Advanced Pharmaceutical Microbiology
Antibiotics
Testing the susceptibility of Staphylococcus aureus to antibiotics
by the Kirby-Bauer disk diffusion method
– antibiotics diffuse from antibiotic-containing disks and inhibit growth of S.
aureus, resulting in a zone of inhibition.
An antibiotic is an agent that
either kills or inhibits the growth of a microorganism.
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. The first antibiotic
discovered was called penicillin by Alexander
Fleming in 1929. 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. Many antibacterial compounds
are relatively small molecules with a molecular
weight of less than 2000 atomic mass
units.
With advances in medicinal chemistry, most modern antibacterials
are semisynthetic
modifications of various natural compounds. These include, for example, the beta-lactam antibiotics, which include the
penicillins
(produced by fungi in the genus Penicillium),
the cephalosporins,
and the carbapenems.
Compounds that are still isolated from living organisms are the aminoglycosides,
whereas other antibacterials—for example, the sulfonamides, the quinolones,
and the oxazolidinones—are produced solely by chemical
synthesis. In accordance with this, many antibacterial compounds are classified
on the basis of chemical/biosynthetic origin into natural,
semisynthetic, and synthetic. Another classification system is based on
biological activity; in this classification, antibacterials are divided into
two broad groups according to their biological effect on microorganisms: Bactericidal
agents kill bacteria, and bacteriostatic agents slow down or stall
bacterial growth.
History
Penicillin, the first natural antibiotic discovered by Alexander
Fleming in 1928
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. Many ancient
cultures, including the Ayurveda, ancient Egyptians and ancient Greeks, used specially selected mold and plant materials
and extracts to treat infections. More recent observations made in the laboratory of
antibiosis between microorganisms led to the discovery of natural
antibacterials produced by microorganisms. Louis Pasteur
observed, "if we could intervene in the antagonism observed between some
bacteria, it would offer perhaps the greatest hopes for therapeutics". 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. These drugs were later
renamed antibiotics by Selman Waksman, an American microbiologist, in
1942. Synthetic antibiotic chemotherapy as a science and development of
antibacterials began in Germany with Paul Ehrlich
in the late 1880s. 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, he discovered a medicinally useful
drug, the synthetic antibacterial salvarsan
now called arsphenamine.
The effects of some types of mold on
infection had been noticed many times over the course of history (see: History of penicillin). In 1928, Alexander
Fleming noticed the same effect in a Petri dish,
where a number of disease-causing bacteria were killed by a fungus of the genus
Penicillium. Fleming postulated that the effect is mediated by an
antibacterial compound he named penicillin,
and 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.
Alexander Fleming
The first sulfonamide and first commercially
available antibacterial, Prontosil, was developed by a research team led by Gerhard
Domagk in 1932 at the Bayer Laboratories of the IG Farben
conglomerate in Germany. Domagk received the 1939 Nobel Prize for Medicine
for his efforts. 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.
In 1939, coinciding with the start of
World War II, Rene Dubos 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 universally and was very effective in treating wounds and ulcers
during World War II. 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 the war.
Florey and Chain succeeded in purifying
the first penicillin, penicillin G, in 1942, but it did not become
widely available outside the Allied military before 1945. The chemical
structure of penicillin was determined 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. The discovery of such a powerful antibiotic was unprecedented,
and the development of penicillin led to renewed interest in the search for
antibiotic compounds with similar efficacy and safety. For their successful
development of penicillin, which Fleming had accidentally discovered but could
not develop himself, as a therapeutic drug, Ernst Chain
and Howard Florey
shared the 1945 Nobel Prize in Medicine with Fleming.
Florey credited 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.
Etymology
The term "antibiotic" derives
from anti + βιωτικός (biōtikos), "fit for life,
lively", which comes from βίωσις (biōsis), "way of life",
and that from βίος (bios), "life".
The term "antibacterial"
derives from Greek ἀντί (anti), "against" +
βακτήριον (baktērion), diminutive of βακτηρία (baktēria),
"staff, cane", because the first ones to be discovered were
rod-shaped.
Medical uses
Treatment
- Bacterial infection
- Protozoan infection, e.g., metronidazole
is effective against several parasitics
- Immunomodulation, e.g., tetracycline,
which is effective in periodontal inflammation, and dapsone,
which is effective in autoimmune diseases such as oral
mucous membrane pemphigoid
- Nonoperative resource for patients who have
non-complicated acute appendicitis. Treatment with antibiotics has proven
to work, with almost no cases of remission.
- Prevention of infection
- Surgical
wound
- Dental antibiotic prophylaxis
- Conditions of neutropenia,
e.g. cancer-related
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. A bactericidal activity of
antibacterials may depend on the bacterial growth phase, and it often requires
ongoing metabolic activity and division of bacterial cells. These findings are
based on laboratory studies, and in clinical settings have also been shown to
eliminate bacterial infection. Since the activity of antibacterials depends
frequently on its concentration, in vitro characterization of
antibacterial activity commonly includes the determination of the minimum inhibitory concentration
and minimum bactericidal concentration of an antibacterial. 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.
Classes
Molecular targets of antibiotics on the bacteria cell
Antibacterial antibiotics are commonly
classified based on their mechanism of action, chemical structure, or spectrum
of activity. Most target bacterial functions or growth processes. Those that
target the bacterial cell wall (penicillins
and cephalosporins)
or the cell membrane (polymyxins), or interfere with essential bacterial enzymes (rifamycins,
lipiarmycins,
quinolones,
and sulfonamides) have bactericidal
activities. Those that target protein synthesis (macrolides,
lincosamides
and tetracyclines)
are usually bacteriostatic (with the exception of
bactericidal aminoglycosides). Further categorization is
based on their target specificity. "Narrow-spectrum" antibacterial
antibiotics target specific types of bacteria, such as Gram-negative
or Gram-positive
bacteria, whereas broad-spectrum antibiotics affect a wide range of bacteria.
Following a 40-year hiatus in discovering new classes of antibacterial
compounds, four new classes of antibacterial antibiotics have been brought into
clinical use: cyclic lipopeptides (such as daptomycin),
glycylcyclines
(such as tigecycline),
oxazolidinones
(such as linezolid),
and lipiarmycins
(such as fidaxomicin).
Production
Since the first pioneering efforts of 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.
Administration
Oral antibiotics are taken by mouth,
whereas intravenous
administration may be used in more serious cases, such as deep-seated systemic infections. Antibiotics may also
sometimes be administered topically, as with eye drops
or ointments.
The topical antibiotics are:
- Erythromycin
- Clindamycin
- Gentamycin
- Tetracycline
- Meclocycline
- (Sodium) sulfacetamide
While topical medications that act as
Comedolytics as well as antibiotics are:
- Benzoyl peroxide
- Azelaic acid
Side-effects
Antibiotics are screened for any
negative effects on humans or other mammals before approval for clinical use,
and are usually considered safe and most are well-tolerated. However, some
antibiotics have been associated with a range of adverse side effects.
Side-effects range from mild to very serious depending on the antibiotics used,
the microbial organisms targeted, and the individual patient. Safety profiles
of newer drugs are often not as well-established as for those that have a long
history of use. Adverse effects range from fever and nausea to major allergic
reactions, including photodermatitis and anaphylaxis. 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. Antibacterials
can also affect the vaginal flora, and may lead to overgrowth of
yeast species of the genus Candida
in the vulvo-vaginal area. Additional 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.
Some scientists have hypothesized that the indiscriminate use of antibiotics
alter the host microbiota and this has been associated with chronic
disease.
