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In order to understand the principles behind antimicrobial resistance, it is Pharmacology Module Outline
important to first have a good foundation regarding some key I. Historical Perspectives
a. Ancient times
pharmacological concepts that may be relevant to this phenomenon.
b. Pre-antibiotic era
Presented in this module are topics on the birth and development of our
c. Antibiotic age
antibiotic arsenal, some basics regarding how antibiotics work and how d. Post-antibiotic era?
they are applied for use in veterinary practice, and lastly, how these should II. Introduction to veterinary antimicrobials
a. Introduction
be prudently utilized in animals. Knowledge on these basic properties of
b. Spectrum of activity
antibiotics will serve as guidelines for chemotherapy, including appropriate
c. Effect of bacteria
selection and other measures for mitigating antibiotic resistance. d. Modes of Action
III. Antimicrobial usage in animals
a. Introduction
b. Therapeutic uses in animals
Module Objectives:
c. Non-therapeutic uses in animals
i. Growth promotion
This module aims to introduce the students to selected pharmacologic ii. Prophylaxis and
metaphylaxis
concepts related to antimicrobial resistance. In particular this module will
IV. Prudent use of animicrobials in veterinary
discuss:
medicine
1. antibiotic discovery and development; V. Summary
2. antibiotic activity, effects and modes of action; VI. References

3. therapeutic and non-therapeutic antibiotic usage and application in

animals; and
4. prudent use of antibiotics in animals.
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ANCIENT TIMES
First Treatments
At around 1550 BC, Egyptians have been recorded Egyptian Papyrus
Many ancient cultures used molds,
to use a concoction of honey, lard and lint for
soil, and plants to treat bacterial dressing wounds. We now know that honey actually The Eber’s papyrus,

infections. In Ancient Serbia, China contains substantial amounts of hydrogen peroxide which dates back from
which can kill bacteria. about 1550 B.C., is the
and Greece, old moldy bread was oldest preserved
pressed against wounds to prevent medical document. It
More than 2,000 years ago, moldy bread was used in contains a list of
infection. In Egypt, crusts of moldy
China, Greece, Serbia, Egypt and probably other formulas and remedies
wheaten bread were applied on ancient civilizations as treatment for some disease to cure illnesses and
conditions, particularly infected wounds. The observed afflictions ranging from
pustular scalp infections and
curative powers may have been due to some raw pains to cancer11.
“medicinal earth” was dispensed for forms of antibiotics produced by the mold growing on

its curative properties15. the bread.

These remedies were believed to influence the spirits or the gods responsible for illness and suffering.
Today we know that the occasional efficacy of these early treatments was due to the active metabolites and
chemicals present in these concoctions.

The Advent of Patented Potions

Historical Bacterial
Probably owing to the dramatic impact of infectious diseases and the lack of any other available Disease Outbreaks

effective cures, people living before the antibiotic era began often relied on a variety of largely untested
Past civilizations were
remedies to treat their illnesses. These remedies were of highly variable efficacy and safety, and constantly confronted
with fatal infectious
sometimes had no bearing in the cure or relief from disease conditions, but were nonetheless patented
diseases, some in
and utilized by desperate people with no other alternatives. catastrophic
proportions. Examples
of bacterial diseases
that have wreaked
Godfrey’s Cordial (also called Mother’s Friend) and Dalby’s Carminative were
havoc to humanity are:
among the most widely used patent medicines given to infants and children in Black death or plague,
England and the United States during the latter years of the 18th and early part cholera and syphilis. If
of the 19th centuries. Both preparations were used-almost always without a antimicrobials had been

physician’s advice for a wide variety of symptoms ranging from run of-the mill available, mankind’s
history would have been
fretfulness and colic, to the severest forms of dehydration caused by explosive,
altogether different.
bloody diarrhea.

Despite their innocuous names, they were sinister preparations because of their opium content; Godfrey’s Cordial contained
one grain of opium in each two ounces; Dalby’s Carminative contained 3ı grain of opium in the same amount. As a result
many infants died of opium poisoning during this time (T.E.C. Jr., 1970 “What Were Godfrey’s Cordial and Dalby’s
Carminative?” Pediatrics 45:1011)
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PRE-ANTIBIOTIC ERA

Dr. Ehrlich
Weapons against bacterial diseases improved just before the turn of the 20th century. The
advent of the germ theory of disease, which proposed that microorganisms are the causes
of many diseases, caused a revolutionary change in the understanding of the vital role of
microbes in infectious diseases. Specific microbial pathogens were identified as the
causative agents of many diseases, and a race immediately began to find effective means
to kill these implicated microbes.

The first recorded microbial by-product shown to have antimicrobial activity was the blue
Dr. Ehrlich set aim to find
pigment from Bacillus pyocyaneus (now Pseudomonas aeruginosa) which stopped the “magic bullets” specific
substances which have specific
growth of some kinds of bacteria in the test tube. This was serendipitously observed by E.
affinities for pathogenic
de Freudenreich (Germany) in 1888. Rudolf Emmerich and Oscar Loew (Germany), who organisms at which they were

later named the substance “pyocyanase”, performed clinical trials in 1889 showing some aimed.

effectiveness against many of the infectious diseases of that time. This understandably To achieve this, Ehrlich and his
raised excitement in the scientific community, however, this compound’s instability and assistants tested hundreds of
chemical substances. Ehrlich’s
inherent toxicity in patients later made it clear that pyocyanase had no real clinical
606th preparation of an
application, and thus its popularity eventually declined16. arsenobenzene compund was
previously set aside in 1907 as
being ineffective. But when
Another German physician, named Paul Ehrlich, tirelessly searched for a “magic bullet” that Ehrlich asked a Japanese

could selectively kill microorganisms. After several failures, in 1910 he finally came up with colleague named Hata, who
had succeeded in infecting
an arsphenamine chemical dye they referred to as compund 606 and later named rabbits with syphilis, to test this
Salvarsan - the first chemical compound shown to cure a human disease, syphilis 22, 25, 28. discarded drug on these
rabbits, they found that it was
very effective. Thus came the
Alexander Fleming, more notable for his discovery of penicllin in the later years, reported in birth of the first
chemotherapeutic agent, later
1920 of a naturally occurring antibacterial substance in human tears that causes lysis in
named Salvarsan.
some bacterial cells. He later called this lysozyme. Unfortunately, this too did not realize
clinical application because of its limited effect on mostly non-pathogenic bacteria, and
because it could not be produced in quantities large enough for further trials12,16.

