Antibiotic

Testing the susceptibility of Staphylococcus aureus to antibiotics by the Kirby-Bauer disk diffusion method. Antibiotics diffuse out from antibiotic-containing disks and inhibit growth of S. aureus resulting in a zone of inhibition.

In modern usage, an antibiotic is a chemotherapeutic agent with activity against microorganisms such as bacteria, fungi or protozoa.^[1]

The term "antibiotic" (from the Greek αντί – anti, "against" + βιοτικός – biotikos, "fit for life"^[2][3]) was coined by Selman Waksman in 1942 to describe any substance produced by a micro-organism that is antagonistic to the growth of other micro-organisms in high dilution. This original definition excluded naturally occurring substances, such as gastric juice and hydrogen peroxide (they kill micro-organisms but are not produced by micro-organisms), and also excluded synthetic compounds such as the sulfonamides (which are antimicrobial agents). Many antibiotics are relatively small molecules with a molecular weight less than 2000 Da.

With advances in medicinal chemistry, most antibiotics are now modified chemically from original compounds found in nature, as is the case with beta-lactams (which include the penicillins, produced by fungi in the genus Penicillium, the cephalosporins, and the carbapenems). Some antibiotics are still produced and isolated from living organisms, such as the aminoglycosides; in addition, many more have been created through purely synthetic means, such as the quinolones.

Overview

Unlike many previous treatments for infections, which often consisted of administering chemical compounds such as strychnine and arsenic, with high toxicity also against mammals, antibiotics from microbes had no or few side effects and high effective target activity. Most anti-bacterial antibiotics do not have activity against viruses, fungi, or other microbes. Anti-bacterial antibiotics can be categorized based on their target specificity: "narrow-spectrum" antibiotics target particular types of bacteria, such as Gram-negative or Gram-positive bacteria, while broad-spectrum antibiotics affect a wide range of bacteria.

The environment of individual antibiotics varies with the location of the infection, the ability of the antibiotic to reach the infection site, and the ability of the microbe to inactivate or excrete the antibiotic. Some anti-bacterial antibiotics destroy bacteria (bactericidal), whereas others prevent bacteria from multiplying (bacteriostatic).

Oral antibiotics are simply ingested, while intravenous antibiotics are used in more serious cases, such as deep-seated systemic infections. Antibiotics may also sometimes be administered topically, as with eye drops or ointments.

In the last few years three new classes of antibiotics have been brought into clinical use. This follows a 40-year hiatus in discovering new classes of antibiotic compounds. These new antibiotics are of the following three classes: cyclic lipopeptides (daptomycin), glycylcyclines (tigecycline), and oxazolidinones (linezolid). Tigecycline is a broad-spectrum antibiotic, while the two others are used for Gram-positive infections. These developments show promise as a means to counteract the growing bacterial resistance to existing antibiotics.

Although potent antibiotic compounds for treatment of ancient human cultures, including the ancient Egyptians, ancient Greeks and medieval Arabs already used molds and plants to treat infections, owing to the production of antibiotic substances by these organisms, a phenomenon known as antibiosis.

Quinine became widely applied as a therapeutic agent in the 17th century for the treatment of malaria, the disease caused by Plasmodium falciparum, a protozoanparasite.

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. to the discovery of penicillin,The antibiotic properties of Penicillium sp. were first described in england by John Tyndall in 1875.However, his work went by without much notice from the scientific community until Alexander Fleming's discovery of Penicillin.

Modern research on antibiotic therapy began in Germany with the development of the narrow-spectrum antibiotic Salvarsan by Paul Ehrlich in 1909, for the first time allowing an efficient treatment of the then-widespread problem of Syphilis. The drug, which was also effective against other spirochaeta infections, is no longer in use in modern medicine.

