Testing the susceptibility ofStaphylococcus aureus to antibiotics by theKirby-Bauer disk diffusion method – antibiotics diffuse from antibiotic-containing disks and inhibit growth ofS. aureus, resulting in a zone of inhibition.
Sometimes, the termantibiotic—literally "opposing life", from theGreek roots ἀντιanti, "against" and βίοςbios, "life"—is broadly used to refer to any substance used againstmicrobes, but in the usual medical usage, antibiotics (such aspenicillin) are those produced naturally (by onemicroorganism fighting another), whereas non-antibiotic antibacterials (such assulfonamides andantiseptics) arefully synthetic. However, both classes have the same effect of killing or preventing the growth of microorganisms, and both are included inantimicrobial chemotherapy. "Antibacterials" includebactericides,bacteriostatics,antibacterial soaps, and chemicaldisinfectants, whereas antibiotics are an important class of antibacterials used more specifically in medicine[6] andsometimes in livestock feed.
Antibiotics have been used since ancient times. Many civilizations used topical application of moldy bread, with many references to its beneficial effects arising from ancient Egypt,Nubia,China,Serbia, Greece, and Rome.[7] The first person to directly document the use of molds to treat infections wasJohn Parkinson (1567–1650). Antibiotics revolutionized medicine in the 20th century. Synthetic antibiotic chemotherapy as a science and development of antibacterials began in Germany withPaul Ehrlich in the late 1880s.[8]Alexander Fleming (1881–1955) discovered modern daypenicillin in 1928, the widespread use of which proved significantly beneficial during wartime. The firstsulfonamide and the firstsystemically active antibacterial drug,Prontosil, was developed by a research team led byGerhard Domagk in 1932 or 1933 at theBayer Laboratories of theIG Farben conglomerate in Germany.[9][10][11] However, the effectiveness and easy access to antibiotics have also led to theiroveruse[12] and some bacteria have evolvedresistance to them.[1][13][14][15]Antimicrobial resistance (AMR), a naturally occurring process, is driven largely by the misuse and overuse of antimicrobials.[16][17] Yet, at the same time, many people around the world do not have access to essential antimicrobials.[17] TheWorld 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".[18] Each year, nearly 5 million deaths are associated with AMR globally.[17] Global deaths attributable to AMR numbered 1.27 million in 2019.[19]
The term 'antibiosis', meaning "against life", was introduced by the French bacteriologistJean Paul Vuillemin as a descriptive name of the phenomenon exhibited by these early antibacterial drugs.[8][20][21] Antibiosis was first described in 1877 in bacteria whenLouis Pasteur andRobert Koch observed that an airborne bacillus could inhibit the growth ofBacillus anthracis.[20][22] These drugs were later renamed antibiotics bySelman Waksman, an American microbiologist, in 1947.[23]
The termantibiotic was first used in 1942 bySelman Waksman and his collaborators in journal articles to describe any substance produced by a microorganism that isantagonistic to the growth of other microorganisms in high dilution.[20][24] This definition excluded substances that kill bacteria but that are not produced by microorganisms (such asgastric juices andhydrogen peroxide). It also excludedsynthetic antibacterial compounds such as thesulfonamides. 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.[25][26]
The term "antibiotic" derives fromanti + βιωτικός (biōtikos), "fit for life, lively",[27] which comes from βίωσις (biōsis), "way of life",[28] and that from βίος (bios), "life".[29][30] The term "antibacterial" derives fromGreek ἀντί (anti), "against"[31] + βακτήριον (baktērion), diminutive of βακτηρία (baktēria), "staff, cane",[32] because the first bacteria to be discovered were rod-shaped.[33]
Antibiotics are used to treat or prevent bacterial infections,[34] and sometimesprotozoan infections. (Metronidazole is effective against a number ofparasitic diseases). When an infection is suspected of being responsible for an illness but the responsible pathogen has not been identified, anempiric therapy is adopted.[35] This involves the administration of abroad-spectrum antibiotic based on the signs and symptoms presented and is initiated pending laboratory results that can take several days.[34][35]
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.[35] To avoid surgery, antibiotics may be given for non-complicated acuteappendicitis.[36]
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.[39]