The impact of Dr. Ehrlich’s

contribution to medicine can be
best appreciated in the fact that
his story was immortalized in a
1940 Warners Bros. movie
entitled “Dr. Ehrlich’s Magic
Bullet”.
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The Penicillin Story

GOLDEN AGE OF ANTIBACTERIALS
One morning in September 1928,
Domagk thought that because dyes have affinity for bacterial cells, they
Sir Alexander Fleming who just
In 1928, Fleming’s major medical may possibly alter their growth once taken inside. He tested the
got back from a holiday, returned
synthetic newly patented red dye, Prontosil. Luckily, he also tested this
breakthrough came about as he chemical in mice; if he relied on test tubes alone, no activity would have
to a lab full of contaminated and
overgrown plates of
serendipitously discovered penicillin, later to been observed and the discovery would have not been made. This is
staphylococci. While
because the active component of the dye, the sulfonamide requires
be claimed as the miracle drug of the 20th decontaminating the old plates, he
release during a necessary metabolic processes in vivo16.
noticed some inhibition of bacterial
century. However, the impact of this
growth around a mold contaminant
discovery was not realized until the 1940s, The first to receive this was drug his own young daughter. A needle was
and took interest because his
accidentally embedded in her wrist bone, eye first, and broke off when
previous works have been on
when its applicability as a therapeutic agent she fell from the stairs. It was surgically removed but a secondary
finding effective antibacterial
was made possible by Florey and Chain. streptococci infection, which Domagk himself identified, resulted in a life-
agents. He later identified the
threatening fever. Left with very little option, he asked permission from
Blamed for this delay was the lack of mold as Penicillium spp/, named
the attending doctor to give her Prontosil. His daughter recovered
the extract as penicillin, and
biochemical and microbiological expertise at almost immediately20.
published his findings in British
that time, as well as the lack of interest and Journal of Experimental Pathology
For this monumental discovery, Domagk was awarded the 1939 Nobel in 1929.
support from the scientific community Prize in Physiology or Medicine, but, being a German national, was
brought about by previous experience with forbidden by the Nazi regime to receive it. He was instead arrested and
jailed. He finally received the award in 1947, after the war.
the failure of pyocyanase and the toxicity of
Salvarsan.

In 1935, a breakthrough that ushered the era of antibacterials was made by the German biochemist
After realizing the inherent
Gerhard Domagk at the Bayer Laboratories of the I.G. Farben company in Germany19. He discovered difficulty in cultivating the mold

and developed the first sulfonamide, a synthetic red dye more popularly known by its trade name of and purifying the active agent, he
thought this disco very had little
Prontosil, the first commercially available antibacterial. Impressive clinical successes resulted in a application.
sharp decline in mortaliy due to killer diseases such as meningitis, child bed fever and pneumonia.
However, about nine years later,
Domagk’s discovery saved many lives, including prominent figures such as Winston Churchill6 and
pharmacologist Howard Florey
Franklin D. Roosevelt, Jr., son of then US President Roosevelt. and biochemist Ernst Boris Chain
read his work and took interest in
exploring it furher chemically.
Inspired by the groundbreaking work of Domagk (with sulfa) and Fleming, Florey and Chain (with They later successfully achieved

Penicllin), a number of subsequent antimicrobial discoveries quickly followed. To this day, newer purification and large-scale
production of the first antibiotic
antimicrobial compounds continue to be discovered and introduced, although the rate has slowed which, after having saved millions
considerably. of lives since its introduction in
1942, was later acclaimed as the
miracle drug of the 20th century.
For this notable achievement
Fleming, Florey and Chain shared
the Nobel Prize for Physiology and
Medicine in 1945.
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POST GOLDEN AGE

Just a few years after the golden Based on his laboratory observations, the famed penicillin discoverer Alexander Fleming
had predicted in 1945 that misuse of this discovery could lead to the election and
age of antimicrobials, warning
propagation of mutant forms of bacteria resistant to the drug. He warned that too small
signs of developing resistance doses that fail to completely clear the infection would breed microbes trained to resist the
drug, which could then eventually be passed on to other susceptible individuals. Against
were observed. It has now
this warning, penicillin was eventually made freely available to the public, driven by the
become clear that microorganisms public clamor for this “miracle drug” and the business opportunities that came along with

are countering the impact of this medical breakthrough. Various preparations of salves, lonzenges, nasal ointments
and even cosmetic creams were sold over-the-counter. And true enough, as Fleming
antimicrobial resistance at an correctly foretold, bacterial resistance to penicillin slowly but steadily built up over the years,
often alarming speed. More and to the point that by 1955, most countries restricted the use of penicillin as “by prescription” only. However, the
uncontrolled usage was already widespread, and so is the observed resistance in several bacterial pathogens, particularly
more bacteria with multiple drug
staphylococci..
resistance are also being
A concerted effort was exerted by pharmaceutical companies to thwart this resistance, which eventually led to the
observed. Although still
discovery and introduction in the early 1960s of a semisynthetic penicillin, called methicillin, which was insensitive to the
surrounded by a number of bacterial enzymes that degrade penicillin. Although this seemed to have initially controlled penicillin resistance in the

controversies and debates as to years that followed, the subsequent emergence of resistance to methicillin, such as that seen in methicillin resistant
Staphylococcus aureus (MRSA), is now a current problem faced in hospitals worldwide.
the nature and gravity of this
resistance phenomenon, various This resistance phenomenon is not restricted to penicillin alone. The same was observed for the other antibiotics which
were subsequently discovered and made commercially available to the public in the latter half of the 20th century. In the
reports support the contention that
recent years, this was made even more complicated by the fact that the observed development of antimicrobial resistance
the abuse and misuse of has superseded the pace at which discoveries and development of better antibiotic treatments are made. It is feared that
if this is not addressed properly in time, the world will be back to the pre-antibiotic era when currently treatable infectious
antibiotics is largely responsible
conditions such as pneumonia, diarrhea, or even wound infections, will eventually be considered as life-threatening due
for the developing resistance to the lack of available effective treatment in the medical arsenal. This has become one of the major medical issues of

problem1, 13, 17, 18, 26. concern in the 21st century.

