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. 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. Many antibacterial compounds are relatively small molecules with a molecular weight of less than 2000 atomic mass units.
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. In accordance with this, many antibacterial compounds are classified on the basis of chemical/biosynthetic origin into natural, semisynthetic, and synthetic. Another classification system is based on biological activity; in this classification, antibacterials are divided into two broad groups according to their biological effect on microorganisms: Bactericidal agents kill bacteria, and bacteriostatic agents slow down or stall bacterial growth.
- 1 History
- 2 Medical uses
- 3 Pharmacodynamics
- 4 Classes
- 5 Production
- 6 Administration
- 7 Side-effects
- 8 Drug-drug interactions
- 9 Resistance
- 10 Alternatives
- 11 Status of new antibiotics development
- 12 See also
- 13 References
- 14 External links
Before the early 20th century, treatments for infections were based primarily on medicinal folklore. Mixtures with antimicrobial properties that were used in treatments of infections were described over 2000 years ago. Many ancient cultures, including the ancient Egyptians and ancient Greeks, used specially selected mold and plant materials and extracts to treat infections. More recent observations made in the laboratory of antibiosis between microorganisms led to the discovery of natural antibacterials produced by microorganisms. Louis Pasteur observed, "if we could intervene in the antagonism observed between some bacteria, it would offer perhaps the greatest hopes for therapeutics". 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 1942. Synthetic antibiotic chemotherapy as a science and development of antibacterials began in Germany with Paul Ehrlich in the late 1880s. 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, he discovered a medicinally useful drug, the synthetic antibacterial salvarsan now called arsphenamine.
The effects of some types of mold on infection had been noticed many times over the course of history (see: History of penicillin). In 1928, Alexander Fleming noticed the same effect in a Petri dish, where a number of disease-causing bacteria were killed by a fungus of the genus Penicillium. Fleming postulated that the effect is mediated by an antibacterial compound he named penicillin, and 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.
The first sulfonamide and first commercially available antibacterial, Prontosil, was developed by a research team led by Gerhard Domagk in 1932 at the Bayer Laboratories of the IG Farben conglomerate in Germany. Domagk received the 1939 Nobel Prize for Medicine for his efforts. Prontosil had a relatively broad effect against Gram-positive cocci, but not against enterobacteria. Research was stimulated apace by its success. The discovery and development of this sulfonamide drug opened the era of antibacterials.
In 1939, coinciding with the start of World War II, Rene Dubos 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 universally and was very effective in treating wounds and ulcers during World War II. 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 the war.
Florey and Chain succeeded in purifying the first penicillin, penicillin G, in 1942, but it did not become widely available outside the Allied military before 1945. The chemical structure of penicillin was determined 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. The discovery of such a powerful antibiotic was unprecedented, and the development of penicillin led to renewed interest in the search for antibiotic compounds with similar efficacy and safety. For their successful development of penicillin, which Fleming had accidentally discovered but could not develop himself, as a therapeutic drug, Ernst Chain and Howard Florey shared the 1945 Nobel Prize in Medicine with Fleming. Florey credited Dubos with pioneering the approach of deliberately and systematically searching for antibacterial compounds, which had led to the discovery of gramicidin and had revived Florey's research in penicillin.
The term "antibacterial" derives from Greek ἀντί (anti), "against" + βακτήριον (baktērion), diminutive of βακτηρία (baktēria), "staff, cane", because the first ones to be discovered were rod-shaped.
- Prevention of infection
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. A bactericidal activity of antibacterials may depend on the bacterial growth phase, and it often requires ongoing metabolic activity and division of bacterial cells. These findings are based on laboratory studies, and in clinical settings have also been shown to eliminate bacterial infection. Since the activity of antibacterials depends frequently on its concentration, in vitro characterization of antibacterial activity commonly includes the determination of the minimum inhibitory concentration and minimum bactericidal concentration of an antibacterial. 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.
Antibacterial antibiotics are commonly classified based on their mechanism of action, chemical structure, or spectrum of activity. Most target bacterial functions or growth processes. 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. Those that target protein synthesis (macrolides, lincosamides and tetracyclines) are usually bacteriostatic (with the exception of bactericidal aminoglycosides). Further categorization is based on their target specificity. "Narrow-spectrum" antibacterial antibiotics target specific types of bacteria, such as Gram-negative or Gram-positive bacteria, whereas broad-spectrum antibiotics affect a wide range of bacteria. Following a 40-year hiatus in discovering new classes of antibacterial compounds, four new classes of antibacterial antibiotics have been brought into clinical use: cyclic lipopeptides (such as daptomycin), glycylcyclines (such as tigecycline), oxazolidinones (such as linezolid), and lipiarmycins (such as fidaxomicin).