There are many differentroutes of administration for antibiotic treatment. Antibiotics are usuallytaken by mouth. In more severe cases, particularly deep-seatedsystemic infections, antibiotics can be givenintravenously or by injection.[1][35] Where the site of infection is easily accessed, antibiotics may be giventopically in the form ofeye drops onto theconjunctiva forconjunctivitis orear drops for ear infections and acute cases ofswimmer's ear. Topical use is also one of the treatment options for some skin conditions includingacne andcellulitis.[40] 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.[41] Topical antibiotics applied over certain types of surgical wounds have been reported to reduce the risk of surgical site infections.[42] 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 localhypersensitivity reactions orcontact dermatitis occurring.[41] It is recommended to administer antibiotics as soon as possible, especially in life-threatening infections. Many emergency departments stock antibiotics for this purpose.[43]
Antibiotic consumption varies widely between countries. TheWHO 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 andamoxicillin/clavulanic acid were the most frequently consumed.[44]
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 adverseside effects ranging from mild to very severe depending on the type of antibiotic used, the microbes targeted, and the individual patient.[45][46] Side effects may reflect the pharmacological or toxicological properties of the antibiotic or may involve hypersensitivity orallergic reactions.[4] Adverse effects range from fever and nausea to major allergic reactions, includingphotodermatitis andanaphylaxis.[47]
Common side effects of oral antibiotics includediarrhea, resulting from disruption of the species composition in theintestinal flora, resulting, for example, in overgrowth of pathogenic bacteria, such asClostridioides difficile.[48] Takingprobiotics during the course of antibiotic treatment can help prevent antibiotic-associated diarrhea.[49] Antibacterials can also affect thevaginal flora, and may lead to overgrowth ofyeast species of the genusCandida in the vulvo-vaginal area.[50] Additional side effects can result frominteraction with other drugs, such as the possibility oftendon damage from the administration of aquinolone antibiotic with a systemiccorticosteroid.[51]
Some antibiotics may also damage themitochondrion, a bacteria-derived organelle found in eukaryotic, including human, cells.[52] Mitochondrial damage causeoxidative stress in cells and has been suggested as a mechanism for side effects fromfluoroquinolones.[53] They are also known to affectchloroplasts.[54]
There are few well-controlled studies on whether antibiotic use increases the risk oforal contraceptive failure.[55] The majority of studies indicate antibiotics do not interfere withbirth control pills,[56] such as clinical studies that suggest the failure rate of contraceptive pills caused by antibiotics is very low (about 1%).[57] Situations that may increase the risk of oral contraceptive failure includenon-compliance (missing taking the pill), vomiting, or diarrhea. Gastrointestinal disorders or interpatient variability in oral contraceptive absorption affectingethinylestradiolserum levels in the blood.[55] Women withmenstrual irregularities may be at higher risk of failure and should be advised to usebackup 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.[55]
In cases where antibiotics have been suggested to affect the efficiency of birth control pills, such as for the broad-spectrum antibioticrifampicin, these cases may be due to an increase in the activities of hepatic liver enzymes' causing increased breakdown of the pill's active ingredients.[56] Effects on theintestinal flora, which might result in reduced absorption ofestrogens in the colon, have also been suggested, but such suggestions have been inconclusive and controversial.[58][59] Clinicians have recommended that extra contraceptive measures be applied during therapies using antibiotics that are suspected to interact with oralcontraceptives.[56] 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.[55]
Interactions between alcohol and certain antibiotics may occur and may cause side effects and decreased effectiveness of antibiotic therapy.[60][61] 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.[62] Therefore, potential risks of side effects and effectiveness depend on the type of antibiotic administered.[63]
The successful outcome of antimicrobial therapy with antibacterial compounds depends on several factors. These includehost defense mechanisms, the location of infection, and the pharmacokinetic and pharmacodynamic properties of the antibacterial.[65] The bactericidal activity of antibacterials may depend on the bacterial growth phase, and it often requires ongoing metabolic activity and division of bacterial cells.[66] These findings are based on laboratory studies, and in clinical settings have also been shown to eliminate bacterial infection.[65][67] Since the activity of antibacterials depends frequently on its concentration,[68]in vitro characterization of antibacterial activity commonly includes the determination of theminimum inhibitory concentration and minimum bactericidal concentration of an antibacterial.[65][69]To predict clinical outcome, the antimicrobial activity of an antibacterial is usually combined with itspharmacokinetic profile, and several pharmacological parameters are used as markers of drug efficacy.[70]
