016). "Escherichia coli Harboring mcr-1 and blaCTX-M on a Novel IncF Plasmid: First Report of mcr-1 in the United States". Antimicrobial Agents and Chemotherapy. 60 (7): 4420–1. doi:10.1128/AAC.01103-16. PMC   4914657 . PMID   27230792.
  76. Moyer, Melinda Wenner. "Dangerous New Antibiotic-Resistant Bacteria Reach U.S." Scientific American. Retrieved 27 May 2016.
  77. Marino PL (2007). "Antimicrobial therapy". The ICU book. Hagerstown, MD: Lippincott Williams & Wilkins. p. 817. ISBN   978-0-7817-4802-5.
  78. 1 2 3 Larson E (2007). "Community factors in the development of antibiotic resistance". Annual Review of Public Health. 28 (1): 435–47. doi:10.1146/annurev.publhealth.28.021406.144020. PMID   17094768.
  79. 1 2 Hawkey PM (September 2008). "The growing burden of antimicrobial resistance". The Journal of Antimicrobial Chemotherapy. 62 Suppl 1 (Supplement 1): i1–9. CiteSeerX   10.1.1.629.3960 . doi:10.1093/jac/dkn241. PMID   18684701.
  80. Ong S, Nakase J, Moran GJ, Karras DJ, Kuehnert MJ, Talan DA (September 2007). "Antibiotic use for emergency department patients with upper respiratory infections: prescribing practices, patient expectations, and patient satisfaction". Annals of Emergency Medicine. 50 (3): 213–20. doi:10.1016/j.annemergmed.2007.03.026. PMID   17467120.
  81. Metlay JP, Camargo CA, MacKenzie T, McCulloch C, Maselli J, Levin SK, Kersey A, Gonzales R (September 2007). "Cluster-randomized trial to improve antibiotic use for adults with acute respiratory infections treated in emergency departments". Annals of Emergency Medicine. 50 (3): 221–30. doi:10.1016/j.annemergmed.2007.03.022. PMID   17509729.
  82. Coxeter P, Del Mar CB, McGregor L, Beller EM, Hoffmann TC (November 2015). "Interventions to facilitate shared decision making to address antibiotic use for acute respiratory infections in primary care". The Cochrane Database of Systematic Reviews. 11 (11): CD010907. doi:10.1002/14651858.CD010907.pub2. PMID   26560888.
  83. "." Centers for Disease Control and Prevention. Retrieved 12 March 2009.
  84. "Keep Antibiotics Working". Keep Antibiotics Working. Archived from the original on 18 November 2010. Retrieved 21 May 2010.
  85. Sabuncu E, David J, Bernède-Bauduin C, Pépin S, Leroy M, Boëlle PY, Watier L, Guillemot D (June 2009). Klugman KP (ed.). "Significant reduction of antibiotic use in the community after a nationwide campaign in France, 2002-2007". PLoS Medicine. 6 (6): e1000084. doi:10.1371/journal.pmed.1000084. PMC   2683932 . PMID   19492093.
  86. "Regulation (EC) No 1831/2003 of the European Parliament and of the Council". Archived from the original on 9 January 2009.
  87. "The Overuse of Antibiotics in Food Animals Threatens Public Health". Consumer Reports. Retrieved 4 July 2016.[ unreliable medical source? ]
  88. 1 2 "Preservation of Antibiotics for Medical Treatment Act of 2005 (2005 - S. 742)". GovTrack.us. Retrieved 15 April 2019.
  89. 1 2 "Preservation of Antibiotics for Medical Treatment Act of 2005 (2005 - H.R. 2562)". GovTrack.us. Retrieved 15 April 2019.
  90. "Kee Antibiotics Working" (PDF). Archived from the original (PDF) on 25 March 2009. Retrieved 12 November 2008.
  91. "Despite Pledges To Cut Back, Farms Are Still Using Antibiotics". npr.org.
  92. John Gever (23 March 2012). "FDA Told to Move on Antibiotic Use in Livestock". MedPage Today. Retrieved 24 March 2012.
  93. Lindblad WJ (June 2008). "Considerations for determining if a natural product is an effective wound-healing agent". The International Journal of Lower Extremity Wounds. 7 (2): 75–81. doi:10.1177/1534734608316028. PMID   18483011.
