Antibiotic

The earliest use of antibiotics was found in northern Sudan, where ancient Sudanese societies as early as 350–550 CE were systematically consuming antibiotics as part of their diet. Chemical analyses of Nubian skeletons show consistent, high levels of tetracycline, a powerful antibiotic. Researchers believe they were brewing beverages from grain fermented with Streptomyces, a bacterium that naturally produces tetracycline. This intentional routine use of antibiotics marks a foundational moment in medical history. In other ancient civilizations, including Egypt, China, Serbia, Greece, and Rome, later evidence shows topical application of moldy bread to treat infections. The first person to directly document the use of molds to treat infections was John Parkinson (1567–1650). Antibiotics revolutionized medicine in the 20th century. Synthetic antibiotic chemotherapy as a science and the development of antibacterials began in Germany with Paul Ehrlich in the late 1880s. and some bacteria have evolved resistance to them. Antimicrobial resistance (AMR), a naturally occurring process, is primarily driven by the misuse and overuse of antimicrobials. The World Health Organization has classified AMR as a widespread "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". Each year, nearly 5 million deaths are associated with AMR globally. ==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. Antibiosis was first described in 1877 in bacteria when Louis Pasteur and Robert Koch observed that an airborne bacillus could inhibit the growth of Bacillus anthracis. These drugs were later renamed antibiotics by Selman Waksman, an American microbiologist, in 1947. The term "antibiotic" derives from anti + βιωτικός (biōtikos), "fit for life, lively", which comes from βίωσις (biōsis), "way of life", and that from βίος (bios), "life". The term "antibacterial" derives from Greek ἀντί (anti), "against" + βακτήριον (baktērion), diminutive of βακτηρία (baktēria), "staff, cane", because the first bacteria to be discovered were rod-shaped. ==Usage==

Medical uses Antibiotics are used to treat or prevent bacterial infections, 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. 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. 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. The use of antibiotics for secondary prevention of coronary heart disease is not supported by current scientific evidence, and may actually increase cardiovascular mortality, all-cause mortality and the occurrence of stroke. Routes of 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. 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. Topical antibiotics applied over certain types of surgical wounds have been reported to reduce the risk of surgical site infections. 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. Global consumption 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. ==Side effects==

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. Side effects may reflect the pharmacological or toxicological properties of the antibiotic or may involve hypersensitivity or allergic reactions. Common side effects of oral antibiotics include diarrhea, resulting from disruption of the species composition in the intestinal flora, resulting, for example, in overgrowth of pathogenic bacteria, such as Clostridioides difficile. Taking probiotics during the course of antibiotic treatment can help prevent antibiotic-associated diarrhea. Antibacterials can also affect the vaginal flora, and may lead to overgrowth of yeast species of the genus Candida in the vulvo-vaginal area. Some antibiotics may also damage the mitochondrion, a bacteria-derived organelle found in eukaryotic, including human, cells. Mitochondrial damage causes oxidative stress in cells and has been suggested as a mechanism for side effects from fluoroquinolones. Antibiotics can also damage the endoplasmic reticulum. It is also known to affect chloroplasts. == Interactions ==

Birth control pills There are few well-controlled studies on whether antibiotic use increases the risk of oral contraceptive failure. The majority of studies indicate antibiotics do not interfere with birth control pills, 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. Other effects of alcohol on antibiotic activity include altered activity of the liver enzymes that break down the antibiotic compound. ==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. Since the activity of antibacterials depends frequently on its concentration, 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. Fosfomycin has the highest number of synergistic combinations among antibiotics and is almost always used as a partner drug. Combination therapy also broadens the antimicrobial spectrum, ensuring that at least one of the antibiotics in the regimen is effective against the pathogen, which is especially important when the causative agent is unknown. Methicillin-resistant Staphylococcus aureus infections may be treated with a combination therapy of fusidic acid and rifampicin. In general, combinations of a bacteriostatic antibiotic and bactericidal antibiotic are antagonistic. ==Classes==

File:Antibiotics action.svg|Molecular targets of antibiotics on the bacteria cell File: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. ==Production==