Antibiotics were further developed in Britain following the discovery of Penicillin in 1928 by Alexander Fleming. More than ten years later, Ernst Chain and Howard Florey became interested in his work, and came up with the purified form of penicillin. The three shared the 1945 Nobel Prize in Medicine. In 1939, Rene Dubos isolated gramicidin, one of the first commercially manufactured antibiotics in use during World War II to prove highly effective in treating wounds and ulcers.

Prontosil, the first commercially available antibacterial antibiotic was developed by a research team led by Gerhard Domagk (who received the 1939 Nobel Prize in Physiology or Medicine for his efforts at the Bayer Laboratories of the IG Farben conglomerate in Germany). Prontosil had a relatively broad effect against Gram-positive Coccus but not against Enterobacteriaceae. The development of this first Sulfonamide drug opened the era of antibiotics.

Antimicrobial pharmacodynamics

Main article: Antimicrobial pharmacodynamics

Points of attack on bacteria by antibiotics

At the highest level, antibiotics can be classified as either bactericidal or bacteriostatic. Bactericidals kill bacteria directly where bacteriostatics prevent cell division. However, these classifications are based on laboratory behavior; in practice, both of these are capable of ending a bacterial infection.^[4] The bactericidal activity of antibiotics may be growth phase dependent and in most but not all cases action of many bactericidal antibiotics requires ongoing cell activity and cell division for the drugs' killing activity.^[5] The minimum inhibitory concentration and minimum bactericidal concentration are used to measure in vitro activity antimicrobial and is an excellent indicator of antimicrobial potency. However, in clinical practice these measurements alone are insufficient to predict clinical outcome. By combining the pharmacokinetic profile of antibiotic with the antimicrobial activity several pharmacological parameters appear to be significant markers of drug efficacy.^[6][7] The activity of antibiotics maybe concentration-dependent and characteristic antimicrobial activity increases with the progressively higher antibiotic concentrations.^[8] They may also be time-dependent where the antimicrobial activity does not increase with increasing antibiotic concentrations, however it is critical that the minimum inhibitory serum concentrations is maintained for a certain length of time.^[8]

Antibiotic classes

Main article: List of antibiotics

Antibiotics target bacterial cell wall, penicillins, cephalosporins or cell membrane, polymixins or interfere with essential bacterial enzymes quinolones, sulfonamides usually are bactericidal in nature. Whilst those which target protein synthesis such as the aminoglycosides, macrolides and tetracyclines are usually bacteriostatic.^[9]

Production

Main article: Production of antibiotics

Since the first pioneering efforts of Florey and Chain in 1939, the importance of antibiotics to medicine has led to much research into discovering and producing them. The process of production usually involves screening of wide ranges of microorganisms, testing and modification. Production is carried out using fermentation, usually in strongly aerobic form.

Side effects

Possible side effects are varied, depending on the antibiotics used and the microbial organisms targeted. Adverse effects can range from fever and nausea to major allergic reactions including photodermatitis. One of the more common side effects is diarrhea, sometimes caused by the anaerobic bacterium Clostridium difficile, which results from the antibiotic disrupting the normal balance of the intestinal flora,^[10] Such overgrowth of pathogenic bacteria may be alleviated by ingesting probiotics during a course of antibiotics. . An antibiotic-induced disruption of the population of the bacteria normally present as constituents of the normal vaginal flora may also occur, and may lead to overgrowth of yeast species of the genus Candida in the vulvo-vaginal area. ^[11] Other 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.

Hypothetically, some antibiotics might interfere with the efficiency of birth control pills. However there have been no conclusive studies that proved that; on the contrary, the majority of the studies indicate that antibiotics do not interfere with contraception^[12], even though there is a possibility that a small percentage of women may experience decreased effectiveness of birth control pills while taking an antibiotic.^[13]

