Antibiotics

An antibiotic is a type of substance active against  and is the most important type of  for fighting. Antibiotic s are widely used in the and  of such infections. They may either or  of. A limited number of antibiotics also possess activity. Antibiotics are not effective against es such as the or ; drugs which inhibit viruses are termed s or antivirals rather than antibiotics.

Sometimes, the term antibiotic which means "opposing life", based on roots, (??t?-) anti: "against" and (ß???-) biotic: "life", is broadly used to refer to any substance used against s, but in the usual medical usage, antibiotics (such as ) are those produced naturally (by one  fighting another), whereas nonantibiotic antibacterials (such as s and s) are. However, both classes have the same goal of killing or preventing the growth of microorganisms, and both are included in. "Antibacterials" include drugs, s, and chemical s, whereas antibiotics are an important class of antibacterials used more specifically in medicine and.

Antibiotics have been used 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 revolutionized medicine in the 20th century. (1881–1955) discovered modern day 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. Effectiveness and easy access have also led to their and some bacteria have developed. This has led to widespread problems, and the has 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".

Medical uses
Antibiotics are used to treat or prevent bacterial infections, and sometimes s. ( is effective against a number of s). When an infection is suspected of being responsible for an illness but the responsible pathogen has not been identified, an is adopted. This involves the administration of a based on the signs and symptoms presented and is initiated pending laboratory results that can take several days.

When the responsible pathogenic microorganism is already known or has been identified, 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. To avoid surgery, antibiotics may be given for non-complicated acute.

Antibiotics may be given as a and this is usually limited to at-risk populations such as those with a  (particularly in  cases to prevent ), those taking s,  patients, and those having. Their use in surgical procedures is to help prevent infection of. They have an important role in where their use may prevent  and consequent. Antibiotics are also used to prevent infection in cases of particularly cancer-related.

Administration
There are many different for antibiotic treatment. Antibiotics are usually. In more severe cases, particularly deep-seated, antibiotics can be given or by injection. Where the site of infection is easily accessed, antibiotics may be given in the form of s onto the  for  or s for ear infections and acute cases of. Topical use is also one of the treatment options for some skin conditions including and. 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 reactions or  occurring.

Prevalence
Antibiotic consumption varies widely between countries. The ‘ 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. and 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 s 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 reactions. Adverse effects range from fever and nausea to major allergic reactions, including and. Safety profiles of newer drugs are often not as well established as for those that have a long history of use.

Common side-effects include, resulting from disruption of the species composition in the , resulting, for example, in overgrowth of pathogenic bacteria, such as . Antibacterials can also affect the, and may lead to overgrowth of species of the genus  in the vulvo-vaginal area. Additional side effects can result from with other drugs, such as the possibility of  damage from the administration of a  with a systemic.

Correlation with obesity
Exposure to antibiotics early in life is associated with increased body mass in humans and mouse models. Early life is a critical period for the establishment of the and for  development. Mice exposed to subtherapeutic antibiotic treatment (STAT)– with either penicillin,, or had altered composition of the gut microbiota as well as its metabolic capabilities. One study has reported that mice given low-dose penicillin (1 µg/g body weight) around birth and throughout the process had an increased body mass and fat mass, accelerated growth, and increased  expression of s involved in, compared to control mice. In addition, penicillin in combination with a high-fat diet increased fasting levels in mice. However, it is unclear whether or not antibiotics cause in humans. Studies have found a correlation between early exposure of antibiotics (<6 months) and increased body mass (at 10 and 20 months). Another study found that the type of antibiotic exposure was also significant with the highest risk of being overweight in those given s compared to penicillin and. 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.

Birth control pills
There are few well-controlled studies on whether antibiotic use increases the risk of failure. The majority of studies indicate antibiotics do not interfere with, such as clinical studies that suggest the failure rate of contraceptive pills caused by antibiotics is very low (about 1%). Situations that may increase the risk of oral contraceptive failure include (missing taking the pill), vomiting, or diarrhea. Gastrointestinal disorders or interpatient variability in oral contraceptive absorption affecting  in the blood. Women with may be at higher risk of failure and should be advised to use  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.

