Antibiotic

An antibiotic is a kind of medicine that fights germs called bacteria. It is the most important type of antibacterial medicine for fighting bacterial infections. Antibiotic medications are widely used for treatment and prevention of these infections. Antibiotics can either kill bacteria or inhibit the growth of them. A few antibiotics also work against some tiny single-celled organisms, but they do not work against viruses or fungi.

The word "antibiotic" comes from Greek roots that mean "opposing life." Some people use the word for any substance used against microbes. In medicine, though, antibiotics such as penicillin are made naturally, when one microorganism fights another. Other antibacterials, such as sulfonamides and antiseptics, are fully synthetic, which means people make them. Both kinds stop microorganisms from growing or kill them, so both are part of antimicrobial chemotherapy.

Antibacterials include bactericides, bacteriostatics, antibacterial soaps, and chemical disinfectants. Antibiotics are a special group of these. They are used more specifically in medicine, and sometimes in livestock feed.

This article is about antibiotics used to treat bacterial infections. The word "Antibacterial" can also lead to other uses. See [Antibacterial (disambiguation)](/wiki/Antibacterial_(disambiguation). For anti-tumor antibiotics, see Chemotherapy § Cytotoxic antibiotics.

Early history

The earliest known use of antibiotics was found in northern Sudan. Ancient people there, as early as 350 to 550 CE, ate antibiotics as part of their food. Chemical tests on Nubian skeletons show steady levels of tetracycline, a strong antibiotic. Researchers think these people brewed drinks from grain that had been fermented with Streptomyces, a bacterium that naturally makes tetracycline.

Given the amount of tetracycline there, they had to know what they were doing.

— George J. Armelagos, biological anthropologist

Other ancient peoples, including those in Egypt, China, Serbia, Greece, and Rome, later used moldy bread on infections. The first person to write down the use of molds to treat infections was John Parkinson (1567–1650). Antibiotics changed medicine in the 20th century. Work on antibacterial medicines began in Germany with Paul Ehrlich in the late 1880s. Alexander Fleming (1881–1955) discovered modern penicillin in 1928, and it was very helpful during wartime. A team led by Gerhard Domagk developed the first sulfonamide and the first medicine of its kind that worked throughout the body, Prontosil, in 1932 or 1933. They worked at the Bayer Laboratories of the IG Farben company in Germany.

Today, antibiotics are sometimes used too much, and some bacteria have become resistant to them. This antimicrobial resistance (AMR) is a natural process, but it is mainly caused by using these medicines the wrong way and too often. At the same time, many people around the world cannot get the medicines they need. The World Health Organization calls AMR a serious threat that is happening right now in every part of the world.

Etymology

The French scientist Jean Paul Vuillemin created the word "antibiosis," which means "against life." He used it to describe what these early drugs did to germs. In 1877, Louis Pasteur and Robert Koch saw that a tiny germ in the air could slow the growth of Bacillus anthracis. In 1947, Selman Waksman, an American scientist who studied microbes, gave these drugs the name antibiotics.

The word antibiotic was first used in 1942 by Selman Waksman and his team in scientific papers. It meant any substance made by a microorganism that could stop other microorganisms from growing. Some substances were left out, such as gastric juices and hydrogen peroxide. They kill bacteria, but microorganisms do not make them. Human-made medicines like the sulfonamides were also left out. Today, "antibiotic" is used for any medicine that kills bacteria or stops them from growing, whether or not a microorganism made it. The word comes from Latin and Greek roots meaning "against" and "life." The word "antibacterial" comes from Greek words meaning "against" and "staff, cane," because the first bacteria discovered were shaped like rods.

Usage

Antibiotics are used to treat or prevent bacterial infections. Sometimes they also treat protozoan infections, since metronidazole works against some parasitic diseases. When doctors think an infection is making someone sick but do not yet know which germ is causing it, they use empiric therapy. This means giving a broad-spectrum antibiotic based on the signs and symptoms. Lab tests, which can take several days, are still being done during this time. Once the germ is known, definitive therapy can start, usually with a narrow-spectrum antibiotic. Cost also matters in the choice. Knowing the germ can lower cost and side effects, and it can reduce the chance that germs become resistant to antibiotics. To avoid surgery, antibiotics may be given for mild, uncomplicated appendicitis.