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 theirsynergistic effects to improve treatment outcome as the combined effect of both antibiotics is better than their individual effect.[71][72]Fosfomycin has the highest number of synergistic combinations among antibiotics and is almost always used as a partner drug.[73]Methicillin-resistantStaphylococcus aureus infections may be treated with a combination therapy offusidic acid and rifampicin.[71] Antibiotics used in combination may also be antagonistic and the combined effects of the two antibiotics may be less than if one of the antibiotics was given as amonotherapy.[71] For example,chloramphenicol andtetracyclines are antagonists topenicillins. However, this can vary depending on the species of bacteria.[74] In general, combinations of a bacteriostatic antibiotic and bactericidal antibiotic are antagonistic.[71][72]
In addition to combining one antibiotic with another, antibiotics are sometimes co-administered with resistance-modifying agents. For example,β-lactam antibiotics may be used in combination withβ-lactamase inhibitors, such asclavulanic acid orsulbactam, when a patient is infected with aβ-lactamase-producing strain of bacteria.[75]
Since the first pioneering efforts ofHoward Florey andChain in 1939, the importance of antibiotics, including antibacterials, tomedicine has led to intense research into producing antibacterials at large scales. Following screening of antibacterials against a wide range ofbacteria, production of the active compounds is carried out usingfermentation, usually in stronglyaerobic conditions.[81]
Antimicrobial resistance (AMR or AR) is a naturally occurring process.[16] AMR is driven largely by the misuse and overuse of antimicrobials.[17] Yet, at the same time, many people around the world do not have access to essential antimicrobials.[17] The emergence ofantibiotic-resistant bacteria is a common phenomenon mainly caused by the overuse/misuse. It represents a threat to health globally.[82][83] Each year, nearly 5 million deaths are associated with AMR globally.[17]
Emergence of resistance often reflectsevolutionary processes that take place during antibiotic therapy. The antibiotic treatment mayselect 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.[84] For example, antibacterial selection for strains having previously acquired antibacterial-resistance genes was demonstrated in 1943 by theLuria–Delbrück experiment.[85] 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.[86]
Resistance may take the form of biodegradation of pharmaceuticals, such as sulfamethazine-degrading soil bacteria introduced to sulfamethazine through medicated pig feces.[87]The survival of bacteria often results from an inheritable resistance,[88] but the growth of resistance to antibacterials also occurs throughhorizontal gene transfer. Horizontal transfer is more likely to happen in locations of frequent antibiotic use.[89]
Antibacterial resistance may impose a biological cost, thereby reducingfitness 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.[90]
Paleontological data show that both antibiotics and antibiotic resistance are ancient compounds and mechanisms.[91] Useful antibiotic targets are those for which mutations negatively impact bacterial reproduction or viability.[92]
Several molecular mechanisms of antibacterial resistance exist. Intrinsic antibacterial resistance may be part of the genetic makeup of bacterial strains.[93][94] For example, an antibiotic target may be absent from the bacterialgenome. Acquired resistance results from a mutation in the bacterial chromosome or the acquisition of extra-chromosomal DNA.[93] Antibacterial-producing bacteria have evolved resistance mechanisms that have been shown to be similar to, and may have been transferred to, antibacterial-resistant strains.[95][96] The spread of antibacterial resistance often occurs through vertical transmission of mutations during growth and by genetic recombination of DNA byhorizontal genetic exchange.[88] For instance, antibacterial resistance genes can be exchanged between different bacterial strains or species viaplasmids that carry these resistance genes.[88][97] Plasmids that carry several different resistance genes can confer resistance to multiple antibacterials.[97] 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.[97]
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 ofmultidrug-resistant tuberculosis (MDR-TB) are estimated to occur worldwide.[98] For example,NDM-1 is a newly identified enzyme conveying bacterial resistance to a broad range ofbeta-lactam antibacterials.[99] The United Kingdom'sHealth Protection Agency has stated that "most isolates with NDM-1 enzyme are resistant to all standard intravenous antibiotics for treatment of severe infections."[100] On 26 May 2016, anE. coli "superbug" was identified in the United States resistant tocolistin,"the last line of defence" antibiotic.[101][102]In recent years, even anaerobic bacteria, historically considered less concerning in terms of resistance, have demonstrated high rates of antibiotic resistance, particularlyBacteroides, for which resistance rates to penicillin have been reported to exceed 90%.[103]
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.