The advent of molecular biological approaches proved that, resistance genes are also horizontally transferred among bacteria at
a rate that was greater than previously expected. This poses a grim scenario for the generation to come when most
antimicrobials might no longer be effective, bringing human and veterinary medicine back again to the pre-antibiotic era where
common bacterial infections could once more prove lethal.

Not losing hope, the fight against microbes continues. Several government agencies, international groups, pharmaceutical
industries and other stakeholders in various countries and continents continue to work to mitigate further emergence and spread
of antimicrobial resistance genes. Alternative drugs are being explored, some antimicrobials have been banned for use in food
animals and regulations such as those requiring antimicrobial prescriptions are often used to promote appropriate use for both
people and animals. Worldwide, health professionals are being re-educated about the responsible and judicial use of
antimicrobials.
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INTRODUCTION

The word antimicrobial was derived from the Greek words anti
Antibiotics Versus Antimicrobials
(against), mikros (little) and bios (life) and refers to all agents
that act against microbial organisms. This is not synonymous An ANTIBIOTIC is a low molecular substance produced by a
microorganism that at a low concentration inhibits or kills other
with antibiotics, a similar term derived from the Greek word anti
microorganisms.
(against) and biotikos (concerning life). By strict definition, the
word “antibiotic” refers to substances produced by An ANTIMICROBIAL is any substance of natural, semisynthetic or
microorganisms that act against another microorganism. synthetic origin that kills or inhibits the growth of microorganisms but
causes little or no damage to the host.
Thus, antibiotics do not include antimicrobial substances that
All antibiotics are antimicrobials, but not all antimicrobials are
are synthetic (sulfonamides and quinolones), or semisynthetic
antibiotics.
(methicillin and amoxicillin), or those which come from plants
(quercetin and alkaloids) or animals (lysozyme).

In contrast, the term “antimicrobials” include all agents that act

against all types of microorganisms – bacteria (antibacterial),
viruses (antiviral), fungi (antifungal) and protozoa
(antiprotozoal).
Notice that the term “antibacterials”, being the largest and
most widely known and studied class of antimicrobials, is often
used interchangeably with the term “antimicrobials” and will be
the major focus of this website.

CLASSIFICATION OF ANTIBACTERIAL AGENTS

Antimicrobials are classified in several ways, including:
1. spectrum of activity
2. effect on bacteria
3. mode of action
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CLASSIFICATION ACCORDING TO SPECTRUM OF ACTIVITY.

Depending on the range of bacterial species susceptible to these agents, antibacterials are classified as broad-spectrum,
intermediate-spectrum, or narrow- spectrum. Note that the spectra of activity may change with acquisition of resistance genes,
as will be discussed in the next module.

1. Broad spectrum antibacterials are active against both Gram-positive and Gram-negative organisms. Examples include:
tetracyclines, phenicols, fluoroquinolones, “third-generation” and “fourth-generation” cephalosporins.

2. Narrow spectrum antibacterials have limited activity and are primarily only useful against particular species of
microorganisms. For example, glycopeptides and bacitracin are only effective against Gram-positive bacteria, whereas
polymixins are usually only effective against Gram negative bacteria. Aminoglycosides and sulfonamides are only
effective against aerobic organisms, while nitroimidazoles are generally only effective for anaerobes.

Clinical Implications: Intrinsic Resistance

Knowledge of the intrinsic resistance of a pathogen of concern is important in practice to avoid inappropriate and ineffective
therapies.

For bacterial pathogens which are naturally insensitive to a large number of classes of antimicrobials, such as Mycobacterium tuber-
culosis and Pseudomonas aeruginosa, this consideration can pose a limitation in the range of options for treatment and thus
consequently further increase the risk for emergence of acquired resistance.
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EFFECT ON BACTERIA

Because of differences in the mechanisms by which antibiotics affect bacteria, the clinical use of antibacterials may have very
different effects on bacterial agents, leading to an endpoint of either inactivation or actual death of the bacteria.

1. Bactericidal drugs are those that kill target organisms. Examples of bactericidal drugs include aminoglycosides,
cephalosporins, penicillins, and quinolones.

2. Bacteriostatic drugs inhibit or delay bacterial growth and replication. Examples of such include tetracyclines,
sulfonamides, and macrolides.

Some antibiotics can be both bacteriostatic and bactericidal, depending on the dose, duration of exposure and the state of the
invading bacteria. For example, aminoglycosides, fluoroquinolones, and metronidazole exert concentration-dependent killing
characteristics; their rate of killing increases as the drug concentration increases.

Clinical Implications: Bacteriostatic Vs. Bactericidal Antibacterials

Onset of action for bacteriostatic agents is generally slower than that of bactericidal agents. In addition, bacteriostatic
drugs require a working immune system for effective elimination of the microorganism by the infected host. Bacteriostaic
antibiotics are therefore not advisable for use in animals with immunosuppressed or immunocompromised conditions and
those suffering from life-threatening acute infections.
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MODE OF ACTION
Different antibiotics have different modes of action, owing to the nature of their structure and degree of affinity to certain target
sites within bacterial cells.

1. Inhibitors of cell wall synthesis. While the cells of humans and animals do not have cell walls, this structure is critical for
the life and survival of bacterial species. A drug that targets cell walls can therefore selectively kill or inhibit bacterial
organisms. Examples: penicllins, cephalosporins, bacitracin and vancomycin.

2. Inhibitors of cell membrane function. Cell membranes are important barriers that segregate and regulate the intra- and
extracellular flow of substances. A disruption or damage to this structure could result in leakage of important solutes
essential for the cell’s survival. Because this structure is found in both eukaryotic and prokaryotic cells, the action of this
class of antibiotic are often poorly selective and can often be toxic for systemic use in the mammalian host. Most clinical
usage is therefore limited to topical applications. Examples: polymixin B and colistin.