In cases where antibiotics have been suggested to affect the efficiency of birth control pills, such as for the broad-spectrum antibiotic, 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, which might result in reduced absorption of s 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 antibiotics that are suspected to interact with oral s. 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.

Alcohol
Interactions between alcohol and certain antibiotics may occur and may cause side effects and decreased effectiveness of antibiotic therapy. 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. Therefore, potential risks of side effects and effectiveness depend on the type of antibiotic administered.

Antibiotics such as, , , , , , and , cause a -like chemical reaction with alcohol by inhibiting its breakdown by , which may result in vomiting, nausea, and shortness of breath. In addition, the efficacy of doxycycline and succinate may be reduced by alcohol consumption. 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, 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 and minimum bactericidal concentration of an antibacterial. To predict clinical outcome, the antimicrobial activity of an antibacterial is usually combined with its profile, and several pharmacological parameters are used as markers of drug efficacy.

Combination therapy
In important infectious diseases, including tuberculosis, (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 effects to improve treatment outcome as the combined effect of both antibiotics is better than their individual effect. infections may be treated with a combination therapy of and rifampicin. 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. For example, and  are antagonists to s and U.S.s. However, this can vary depending on the species of bacteria. In general, combinations of a bacteriostatic antibiotic and bactericidal antibiotic are antagonistic.

Classes
Antibiotics are commonly classified based on their, , or spectrum of activity. Most target bacterial functions or growth processes. Those that target the bacterial cell wall (s and s) or the cell membrane (s), or interfere with essential bacterial enzymes (s, s,, and ) have activities. s (s,, and s) are usually (with the exception of bactericidal s). Further categorization is based on their target specificity. "Narrow-spectrum" antibiotics target specific types of bacteria, such as or, whereas  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 s (such as ), (such as ), s (such as ), and s (such as ).

Production
With advances in, most modern antibacterials are modifications of various natural compounds. These include, for example, the, which include the s (produced by fungi in the genus ), the s, and the s. Compounds that are still isolated from living organisms are the s, whereas other antibacterials—for example, the , the , and the s—are produced solely by. Many antibacterial compounds are relatively s with a of less than 1000.

Since the first pioneering efforts of and  in 1939, the importance of antibiotics, including antibacterials, to  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, usually in strongly aerobic conditions.

Resistance
The emergence of resistance of bacteria to antibiotics is a common phenomenon. Emergence of resistance often reflects ary processes that take place during antibiotic therapy. The antibiotic treatment may 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. 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 transfer is more likely to happen in locations of frequent antibiotic use.

Antibacterial resistance may impose a biological cost, thereby reducing 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. 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. For instance, antibacterial resistance genes can be exchanged between different bacterial strains or species via 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 that are resistant to previously effective antibacterial treatments pose many therapeutic challenges. Every year, nearly half a million new cases of (MDR-TB) are estimated to occur worldwide. For example, is a newly identified enzyme conveying bacterial resistance to a broad range of  antibacterials. The United Kingdom's has stated that "most isolates with NDM-1 enzyme are resistant to all standard intravenous antibiotics for treatment of severe infections." On 26 May 2016 an "" was identified in the  resistant to,.

Misuse
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." Inappropriate antibiotic treatment and overuse of antibiotics have contributed to the emergence of antibiotic-resistant bacteria. 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, has 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 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. One study on s 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 US Interagency Task Force on Antimicrobial Resistance. This task force aims to actively address antimicrobial resistance, and is coordinated by the US, the (FDA), and the  (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 (including the World Health Organization, the, and the ) 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 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).

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 was raised by the US  (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 and others, ordered the FDA to revoke approvals for the use of antibiotics in livestock, which violated FDA regulations.