  94. Forrest RD (March 1982). "Early history of wound treatment". Journal of the Royal Society of Medicine. 75 (3): 198–205. PMC   1437561 . PMID   7040656.
  95. Wainwright M (1989). "Moulds in ancient and more recent medicine". Mycologist. 3 (1): 21–23. doi:10.1016/S0269-915X(89)80010-2.
  96. 1 2 Limbird LE (December 2004). "The receptor concept: a continuing evolution". Molecular Interventions. 4 (6): 326–36. doi:10.1124/mi.4.6.6. PMID   15616162.
  97. 1 2 3 Bosch F, Rosich L (2008). "The contributions of Paul Ehrlich to pharmacology: a tribute on the occasion of the centenary of his Nobel Prize". Pharmacology. 82 (3): 171–9. doi:10.1159/000149583. PMC   2790789 . PMID   18679046.
  98. 1 2 Williams KJ (August 2009). "The introduction of 'chemotherapy' using arsphenamine - the first magic bullet". Journal of the Royal Society of Medicine. 102 (8): 343–8. doi:10.1258/jrsm.2009.09k036. PMC   2726818 . PMID   19679737.
  99. 1 2 3 Goodman LS, Gilman A (1941). The Pharmacological Basis of Therapeutics. New York: Macmillan.
  100. 1 2 Frith J. "Arsenic – the "Poison of Kings" and the "Saviour of Syphilis"". Journal of Military and Veterans' Health. 21 (4). Retrieved 31 January 2017.
  101. "The Nobel Prize in Physiology or Medicine 1908". NobelPrize.org.
  102. "Nomination Archive". NobelPrize.org.
  103. 1 2 Aminov RI (2010). "A brief history of the antibiotic era: lessons learned and challenges for the future". Frontiers in Microbiology. 1: 134. doi:10.3389/fmicb.2010.00134. PMC   3109405 . PMID   21687759.
  104. "Physiology or Medicine 1939 – Presentation Speech". Nobel Foundation. Retrieved 14 January 2015.
  105. Wright PM, Seiple IB, Myers AG (August 2014). "The evolving role of chemical synthesis in antibacterial drug discovery". Angewandte Chemie. 53 (34): 8840–69. doi:10.1002/anie.201310843. PMC   4536949 . PMID   24990531.
  106. Aminov RI (1 January 2010). "A brief history of the antibiotic era: lessons learned and challenges for the future". Frontiers in Microbiology. 1: 134. doi:10.3389/fmicb.2010.00134. PMC   3109405 . PMID   21687759.
  107. Kingston W (June 2008). "Irish contributions to the origins of antibiotics". Irish Journal of Medical Science. 177 (2): 87–92. doi:10.1007/s11845-008-0139-x. PMID   18347757.
  108. Foster W, Raoult A (December 1974). "Early descriptions of antibiosis". The Journal of the Royal College of General Practitioners. 24 (149): 889–94. PMC   2157443 . PMID   4618289. the first scientific observations of the antagonistic actions of various micro-organisms were made ... by William Roberts of Manchester (1874) and John Tyndall of London (1876).
  109. Foster W, Raoult A (December 1974). "Early descriptions of antibiosis". The Journal of the Royal College of General Practitioners. 24 (149): 889–94. PMC   2157443 . PMID   4618289. Both Roberts and Tyndall indicated that the Penicillium molds had some property or had an activity which inhibited bacterial growth.
  110. Bucci R, Gallì P (11 May 2012). "Public Health History Corner Vincenzo Tiberio: a misunderstood researcher". Italian Journal of Public Health. 8 (4). ISSN   1723-7815.
  111. Duchesne E. Duchesne's Antagonism between molds and bacteria, an English Colloquial Translation. Translated by Witty M. ISBN   978-1-5498-1696-3.
  112. 1 2 Straand J, Gradmann C, Simonsen GS, Lindbæk M (2008). International Encyclopedia of Public Health: Antibiotic Development and Resistance. Academic Press. p. 200. Retrieved 31 January 2017.
  113. Tan SY, Tatsumura Y (July 2015). "Alexander Fleming (1881-1955): Discoverer of penicillin". Singapore Medical Journal. 56 (7): 366–7. doi:10.11622/smedj.2015105. PMC   4520913 . PMID   26243971.