3. Inhibitors of protein synthesis. Enzymes and cellular structures are primarily made of proteins. Protein synthesis is an
essential process necessary for the multiplication and survival of all bacterial cells. Several types of antibacterial agents
target bacterial protein synthesis by binding to either the 30S or 50S subunits of the intracellular ribosomes. This activity
then results in the disruption of the normal cellular metabolism of the bacteria, and consequently leads to the death of
the organism or the inhibition of its growth and multiplication. Examples: Aminoglycosides, macrolides, lincosamides,
streptogramins, chloramphenicol, tetracyclines.

4. Inhibitors of nucleic acid synthesis. DNA and RNA are keys to the replication of all living forms, including bacteria. Some
antibiotics work by binding to components involved in the process of DNA or RNA synthesis, which causes interference
of the normal cellular processes which will ultimately compromise bacterial multiplication and survival. Examples:
quinolones, metronidazole, and rifampin.

5. Inhibitors of other metabolic processes. Other antibiotics act on selected cellular processes essential for the survival of
the bacterial pathogens. For example, both sulfonamides and trimethoprim disrupt the folic acid pathway, which is a
necessary step for bacteria to produce precursors important for DNA synthesis. Sulfonamides target and bind to
dihydropteroate synthase, trimethophrim inhibit dihydrofolate reductase; both of these enzymes are essential for the
production of folic acid, a vitamin synthesized by bacteria, but not humans.
 INHIBITORS OF CELL WALL SYNTHESIS
BETA LACTAM ANTIBIOTICS
Mode of action: Inhibition of cell wall synthesis. This particular group is characterized by its four-membered, nitrogen-containing beta-lactam
ring at the core of its structure, which is key to the mode of action of this group of antibiotics. Beta lactam antibiotics target the
penicillin-binding proteins or PBPs - a group of enzymes found anchored in the cell membrane, which is involved in the cross-
linking of the bacterial cell wall. The beta-lactam ring portion of this group of antibiotics binds to these different PBPs,
rendering them unable to perform their role in cell wall synthesis. This then leads to death of the bacterial cell due to osmotic
instability or autolysis.

Penicllins: NATURAL: penicillin G, penicillin V; PENICILLINASE-RESISTANT PENICILLLIN: methicillin; oxacillin, nafcillin;

Examples: EXTENDED SPECTRUM PENICILLIN: ampicillin, amoxicillin, carbenicillin
Cephalosporins: cephalothin; cefamandole, cefotaxime
Carbapenems: primaxin
Monobactams: aztreonam

Source: Penicillin: Penicillum chrysogenum (syn: P. notatum), Aspergillus nidulans

Cephalosporin: Acremonium chrysogenum (syn: Cephalosporium acremonium), Paecilomyces persinicus, Streptomyces
clavuligerus, Nocardia lactamdurans, Flavobacterium sp. Lysobacter lactamgenus

Spectrum of activity: Broad-spectrum: carbapenems, 2nd, 3rd and 4th generation cephalosporins
Narrow-spectrum: penicillin, 1st generation cephalosporins, monobactams

Effect on bacteria: Generally bactericidal

Examples of applications in Ruminants: Anthrax, listeriosis, leptospirosis, clostridial and corynebacterial infections; streptococcal mastitis,
Veterinary Medicine: keratoconjunctivitis
Swine: erysipelas, streptococcal and clostridial infections
Horses: Tetanus, strangles, other strep and clostridial infections, foal pneumonia,
Dogs and cats: streptococcal and clostridial infections, UTI
Poultry: Necrotic enteritis, ulcerative enteritis, and intestinal spirochetosis
Miscellaneous: Although beta – lactam antibiotics should theoretically work against all types of bacteria, this is not the case. This is because
different bacteria have varying PBP content and nature. Also, some bacteria have natural structural characteristics which do
not favor this mode of action (e.g., Gram-negatives have an outer membrane layer which makes the PBPs more difficult to
reach).

GLYCOPEPTIDES
Mode of action: Inhibition of cell wall synthesis. Glycopeptides bind to precursors of cell wall synthesis which leads to interference of the
penicillin-binding protein (PBP) enzymes, such as transpeptidases, to incorporate the precursors into the growing cell wall.
With this, cell wall synthesis stops and cell death often follows.
Example: Vancomycin, teicoplanin, avoparcin

Source: Various species of actinomycetes such as Streptomyces orientalis (vancomycin), Nocardia actinoides (Actinoidin)

Spectrum of activity: Narrow spectrum affecting only Gram-positive bacteria

Effect on bacteria: Bactericidal

Examples of applications in Vancomycin: “Last resort” drug in human medicine with very few applications in animals.
Veterinary Medicine: Avoparcin: Previously used extensively for growth promotion of chickens and pigs in some countries
Miscellaneous: Ristocetin, although also bactericidal like vancomyin, was discontinued for use as an antibiotic because it causes aggregation
of blood platelets. However, this unfavorable attribute was put to good use in helping to diagnose von Willebrand’s disease.

Some glycopeptides like avoparcin, A-4696 or actaplanin and A35512 are being marketed and used as feed additive in some
countries. When it became apparent that avoparcin selected for VRE (vancomycin resistant enterococci) in animals, Denmark
and subsequently all of Europe withdrew it from animal feeds to reduce risk for humans. The ban in Denmark was reportedly
followed by an immediate decrease in VRE isolates in poultry, but not in pigs, until tylosin was also banned from use in feed
(Aarestrup et al., 2001).
 INHIBITORS OF CELL MEMBRANE FUNCTION

POLYMIXINS
Mode of action: Inhibition of cell membrane function. Disrupt the structure of cell membrane phospholipids and increase cell permeability by a
detergent-like action, causing cell death. This binding is competitive with calcium and magnesium. Polymixins have also been
shown to neutralize endotoxins.
Example: Polymixin B, colistin (Polymixin E)

Source: Bacillus polymyxa

Spectrum of activity: Narrow spectrum affecting primarily Gram-negative bacteria

Effect on bacteria: Bactericidal

Examples of applications in Cattle: colibacillosis and salmonellosis in calves, mastitis

Veterinary Medicine: Swine: neonatal porcine colibacillosis
Horses: bacterial keratitis or metritis caused by Klebsiella spp.
Dogs and cats: bacterial keratitis, otitis externa, skin infections
Miscellaneous: Polymixins are not absorbed from the gastrointestinal tract. Because of their excessive nephrotoxic nature, other polymixin
classes have been discarded.