History
Before the early 20th century, treatments for infections were based primarily on. Mixtures with antimicrobial properties that were used in treatments of infections were described over 2,000 years ago. Many ancient cultures, including the and, used specially selected  and plant materials and extracts to treat s.

The use of antibiotics in modern medicine began with the discovery of synthetic antibiotics derived from dyes.

Synthetic antibiotics derived from dyes
Synthetic antibiotic chemotherapy as a science and development of antibacterials began in Germany with 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, in 1907, he discovered a medicinally useful drug, the first synthetic antibacterial now called arsphenamine.

The era of antibacterial treatment began with the discoveries of arsenic-derived synthetic antibiotics by and Ehrlich in 1907. Ehrlich and Bertheim experimented with various chemicals derived from dyes to treat in mice and  infection in rabbits. While their early compounds were too toxic, Ehrlich and, a Japanese bacteriologist working with Erlich in the quest for a drug to treat , 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. The company began to market the compound toward the end of 1910 under the name Salvarsan. This drug is now known as. The drug was used to treat syphilis in the first half of the 20th century. In 1908, Ehrlich received the for his contributions to. Hata was nominated for the in 1911 and for the Nobel Prize in Physiology or Medicine in 1912 and 1913.

The first and the first  active antibacterial drug,, was developed by a research team led by  in 1932 or 1933 at the  Laboratories of the  conglomerate in Germany, for which Domagk received the 1939 Nobel Prize in Physiology or Medicine. Sulfanilamide, the active drug of Prontosil, was not patentable as it had already been in use in the dye industry for some years. Prontosil had a relatively broad effect against, but not against. Research was stimulated apace by its success. The discovery and development of this sulfonamide opened the era of antibacterials.

Penicillin and other natural antibiotics
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. observed, "if we could intervene in the antagonism observed between some bacteria, it would offer perhaps the greatest hopes for therapeutics".

In 1874, physician Sir noted that cultures of the mold  that is used in the making of some types of  did not display bacterial contamination. In 1876, physicist also contributed to this field. Pasteur conducted research showing that ' would not grow in the presence of the related mold '.

In 1895, Italian physician, published a paper on the antibacterial power of some extracts of mold.

In 1897, doctoral student 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), 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  was eliminated by Penicillium glaucum when they were both grown in the same culture. He also observed that when he laboratory animals with lethal doses of  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. Duchesne died of, a disease now treated by antibiotics.

In 1928, Sir postulated the existence of, a molecule produced by certain molds that kills or stops the growth of certain kinds of bacteria. Fleming was working on a culture of bacteria when he noticed the s of a green mold, , in one of his. He observed that the presence of the mold killed or prevented the growth of the bacteria. 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.

, and  succeeded in purifying the first penicillin,, in 1942, but it did not become widely available outside the Allied military before 1945. Later, developed the back extraction technique for efficiently purifying penicillin in bulk. The chemical structure of penicillin was first proposed by Abraham in 1942 and then later confirmed by 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. (see below) 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, Chain and Florey shared the 1945 with Fleming.

Florey credited 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. In 1939, coinciding with the start of, Dubos had reported the discovery of the first naturally derived antibiotic, , a compound of 20% and 80% , 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. 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 and the  during World War II and limited access during the.

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, after this, the number of new classes dropped markedly, with only 2 new classes introduced between 1969 and 2003.

Etymology
The term 'antibiosis', meaning "against life", was introduced by the French bacteriologist 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 observed that an airborne bacillus could inhibit the growth of . These drugs were later renamed antibiotics by, an American microbiologist, in 1942.

The term antibiotic was first used in 1942 by and his collaborators in journal articles to describe any substance produced by a microorganism that is  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 and ). It also excluded antibacterial compounds such as the. 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.

The term "antibiotic" derives from anti + ß??t???? (biotikos), "fit for life, lively", which comes from ß??s?? (biosis), "way of life", and that from ß??? (bios), "life". The term "antibacterial" derives from ??t? (anti), "against" + ßa?t????? (bakterion), diminutive of ßa?t???a (bakteria), "staff, cane", because the first bacteria to be discovered were rod-shaped.