Antibiotics and alcohol

Alcohol can interfere with the activity or metabolization of antibiotics. ^[14] It may affect the activity of liver enzymes, which break down the antibiotics.^[15] Moreover, certain antibiotics, including metronidazole, tinidazole, co-trimoxazole, cephamandole, ketoconazole, latamoxef, cefoperazone, cefmenoxime, and furazolidone, chemically react with alcohol, leading to serious side effects, which include severe vomiting, nausea, and shortness of breath. Alcohol consumption while taking such antibiotics is therefore explicitly prohibited.^[16] Additionally, serum levels of doxycycline and erythromycin succinate may, in certain circumstances, be significantly reduced by alcohol consumption. ^[17]

Antibiotic misuse

Common forms of antibiotic misuse include failure to take into account the patient's weight and history of prior antibiotic use when prescribing, since both can strongly affect the efficacy of an antibiotic prescription, failure to take the entire prescribed course of the antibiotic, failure to prescribe or take the course of treatment at fairly precise correct daily intervals (e.g. "every 8 hours" rather than merely "3x per day"), or failure to rest for sufficient recovery to allow clearance of the infecting organism. These practices may facilitate the development of bacterial populations with antibiotic resistance. Inappropriate antibiotic treatment is another common form of antibiotic misuse. A common example is the prescription and use of antibiotics to treat viral infections such as the common cold that have no effect.

Animals

It is estimated that greater than 70% of the antibiotics used in U.S. are given to feed animals (e.g. chickens, pigs and cattle) in the absence of disease.^[18] Antibiotic use in food animal production has been associated with the emergence of antibiotic-resistant strains of bacteria including Salmonella spp., Campylobacter spp., Escherichia coli, and Enterococcus spp.^[19][20] Evidence from some US and European studies suggest that these resistant bacteria cause infections in humans that do not respond to commonly prescribed antibiotics. In response to these practices and attendant problems, 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 non-therapeutic uses. However, delays in regulatory and legislative actions to limit the use of antibiotics are common, and may include resistance to these changes by industries using or selling antibiotics, as well as time spent on research to establish causal links between antibiotic use and emergence of untreatable bacterial diseases. Two federal bills (S.742^[21] and H.R. 2562^[22]) aimed at phasing out non-therapeutic antibiotics in US food animal production were proposed but not passed.^[21][22] 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).^[23] The EU has banned the use of antibiotics as growth promotional agents since 2003.^[24]

Humans

One study on respiratory tract infections found "physicians were more likely to prescribe antibiotics to patients who they believed expected them, although they correctly identified only about 1 in 4 of those patients".^[25] Multifactorial interventions aimed at both physicians and patients can reduce inappropriate prescribing of antibiotics. ^[26] Delaying antibiotics for 48 hours while observing for spontaneous resolution of respiratory tract infections may reduce antibiotic usage; however, this strategy may reduce patient satisfaction.^[27]

Excessive use of prophylactic antibiotics in travelers may also be classified as misuse.

Antibiotic resistance

Main article: Antibiotic resistance

SEM depicting methicillin-resistant Staphylococcus aureus bacteria.

The emergence of antibiotic resistance is an evolutionary process that is based on selection for organisms that have enhanced ability to survive doses of antibiotics that would previously been lethal.^[28] Survival of bacteria often results from an inheritable resistance.^[29] Antibiotics themselves act as a selective pressure which allows the growth of resistant bacteria within a population and inhibits susceptible bacteria.^[30]The underlying molecular mechanisms leading to antibiotic resistance can vary. Intrinsic resistance may naturally occur as a result of the bacteria's genetic makeup.^[31] The bacterial chromosome may fail to encode a protein which the antibiotic targets. Acquired resistance results from a mutation in the bacterial chromosome or the acquisition of extra-chromosomal DNA.^[31] The spread of antibiotic resistance between different bacteria may also be mediated by horizontal transfer of plasmids that carry genes which encode antibiotic resistance which may result in co-resistance to multiple antibiotics.^[29][32] These plasmids can carry different genes with diverse resistance mechanisms to unrelated antibiotics but because they are located on the same plamid multiple antibiotic resistance to more than one antibiotic is transferred.^[32] Alternatively, cross-resistance to other antibiotics within the bacteria results when the same resistance mechanism is responsible for resistance to more than one antibiotic is selected for.^[32]