INHIBITORS OF PROTEIN SYNTHESIS

AMINOGLYCOSIDES
Mode of action: Inhibition of protein synthesis. Once inside the bacterial cell, aminoglycosides bind to the 30s ribosomal sub-unit and cause a
misreading of the genetic code. This subsequently leads to the interruption of normal bacterial protein synthesis.

Example: Gentamicin, tobramycin, amikacin, streptomycin, kanamycin, neomycin

Source: Streptomyces spp.

Microsmonospora spp.

Spectrum of activity: Broad-spectrum but NOT effective against anaerobic bacteria

Effect on bacteria: Bactericidal (dose dependent)

Examples of applications in Due to its toxicity, aminoglycoside use has been clinically limited to severe infections. The more toxic antibiotics in this class
Veterinary Medicine: have been restricted to topical or oral use for the treatment of infections caused by Enterobacteriaceae. The less toxic
aminoglycosides are used for parenteral treatment of severe sepsis caused by Gram-negative aerobes.
Miscellaneous: Nephrotoxic and ototoxic; not effective against anaerobic bacteria.

CHLORAMPHENICOL
Mode of action: Inhibition of protein synthesis, Chloramphenicol irreversibly binds to a receptor site on the 50S subunit of the bacterial
ribosome, inhibiting peptidyl transferase. This inhibition consequently results in the prevention of amino acid transfer to
growing peptide chains, ultimately leading to inhibition of protein formation.

Spectrum of activity: Broad-spectrum

Effect on bacteria: Bacteriostatic

Examples of applications in Because of its capacity to cause fatal aplastic anemia in humans, chloramphenicol is prohibited in food animals in the U.S. and
Veterinary Medicine: many countries.
May be considered for some anaerobic infections in companion animals, such as serious ocular infections, prostatitis, otitis
media/interna and salmonellosis.
Miscellaneous: Causes bone marrow depression and may compromise antibody production if given prior to vaccination.
Anaphylaxis, vomiting and diarrhea have been reported in dogs and cats. Cats are more likely to be susceptible to toxicity.

TETRACYCLINES
Mode of action: Inhibition of protein synthesis. Once tetracyclines have been transported into the cell, this class of antibiotic reversibly binds to
receptors on the 30S ribosomal subunit of the bacteria, preventing attachment of aminoacyl-tRNA to the RNA-ribosome
complex. This prevents the addition of amino acids to the elongating peptide chain, preventing synthesis of proteins.
Example: Chlortetracycline, oxytetracycline, demethylchlortetracycline, rolitetracycline, limecycline, clomocycline, methacycline,
doxycycline, minocycline
Source: Streptomyces spp.; some are also semi-synthetic

Spectrum of activity: Broad-spectrum. Exhibits activity against a wide range of Gram-positive, Gram-negative bacteria, atypical organisms such as
chlamydiae, mycoplasmas, rickettsiae and protozoan parasites.

Effect on bacteria: Bacteriostatic

Examples of applications in Tetracyclines are primarily indicated in the treatment of borreliosis, brucellosis (usually in combination with rifampin or
Veterinary Medicine: streptomycin), chlamydiosis, ehrlichiosis, leptospirosis, listeriosis, rickettsiosis, and tularemia.

Miscellaneous: Tetracyclines have also been used for non-antibacterial purposes, having shown properties such as anti-inflammatory activity,
immunosuppresion, inhibition of lipase and collagenase activity, and wound healing.

MACROLIDES
Mode of action: Inhibition of protein synthesis. Macrolides reversibly bind to 50S subunit of the ribosomes and inhibit transpeptidation and
translocation processes, resulting in premature detachment of incomplete polypeptide chains.

Examples: Macrolides approved for veterinary use: Erythromycin, Tylosin, Spiramycin, Tilmicosin, Tulathromycin

Source: Saccharopolyspora erythaea (Erythromycin)

Streptomyces fradiae (Tylosin)
Some are semisynthetic (Tilmicosin, Tulathromycin)
Spectrum of activity: Narrow-spectrum

Effect on bacteria: Generally bacteriostatic, but may be bactericidal at high concentrations or against low numbers of a highly susceptible
bacterial organism.

Examples of applications in Erythromycin – drug of choice against Campylobacter jejuni. Can be an alternative to penicillin in penicillin-allergic animals and
Veterinary Medicine: second choice for anaerobic infections.
Tylosin and spiramycin – used against Mycoplasma infections; used as growth promotants.
Tilmicosin – against Mannheimia, Actinobaciullus, Pasteurella, Mycoplasma;
Miscellaneous: Parenteral use of tylosin in horses has been fatal, while oral administration has no indication for use and might result in
enterocolitis.
Tilmicosin can be fatal to pigs if given parenterally, and is not recommended for use in goats due to toxicity.
LINCOSAMIDES
Mode of action: Inhibition of protein synthesis. Lincosamides bind to the 50S ribosomal subunit and inhibit peptidyl transferases.

Example: Lincomycin, Clindamycin and Pirlimycin

Source: Streptomyces lincolnensis subsp. lincolnensis

Spectrum of activity: Moderate-spectrum; they are primarily active against Gram-positive bacteria, most anaerobic bacteria and some mycoplasma.

Effect on bacteria: Can be bactericidal or bacteriostatic, depending on the drug concentration, bacterial species and concentration of bacteria.

Examples of applications in ‰ General: clindamycin has an excellent activity against anaerobes;

Veterinary Medicine: ‰ Swine: lincomycin is used extensively in the prevention and treatment of dysentery and sometimes in mycoplasma
infections.
‰ Cattle: used as intramammary infusion in mastitis (pilrimycin);
‰ Horses: should not be used in horses;
‰ Dogs and cats: for infections with Gram-positive cocci and anaerobes
‰ Poultry: for the control of mycoplasmosis (usually in combination with spectinomycin) and necrotic enteritis.
Miscellaneous: Should not be used in horses due to their potential to cause fatal enterocolitis.