  114. Fleming A (1980). "Classics in infectious diseases: on the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzae by Alexander Fleming, Reprinted from the British Journal of Experimental Pathology 10:226-236, 1929". Reviews of Infectious Diseases. 2 (1): 129–39. doi:10.1093/clinids/2.1.129. PMC   2566493 . PMID   6994200.; Reprint of Krylov AK (929). "[Gastroenterologic aspects of the clinical picture of internal diseases]". Terapevticheskii Arkhiv. 63 (2): 139–41. PMC   2048009 . PMID   2048009.
  115. Sykes R (2001). "Penicillin: from discovery to product". Bulletin of the World Health Organization. 79 (8): 778–9. PMC   2566502 . PMID   11545336.
  116. Jones DS, Jones JH (1 December 2014). "Sir Edward Penley Abraham CBE. 10 June 1913 – 9 May 1999". Biographical Memoirs of Fellows of the Royal Society. 60: 5–22. doi:10.1098/rsbm.2014.0002. ISSN   0080-4606.
  117. Florey HW (November 1945). "Use of Micro-organisms for Therapeutic Purposes". British Medical Journal. 2 (4427): 635–42. doi:10.1136/bmj.2.4427.635. PMC   2060276 . PMID   20786386.
  118. "The Nobel Prize in Physiology or Medicine 1945". The Nobel Prize Organization. Retrieved 13 January 2018.
  119. 1 2 Van Epps HL (February 2006). "René Dubos: unearthing antibiotics". The Journal of Experimental Medicine. 203 (2): 259. doi:10.1084/jem.2032fta. PMC   2118194 . PMID   16528813.
  120. Capocci M (1 January 2014). "Cold drugs. Circulation, production and intelligence of antibiotics in post-WWII years". Medicina Nei Secoli. 26 (2): 401–21. PMID   26054208.
  121. 1 2 3 4 Saxena S (2015). "Chapter 8: Microbes in Production of Fine Chemicals (Antibiotics, Drugs, Vitamins, and Amino Acids". Applied Microbiology. Springer India. pp. 83–120. doi:10.1007/978-81-322-2259-0. ISBN   978-81-322-2258-3.
  122. Foster W, Raoult A (December 1974). "Early descriptions of antibiosis". The Journal of the Royal College of General Practitioners. 24 (149): 889–94. PMC   2157443 . PMID   4618289.
  123. Landsberg H (1949). "Prelude to the discovery of penicillin". Isis. 40 (3): 225–7. doi:10.1086/349043.
  124. 1 2 Waksman SA (1947). "What is an antibiotic or an antibiotic substance?". Mycologia. 39 (5): 565–9. doi:10.2307/3755196. JSTOR   3755196. PMID   20264541.
  125. Scholar EM, Pratt WB (2000). The Antimicrobial Drugs. Oxford University Press, US. p. 3. ISBN   978-0-19-512529-0.
  126. Davies J, Davies D (September 2010). "Origins and evolution of antibiotic resistance". Microbiology and Molecular Biology Reviews. 74 (3): 417–33. doi:10.1128/MMBR.00016-10. PMC   2937522 . PMID   20805405.
  127. Liddell HG, Scott R (eds.). "βιωτικός". A Greek-English Lexicon via Perseus Project.
  128. Liddell HG, Scott R (eds.). "βίωσις". A Greek-English Lexicon via Perseus Project.
  129. Liddell HG, Scott R (eds.). "βίος". A Greek-English Lexicon via Perseus Project.
  130. Liddell HG, Scott R (eds.). "ἀντί". A Greek-English Lexicon via Perseus Project.
  131. Liddell HG, Scott R (eds.). "βακτηρία". A Greek-English Lexicon via Perseus Project.
  132. bacterial, on Oxford Dictionaries
  133. 1 2 Moloney MG (August 2016). "Natural Products as a Source for Novel Antibiotics". Trends in Pharmacological Sciences. 37 (8): 689–701. doi:10.1016/j.tips.2016.05.001. PMID   27267698.
  134. Abedon ST, Kuhl SJ, Blasdel BG, Kutter EM (March 2011). "Phage treatment of human infections". Bacteriophage. 1 (2): 66–85. doi:10.4161/bact.1.2.15845. PMC   3278644 . PMID   22334863.