PerThe 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."[104] Inappropriate antibiotic treatment and overuse of antibiotics have contributed to the emergence of antibiotic-resistant bacteria. However, potential harm from antibiotics extends beyond selection of antimicrobial resistance and their overuse is associated with adverse effects for patients themselves, seen most clearly incritically ill patients inIntensive care units.[105]Self-prescribing of antibiotics is an example of misuse.[106] 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.[45][106] The overuse of antibiotics, like penicillin and erythromycin, has been associated with emerging antibiotic resistance since the 1950s.[86][107] 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.[107]
Common forms of antibiotic misuse include excessive use ofprophylactic 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 thecommon cold. One study onrespiratory tract infections found "physicians were more likely to prescribe antibiotics to patients who appeared to expect them".[108] Multifactorial interventions aimed at both physicians and patients can reduce inappropriate prescription of antibiotics.[109][110] The lack of rapid point of care diagnostic tests, particularly in resource-limited settings is considered one of the drivers of antibiotic misuse.[111]
Several organizations concerned with antimicrobial resistance are lobbying to eliminate the unnecessary use of antibiotics.[106] 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 USCenters for Disease Control and Prevention, theFood and Drug Administration (FDA), and theNational Institutes of Health, as well as other US agencies.[112] A non-governmental organization campaign group isKeep Antibiotics Working.[113] 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.[114]
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.[115] Moreover, several organizations (including the World Health Organization, theNational Academy of Sciences, and theU.S. Food and Drug Administration) have advocated restricting the amount of antibiotic use in food animal production.[116][unreliable medical source?] 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[117] and H.R. 2562[118]) aimed at phasing out nontherapeutic use of antibiotics in US food animals were proposed, but have not passed.[117][118] These bills were endorsed by public health and medical organizations, including the American Holistic Nurses' Association, theAmerican Medical Association, and theAmerican Public Health Association.[119][120]
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.[121]
There has been extensive use of antibiotics in animal husbandry. In the United States, the question of emergence of antibiotic-resistant bacterial strains due touse of antibiotics in livestock was raised by the USFood 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 theNatural Resources Defense Council and others, ordered the FDA to revoke approvals for the use of antibiotics in livestock, which violated FDA regulations.[122]
Studies have shown thatcommon misconceptions about the effectiveness and necessity of antibiotics to treat common mild illnesses contribute to their overuse.[123][124]
Other forms of antibiotic-associated harm includeanaphylaxis,drug toxicity most notably kidney and liver damage, and super-infections with resistant organisms. Antibiotics are also known to affectmitochondrial function,[125] and this may contribute to thebioenergetic failure ofimmune cells seen insepsis.[126] They also alter themicrobiome of the gut, lungs, and skin,[127] which may be associated with adverse effects such asClostridioides 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.[105]
Before the early 20th century, treatments for infections were based primarily onmedicinal folklore. Mixtures with antimicrobial properties that were used in treatments of infections were described over 2,000 years ago.[128] Many ancient cultures, including theancient Egyptians andancient Greeks, used specially selectedmold and plant materials to treatinfections.[129][130]Nubian mummies studied in the 1990s were found to contain significant levels oftetracycline. The beer brewed at that time was conjectured to have been the source.[131]
The use of antibiotics in modern medicine began with the discovery of synthetic antibiotics derived from dyes.[8][132][11][133][9] VariousEssential oils have been shown to have anti-microbial properties.[134] Along with this, the plants from which these oils have been derived can be used as niche anti-microbial agents.[135]
Arsphenamine, also known as salvarsan, discovered in 1907 by Paul Ehrlich
Synthetic antibiotic chemotherapy as a science and development of antibacterials began in Germany withPaul Ehrlich in the late 1880s.[8] Ehrlich noted certain dyes would colour 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 antibacterialorganoarsenic compoundsalvarsan,[8][132][11] now called arsphenamine.