STREPTOGRAMINS
Mode of action: Inhibition of protein synthesis. Streptogramins irreversibly bind to the 50S ribosomal subunit. Group A streptogramins prevent
peptide bond formation during chain elongation step, while group B components cause the release of incomplete peptide
chains from the 50S ribosomal subunit.

Example: Virginiamycin

Source: Streptomyes virginiae.

Spectrum of activity: Narrow spectrum; mainly Gram-positive bacteria

Effect on bacteria: Group A OR Group B – Bacteriostatic

Group A AND Group B - Bacteriocidal

Examples of applications in Used largely as a growth promotant for livestock, but has also been used to prevent laminitis in horses.
Veterinary Medicine:

Miscellaneous: Virginiamycin has been developed largely as a growth promotant and is still used in many countries. It has been banned by
the European Union since 1999.
 INHIBITORS OF NUCLEIC ACID SYNTHESIS

FLUOROQUINOLONES
Mode of action: Inhibition of nucleic acid synthesis. Fluoroquinolones have been shown to bind to the DNA gyrase-DNA complex and interrupt
a process that leads to the negative supercoiling of bacterial DNA. This disruption leads to defects in the necessary
supercoiling, and render the bacteria unable to multiply and survive.

Example: Enrofloxacin, ciprofloxacin, Danofloxacin, Difloxacin, Ibafloxacin, Marbofloxacin, Pradofloxacin, Orbifloxacin

Source: Synthetic

Spectrum of activity: Broad-spectrum – 3rd generation fluoroquinolones

Narrow-spectrum – other fluoroquinolones

Effect on bacteria: Bactericidal

Examples of applications in Ruminants – acute respiratory disease, infections with E. coli, Salmonella, Mycoplasma, mastitis, metritis, conjunctivitis.
Veterinary Medicine: Swine – treatment of infections caused by Mycoplasma hyopneumoniae, Actinobacillus pleuropneumoniae, E. coli, and
Pasteurella multocida. Should never be administered in feeds because residues can contaminate the environment; prohibited
for use in pigs in some countries.
Horses – for infections with bacteria resistant to the first drug of choice; not recommended in young growing horses (may
cause cartilage erosion).
Dogs and Cats – prostatitis, mastitis, rhinitis, pyoderma, otitis, wound infections, peritonitis, osteomyelitis, and soft tissue
infections; not recommended for use in animals less than eight months of age (or <18 months of age for large breed dogs to
avoid arthropathoc effects).
Miscellaneous: Available formulations and/or approved use in different animal species vary widely between countries; some extra-label use,
but may be prohibited in some countries.

RIFAMYCINS
Mode of action: Inhibition of nucleic acid synthesis. Enters neutrophils and macrophages and inhibits DNA-dependent RNA polymerase in
bacteria

Example: Rifampin, Rifabutin, Rifapentine

Source: Amycolaptosis mediterrainei

Spectrum of activity: Broad-spectrum; also has antiviral and antifungal activity

Effect on bacteria: Bactericidal

Miscellaneous: Rifampin is used as a first line oral drug treatment for tuberculosis in humans.
 INHIBITORS OF METABOLIC PROCESSES

SULFONAMIDES
Mode of action: Inhibition of other metabolic processes. Sulfonamides interfere with folic acid synthesis by preventing addition of para-
aminobenzoic acid (PABA) into the folic acid molecule through competing for the enzyme dihydropteroate synthetase.

Example: Sulfadiazine, sulfamethoxazole, sulfadoxine

Source: Synthetic

Spectrum of activity: Broad-spectrum; affects Gram-positive and many Gram-negative bacteria, toxoplasma and protozoal agents

Effect on bacteria: Bacteriostatic

Miscellaneous: Act synergistically (and becomes bactericidal) in combination with diaminopyrimidines (trimethoprim)

DIAMINOPYRIMIDINES (TRIMETHOPRIM)
Mode of action: Inhibition of other metabolic processes. Trimethoprim interferes with the folic acid pathway by binding the enzyme
dihydrofolate reductase.

Example: Trimethoprim, Aditoprim, Baquiloprim, Ormetoprim

Source: Synthetic

Spectrum of activity: Broad-spectrum; affects Gram-positive and many Gram-negative bacteria

Effect on bacteria: Bacteriostatic

Miscellaneous: Act synergistically (and becomes bactericidal) in combination with sulfonamides

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INTRODUCTION
The use of antimicrobials in animals closely parallels their discovery and usage in humans. Sulfonamide was the first
antimicrobial to be introduced to food animal medicine in the 1940s. The subsequent discoveries and availabilities of newer
antibiotics in the early 50’s quickly led to their widespread therapeutic usage for a multitude of infectious diseases in virtually all
food animal species. Antibiotics are also given to food animals for growth promotion and prophylactic medication, which are
discussed in the species specific sections of this website.

The introduction and use of antimicrobials in animals has brought major benefits to both animals and humans. Some of these
benefits are:
1. Reduction of animal pain and suffering;
2. Protection of livelihood and animal resources;
3. Assurance of continuous production of foods of animal origin;
4. Prevention or minimizing shedding of zoonotic bacteria into the environment and the food chain;
5. Containment of potentially large-scale epidemics that could result in severe loss of animal and human lives.

