Download The successful outcome of antimicrobial therapy with

Antibacterial
1. Introduction :
An antibacterial is an agent that inhibits bacterial growth or kills bacteria. The term is often
used synonymously with the term antibiotic(s); today, however, with increased knowledge of
the causative agents of various infectious diseases, antibiotic(s) has come to denote a broader
range of antimicrobial compounds, including anti-fungal and other compounds.
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. This definition excluded substances that
kill bacteria, but 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 of today's antibacterials chemically are
semisynthetic modifications of various natural compounds. These include, for example, the
beta-lactam antibacterials, 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.
Amoxicillin capsules, one of the most prescribed antibiotics in the world, belonging to the
family of beta-lactam
2. 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. Many ancient cultures, including the 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 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. John Tyndall first described
antagonistic activities by fungi against bacteria in England in 1875. 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, while 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.
Penicillin, the first natural antibiotic discovered by Alexander Fleming in 1928
In 1895, Vincenzo Tiberio, physician of the University of Naples discovered that a mold
(Penicillium) in a water well has an antibacterial action. After this initial chemotherapeutic
compound proved effective, others pursued similar lines of inquiry, but it was not until in
1928 that Alexander Fleming observed antibiosis against bacteria by a fungus of the genus
Penicillium. Fleming postulated the effect was mediated by an antibacterial compound named
penicillin, and that its antibacterial properties could be exploited for chemotherapy. He
initially characterized some of its biological properties, but he did not pursue its further
development.
Alexander Fleming
The first sulfonamide and first commercially available antibacterial antibiotic, 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 antibacterial antibiotics. In 1939,
coinciding with the start of World War II, Rene Dubos reported the discovery of the first
naturally derived antibiotic, gramicidin from B. brevis. It was one of the first commercially
manufactured antibiotics universally and very effectively used to treat wounds and ulcers
during World War II. 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 procaine in 1942, but it did not become widely available outside
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 discovery and development of penicillin as a therapeutic drug, Ernst Chain, Howard
Florey, and Alexander Fleming shared the 1945 Nobel Prize in Medicine. 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
2.1. Etymology :
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, and the term "antibiotic" derives from anti + βιωτικός
(biōtikos), "fil for life, lively", which comes from βίωσις (biōsis), "way of life",and that
from βίος (bios), "life".
3. Medical Uses :

Treatment
o
o
o

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
Prevention of infection
o Surgical wound
o Dental antibiotic prophylaxisConditions of neutropenia, e.g. cancer-related
4. 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 finding 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.
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.
5. Classes :
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 (polymixins), or interfere with essential bacterial enzymes (rifamycins,
lipiarmycins, quinolones, and sulfonamides) have bactericidal activities. Those that
target protein synthesis (aminoglycosides, macrolides, and tetracyclines) are usually
bacteriostatic. Further categorization is based on their target specificity. "Narrowspectrum" antibacterial antibiotics target specific types of bacteria, such as Gramnegative 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).
6. 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.
7. Administration :
Oral antibacterials are orally ingested, 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.
8. Side-effects :
Antibacterials 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 antibacterials have been associated with a range of adverse
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. Flouroquinolone antibiotics, such as moxifloxacin,
are especially notorious for their side effects, which include prolongation of the QT
interval and toxic psychosis. 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.There are new evidence shown that the
indiscriminate use of antibiotics alter the host microbiota and this has been associated
with chronic diseas.
9. Drug-drug interactions :
9.1. Birth control pills :
The majority of studies indicate antibiotics do not interfere with contraceptive pills, such as
clinical studies that suggest the failure rate of contraceptive pills caused by antibiotics is very
low (about 1%). In cases where antibacterials have been suggested to affect the efficiency of
birth control pills, such as for the broad-spectrum antibacterial 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. 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. Clinicians have recommended that extra contraceptive
measures be applied during therapies using antibacterials that are suspected to interact with
oral contraceptives.
9.2. Alcohol :
Interactions between alcohol and certain antibacterials may occur and may cause side-effects
and decreased effectiveness of antibacterial therapy.
"It is sensible to avoid drinking alcohol when taking medication. However, it is
unlikely that drinking alcohol in moderation will cause problems if you are taking
most common antibiotics. However, there are specific types of antibiotics with which
alcohol should be avoided completely, because of serious side-effects.
Therefore, potential risks of side-effects and effectiveness depend on the type of antibacterial
administered. Despite the lack of a categorical counterindication, the belief that alcohol and
antibacterials should never be mixed is widespread.