This heralded the era of antibacterial treatment that was begun with the discovery of a series of arsenic-derived synthetic antibiotics by bothAlfred Bertheim and Ehrlich in 1907.[133][9] Ehrlich and Bertheim had experimented with various chemicals derived from dyes to treattrypanosomiasis in mice andspirochaeta infection in rabbits. While their early compounds were too toxic, Ehrlich andSahachiro Hata, a Japanese bacteriologist working with Ehrlich in the quest for a drug to treatsyphilis, 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 atWiesbaden.[136] TheHoechst company began to market the compound toward the end of 1910 under the name Salvarsan, now known asarsphenamine.[136] The drug was used to treat syphilis in the first half of the 20th century. In 1908, Ehrlich received theNobel Prize in Physiology or Medicine for his contributions toimmunology.[137] Hata was nominated for theNobel Prize in Chemistry in 1911 and for the Nobel Prize in Physiology or Medicine in 1912 and 1913.[138]
The firstsulfonamide and the firstsystemically active antibacterial drug,Prontosil, was developed by a research team led byGerhard Domagk in 1932 or 1933 at theBayer Laboratories of theIG Farben conglomerate in Germany,[9][10][11] for which Domagk received the 1939 Nobel Prize in Physiology or Medicine.[139] Sulfanilamide, the active drug of Prontosil, was not patentable as it had already been in use in the dye industry for some years.[10] Prontosil had a relatively broad effect againstGram-positivecocci, but not againstenterobacteria. Research was stimulated apace by its success. The discovery and development of this sulfonamidedrug opened the era of antibacterials.[140][141]
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".[142]
In 1895Vincenzo Tiberio, Italian physician, published a paper on the antibacterial power of some extracts of mold.[144]
In 1897, doctoral studentErnest 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 moulds and microbes),[145] 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 thatE. coli was eliminated byPenicillium glaucum when they were both grown in the same culture. He also observed that when heinoculated laboratory animals with lethal doses oftyphoid bacilli together withPenicillium glaucum, the animals did not contract typhoid. Duchesne's army service after getting his degree prevented him from doing any further research.[146] Duchesne died oftuberculosis, a disease now treated by antibiotics.[146]
In 1928, SirAlexander Fleming postulated the existence ofpenicillin, a molecule produced by certain moulds that kills or stops the growth of certain kinds of bacteria. Fleming was working on a culture ofdisease-causing bacteria when he noticed thespores of a green mold,Penicillium rubens,[147] in one of hisculture plates. He observed that the presence of the mould killed or prevented the growth of the bacteria.[148] 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.[149][150]
Ernst Chain,Howard Florey andEdward 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[151] and then later confirmed byDorothy 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 syntheticsulfonamides. (see below) The development of penicillin led to renewed interest in the search for antibiotic compounds with similar efficacy and safety.[152] 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 1945Nobel Prize in Medicine with Fleming.[153]
Florey creditedRené 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.[154] In 1939, coinciding with the start ofWorld War II, Dubos had reported the discovery of the first naturally derived antibiotic,tyrothricin, a compound of 20%gramicidin and 80%tyrocidine, fromBacillus brevis. It was one of the first commercially manufactured antibiotics and was very effective in treating wounds and ulcers during World War II.[154] 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 theAxis and theAllied powers during World War II and limited access during theCold War.[155]
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, after this, the number of new classes dropped markedly, with only two new classes introduced between 1969 and 2003.[156]
Both the WHO and theInfectious Disease Society of America report that the weak antibiotic pipeline does not match bacteria's increasing ability to develop resistance.[157][158] 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 theGram-negative bacilli currently inphase 2 orphase 3 clinical trials. However, these drugs did not address the entire spectrum of resistance of Gram-negative bacilli.[159][160] According to the WHO fifty one new therapeutic entities - antibiotics (including combinations), are in phase 1–3 clinical trials as of May 2017.[157] Antibiotics targeting multidrug-resistant Gram-positive pathogens remains a high priority.[161][157]
A few antibiotics have received marketing authorization in the last seven years. The cephalosporin ceftaroline and the lipoglycopeptides oritavancin and telavancin have been approved for the treatment of acute bacterial skin and skin structure infection and community-acquired bacterial pneumonia.[162] 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-spectrummacrocyclic antibiotics, fidaxomicin, has been approved for the treatment ofC. difficile colitis.[162] New cephalosporin-lactamase inhibitor combinations also approved include ceftazidime-avibactam and ceftolozane-avibactam for complicated urinary tract infection and intra-abdominal infection.[162]