Clearly, the advantages generated by the use of antimicrobials for food animals transcends more than just the well-being of the
animals, as it has also brought about economic benefits for the food animal producers and a more secured and safer health for
the general public. However, there are conflicting opinions regarding the proper role of antimicrobials in the production of poultry
and livestock. Many believe that the current scientific evidence sufficiently supports a curtailment of current U.S. antibiotic usage
practices because they may pose a serious risk to both animal and human health through ever increasing rates of antimicrobial
resistance. Others argue that current U.S. regulatory policies regarding antibiotic usage are appropriate, and that further
curtailment in antibiotic usage for food animals would be economically harmful to both consumers and producers, and quite
unnecessary given the ill-defined risks of inducing greater rates of antimicrobial resistance. One thing, upon which all can all
agree, is that the unnecessary or wasteful use of antibiotics should be curtailed when non-antibiotic solutions are readily
available or when the use of antibiotics for a particular disease condition are clearly not efficacious. It is upon this common
ground that the human medical and veterinary medical communities call for the proper and prudent use of antibiotics, and
mandate the proper training of human and animal health professionals regarding the judicious, proper and non-wasteful use of
all antibiotics.
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THERAPEUTIC USE OF ANTIBIOTICS IN ANIMALS

Therapeutic use of antibiotics refers to their use to treat clinically ill animals. Although the importance of Some Points to Consider
in Making Antibiotic-
good management and preventive medicine should not be underestimated, there are many disease
Related Decisions
conditions in animals that can only be addressed by antimicrobial therapy. Therapeutic use of antibiotics
in animals is probably a little more complicated than it is for human medicine, given the variations TO TREAT OR NOT TO
TREAT:
between species and the reasons for which animals are owned and are being treated.
1. Does the condition

Ideally, antimicrobial susceptibility testing is done to determine the available options for therapy. It is necessitate treatment?
2. Are there other options
important to note, however, that bacterial susceptibility is not the only consideration when selecting an besides treatment?
antibiotic from a range of options. Aside from the susceptibility and species of the invading pathogen, 3. Will the potential
consequences outweigh
factors to consider in the appropriate selection of antimicrobial therapies should include the drug’s
the benefit of
attributes (such as pharmacodynamics, pharmacokinetics, toxicity, tissue distribution), the host treatment?
4. What is the host
characteristics (such as age, species, immune status), the accountability to the public and other issues
species involved? Is it
such as cost effectiveness. worth treating?
5. Will treatment work for
the pathogen involved?
Each of these issues is important in making sound decision regarding the advisability of each 6. Are there any risks to
antimicrobial therapy. Details on each of these considerations, although not covered here, should be public health when this
is done?
further explored.

WHEN TREATMENT IS
THE BEST OPTION:

1. Which drug would be

best against the
condition of interest?
2. What is the optimal
dosage, duration and
route for the drug of
choice?
3. Will the drug’s attributes
work for the current
condition at hand?
4. What are the hosts’
attributes? Will the drug
not put the animals at
further risk given these?
5. What are the
pathogen’s attributes
and where is it? Will
the drug s gain effective
access to it?
6. Will the public be put to
further risks with these
choices?
7. Will the treatment be
cost-effective?
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NON-THERAPEUTIC USE OF ANTIBIOTICS IN ANIMALS

The continuously increasing world demand for animal protein has led to increasingly efficient intensive
farming systems where animals are raised to maximize the amount of utilizable product at the least
cost. High stocking densities and rapid animal growth, coupled with the reduction of available
agricultural space, can sometimes facilitate the transmission of infectious agents and the susceptibility
of the animals to infectious diseases. It has long been established that antibiotics may help improve
production and prevent disease; for this reason, food animal producers utilize antibiotics for non-
therapeutic purposes. These uses are generally referred to as non-therapeutic applications of
antibiotics; of which there are two main categories:

1. Use of antibiotics in animals for growth promotion

2. Use of antibiotics in animals for metaphylaxis
Unlike in humans, an
even larger proportion of
antibiotics produced for
veterinary use are utilized
in animal herds or flocks
for purposes other than
treatment. A report by
the Union of Concerned
Scientists estimated that
in the United States
alone, the livestock
producers use about 24.6
million pounds of
antimicrobials for non-
therapeutic purposes, a
volume about eight times
greater than the 3 million
pounds estimated use for
human medicine (Mellon
et al., 2001).
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NON-THERAPEUTIC USE OF ANTIBIOTICS IN ANIMALS

Use of antibiotics in animals for growth promotion

ANTIMICROBIAL GROWTH
Antibiotics as growth promoatant was PROMOTANTS

discovered in the 1940s, when it was

The use of subtherapeutic
observed that chicks improve in growth doses of antibiotics as
when fed bacterial shells of growth promotants was yet
another unintentional
Streptomyces aureofaciens from which
discovery. In 1948, animal
antibiotics had been extracted. nutritionist Robert Stokstad
and biochemist Thomas
Because the amount of antibiotic that
Jukes of the Lederle
can provide growth enhancement was company, were then

extremely small, the effect was regarded extensively working on a

variety of vitamin B12 which
as largely nutritional by producers and was believed to be the
authorities in the food industry16. In the “animal protein factor” that
can enhance the growth of
years to follow, other countries also
chickens. Because the
allowed the use of antibiotics in animal feeds. Subsequently, however, when the emergence of Lederle laboratories (the
laboratory where the very
antibiotic resistance was recognized as an increasing risk, the use of growth promoters became the
first tetracycline,
focus of numerous regulatory interventions, and bans on growth promotants were often enacted on chlortetracycline, was

particular classes of antibiotics. To date, different countries have different lists of approved and banned discovered) uses vats of
Streptomyces auerofaciens
growth promoter antibiotics in their respective livestock industries. for the production of the
antibiotic aureomycin, they
utilized its cellular remains
after the antibiotic had been
extracted because they
found that this contain
substantial amounts of Vit
HOW DO SUBTHERAPEUTIC LEVELS OF ANTIBIOTICS PROMOTE GROWTH?
B12. They found that chicks
Although repeatedly proven in various studies, the mechanism of action for the enhancement of growth of subtherapeutic
receiving supplements of S.
levels of antibiotics remains unclear. Among the hypotheses tested are the following:
aureofasciens fermentation
grow 24% more rapidly than
1. Stimulation of intestinal synthesis of vitamins by bacteria. those receiving liver extract,
2. Reduction in total numbers of bacteria in the intestinal tract with a lowering of competition between microorganisms another source of this

and host animals for nutrients. vitamin. They later realized

that this observed growth
3. Inhibition of harmful bacteria which may be mildly pathogenic or toxin-producing.
enhancement was not
4. Inhibition of bacterial urease.
because of the vitamin, but
5. Improved energy efficiency of the gut.
due to the minimal residues
6. Inhibition of bacterial cholytaurin hydrolase activity. of antibiotics left in the
7. Nutrient sparing. bacterial carcasses. This
8. Improved nutrient absorption from morphological changes to small intestinal epithelium. opened a whole new market