With advances in medicinal chemistry, most modern antibacterials are semisynthetic modifications of various natural compounds. 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. 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. ==Resistance==

of a human neutrophil ingesting methicillin-resistant Staphylococcus aureus (MRSA) Antimicrobial resistance (AMR or AR) is a naturally occurring process. Each year, nearly 5 million deaths are associated with AMR globally. The survival of bacteria often results from an inheritable resistance, Antibacterial resistance may impose a biological cost, thereby reducing fitness of resistant strains, which can limit the spread of antibacterial-resistant bacteria, for example, in the absence of antibacterial compounds. Additional mutations, however, may compensate for this fitness cost and can aid the survival of these bacteria. For example, 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. For example, NDM-1 is a newly identified enzyme conveying bacterial resistance to a broad range of beta-lactam antibacterials. In recent years, even anaerobic bacteria, historically considered less concerning in terms of resistance, have demonstrated high rates of antibiotic resistance, particularly Bacteroides, for which resistance rates to penicillin have been reported to exceed 90%. Misuse Per The ICU Book, "The first rule of antibiotics is to try not to use them, and the second rule is try not to use too many of them." Self-prescribing of antibiotics is an example of misuse. The lack of rapid point of care diagnostic tests, particularly in resource-limited settings is considered one of the drivers of antibiotic misuse. Several organizations concerned with antimicrobial resistance are lobbying to eliminate the unnecessary use of antibiotics. The emergence of antibiotic resistance has prompted restrictions on their use in the UK in 1970 (Swann report 1969), and the European Union has banned the use of antibiotics as growth-promotional agents since 2003. 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. 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 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. 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. Studies have shown that common misconceptions about the effectiveness and necessity of antibiotics to treat common mild illnesses contribute to their overuse. Other forms of antibiotic-associated harm include anaphylaxis, drug toxicity most notably kidney and liver damage, and super-infections with resistant organisms. Antibiotics are also known to affect mitochondrial function, and this may contribute to the bioenergetic failure of immune cells seen in sepsis. They also alter the microbiome of the gut, lungs, and skin, which may be associated with adverse effects such as Clostridioides difficile associated diarrhoea. Whilst antibiotics can clearly be lifesaving in patients with bacterial infections, their overuse, especially in patients where infections are hard to diagnose, can lead to harm via multiple mechanisms. ==History==

Before the early 20th century, treatments for infections were based primarily on medicinal folklore. Mixtures with antimicrobial properties used in the treatment of infections were described over 2,000 years ago. The use of antibiotics in modern medicine began with the discovery of synthetic antibiotics derived from dyes. Various essential oils have been shown to have anti-microbial properties. Along with this, the plants from which these oils have been derived can be used as niche anti-microbial agents. Synthetic antibiotics derived from dyes Synthetic antibiotic chemotherapy as a science and the development of antibacterials began in Germany with Paul Ehrlich in the late 1880s. The Hoechst company began to market the compound toward the end of 1910 under the name Salvarsan, now known as arsphenamine. Hata was nominated for the Nobel Prize in Chemistry in 1911 and for the Nobel Prize in Physiology or Medicine in 1912 and 1913. 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, Sulfanilamide, the active drug of Prontosil, was not patentable as it had already been in use in the dye industry for some years. Penicillin and other natural antibiotics , 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". In 1895, Vincenzo Tiberio, an Italian physician, published a paper on the antibacterial power of some extracts of mold. In 1897, doctoral student Ernest Duchesne submitted a dissertation, "" (Contribution to the study of vital competition in micro-organisms: antagonism between moulds and microbes), the first known scholarly work to consider the therapeutic capabilities of moulds resulting from their anti-microbial activity. In his thesis, Duchesne proposed that bacteria and moulds engage in a perpetual battle for survival. Duchesne observed that E. coli was eliminated by Penicillium glaucum when 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. Duchesne's army service after getting his degree prevented him from doing any further research. Duchesne died of tuberculosis, a disease now treated by antibiotics. in one of his culture plates. He observed that the presence of the mould killed or prevented the growth of the bacteria. Fleming postulated that the mould must secrete an antibacterial substance, which he named penicillin in 1928. Fleming believed that its antibacterial properties could be exploited for chemotherapy. He initially characterised 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. 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. Florey credited René 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. Late 20th century During the mid-20th century, the number of new antibiotic substances introduced for medical use increased significantly. From 1935 to 1968, 12 new classes were launched. However, the number of new classes dropped markedly, with only two new classes introduced between 1969 and 2003. ==Antibiotic pipeline==

