antagonistic and the combined effects of the two antibiotics may be less than if one of the antibiotics was given as a monotherapy. for example, chloramphenicol and tetracyclines are antagonists to penicillins. however, this can vary depending on the species of bacteria. in general, combinations of a bacteriostatic antibiotic and bactericidal antibiotic are antagonistic. 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 with β-lactamase inhibitors, such as clavulanic acid or sulbactam, when a patient is infected with a β-lactamase-producing strain of bacteria. classes main article: list of antibiotics molecular targets of antibiotics on the bacteria cell protein synthesis inhibitors (antibiotics) antibiotics are commonly classified based on their mechanism of action, chemical structure, or spectrum of activity. most target bacterial functions or growth processes. 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, killing the bacteria. protein synthesis inhibitors (macrolides, lincosamides, and tetracyclines) are usually bacteriostatic, inhibiting further growth (with the exception of bactericidal aminoglycosides). further categorization is based on their target specificity. "narrow-spectrum" antibiotics target specific types of bacteria, such as gram-negative or gram-positive, whereas broad-spectrum antibiotics affect a wide range of bacteria. following a 40-year break in discovering classes of antibacterial compounds, four new classes of antibiotics were introduced to clinical use in the late 2000s and early 2010s: cyclic lipopeptides (such as daptomycin), glycylcyclines (such as tigecycline), oxazolidinones (such as linezolid), and lipiarmycins (such as fidaxomicin). production main article: production of antibiotics 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. many antibacterial compounds are relatively small molecules with a molecular weight of less than 1000 daltons. since the first pioneering efforts of howard florey and chain in 1939, the importance of antibiotics, including antibacterials, to medicine has led to intense research into producing antibacterials at large scales. following screening of antibacterials against a wide range of bacteria, production of the active compounds is carried out using fermentation, usually in strongly aerobic conditions. resistance main article: antibiotic resistance scanning electron micrograph of a human neutrophil ingesting methicillin-resistant staphylococcus aureus (mrsa) the emergence of antibiotic-resistant bacteria is a common phenomenon mainly caused by the overuse/misuse. it represents a threat to health globally. 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 biodegradation 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 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." on 26 may 2016, an e. coli "superbug" was identified in the united states resistant to colistin, "the last line of defence" antibiotic. misuse this poster from the us centers for disease control and prevention "get smart" campaign, intended for use in doctors' offices and other healthcare facilities, warns that antibiotics do not work for viral illnesses such as the common cold. main article: antibiotic misuse per the icu book "the first rule of antibiotics is to try not to use them, and the second rule is try not to use too many of them." 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 in critically ill patients in intensive care units. self-prescribing 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 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. the lack of rapid point of care diagnostic tests, particularly in resource-limited settings is considered one of the drivers of antibiotic misuse. several organizations concerned with antimicrobial resistance are lobbying to eliminate the unnecessary use of antibiotics. the issues of misuse and overuse of antibiotics have been addressed by the formation of the us interagency task force on antimicrobial resistance. this task force aims to actively address antimicrobial resistance, and is coordinated by the us centers for disease control and prevention, the food and drug administration (fda), and the national institutes of health, as well as other us agencies. a non-governmental organization 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 european union has banned the use of antibiotics as growth-promotional agents since 2003. moreover, several organizations (including the world health organization, the national academy of sciences, and the u.s. food and drug administration) have advocated restricting the amount of antibiotic use in food animal production. however, commonly there are delays in regulatory and legislative actions to limit the use of antibiotics, attributable partly to resistance against such regulation by industries using or selling antibiotics, and to the time required for research to test causal links between their use and resistance to them. two federal bills (s.742 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. despite pledges by food companies and restaurants to reduce or eliminate meat that comes from animals treated with antibiotics, the purchase of antibiotics for use on farm animals has been increasing every year. there has been extensive use of antibiotics in animal husbandry. in the united states, the question of emergence of antibiotic-resistant bacterial strains due to use of antibiotics in livestock was raised by the us food and drug administration (fda) in 1977. in march 2012, the united states district court for the southern district of new york, ruling in an action brought by the natural resources defense council and others, ordered the fda to revoke approvals for the use of antibiotics in livestock, which violated fda regulations. studies have shown that common misconceptions about the effectiveness and necessity of antibiotics to treat common mild illnesses contribute to their overuse. other forms of antibiotic associated harm include anaphylaxis, drug toxicity most notably kidney and liver damage, and super-infections with resistant organisms. antibiotics are also known to affect mitochondrial function, and this may contribute to the bioenergetic failure of immune cells seen in sepsis. they also alter the microbiome of the gut, lungs and skin, which may be associated with adverse effects such as clostridium difficile associated diarrhoea. whilst antibiotics can clearly be lifesaving in patients with bacterial infections, their overuse, especially in patients where infections are hard to diagnose, can lead to harm via multiple mechanisms. history