Resistance modifying agents

One solution to combat resistance currently being researched is the development of pharmaceutical compounds that would revert multiple antibiotic resistance. These so called resistance modifying agents may target and inhibit MDR mechanisms, rendering the bacteria susceptible to antibiotics to which they were previously resistant. These compounds targets include among others

• Efflux inhibition(Phe-Arg-β-naphthylamide)^[33]
• Beta Lactamase inhibitors - Including Clavulanic acid and Sulbactam

Beyond antibiotics

The comparative ease of identifying compounds which safely cured bacterial infections was more difficult to duplicate in treatments of fungal and viral infections. Antibiotic research led to great strides in the knowledge of biochemistry, establishing large differences between the cellular and molecular physiology of the bacterial cell and that of the mammalian cell. This explained the observation that many compounds that are toxic to bacteria are non-toxic to human cells. In contrast, the basic biochemistries of the fungal cell and the mammalian cell are much more similar. This restricts the development and use of therapeutic compounds that attack a fungal cell, while not harming mammalian cells. Similar problems exist in antibiotic treatments of viral diseases. Human viral metabolic biochemistry is very closely similar to human biochemistry, and the possible targets of antiviral compounds are restricted to very few components unique to a mammalian virus.

Research into bacteriophages for use as antibiotics is presently ongoing. Several types of bacteriophage appear to exist that are specific for each bacterial taxonomic group or species. Research into bacteriophages for medicinal use is just beginning, but has led to advances in microscopic imaging.^[34] While bacteriophages provide a possible solution to the problem of antibiotic resistance, there is no clinical evidence yet that they can be deployed as therapeutic agents to cure disease.

Phage therapy has been used in the past on humans in the US and Europe during the 1920s and 1930s, but these treatments had mixed results. With the discovery of penicillin in the 1940s, Europe and the US changed therapeutic strategies to using antibiotics. However, in the former Soviet Union phage therapies continued to be studied. In the Republic of Georgia, the Eliava Institute of Bacteriophage, Microbiology & Virology continues to research the use of phage therapy. Various companies and foundations in North America and Europe are currently researching phage therapies. However, phage are living and reproducing; concerns about genetic engineering in freely released viruses currently limit certain aspects of phage therapy.

Bacteriocins are also a growing alternative to the classic small-molecule antibiotics ^[35]. Different classes of bacteriocins have different potential as therapeutic agents. Small molecule bacteriocins (microcins, for example, and lantibiotics) may be similar to the classic antibiotics; colicin-like bacteriocins are more likely to be narrow-spectrum, demanding new molecular diagnostics prior to therapy but also not raising the spectre of resistance to the same degree. One drawback to the large molecule antibiotics is that they will have relative difficulty crossing membranes and travelling systemically throughout the body. For this reason, they are most often proposed for application topically or gastrointestinally^[36]. Because bacteriocins are peptides, they are more readily engineered than small molecules^[37]. This may permit the generation of cocktails and dynamically improved antibiotics that are modified to overcome resistance.

Probiotics are another alternative that goes beyond traditional antibiotics by employing a live culture which may establish itself as a symbiont, competing, inhibiting, or simply interfering with colonization by pathogens. It may produce antibiotics or bacteriocins, essentially providing the drug in vivo and in situ, potentially avoiding the side effects of systemic administration.

References

External links

• Antibiotic News from Genome News Network (GNN)
• JAAPA: New antibiotics useful in primary care
• A new method for controlling bacterial activity without antibiotics - Research conducted at the Hebrew University
• BURDEN of Resistance and Disease in European Nations
• Antibiogram technique video
• European Surveillance of Antimicrobial Consumption (ESAC)

Resources

• Bacteria Tower Defense - Antibiotic Coverage Resource and Game
• Alliance for the Prudent Use of Antibiotics