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 has prompted the development of bacterial disease treatment strategies that are alternatives to conventional antibacterials. Non-compound approaches (that is, products other than classical antibacterial agents) that target bacteria or approaches that target the host including and s are also being investigated to combat the problem.

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. For example, some resistance-modifying agents may inhibit multidrug resistance mechanisms, such as from the cell, thus increasing the susceptibility of bacteria to an antibacterial. Targets include: Metabolic stimuli such as sugar can help eradicate a certain type of antibiotic-tolerant bacteria by keeping their metabolism active.
 * The Phe-Arg-ß-naphthylamide.
 * s, such as and

Vaccines
s rely on modulation or augmentation. Vaccination either excites or reinforces the immune competence of a host to ward off infection, leading to the activation of, the production of , , 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.

Phage therapy
is another method for treating antibiotic-resistant strains of bacteria. Phage therapy infects pathogenic bacteria with their own viruses. s and their host ranges are extremely specific for certain bacteria, thus, unlike antibiotics, they do not disturb the host organism and intestinal microflora. Bacteriophages, also known simply as phages, infect and can kill bacteria and affect bacterial growth primarily during lytic cycles. 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. The high specificity of phage protects "good" bacteria from destruction.

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.

Phytochemicals
Plants are an important source of antimicrobial compounds and traditional healers have long used plants to prevent or cure infectious diseases. 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. s are the active biological component of plants and some phytochemicals including s, s, s, and s possess antimicrobial activity. Some s also contain phytochemicals (s), such as, and demonstrate  anti-bacterial properties. Phytochemicals are able to inhibit peptidoglycan synthesis, damage microbial membrane structures, modify bacterial membrane surface hydrophobicity and also modulate. With increasing antibiotic resistance in recent years, the potential of new plant-derived antibiotics is under investigation.

New antibiotics development
Both the WHO and the (IDSA) reported that the weak antibiotic pipeline does not match bacteria's increasing ability to develop resistance. The IDSA report noted that the number of new antibiotics approved for marketing per year had been declining and identified seven antibiotics against the (GNB) currently in  or  clinical trials. These drugs however, did not address the entire spectrum of resistance of GNB. According to the WHO fifty one new therapeutic entities (NTEs) - antibiotics (including combinations), are in phase 1-3 clinical trials as of May 2017. 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. 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.

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. 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 antibiotics, fidaxomicin, has been approved for the treatment of C. difficile colitis. New cephalosporin-lactamase inhibitor combinations also approved include ceftazidime-avibactam and ceftolozane-avibactam for complicated urinary tract infection and intra-abdominal infection.

• / (CXA-201; CXA-101/tazobactam): / inhibitor combination (cell wall synthesis inhibitor). FDA approved on 19 December 2014.

• / (ceftazidime/NXL104): Antipseudomonal cephalosporin/ß-lactamase inhibitor combination (cell wall synthesis inhibitor). In phase 3.

• /avibactam (CPT-avibactam; ceftaroline/NXL104): Anti- cephalosporin/ ß-lactamase inhibitor combination (cell wall synthesis inhibitor)

• /MK-7655: / ß-lactamase inhibitor combination (cell wall synthesis inhibitor). In phase 2.

•  (ACHN-490):. is under.

•  (TP-434): Synthetic  derivative / protein synthesis inhibitor targeting the ribosome. Development by Tetraphase, Phase 2 trials complete.

•  (PMX-30063): Peptide defense protein mimetic (cell membrane disruption). In phase 2.Streptomyces research is expected to provide new antibiotics, including treatment against and infections resistant to commonly used medication. Efforts of 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 -based compound NVB302 (in phase 1) to treat Clostridium difficile infections. Possible improvements include clarification of clinical trial regulations by FDA. Furthermore, appropriate economic incentives could persuade pharmaceutical companies to invest in this endeavor. In the US, the (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 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. 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."