From Wikipedia, the free encyclopedia
An
antibiotic (from
ancient Greek αντιβιοτικά,
antibiotiká), also called an
antibacterial, is a type of
antimicrobial drug used in the
treatment and
prevention of
bacterial infections. They
may either kill or
inhibit the growth of
bacteria. A limited number of antibiotics also possess
antiprotozoal activity. Antibiotics are not effective against
viruses such as the
common cold or
influenza; drugs which inhibit viruses are termed
antiviral drugs or antivirals rather than antibiotics.
Sometimes the term antibiotic (which means "opposing life") is used to refer to any substance used against
microbes.
However, the difference between antibiotics (ie, penicillin) and
antimicrobials (ie, sulfonamide) is that the former is produced
naturally, while the latter is synthetic (although both maintain the
same goal of killing or preventing the growth of microorganisms). Some
sources distinguish between antibacterial and antibiotic; antibacterials
are used in
soaps and
disinfectants, while antibiotics are used as medicine.
Antibiotics revolutionized medicine in the 20th century.
[8] However, their effectiveness and easy access have also led to their
overuse,
[9][10][11] prompting bacteria to develop
resistance.
[2][12] This has led to widespread problems, so much as to prompt the
World Health Organization
to classify 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".
[13]
Medical uses
Antibiotics are used to treat or prevent bacterial infections,
[14] and sometimes
protozoan infections. (
Metronidazole is effective against a number of
parasitic diseases). When an infection is suspected of being responsible for an illness but the responsible pathogen has not been identified, an
empiric therapy is adopted.
[15] This involves the administration of a
broad-spectrum antibiotic based on the signs and symptoms presented and is initiated pending laboratory results that can take several days.
[14][15]
When the responsible pathogenic microorganism is already known or has been identified,
definitive therapy
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.
[15] To avoid surgery, antibiotics may be given for non-complicated acute
appendicitis.
[16]
Antibiotics may be given as a
preventive measure (prophylactic) and this is usually limited to at-risk populations such as those with a
weakened immune system (particularly in
HIV cases to prevent
pneumonia), those taking
immunosuppressive drugs,
cancer patients and those having
surgery.
[14] Their use in surgical procedures is to help prevent infection of
incisions. They have an important role in
dental antibiotic prophylaxis where their use may prevent
bacteremia and consequent
infective endocarditis. Antibiotics are also used to prevent infection in cases of
neutropenia particularly cancer-related.
[17][18]
Administration
There are many different
routes of administration for antibiotic treatment. Antibiotics are usually
taken by mouth. In more severe cases, particularly deep-seated
systemic infections, antibiotics can be given
intravenously or by injection.
[2][15] Where the site of infection is easily accessed, antibiotics may be given
topically in the form of
eye drops onto the
conjunctiva for
conjunctivitis or
ear drops for ear infections and acute cases of
swimmer's ear. Topical use is also one of the treatment options for some skin conditions including
acne and
cellulitis.
[19]
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.
[20]
Topical antibiotics applied over certain types of surgical wounds have
been reported to reduce the risk of surgical site infections.
[21]
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
hypersensitivity reactions or
contact dermatitis occurring.
[20]
Side-effects
Health advocacy messages such as this one encourage patients to talk with their doctor about safety in using antibiotics.
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
side effects ranging from mild to very severe depending on the type of antibiotic used, the microbes targeted, and the individual patient.
[22][23] Side effects may reflect the pharmacological or toxicological properties of the antibiotic or may involve hypersensitivity or
allergic reactions.
[5] Adverse effects range from fever and nausea to major allergic reactions, including
photodermatitis and
anaphylaxis.
[24] Safety profiles of newer drugs are often not as well established as for those that have a long history of use.
[22]
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.
[25] Antibacterials can also affect the
vaginal flora, and may lead to overgrowth of
yeast species of the genus
Candida in the vulvo-vaginal area.
[26] Additional side-effects can result from
interaction with other drugs, such as the possibility of
tendon damage from the administration of a
quinolone antibiotic with a systemic
corticosteroid.
[27]
Correlation with obesity
Exposure to antibiotics early in life is associated with increased body mass in humans and mouse models.