  135. Czaplewski L, Bax R, Clokie M, Dawson M, Fairhead H, Fischetti VA, Foster S, Gilmore BF, Hancock RE, Harper D, Henderson IR, Hilpert K, Jones BV, Kadioglu A, Knowles D, Ólafsdóttir S, Payne D, Projan S, Shaunak S, Silverman J, Thomas CM, Trust TJ, Warn P, Rex JH (February 2016). "Alternatives to antibiotics-a pipeline portfolio review" (PDF). The Lancet. Infectious Diseases. 16 (2): 239–51. doi:10.1016/S1473-3099(15)00466-1. PMID   26795692.
  136. 1 2 Abreu AC, McBain AJ, Simões M (September 2012). "Plants as sources of new antimicrobials and resistance-modifying agents". Natural Product Reports. 29 (9): 1007–21. doi:10.1039/c2np20035j. PMID   22786554.
  137. 1 2 Marquez B (December 2005). "Bacterial efflux systems and efflux pumps inhibitors". Biochimie. 87 (12): 1137–47. doi:10.1016/j.biochi.2005.04.012. PMID   15951096.
  138. Drawz SM, Bonomo RA (January 2010). "Three decades of beta-lactamase inhibitors". Clinical Microbiology Reviews. 23 (1): 160–201. doi:10.1128/CMR.00037-09. PMC   2806661 . PMID   20065329.
  139. Allison KR, Brynildsen MP, Collins JJ (May 2011). "Metabolite-enabled eradication of bacterial persisters by aminoglycosides". Nature. 473 (7346): 216–20. Bibcode:2011Natur.473..216A. doi:10.1038/nature10069. PMC   3145328 . PMID   21562562.
  140. Donald RG, Anderson AS (2011). "Current Strategies for Antibacterial Vaccine development". In Miller AA, Miller PF (eds.). Emerging Trends in Antibacterial Discovery: Answering the Call to Arms. Horizon Scientific Press. p. 283.
  141. Miller AA (2011). Miller PF (ed.). Emerging Trends in Antibacterial Discovery: Answering the Call to Arms. Caister Academic Press. ISBN   978-1-904455-89-9.[ page needed ]
  142. 1 2 3 4 Gill EE, Franco OL, Hancock RE (January 2015). "Antibiotic adjuvants: diverse strategies for controlling drug-resistant pathogens". Chemical Biology & Drug Design. 85 (1): 56–78. doi:10.1111/cbdd.12478. PMC   4279029 . PMID   25393203.
  143. 1 2 Sulakvelidze A, Alavidze Z, Morris JG (March 2001). "Bacteriophage therapy". Antimicrobial Agents and Chemotherapy. 45 (3): 649–59. doi:10.1128/aac.45.3.649-659.2001. PMC   90351 . PMID   11181338.
  144. Opal SM (December 2016). "Non-antibiotic treatments for bacterial diseases in an era of progressive antibiotic resistance". Critical Care. 20 (1): 397. doi:10.1186/s13054-016-1549-1. PMC   5159963 . PMID   27978847.
  145. 1 2 Cowan MM (October 1999). "Plant products as antimicrobial agents". Clinical Microbiology Reviews. 12 (4): 564–82. doi:10.1128/CMR.12.4.564. PMC   88925 . PMID   10515903.
  146. Abreu AC, McBain AJ, Simões M (September 2012). "Plants as sources of new antimicrobials and resistance-modifying agents". Natural Product Reports. 29 (9): 1007–21. doi:10.1039/c2np20035j. PMID   22786554.
  147. 1 2 Kenny CR, Furey A, Lucey B (2015). "A post-antibiotic era looms: can plant natural product research fill the void?". British Journal of Biomedical Science. 72 (4): 191–200. doi:10.1080/09674845.2015.11665752. PMID   26738402.
  148. 1 2 Monte J, Abreu AC, Borges A, Simões LC, Simões M (June 2014). "Antimicrobial Activity of Selected Phytochemicals against Escherichia coli and Staphylococcus aureus and Their Biofilms". Pathogens. 3 (2): 473–98. doi:10.3390/pathogens3020473. PMC   4243457 . PMID   25437810.