Antibacterials 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.
Other effects of alcohol on antibacterial activity include altered activity of the liver enzymes
that break down the antibacterial compound.In addition, serum levels of doxycycline and
erythromycin succin two bacteriostatic antibacterials (see above) may be reduced by alcohol
consumption, resulting in reduced efficacy and diminished pharmacotherapeutic effect.
10. Resistance :
The emergence of resistance of bacteria to antibacterial drugs is a common phenomenon.
Emergence of resistance often reflects evolutionary processes that take place during antibacterial
drug therapy. The antibacterial treatment may select for bacterial strains with physiologically or
genetically enhanced capacity to survive high doses of antibacterials. Under certain conditions, it
may result in preferential growth of resistant bacteria, while growth of susceptible bacteria is
inhibited by the drug. For example, antibacterial selection within whole bacterial populations for
strains having previously acquired antibacterial-resistance genes was demonstrated in 1943 by the
Luria–Delbrück experiment. Survival of bacteria often results from an inheritable resistance.
Resistance to antibacterials also occurs through horizontal gene transfer. Horizontal transfer is more
likely to happen in locations of frequent antibiotic use. Antibacterials such as penicillin and
erythromycin, which used to have high efficacy against many bacterial species and strains, have
become less effective, because of increased resistance of many bacterial strains. 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.
Several molecular mechanisms of antibacterial resistance exist. Intrinsic antibacterial
resistance may be part of the genetic makeup of bacterial strains. 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. Antibacterialproducing bacteria have evolved resistance mechanisms that have been shown to be similar
to, and may have been transferred to, antibacterial-resistant strains. The spread of antibacterial
resistance often occurs through vertical transmission of mutations during growth and by
genetic recombination of DNA by horizontal genetic exchange. For instance, antibacterial
resistance genes can be exchanged between different bacterial strains or species via plasmids
that carry these resistance genes. Plasmids that carry several different resistance genes can
confer resistance to multiple antibacterials. 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.
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 (TB) 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.
For example, NDM-1 is a newly identified enzyme conveying bacterial resistance to a broad
range of beta-lactam antibacterials. United Kingdom Health Protection Agency has stated that
"most isolates with NDM-1 enzyme are resistant to all standard intravenous antibiotics for
treatment of severe infections."
SEM depicting methicillin-resistant Staphylococcus aureus bacteria
10.1. Misuse :
The first rule of antibiotics is try not to use them, and the second rule is try not to use too
many of them.
—Paul L. Marino, The ICU Book
Inappropriate antibacterial treatment and overuse of antibiotics have contributed to the
emergence of antibacterial-resistant bacteria. Self prescription of antibacterials is an example
of misuse. Many antibacterials are frequently prescribed to treat symptoms or diseases that do
not respond to antibacterial therapy or are likely to resolve without treatment, or incorrect or
suboptimal antibacterials are prescribed for certain bacterial infections. The overuse of
antibacterials, like penicillin and erythromycin, have been associated with emerging
antibacterial resistance since the 1950s. Widespread usage of antibacterial drugs in hospitals
has also been associated with increases in bacterial strains and species that no longer respond
to treatment with the most common antibacterials.
Common forms of antibacterial misuse include excessive use of prophylactic antibiotics in
travelers and failure of medical professionals to prescribe the correct dosage of antibacterials
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 antibacterial, incorrect dosage and
administration, or failure to rest for sufficient recovery. Inappropriate antibacterial treatment,
for example, is the prescription of antibacterials 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". Multifactorial interventions aimed at
both physicians and patients can reduce inappropriate prescription of antibiotics.
Several organizations concerned with antimicrobial resistance are lobbying to eliminate the
unnecessary use of antibacterials. The issues of misuse and overuse of antibiotics have been
addressed by the formation of the U.S. 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. An NGO campaign
group is Keep Antibiotics Working. In France, an "Antibiotics are not automatic" government
campaign started in 2002 and led to a marked reduction of unnecessary antibacterial
prescriptions, especially in children.
The emergence of antibacterial resistance has prompted restrictions on antibacterial use in
the UK in 1970 (Swann report 1969), and the EU has banned the use of antibacterials as
growth-promotional agents since 2003. Moreover, 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 nontherapeutic uses. However, commonly there are delays
in regulatory and legislative actions to limit the use of antibacterials, attributable partly to
resistance against such regulation by industries using or selling antibacterials, and to the time
required for research to test causal links between antibacterial use and resistance. Two federal
bills (S.742 and H.R. 2562) aimed at phasing out nontherapeutic use of antibacterials in US
food animals were proposed, but have 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).