[28] Early life is a critical period for the establishment of the
intestinal microbiota and for
metabolic development.
[29] Mice exposed to subtherapeutic antibiotic treatment (STAT)– with either penicillin,
vancomycin, or
chlortetracycline had altered composition of the gut microbiota as well as its metabolic capabilities.
[30] One study has reported that mice given low-dose penicillin (1 μg/g body weight) around birth and throughout the
weaning process had an increased body mass and fat mass, accelerated growth, and increased
hepatic expression of
genes involved in
adipogenesis, compared to control mice.
[31] In addition, penicillin in combination with a high-fat diet increased fasting
insulin levels in mice.
[31] However, it is unclear whether or not antibiotics cause
obesity
in humans. Studies have found a correlation between early exposure of
antibiotics (<6 10="" 20="" and="" at="" body="" class="reference" id="cite_ref-32" increased="" mass="" months="" sup="">
[32]6>
Another study found that the type of antibiotic exposure was also
significant with the highest risk of being overweight in those given
macrolides compared to penicillin and
cephalosporin.
[33]
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.
[29]
Interactions
Birth control pills
There are few well controlled studies on whether antibiotic use increases the risk of
oral contraceptive failure.
[34] The majority of studies indicate antibiotics do not interfere with
birth control pills,
[35] such as clinical studies that suggest the failure rate of contraceptive pills caused by antibiotics is very low (about 1%).
[36] Situations that may increase the risk of oral contraceptive failure include
non-compliance
(missing taking the pill), vomiting or diarrhea. Gastrointestinal
disorders or interpatient variability in oral contraceptive absorption
affecting
ethinylestradiol serum levels in the blood.
[34] Women with
menstrual irregularities may be at higher risk of failure and should be advised to use
backup contraception
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.
[34]
In cases where antibiotics have been suggested to affect the
efficiency of birth control pills, such as for the broad-spectrum
antibiotic
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.
[35] 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.
[37][38]
Clinicians have recommended that extra contraceptive measures be
applied during therapies using antibiotics that are suspected to
interact with oral
contraceptives.
[35]
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.
[34]
Alcohol
Interactions
between alcohol and certain antibiotics may occur and may cause
side-effects and decreased effectiveness of antibiotic therapy.
[39][40]
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.
[41] Therefore, potential risks of side-effects and effectiveness depend on the type of antibiotic administered.
[42]
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.
[41] In addition, the efficacy of doxycycline and
erythromycin succinate may be reduced by alcohol consumption.
[43]
Other effects of alcohol on antibiotic activity include altered
activity of the liver enzymes that break down the antibiotic compound.
[44] However,
red wine with a high degree of
polyphenols demonstrates in-vitro antibacterial properties.
[45]
Pharmacodynamics
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.
[46]
A bactericidal activity of antibacterials may depend on the bacterial
growth phase, and it often requires ongoing metabolic activity and
division of bacterial cells.
[47] These findings are based on laboratory studies, and in clinical settings have also been shown to eliminate bacterial infection.
[46][48] Since the activity of antibacterials depends frequently on its concentration,
[49] in vitro characterization of antibacterial activity commonly includes the determination of the
minimum inhibitory concentration and minimum bactericidal concentration of an antibacterial.
[46][50]
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.
[51]
Combination therapy
In important infectious diseases, including tuberculosis,
combination therapy
(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
synergistic effects to improve treatment outcome as the combined effect of both antibiotics is better than their individual effect.
[52][53] Methicillin-resistant Staphylococcus aureus infections may be treated with a combination therapy of
fusidic acid and rifampicin.
[52]
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
monotherapy.
[52] For example,
chloramphenicol and
tetracyclines are antagonists to
penicillins and
aminoglycosides. However, this can vary depending on the species of bacteria.
[54] In general, combinations of a bacteriostatic antibiotic and bactericidal antibiotic are antagonistic.
[52][53]
Classes
Molecular targets of antibiotics on the bacteria cell
Antibiotics are commonly classified based on their
mechanism of action,
chemical structure, or spectrum of activity. Most target bacterial functions or growth processes.