Since the first pioneering efforts of Florey and Chain in 1939, the importance of antibiotics, including antibacterials, to medicine has led to intense research into producing antibacterials at large scales. Following screening of antibacterials against a wide range of bacteria, production of the active compounds is carried out using fermentation, usually in strongly aerobic conditions.
Oral antibiotics are taken by mouth, whereas intravenous administration may be used in more serious cases, such as deep-seated systemic infections. Antibiotics may also sometimes be administered topically, as with eye drops or ointments.
The topical antibiotics are:
- (Sodium) sulfacetamide
While topical medications that act as Comedolytics as well as antibiotics are:
- Benzoyl peroxide
- Azelaic acid
- Benzoyl peroxide
Antibiotics are screened for any negative effects on humans or other mammals before approval for clinical use, and are usually considered safe and most are well-tolerated. However, some antibiotics have been associated with a range of adverse side effects. Side-effects range from mild to very serious depending on the antibiotics used, the microbial organisms targeted, and the individual patient. Safety profiles of newer drugs are often not as well-established as for those that have a long history of use. Adverse effects range from fever and nausea to major allergic reactions, including photodermatitis and anaphylaxis. 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. Antibacterials can also affect the vaginal flora, and may lead to overgrowth of yeast species of the genus Candida in the vulvo-vaginal area. Additional side-effects can result from interaction with other drugs, such as elevated risk of tendon damage from administration of a quinolone antibiotic with a systemic corticosteroid. Some scientists have hypothesized that the indiscriminate use of antibiotics alter the host microbiota and this has been associated with chronic disease.
Birth control pills
The majority of studies indicate antibiotics do not interfere with contraceptive pills, such as clinical studies that suggest the failure rate of contraceptive pills caused by antibiotics is very low (about 1%). In cases where antibacterials have been suggested to affect the efficiency of birth control pills, such as for the broad-spectrum antibacterial rifampicin, these cases may be due to an increase in the activities of hepatic liver enzymes' causing increased breakdown of the pill's active ingredients. 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. Clinicians have recommended that extra contraceptive measures be applied during therapies using antibacterials that are suspected to interact with oral contraceptives.
- "It is sensible to avoid drinking alcohol when taking medication. However, it is unlikely that drinking alcohol in moderation will cause problems if you are taking most common antibiotics. However, there are specific types of antibiotics with which alcohol should be avoided completely, because of serious side-effects."
Therefore, potential risks of side-effects and effectiveness depend on the type of antibiotic administered. Despite the lack of a categorical counterindication, the belief that alcohol and antibiotics should never be mixed is widespread.
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. In addition, serum levels of doxycycline and erythromycin succinate[clarification needed] two bacteriostatic antibiotics (see above) may be reduced by alcohol consumption, resulting in reduced efficacy and diminished pharmacotherapeutic effect.
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. For example, antibacterial selection for strains having previously acquired antibacterial-resistance genes was demonstrated in 1943 by the Luria–Delbrück experiment. 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.
Resistance may take the form of biodegredation of pharmaceuticals, such as sulfamethazine-degrading soil bacteria introduced to sulfamethazine through medicated pig feces. The survival of bacteria often results from an inheritable resistance, 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.
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.
Paleontological data show that both antibiotics and antibiotic resistance are ancient compounds and mechanisms. Useful antibiotic targets are those for which mutations negatively impact bacterial reproduction or viability.
Several molecular mechanisms of antibacterial resistance exist. Intrinsic antibacterial resistance may be part of the genetic makeup of bacterial strains. 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. Antibacterial-producing bacteria have evolved resistance mechanisms that have been shown to be similar to, and may have been transferred to, antibacterial-resistant strains. The spread of antibacterial resistance often occurs through vertical transmission of mutations during growth and by genetic recombination of DNA by horizontal genetic exchange. For instance, antibacterial resistance genes can be exchanged between different bacterial strains or species via plasmids that carry these resistance genes. Plasmids that carry several different resistance genes can confer resistance to multiple antibacterials. 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.
Antibacterial-resistant strains and species, sometimes referred to as "superbugs", now contribute to the emergence of diseases that were for a while well-controlled. For example, emergent bacterial strains causing tuberculosis (TB) that are resistant to previously effective antibacterial treatments pose many therapeutic challenges. Every year, nearly half a million new cases of multidrug-resistant tuberculosis (MDR-TB) are estimated to occur worldwide. For example, NDM-1 is a newly identified enzyme conveying bacterial resistance to a broad range of beta-lactam antibacterials. 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."
Per the 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."
Inappropriate antibiotic treatment and overuse of antibiotics have contributed to the emergence of antibiotic-resistant bacteria. Self prescription of antibiotics is an example of misuse. 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. The overuse of antibiotics, like penicillin and erythromycin, have been associated with emerging antibiotic resistance since the 1950s. 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.
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". Multifactorial interventions aimed at both physicians and patients can reduce inappropriate prescription of antibiotics.