Both the WHO and the Infectious Disease Society of America report that the weak antibiotic pipeline does not match bacteria's increasing ability to develop resistance. The Infectious Disease Society of America 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 currently in phase 2 or phase 3 clinical trials. However, these drugs did not address the entire spectrum of resistance of Gram-negative bacilli. According to the WHO fifty one new therapeutic entities - antibiotics (including combinations), are in phase 1–3 clinical trials as of May 2017. 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. 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." Replenishing the antibiotic pipeline and developing other new therapies Because antibiotic-resistant bacterial strains continue to emerge and spread, there is a constant need to develop new antibacterial treatments. Current strategies include traditional chemistry-based approaches such as natural product-based drug discovery, newer chemistry-based approaches such as drug design, traditional biology-based approaches such as immunoglobulin therapy, fecal microbiota transplants, antisense RNA-based treatments, Natural product-based antibiotic discovery Most of the antibiotics in current use are natural products or natural product derivatives, and bacterial, fungal, plant and animal extracts are being screened in the search for new antibiotics. Organisms may be selected for testing based on ecological, ethnomedical, genomic, or historical rationales. In addition to screening natural products for direct antibacterial activity, they are sometimes screened for the ability to suppress antibiotic resistance and antibiotic tolerance. Natural products known to inhibit bacterial efflux pumps include the alkaloid lysergol, the carotenoids capsanthin and capsorubin, and the flavonoids rotenone and chrysin. Natural products may be screened for the ability to suppress bacterial virulence factors too. Virulence factors are molecules, cellular structures and regulatory systems that enable bacteria to evade the body's immune defenses (e.g. urease, staphyloxanthin), move towards, attach to, and/or invade human cells (e.g. type IV pili, adhesins, internalins), coordinate the activation of virulence genes (e.g. quorum sensing), and cause disease (e.g. exotoxins). Examples of natural products with antivirulence activity include the flavonoid epigallocatechin gallate (which inhibits listeriolysin O), and the sesquiterpene zerumbone (which inhibits Acinetobacter baumannii motility). Immunoglobulin therapy Antibodies (anti-tetanus immunoglobulin) have been used in the treatment and prevention of tetanus since the 1910s, and this approach continues to be a useful way of controlling bacterial diseases. The monoclonal antibody bezlotoxumab, for example, has been approved by the US FDA and EMA for recurrent Clostridioides difficile infection, and other monoclonal antibodies are in development (e.g. AR-301 for the adjunctive treatment of S. aureus ventilator-associated pneumonia). Antibody treatments act by binding to and neutralizing bacterial exotoxins and other virulence factors. 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 that are able to infect and destroy further bacteria of the same strain. Some disadvantages to the use of bacteriophages also exist, however. Bacteriophages may harbour virulence factors or toxic genes in their genomes and, prior to use, it may be prudent to identify genes with similarity to known virulence factors or toxins by genomic sequencing. In addition, the oral and IV administration of phages for the eradication of bacterial infections poses a much higher safety risk than topical application. Also, 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. Despite numerous challenges, the use of bacteriophages as a replacement for antimicrobial agents against MDR pathogens that no longer respond to conventional antibiotics, remains an attractive option. Fecal microbiota transplants s that encode essential proteins (e.g. the Pseudomonas aeruginosa genes acpP, lpxC, and rpsJ), (b) synthesizing single-stranded RNA that is complementary to the mRNA encoding these essential proteins, and (c) delivering the single-stranded RNA to the infection site using cell-penetrating peptides or liposomes. The antisense RNA then hybridizes with the bacterial mRNA and blocks its translation into the essential protein. Antisense RNA-based treatment has been shown to be effective in in vivo models of P. aeruginosa pneumonia. Although the function of CRISPR-Cas9 in nature is to protect bacteria, the DNA sequences in the CRISPR component of the system can be modified so that the Cas9 nuclease targets bacterial resistance genes or bacterial virulence genes instead of viral genes. The modified CRISPR-Cas9 system can then be administered to bacterial pathogens using plasmids or bacteriophages. In addition to developing new antibacterial treatments, it is important to reduce the selection pressure for the emergence and spread of antimicrobial resistance (AMR), such as antibiotic resistance. Strategies to accomplish this include well-established infection control measures such as infrastructure improvement (e.g. less crowded housing), better sanitation (e.g. safe drinking water and food), better use of vaccines and vaccine development, and experimental approaches such as the use of prebiotics and probiotics to prevent infection. Antibiotic cycling, where antibiotics are alternated by clinicians to treat microbial diseases, is proposed, but recent studies revealed such strategies are ineffective against antibiotic resistance. Vaccines Vaccines are an essential part of the response to reduce AMR as they prevent infections, reduce the use and overuse of antimicrobials, and slow the emergence and spread of drug-resistant pathogens. == See also ==