[55] 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.
Protein synthesis inhibitors (
macrolides,
lincosamides and
tetracyclines) are usually
bacteriostatic (with the exception of bactericidal
aminoglycosides).
[56]
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 new classes of antibacterial compounds, four new classes of
antibiotics have been brought into 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).
[57][58]
Production
With advances in
medicinal chemistry, most modern antibacterials are
semisynthetic modifications of various natural compounds.
[59] 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.
[59] Many antibacterial compounds are relatively
small molecules with a
molecular weight of less than 1000
daltons.
[60]
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.
[citation needed]
Resistance
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.
[61]
For example, antibacterial selection for strains having previously
acquired antibacterial-resistance genes was demonstrated in 1943 by the
Luria–Delbrück experiment.
[62]
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.
[63]
Resistance may take the form of biodegredation of
pharmaceuticals, such as sulfamethazine-degrading soil bacteria
introduced to sulfamethazine through medicated pig feces.
[64]
The survival of bacteria often results from an inheritable resistance,
[65] 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.
[66]
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.
[67]
Paleontological data show that both antibiotics and antibiotic resistance are ancient compounds and mechanisms.
[68] Useful antibiotic targets are those for which mutations negatively impact bacterial reproduction or viability.
[69]
Several molecular mechanisms of antibacterial resistance exist.
Intrinsic antibacterial resistance may be part of the genetic makeup of
bacterial strains.
[70][71] 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.
[70]
Antibacterial-producing bacteria have evolved resistance mechanisms
that have been shown to be similar to, and may have been transferred to,
antibacterial-resistant strains.
[72][73]
The spread of antibacterial resistance often occurs through vertical
transmission of mutations during growth and by genetic recombination of
DNA by
horizontal genetic exchange.
[65] For instance, antibacterial resistance genes can be exchanged between different bacterial strains or species via
plasmids that carry these resistance genes.
[65][74] Plasmids that carry several different resistance genes can confer resistance to multiple antibacterials.
[74]
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.
[74]
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.
[75] For example,
NDM-1 is a newly identified enzyme conveying bacterial resistance to a broad range of
beta-lactam antibacterials.
[76] 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."
[77] On 26 May 2016 an
E coli bacteria "
superbug" was identified in the
United States resistant to
colistin,
"the last line of defence" antibiotic.
[78][79]
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.
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."
[80]
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.
[81]
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.
[22][81]
The overuse of antibiotics, like penicillin and erythromycin, has been
associated with emerging antibiotic resistance since the 1950s.
[63][82]
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.
[82]
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".
[83] Multifactorial interventions aimed at both physicians and patients can reduce inappropriate prescription of antibiotics.
[84][85]
Several organizations concerned with antimicrobial resistance are lobbying to eliminate the unnecessary use of antibiotics.
[81]
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 (NIH), as well as other US agencies.
[86] An NGO campaign group is
Keep Antibiotics Working.
[87]
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.
[88]
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.
[89] 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.
[90]
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
[91] and H.R. 2562
[92]) aimed at phasing out nontherapeutic use of antibiotics in US food animals were proposed, but have not passed.
[91][92]
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).
[93]
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.
[94]
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.
[95]
History
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.
[96] Many ancient cultures, including the
ancient Egyptians and
ancient Greeks, used specially selected
mold and plant materials and extracts to treat
infections.
[97][98]
The use of antibiotics in modern medicine began with the discovery of synthetic antibiotics derived from dyes.
Synthetic antibiotics derived from dyes
Arsphenamine, also known as salvarsan, discovered in 1907 by Paul Ehrlich.
Synthetic antibiotic chemotherapy as a science and development of antibacterials began in Germany with
Paul Ehrlich in the late 1880s.
[55]
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
salvarsan[55][99][100] now called arsphenamine.
The era of antibacterial treatment began with the discoveries of arsenic-derived synthetic antibiotics by
Alfred Bertheim and Ehrlich in 1907.
[101][102] Ehrlich and Bertheim experimented with various chemicals derived from dyes to treat
trypanosomiasis in mice and
spirochaeta infection in rabbits. While their early compounds were too toxic, Ehrlich and
Sahachiro Hata, a Japanese bacteriologist working with Erlich in the quest for a drug to treat
syphilis,
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
Wiesbaden.