Antibiotics may also be given as a preventive measure. This is usually for people who are at higher risk, such as people with a weakened immune system (especially people with HIV, to help prevent pneumonia), people taking immunosuppressive drugs, cancer patients, and people having surgery to help prevent infection of incisions. They are also important in dental antibiotic prophylaxis, where they may prevent bacteremia and infective endocarditis. They are also used to prevent infection in neutropenia, especially when it is related to cancer.

Antibiotics are usually taken by mouth. In more serious illness, they can be given intravenously or by injection. They can also be applied topically, such as eye drops for conjunctivitis or ear drops for ear infections. Antibiotic use differs a lot between countries. A WHO report from 2018 looked at data from many countries. The most frequently used antibiotics were Amoxicillin and amoxicillin/clavulanic acid.

Side effects

Before antibiotics are approved for use, they are tested for harmful effects. They are usually safe and well tolerated. However, some antibiotics have been linked to many side effects, which can be mild or very serious. This depends on the type of antibiotic, the microbes it targets, and the person taking it. Side effects may come from how the medicine works in the body, or they may be allergic reactions. They can include fever and nausea, and sometimes stronger allergic reactions, such as photodermatitis and anaphylaxis.

Common side effects of antibiotics taken by mouth include diarrhea. This happens when the balance of bacteria in the intestinal flora is upset. This can let harmful bacteria such as Clostridioides difficile grow too much. Taking probiotics during antibiotic treatment can help prevent this kind of diarrhea. Antibiotics can also affect the vaginal flora. This may lead to too much growth of yeast of the genus Candida in the vulvo-vaginal area. Side effects can also happen when medicines work together in the body. For example, a quinolone antibiotic given with a corticosteroid may increase the chance of tendon damage. Some antibiotics may also affect the mitochondrion, a part of cells that came from bacteria and is found in human and similar cells. This can cause oxidative stress in cells. It has been suggested as a reason for side effects from fluoroquinolones. Antibiotics can also affect the endoplasmic reticulum, and they are known to affect chloroplasts.

Interactions

Only a few well-controlled studies show whether antibiotics make oral contraceptive pills fail. Most studies suggest that antibiotics do not stop birth control pills from working. Clinical studies suggest that pill failure caused by antibiotics is very rare. Missing a pill (non-compliance), vomiting, or diarrhea may raise the risk. Stomach problems or differences in how well the body absorbs the pill may also matter. These can change the amount of ethinylestradiol in the blood, measured as serum levels. Women with menstrual irregularities may be at higher risk. They should use backup contraception during antibiotic treatment and for one week after it ends. For the antibiotic rifampicin, the effect may be due to liver enzymes breaking down the pill's active ingredients more quickly. Changes to the intestinal flora, the good bacteria in the gut, might reduce how much estrogens the body absorbs. However, these ideas are not proven and are still debated. Doctors have recommended extra contraceptive measures during antibiotic treatment that may interact with contraceptives. More studies are needed.

Alcohol and some antibiotics may interact. This can cause side effects and make the treatment work less well. Moderate drinking is unlikely to affect many common antibiotics. However, some types can cause serious side effects when mixed with alcohol, so the risk depends on the type of antibiotic. Antibiotics such as metronidazole, tinidazole, cephamandole, latamoxef, cefoperazone, cefmenoxime, and furazolidone cause a disulfiram-like reaction with alcohol. This happens because they block the enzyme acetaldehyde dehydrogenase. The reaction may cause vomiting, nausea, and shortness of breath. Alcohol may also reduce how well doxycycline and erythromycin succinate work. It can also change how the liver breaks down antibiotic compounds.

Pharmacodynamics

Main article: Antimicrobial pharmacodynamics

How well an antibacterial medicine works depends on several things. These include host defense mechanisms, where the infection is, and how the medicine moves through and acts in the body (pharmacokinetic and pharmacodynamic properties). Whether an antibacterial kills bacteria may depend on the stage of bacterial growth. It often needs the bacteria to be active and dividing. Lab studies show this, and it has also been seen in patients with bacterial infections. Because an antibacterial's effect often depends on its strength, scientists usually measure the minimum inhibitory concentration and minimum bactericidal concentration. To predict how a patient will do, the medicine's effect is usually considered together with its pharmacokinetic profile.