  149. Cushnie TP, Cushnie B, Lamb AJ (November 2014). "Alkaloids: an overview of their antibacterial, antibiotic-enhancing and antivirulence activities". International Journal of Antimicrobial Agents. 44 (5): 377–86. doi:10.1016/j.ijantimicag.2014.06.001. PMID   25130096.
  150. Al-Habib A, Al-Saleh E, Safer AM, Afzal M (June 2010). "Bactericidal effect of grape seed extract on methicillin-resistant Staphylococcus aureus (MRSA)". The Journal of Toxicological Sciences. 35 (3): 357–64. doi:10.2131/jts.35.357. PMID   20519844.
  151. Smullen J, Koutsou GA, Foster HA, Zumbé A, Storey DM (2007). "The antibacterial activity of plant extracts containing polyphenols against Streptococcus mutans". Caries Research. 41 (5): 342–9. doi:10.1159/000104791. PMID   17713333.
  152. Cushnie TP, Lamb AJ (August 2011). "Recent advances in understanding the antibacterial properties of flavonoids". International Journal of Antimicrobial Agents. 38 (2): 99–107. doi:10.1016/j.ijantimicag.2011.02.014. PMID   21514796.
  153. 1 2 3 4 Antibacterial agents in clinical development: an analysis of the antibacterial clinical development pipeline, including tuberculosis. Geneva: World Health Organization; 2017 (WHO/EMP/IAU/2017.12). Licence: CC BY-NC-SA 3.0 IGO.
  154. Boucher HW, Talbot GH, Benjamin DK, Bradley J, Guidos RJ, Jones RN, Murray BE, Bonomo RA, Gilbert D (June 2013). "10 x '20 Progress--development of new drugs active against gram-negative bacilli: an update from the Infectious Diseases Society of America". Clinical Infectious Diseases. 56 (12): 1685–94. doi:10.1093/cid/cit152. PMC   3707426 . PMID   23599308.
  155. Steenhuysen, Julie (18 April 2013). "Drug pipeline for worst superbugs 'on life support': report". Reuters. Retrieved 23 June 2013.
  156. 1 2 Boucher HW, Talbot GH, Benjamin DK, Bradley J, Guidos RJ, Jones RN, Murray BE, Bonomo RA, Gilbert D (June 2013). Infectious Diseases Society of America. "10 x '20 Progress--development of new drugs active against gram-negative bacilli: an update from the Infectious Diseases Society of America". Clinical Infectious Diseases. 56 (12): 1685–94. doi:10.1093/cid/cit152. PMC   3707426 . PMID   23599308.
  157. Liu J, Bedell TA, West JG, Sorensen EJ (June 2016). "Design and Synthesis of Molecular Scaffolds with Anti-infective Activity". Tetrahedron. 72 (25): 3579–3592. doi:10.1016/j.tet.2016.01.044. PMC   4894353 . PMID   27284210.
  158. 1 2 3 Fernandes P, Martens E (June 2017). "Antibiotics in late clinical development". Biochemical Pharmacology. 133: 152–163. doi:10.1016/j.bcp.2016.09.025. PMID   27687641.
  159. Stynes, T. Tetraphase Pharma's Eravacycline Gets Qualified-Infectious-Disease-Product Status. Wall Street J. Monday, 15 July 2013.
  160. Osbourn A, Goss RJ, Carter GT (28 March 2014). "Discovery and Development of NVB302, a Semisynthetic Antibiotic for Treatment of Clostridium difficile Infection". Natural Products: Discourse, Diversity, and Design. John Wiley & Sons. pp. 455–468. doi:10.1002/9781118794623.ch24. ISBN   978-1-118-79462-3.
  161. "Antibiotic Development to Advance Patient Treatment Act of 2013" (PDF). US Congress. 12 December 2013.
  162. Clarke T (19 September 2014). "U.S. Congress urged to pass bill to speed development of antibiotics". Reuters. Reuters. Retrieved 19 September 2014.

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Further reading

Portal-puzzle.svg Antibioticsportal

  1. Gould, K (2016). "Antibiotics: From prehistory to the present day". Journal of Antimicrobial Chemotherapy. 71 (3): 572–575. Retrieved 20 February 2019.