[103] The
Hoechst company began to market the compound toward the end of 1910 under the name Salvarsan. This drug is now known as
arsphenamine.
[103] The drug was used to treat syphilis in the first half of the 20th century. In 1908, Ehrlich received the
Nobel Prize in Physiology or Medicine for his contributions to
immunology.
[104] Hata was nominated for the
Nobel Prize in Chemistry in 1911 and for the Nobel Prize in Physiology or Medicine in 1912 and 1913.
[105]
The first
sulfonamide and the first
systemically active antibacterial drug,
Prontosil, was developed by a research team led by
Gerhard Domagk in 1932 or 1933 at the
Bayer Laboratories of the
IG Farben conglomerate in Germany,
[102][106][100] for which Domagk received the 1939 Nobel Prize in Physiology or Medicine.
[107]
Sulfanilamide, the active drug of Prontosil, was not patentable as it
had already been in use in the dye industry for some years.
[106] 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.
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.
Louis Pasteur
observed, "if we could intervene in the antagonism observed between
some bacteria, it would offer perhaps the greatest hopes for
therapeutics".
[110]
In 1874, physician Sir
William Roberts noted that cultures of the mold
Penicillium glaucum that is used in the making of some types of
blue cheese did not display bacterial contamination.
[111] In 1876, physicist
John Tyndall also contributed to this field.
[112] Pasteur conducted research showing that
Bacillus anthracis would not grow in the presence of the related mold
Penicillium notatum.
In 1895
Vincenzo Tiberio, Italian physician, published a paper on the antibacterial power of some extracts of mold.
[113]
In 1897, doctoral student
Ernest Duchesne
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),
[114]
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
E. coli was eliminated by
Penicillium glaucum when they were both grown in the same culture. He also observed that when he
inoculated laboratory animals with lethal doses of
typhoid 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.
[115] Duchesne died of
tuberculosis, a disease now treated by antibiotics.
[115]
Alexander Fleming was awarded a Nobel prize for his role in the discovery of penicillin
In 1928, Sir
Alexander Fleming postulated the existence of
penicillin,
a molecule produced by certain molds that kills or stops the growth of
certain kinds of bacteria. Fleming was working on a culture of
disease-causing bacteria when he noticed the
spores of a green mold,
Penicillium chrysogenum, in one of his
culture plates. He observed that the presence of the mold killed or prevented the growth of the bacteria.
[116]
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.
[117][118]
Ernst Chain,
Howard Florey and
Edward Abraham succeeded in purifying the first penicillin,
penicillin G, in 1942, but it did not become widely available outside the Allied military before 1945. Later,
Norman Heatley
developed the back extraction technique for efficiently purifying
penicillin in bulk. The chemical structure of penicillin was first
proposed by Abraham in 1942
[119] and then later confirmed 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.
(see below) The development of penicillin led to renewed interest in
the search for antibiotic compounds with similar efficacy and safety.
[120]
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
Nobel Prize in Medicine with Fleming.
[citation needed]
Florey credited
Rene 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.
[121] In 1939, coinciding with the start of
World War II, Dubos had 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 and was
very effective in treating wounds and ulcers during World War II.
[121]
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 World War II and limited access during the
Cold War.
[122]
Etymology
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.
[123][125] These drugs were later renamed antibiotics by
Selman Waksman, an American microbiologist, in 1942.
[55][123][126]
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.
[123][126] 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.
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.
[127][128]
The term "antibiotic" derives from
anti + βιωτικός (
biōtikos), "fit for life, lively",
[129] which comes from βίωσις (
biōsis), "way of life",
[130] and that from βίος (
bios), "life".
[44][131] The term "antibacterial" derives from
Greek ἀντί (
anti), "against"
[132] + βακτήριον (
baktērion), diminutive of βακτηρία (
baktēria), "staff, cane",
[133] because the first bacteria to be discovered were rod-shaped.
[134]
Research
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
drug pipeline has prompted the development of bacterial disease treatment strategies that are alternatives to conventional antibacterials.