Several organizations concerned with antimicrobial resistance are lobbying to eliminate the unnecessary use of antibiotics. The issues of misuse and overuse of antibiotics have been addressed by the formation of the U.S. Interagency Task Force on Antimicrobial Resistance. This task force aims to actively address antimicrobial resistance, and is coordinated by the US Centers for Disease Control and Prevention, the Food and Drug Administration (FDA), and the National Institutes of Health (NIH), as well as other US agencies. An NGO campaign group is Keep Antibiotics Working. 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.
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. Moreover, several organizations (e.g., The American Society for Microbiology (ASM), American Public Health Association (APHA) and the American Medical Association (AMA)) have called for restrictions on antibiotic use in food animal production and an end to all nontherapeutic uses. 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 and H.R. 2562) aimed at phasing out nontherapeutic use of antibiotics in US food animals were proposed, but have not passed. These bills were endorsed by public health and medical organizations, including the American Holistic Nurses' Association, the American Medical Association, and the American Public Health Association (APHA).
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 U.S. 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.
The increase in bacterial strains that are resistant to conventional antibacterial therapies has prompted the development of bacterial disease treatment strategies that are alternatives to conventional antibacterials.
One strategy to address bacterial drug resistance is the discovery and application of compounds that modify resistance to common antibacterials. For example, some resistance-modifying agents may inhibit multidrug resistance mechanisms, such as drug efflux from the cell, thus increasing the susceptibility of bacteria to an antibacterial. Targets include:
- The efflux inhibitor Phe-Arg-β-naphthylamide.
- Beta-lactamase inhibitors, such as clavulanic acid and sulbactam.
Metabolic stimuli such as sugar can help eradicate a certain type of antibiotic-tolerant bacteria by keeping their metabolism active.
Vaccines rely on immune modulation or augmentation. Vaccination either excites or reinforces the immune competency of a host to ward off infection, leading to the activation of macrophages, the production of antibodies, inflammation, and other classic immune reactions. Antibacterial vaccines have been responsible for a drastic reduction in global bacterial diseases. 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.
Status of new antibiotics development
In a policy report released by the Infectious Disease Society of America (IDSA) on April 2013, IDSA expressed grave concern over the weak pipeline of antibiotics to combat the growing ability of bacteria, especially the Gram-negative bacilli (GNB), to develop resistance to antibiotics. Since 2009, only 2 new antibiotics were approved in United States, and the number of new antibiotics annually approved for marketing continues to decline. The report could identify only seven antibiotics currently in phase 2 or phase 3 clinical trials to treat the GNB, which includes E. coli, Salmonella, Shigella, and the Enterobacteriaceae bacteria, and these drugs do not address the entire spectrum of the resistance developed by those bacteria. Some of these seven new antibiotics are combination of existent antibiotics, including:
- Ceftolozane/tazobactam (CXA-201; CXA-101/tazobactam): Antipseudomonal cephalosporin/β-lactamase inhibitor combination (cell wall synthesis inhibitor). In phase 3.
- Ceftazidime/avibactam (ceftazidime/NXL104): Antipseudomonal cephalosporin/β-lactamase inhibitor combination (cell wall synthesis inhibitor). In phase 3.
- Ceftaroline/avibactam (CPT-avibactam; ceftaroline/NXL104): Anti-MRSA cephalosporin/ β-lactamase inhibitor combination (cell wall synthesis inhibitor)
- Imipenem/MK-7655: Carbapenem/ β-lactamase inhibitor combination (cell wall synthesis inhibitor). In phase 2.
- Plazomicin (ACHN-490): Aminoglycoside (protein synthesis inhibitor). In phase 2.
- Eravacycline (TP-434): A synthetic tetracycline derivative / protein synthesis inhibitor targeting the ribosome being developed by Tetraphase. Phase 2 trials complete.
- Brilacidin (PMX-30063): Peptide defense protein mimetic (cell membrane disruption). In phase 2.
The IDSA’s prognosis for sustainable R&D infrastructure for antibiotics development will depend upon clarification of FDA regulatory clinical trial guidance that would facilitate the speedy approval of new drugs, and the appropriate economic incentives for the pharmaceuticals companies to invest in this endeavor. On 12 December 2013, the Antibiotic Development to Advance Patient Treatment (ADAPT) Act of 2013 was introduced in the U.S. Congress. The ADAPT Act aims to fast track the drug development in order to combat the growing public health threat of 'superbugs'. Under this Act, FDA can approve antibiotics and antifungals needed for life-threatening infections based on data from smaller clinical trials. The CDC will reinforce the monitoring of the use of antibiotics that treat serious and life-threatening infections and the emerging resistance, and make the data publicly available. The FDA antibiotics labeling process, 'Susceptibility Test Interpretive Criteria for Microbial Organisms'’ or 'breakpoints' is also streamlined to allow the most up-to-date and cutting-edge data available to healthcare professionals under the new Act.
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