In serious infections, including tuberculosis, doctors may use combination therapy. This means giving two or more antibiotics at the same time. It has been used to delay or prevent resistance. In acute bacterial infections, antibiotics are sometimes chosen to work together. Two antibiotics together can work better than either one alone. This is called a synergistic effect. Fosfomycin has the most synergistic combinations among antibiotics and is almost always used as a partner drug. Combination therapy also covers a wider range of bacteria, so at least one antibiotic is likely to work. This matters most when the cause of an infection is unknown. Methicillin-resistant Staphylococcus aureus infections may be treated with fusidic acid and rifampicin together. Some antibiotics given together can work against each other. The combined effect may be weaker than using one alone (monotherapy). For example, chloramphenicol and tetracyclines work against penicillins. This can vary depending on the type of bacteria. In general, combining a bacteriostatic antibiotic with a bactericidal antibiotic makes them work against each other. Antibiotics are also sometimes given with resistance-modifying agents. For example, β-lactam antibiotics may be used with β-lactamase inhibitors, such as clavulanic acid or sulbactam. This is done when a patient has an infection caused by bacteria that produce β-lactamase.

Classes

For a more comprehensive list, see List of antibiotics.

Antibiotics are sorted into groups. The groups can be based on how they work (mechanism of action), their chemical structure, or the range of bacteria they affect. Most of them work by targeting bacterial functions or growth. Some groups, such as penicillins and cephalosporins, attack the bacterial cell wall. Polymyxins target the cell membrane. Rifamycins, lipiarmycins, quinolones, and sulfonamides interfere with important bacterial enzymes. These groups are bactericidal, which means they kill bacteria.

Protein synthesis inhibitors, including macrolides, lincosamides, and tetracyclines, usually stop bacteria from growing further. Most of these are bacteriostatic, which means they slow bacteria down rather than kill them. The aminoglycosides are an exception, because they are bactericidal.

Antibiotics can also be grouped by their target. "Narrow-spectrum" antibiotics work on specific types of bacteria, such as gram-negative or gram-positive bacteria. Broad-spectrum antibiotics affect a wide range of bacteria.

After about 40 years with few new types of antibacterial medicine, four new groups were introduced for medical use in the late 2000s and early 2010s. These were cyclic lipopeptides (such as daptomycin), glycylcyclines (such as tigecycline), oxazolidinones (such as linezolid), and lipiarmycins (such as fidaxomicin).

Production

Main article: Production of antibiotics

As medical science has improved, most modern antibacterials are semisynthetic medicines, which means they are changed versions of natural compounds. Some examples are the beta-lactam antibiotics, such as the penicillins, which are made by fungi in the genus Penicillium, the cephalosporins, and the carbapenems. Some antibacterials still come from living organisms, such as the aminoglycosides. Others, like the sulfonamides, the quinolones, and the oxazolidinones, are made only through chemical synthesis. Many of these medicines are small molecules with a molecular weight of less than 1000 daltons.

Since the early work of Howard Florey and Chain in 1939, antibiotics have become very important to medicine. This has led to a lot of research into making antibacterials in large amounts. After testing antibacterials against many kinds of bacteria, the useful compounds are made using fermentation, usually in conditions with plenty of oxygen.