[135][136]
Non-compound approaches (that is, products other than classical
antibacterial agents) that target bacteria or approaches that target the
host including
phage therapy and
vaccines are also being investigated to combat the problem.
[137]
Resistance-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.
[138] 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.
[138][139] Targets include:
Metabolic stimuli such as sugar can help eradicate a certain type of
antibiotic-tolerant bacteria by keeping their metabolism active.
[141]
Vaccines
Vaccines rely on
immune
modulation or augmentation. Vaccination either excites or reinforces
the immune competence 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.
[142]
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.
[143]
Phage therapy
Phage injecting its genome into bacterial cell
Phage therapy
is another method for treating antibiotic-resistant strains of
bacteria. Phage therapy infects pathogenic bacteria with their own
viruses.
Bacteriophages
and their host ranges are extremely specific for certain bacteria, thus
they do not disturb the host organism and intestinal microflora unlike
antibiotics.
[144]
Bacteriophages, also known simply as phages, infect and can kill
bacteria and affect bacterial growth primarily during lytic cycles.
[144][145]
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 able to infect and destroy further bacteria of the same strain.
[145]
The high specificity of phage protects "good" bacteria from
destruction. However, some disadvantages to use of bacteriophages also
exist. Bacteriophages may harbour virulence factors or toxic genes in
their genomes and identification of genes with similarity to known
virulence factors or toxins by genomic sequencing may be prudent prior
to use. In addition, the oral and IV administration of phages for the
eradication of bacterial infections poses a much higher safety risk than
topical application, and 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.
[144]
The use of bacteriophages as a replacement for antimicrobial agents
against MDR pathogens no longer respond to conventional antibiotics
remains an attractive option despite numerous challenges.
[144][146]
Phytochemicals
Plants
are an important source of antimicrobial compounds and traditional
healers have long used plants to prevent or cure infectious diseases.
[147][148]
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
the genomics era.
[135][149] Phytochemicals are the active biological component of plants and some phytochemicals including
tannins,
alkaloids,
terpenoids and
flavonoids possess antimicrobial activity. Some
antioxidant dietary supplements also contain phytochemicals (
polyphenols), such as
grape seed extract, and demonstrate
in vitro anti-bacterial properties.
[152][153][154]
Phytochemicals are able to inhibit peptidoglycan synthesis, damage
microbial membrane structures, modify bacterial membrane surface
hydrophobicity and also modulate
quorum sensing.
[150] With increasing antibiotic resistance in recent years, the potential of new plant-derived antibiotics is under investigation.
[149]
New antibiotics development
Both the WHO and the
Infectious Disease Society of America (IDSA) reported that the weak antibiotic pipeline does not match bacteria's increasing ability to develop resistance.
[155][156]
The IDSA report noted that the number of new antibiotics approved for
marketing per year had been declining and identified seven antibiotics
against the
Gram-negative bacilli (GNB) currently in
phase 2 or
phase 3 clinical trials. These drugs however, did not address the entire spectrum of resistance of GNB.
[157][158]
According to the WHO fifty one new therapeutic entities (NTEs) -
antibiotics (including combinations), are in phase 1-3 clinical trials
as of May 2017.
[155]
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.
[155]
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.
[155]
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.
[159]
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
macrocyclic antibiotics, fidaxomicin, has been approved for the treatment of
C. difficile colitis.
[159]
New cephalosporin-lactamase inhibitor combinations also approved
include ceftazidime-avibactam and ceftolozane-avibactam for complicated
urinary tract infection and intra-abdominal infection.
[159]
Streptomyces research is expected to provide new antibiotics, including treatment against
MRSA and infections resistant to commonly used medication. Efforts of
John Innes Centre
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
lantibiotic-based compound NVB302 (in phase 1) to treat
Clostridium difficile infections.
[161]
Possible improvements include clarification of clinical trial
regulations by FDA. Furthermore, appropriate economic incentives could
persuade pharmaceutical companies to invest in this endeavor.
[158] In the US, the
Antibiotic Development to Advance Patient Treatment
(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
CDC
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.
[162]
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."