9. Modification of intestinal enzyme activity. for antibiotics to the multi-

billion dollar industry that it is
10. Reduced immune stimulation.
today; a surprising offshoot
11. Modification of rumen microbial metabolism.
from the vitamin research
that had no direct
(From Giguere et al., 2006) investment return to the
laboratory.
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NON-THERAPEUTIC USE OF ANTIBIOTICS IN ANIMALS

Use of Antibiotics in Animals for Prophylactic or Metaphylactic Purposes

It is not uncommon for veterinarians to give antibiotics to animals that are not currently ill with a particular disease, but are at
high risk of acquiring an infection. For example, an animal may be treated with antibiotics after having undergone surgery or
injurious trauma (prophylaxis) or herds and flocks may be given antibiotics if they are at risk of suffering an outbreak of infectious
disease due to exposure to disease agents or extremely unfavorable host or environmental conditions (metaphylaxis). In
companion animal veterinary medicine, antibiotics are commonly used to control secondary bacterial invasions such as during
surgical procedures and managing infection-promoting disease conditions such as urolithiasis. In poultry and livestock, mass
administration of antibiotics is often practiced when transporting or moving young animals, during dry-cow therapy in dairy cows
and in preventing respiratory and intestinal maladies when animals have been subjected to severely stressful conditions.

Prophylactic or metaphylactic use of antibiotics can be a substantial aid in the control and prevention of numerous animal
diseases in both food and companion animals. However, this use of antibiotics should never be intended to replace the need for
good management practices, given that the use of antibiotics will eventually lead to resistance. As was the case with therapeutic
uses of antimicrobials, issues to be considered when deciding whether or not to use an antibiotic include knowledge of the
pathogen involved and knowledge of the antibiotic’s properties given the species of animal and its intended use for food or
companionship.
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Prudent use of antimicrobials, which is also referred to as “judicious use” or “antimicrobial stewardship”, is the optimal selection
of drug, dose and duration of antimicrobial treatment, along with reduction of the inappropriate and excessive use as a means of
slowing the emergence of antimicrobial resistance (Shales et al., 1997 as cited by Weese JS, 2006).
Although this may be more straightforward for human medicine, the nature by which antimicrobials are utilized in animals and
the influences of various stakeholders in the standards by which these are raised, make such practice more complicated for
veterinary medicine. The prudent use of antimicrobials in veterinary medicine are principled guidelines created to prevent
abusive use of antimicrobials in animals, primarily to curb or mitigate the imminent risk of breeding resistant microorganisms
unresponsive to currently available chemotherapy in both animals and humans. Veterinarians are on the forefront of upholding
such manner of use having dual roles of protecting animals from pain and suffering, while safeguarding the interest of the public
health.
More details on antimicrobial practices and prudent use in particular animal species can be found in the modules on clinical
applications.
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Summary
• The advent of antibiotics revolutionized the means by which infectious diseases were treated. Suddenly, common
infections became easily curable and outbreaks of infectious disease were readily controlled. However, the declaration
of victory over bacterial pathogens was premature. Antimicrobial resistance quickly emerged to reduce the clinical
usefulness of each new antibiotic that was developed. Mitigation of antimicrobial resistance is therefore necessary, and
requires that veterinarians and other health professionals understand antibiotic sensitivity and resistance at the
population, organism, cellular and molecular levels.

• An antimicrobial is any substance of natural, semisynthetic or synthetic origin that kills or inhibits the growth of
microorganisms while hopefully causing minimal damage to the host. Antimicrobials can be used as therapy for bacteria
(antibacterial), viruses (antiviral), fungi (antifungal) or protozoa (antiprotozoal). The term antibiotic, however, refers to
antimicrobials produced by another living microorganism. Sulfa drugs and other synthetic antimicrobials are not
classified as antibiotics, in the strictest sense of the word.

• Antibiotics may be as classified as either broad spectrum or narrow spectrum depending on how many types of
microorganism are naturally susceptible to its action; and bactericidal or bacteriostatic depending on whether the
antibiotic kills or inhibits the growth of the target bacteria. Antibiotics may also be classified according to their specific
targets and modes of action in that they can be inhibitors of cell wall synthesis, cell membrane function, protein
synthesis, nucleic acid synthesis or other metabolic processes.

• Antibiotics may be used therapeutically in animals for treating bacterial diseases, but they may also be utilized for non-
therapeutic purposes such as growth promotion, prophylaxis and metaphylaxis.

• On a per-weight basis, large amounts of antibiotics are used for animal agriculture. It is a major public health
responsibility of veterinarians to advocate the prudent and judicious use of antibiotics to preserve their future usefulness
in treating both animals and people.
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References
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Agents for Growth Promotion on Occurrence of Antimicrobial Resistance in Fecal Enterococci from Food Animals in Denmark. Antimicrobial
Agents and Chemotherapy. 45(7):2054-2059.
2 American Veterinary Medical Association. 2005. Judicious Therapeutic Use of Antimicrobials. Accessed Online June, 2008.
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19 Otten H. 1986. Domagk and the Development of the Sulphonamides. Journal of Antimicrobial Chemotherapy 17:689-696.
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23 Shane B and Carpenter KJ. 1997. Biographical Article: E.L. Robert Stokstad (1913-1995). Journal of Nutrition. 127:199-201.
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26 United States General Accounting Office. 2004. Antibiotic Resistance: Federal Agencies Need to Better Focus Efforts to Address Risk to
Humans from Antibiotic Use in Animals. Report to Congressional Requesters. Accessed Online June, 2008.
27 Weese JS. 2006. Prudent Use of Antimicrobials. Antimicrobial therapy in Veterinary Medicine 4th edn , S Giguère, JF Prescott, JD Baggot,
RD Walker and PM Dowling, eds. Blackwell Publishing, Ames Iowa, USA.
28 Winau F, Westphal O, and Winau R. 2004. Paul Ehrlich 0 in search of the Magic Bullet. Mibrobes and Infection. 6:786-789.