Resistance

Main article: Antimicrobial resistance

Antimicrobial resistance (AMR) is a natural process. It is mostly caused by using antimicrobials too much or in the wrong way, even though many people around the world cannot get the medicines they need. Resistance often grows through evolutionary changes during antibiotic treatment. The treatment can select for bacteria that survive high doses. Scientists showed this in 1943 in the Luria–Delbrück experiment. Penicillin and erythromycin once worked well against many bacteria, but they now work less well. Resistance can spread through horizontal gene transfer, which is more likely where antibiotics are used often. Resistance can also make bacteria fitness weaker, though extra changes may help them survive. Resistance can happen when a target is missing from the bacterial genome, or when a mutation or extra DNA appears. Resistance genes can move between bacteria on plasmids. Each year, many deaths are linked to AMR, and antibiotic-resistant bacteria are a threat to health around the world. Some resistant strains, called "superbugs," have made diseases that were once well controlled harder to treat. Each year, many new cases of multidrug-resistant tuberculosis (MDR-TB) are estimated to occur. The NDM-1 enzyme helps bacteria resist many beta-lactam antibiotics. The UK's Health Protection Agency said that most bacteria with NDM-1 resist all standard antibiotics given through a vein for serious infections. In 2016, an E. coli superbug that resisted colistin, "the last line of defence" antibiotic, was found in the United States. Even Bacteroides bacteria, which were once seen as less of a concern, now show high levels of resistance.

Misuse also plays a large part. Antibiotics are sometimes used for viral infections like the common cold, which they cannot treat. Some people also ask for them even when they are not needed. Overuse can harm critically ill patients in Intensive care units, and self-prescribing is one example of misuse. Other forms include prophylactic use in travelers, using the wrong dose, and not finishing a course of treatment. Studies of respiratory tract infections and common misconceptions about antibiotics show that these beliefs can lead to overuse. Several groups, including the Centers for Disease Control and Prevention, the National Institutes of Health, the National Academy of Sciences, the U.S. Food and Drug Administration, the American Medical Association, the American Public Health Association, and the Natural Resources Defense Council, have worked to limit unnecessary use, including in use of antibiotics in livestock. Antibiotics can also cause harm, such as anaphylaxis, drug toxicity, and Clostridioides difficile associated diarrhoea. They can affect mitochondrial function, the microbiome of the body, immune cells, and sepsis. Antibiotics can save lives, but using them too often can cause harm.

History

Before the early 20th century, people treated infections mainly with medicinal folklore. Mixtures that could fight germs were described over 2,000 years ago. Many ancient cultures, including the ancient Egyptians and ancient Greeks, used carefully chosen mold and plant materials to treat infections. Nubian mummies studied in the 1990s were found to contain tetracycline. For a timeline of these medicines, see Timeline of antibiotics. Modern antibiotic medicine began with synthetic antibiotics made from dyes. In Germany, Paul Ehrlich started this work in the late 1880s. In 1907, he discovered salvarsan, the first synthetic medicine of its kind to fight bacteria. It is a type of organoarsenic compound, now called arsphenamine. In 1908, Ehrlich received the Nobel Prize in Physiology or Medicine.

The first sulfonamide, Prontosil, was developed by a team led by Gerhard Domagk in the early 1930s at the Bayer Laboratories in Germany. Domagk received the Nobel Prize in Physiology or Medicine in 1939 for this work. In 1928, Alexander Fleming noticed that a green mold killed bacteria on one of his culture plates. He named the substance penicillin. In 1942, Ernst Chain, Howard Florey, and Edward Abraham succeeded in purifying the first penicillin, called penicillin G. Chain, Florey, and Fleming shared the 1945 Nobel Prize in Medicine for penicillin. During the mid-20th century, many new antibiotics were introduced. Later, far fewer new types were found.

See also: History of penicillin

Antibiotic pipeline

Experts from the WHO and the Infectious Disease Society of America say that there are not enough new antibiotics being made. Bacteria are getting better at resisting medicines, and fewer new antibiotics have been approved each year. Seven antibiotics against Gram-negative bacilli were in phase 2 or phase 3 clinical trials, but these drugs do not work against every kind of resistance. As of May 2017, the WHO counted fifty-one new antibiotics, including combinations, in phase 1 to 3 trials. Medicines against resistant Gram-positive germs are still a high priority. In the US, the Antibiotic Development to Advance Patient Treatment (ADAPT) Act was proposed to help make new antibiotics against dangerous "superbugs" faster. The CDC would also keep track of how antibiotics are used and how resistance grows.

Because resistant bacteria keep appearing and spreading, scientists are always looking for new ways to treat infections. Some ideas use natural sources, and others use newer science. Examples include phage therapy, fecal microbiota transplants, antisense RNA, and CRISPR-Cas9. Lowering the pressure that helps resistance spread is also important. Vaccines help too, because they prevent infections and reduce the need for antibiotics.