Possible improvements include clarification of clinical trial regulations by FDA. Furthermore, appropriate economic incentives could persuade pharmaceutical companies to invest in this endeavor.[160] In the US, theAntibiotic Development to Advance Patient Treatment (ADAPT) Act was introduced with the aim of fast tracking thedrug 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. TheCDC 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.[167] 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."[168]
Replenishing the antibiotic pipeline and developing other new therapies
Phage injecting its genome into a bacterium. Viral replication and bacterial cell lysis will ensue.[200]
Phage therapy is under investigation as a method of treating antibiotic-resistant strains of bacteria. Phage therapy involves infecting bacterial pathogens withviruses.Bacteriophages and their host ranges are extremely specific for certain bacteria, thus, unlike antibiotics, they do not disturb the host organism'sintestinal microbiota.[201] Bacteriophages, also known as phages, infect and kill bacteria primarily during lytic cycles.[201][200] 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.[200] The high specificity of phage protects"good" bacteria from destruction.[202]
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 andIV 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.[citation needed]
There are considerableregulatory hurdles that must be cleared for such therapies.[201] 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.[201][203]
Fecal microbiota transplants are an experimental treatment forC. difficile infection.[173]
Fecal microbiota transplants involve transferring the fullintestinal microbiota from a healthy human donor (in the form ofstool) to patients withC. difficile infection. Although this procedure has not been officially approved by theUS FDA, its use is permitted under some conditions in patients with antibiotic-resistantC. difficile infection. Cure rates are around 90%, and work is underway to develop stoolbanks, standardized products, and methods oforal delivery.[173] Fecal microbiota transplantation has also been used more recently for inflammatory bowel diseases.[204]
Antisense RNA-based treatment (also known as gene silencing therapy) involves (a) identifying bacterialgenes that encode essentialproteins (e.g. thePseudomonas aeruginosa genesacpP,lpxC, andrpsJ), (b) synthesizing single-strandedRNA that is complementary to themRNA encoding these essential proteins, and (c) delivering the single-stranded RNA to the infection site using cell-penetrating peptides orliposomes. The antisense RNA thenhybridizes with the bacterial mRNA and blocks itstranslation into the essential protein. Antisense RNA-based treatment has been shown to be effective inin vivo models ofP. aeruginosapneumonia.[173][174]
In addition to silencing essential bacterial genes, antisense RNA can be used to silence bacterial genes responsible for antibiotic resistance.[173][174] For example, antisense RNA has been developed that silences theS. aureusmecA gene (the gene that encodes modifiedpenicillin-binding protein 2a and rendersS. aureus strainsmethicillin-resistant). Antisense RNA targetingmecA mRNA has been shown to restore the susceptibility of methicillin-resistant staphylococci tooxacillin in bothin vitro andin vivo studies.[174]
In the early 2000s, a system was discovered that enables bacteria to defend themselves against invading viruses. The system, known as CRISPR-Cas9, consists of (a) an enzyme that destroys DNA (thenucleaseCas9) and (b) the DNA sequences of previously encountered viral invaders (CRISPR). These viral DNA sequences enable the nuclease to target foreign (viral) rather than self (bacterial) DNA.[205]
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 bacterialresistance genes or bacterialvirulence genes instead of viral genes. The modified CRISPR-Cas9 system can then be administered to bacterial pathogens using plasmids or bacteriophages.[173][174] This approach has successfully been used tosilence antibiotic resistance and reduce the virulence ofenterohemorrhagicE. coli in anin vivo model of infection.[174]
Reducing the selection pressure for antibiotic resistance
Share of population using safely managed sanitation facilities in 2015[206]
In addition to developing new antibacterial treatments, it is important to reduce theselection pressure for the emergence and spread ofantimicrobial 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),[207][208] better sanitation (e.g. safe drinking water and food),[209][210] better use of vaccines andvaccine development,[17][176] other approaches such asantibiotic stewardship,[211][212] and experimental approaches such as the use ofprebiotics andprobiotics to prevent infection.[213][214][215][216] 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.[217][218]
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.[17] Vaccination either excites or reinforces the immune competence of a host to ward off infection, leading to the activation ofmacrophages, the production ofantibodies,inflammation, and other classic immune reactions. Antibacterial vaccines have been responsible for a drastic reduction in global bacterial diseases.[219]
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