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 United States Food and Drug Administration 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.
11. Alternatives:
The increase in bacterial strains that are resistant to conventional antibacterial therapies has
prompted the development of alternative strategies to treat bacterial diseases.
11.1. Resistance-modifying agents :
One strategy to address bacterial drug resistance is the discovery and application of
compounds that modify resistance to common antibacterials. For example, some resistancemodifying agents may inhibit multidrug resistance mechanisms, such as drug efflux from the
cell, thus increasing the susceptibility of bacteria to an antibacterial. Targets include:


The efflux inhibitor Phe-Arg-β-naphthylamide.
Beta-lactamase inhibitors, such as clavulanic acid and sulbactam.
Metabolic stimuli such as sugar can help eradicate a certain type of antibiotic tolerant
bacteria by keeping their metabolism active.
11.2. Phage therapy :
Phage therapy is the use of viruses that infect bacteria (i.e. phages) for the treatment of
bacterial infections. Phages are common in bacterial populations and control the growth of
bacteria in many environments, including in the intestine, the ocean, and the soil. Phage
therapy was in use in the 1920s and 1930s in the US, Western Europe, and Eastern Europe.
However, success rates of this therapy have not been firmly established, because only a
limited number of clinical trials testing the efficacy of phage therapy have been conducted.
These studies were performed mainly in the former Soviet Union, at the Eliava Institute of
Bacteriophage, Microbiology and Virology, Republic of Georgia. The development of
antibacterial-resistant bacteria has sparked renewed interest in phage therapy in Western
medicine. Several companies (e.g., Intralytix, Novolytics, and Gangagen), universities, and
foundations across the world now focus on phage therapies. One concern with this therapeutic
strategy is the use of genetically engineered viruses, which limits certain aspects of phage
therapy.
11.3. Bacteriocins :
Bacteriocins are peptides that can be more readily engineered than small molecules, and are
possible alternatives to conventional antibacterial compounds. Different classes of
bacteriocins have different potential as therapeutic agents. Small-molecule bacteriocins
(microcins and lantibiotics) are similar to the classic antibiotics; colicin-like bacteriocins
possess a narrow spectrum, and require molecular diagnostics prior to therapy.[citation needed]
Limitations of large-molecule antibacterials include reduced transport across membranes and
within the human body. For this reason, they are usually applied topically or
gastrointestinally.
11.4. Chelation :
Chelation of micronutrients that are essential for bacterial growth to restrict pathogen spread
in vivo might supplement some antibacterials. For example, limiting the iron availability in
the human body restricts bacterial proliferation. Many bacteria, however, possess mechanisms
(such as siderophores) for scavenging iron within environmental niches in the human body,
and experimental developments of iron chelators, therefore, aim to reduce iron availability
specifically to bacterial pathogens.
11.5. Vaccines :
Vaccines rely on immune modulation or augmentation. Vaccination either excites or
reinforces the immune competency 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. 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.
11.6. Biotherapy :
Biotherapy may employ organisms, such as protozoa, to consume the bacterial pathogens.
Another such approach is maggot therapy.
11.7. Probiotics :
Probiotics consist of a live culture of bacteria, which may become established as competing
symbionts, and inhibit or interfere with colonization by microbial pathogens.
11.8. Host defense peptides :
An additional therapeutic agent is the enhancement of the multifunctional properties of
natural anti-infectives, such as cationic host defense (antimicrobial) peptides (HDPs).
11.9. Antimicrobial coatings :
Functionalization of antimicrobial surfaces can be used for sterilization, self-cleaning, and
surface protection.
11.10. Antimicrobial copper alloy surfaces :
Copper-alloy surfaces have natural intrinsic properties to effectively and quickly destroy
bacteria. The United States Environmental Protection Agency has approved the registration of
355 different antibacterial copper alloys that kill E. coli O157:H7, methicillin-resistant
Staphylococcus aureus (MRSA), Staphylococcus, Enterobacter aerogenes, and Pseudomonas
aeruginosa in less than 2 hours of contact. As a public hygienic measure in addition to regular
cleaning, antimicrobial copper alloys are being installed in healthcare facilities and in a
subway transit system.