1.

Amoxicillin
1.1

General characteristics of aminopenicillins

The aminopenicillins are

derived from one of the oldest
antibiotics, penicillin, which
was discovered in 1928 by
Alexander Fleming.
Fleming observed that an area
free of growth surrounded a
mould of the genus Penicillum
that was a contaminant in a
Petri dish with colonies of
staphylococcus. He suspected
that the fungus manufactured
an antibiotic substance that
could be beneficial for combating staphylococcal infections.
He was not able however to isolate the penicillin in its active
form.
In 1930, Raistrick discovered
that penicillin was a thermolabile organic acid that could be
extracted from an acidified culture medium by using Ether.
Ten more years were needed so
that Florey and his collaborators
from Oxford could isolate penicillin and demonstrate that it
was the most powerful chemotherapeutic agent known up
until that time.

cyclical dipeptide which gains

antibacterial activity due to the
lateral chain connected to position 6.

matic de-acylation of natural

penicillins in the culture medium,
so as to free the nucleus of the 6aminopenicillanic acid (6-APA).

Chemically, penicillins are formed by a group of substances

with a common cyclical structure. The -lactam ring is the
main basis for its elevated and
specific bacterial potency. The
-lactam ring must remain
intact for the penicillin to exercise its action.

The 6-APA is extracted from the

culture and made to react with
the precursors of the lateral
chains so as to obtain the semisynthetic penicillin desired.

The semi-synthetic derivates of

penicillin continue to be the
antibiotics of choice in multiple
cases of infection.
The essential difference between older penicillins and more
modern ones is that, in older or
natural penicillins the lateral
chain is joined to the molecule
by adding the adequate precursors to the culture medium and
allowing the product to form
biosynthetically. However, modern semi-synthetic penicillins
are formed by chemical or enzy-

Many advances have been

made in antimicrobial therapy
from that time up until the present, but penicillin and its semisynthetic derivates continue to be
the antibiotics of choice in multiple
cases of infection.
The penicillin molecule is formed biosynthetically by joining
two amino acids valine and
cysteine, which form a peculiar

The modern era of penicillins

began with the obtaining of the
6-APA and the achievement of
the different semi-synthetic
penicillins, which are presently
in wide use.
The basic penicillin molecule
does not have functional groups
and acts upon the bacteria by
structural interference. The presence of a free amino group in
the substitutes gives the penicillin molecules an extra activity
against Gram-negative germs.
The best known example is that
of ampicillin and later of amoxicillin.

Aminopenicillins have a greater

activity against Gram-negative
microorganisms due to the
existence of a free amino group
in its molecule.

cidal action upon some pathogens, they are used as a first

choice in serious infections.

These two aminopenicillins can

be administered by oral route
because they are acid resistant. Due to their rapid bacteri-

1.2

Chemical structure and properties

Amoxicillin has a bactericidal

action and acts against Grampositive and Gram-negative
microorganisms by inhibiting
the biosynthesis and repair of
the bacterial mucopeptide wall.
It is a semi-synthetic penicillin,
which is susceptible to the
action of the Beta-lactamases.
Amoxicillin presents some outstanding advantages in comparison with other aminopenicillins,
such as: a better absorption from
the intestinal tract, better capacity for reaching effective concentrations at the sites where it
acts and a more rapid capacity
for penetrating the cellular wall of
Gram-negative microorganisms.

for reaching effective concentrations at the sites where it acts and

a more rapid capacity for penetrating the cellular wall of Gramnegative microorganisms.

Amoxicillin presents some outstanding advantages in comparison with other aminopenicillins,

such as: a better absorption from
the intestinal tract, better capacity

HO

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1.3

Mechanism of action

The antibacterial mechanism of

action of amoxicillin consists of
the inhibition of the biochemical processes of synthesis of
the bacterial wall. This is done
by means of selective and irreversible blockage of different
enzymes that are involved in
such processes, principally
transpeptidases, endopeptidases and carboxypeptidases.
The inadequate formation of
the bacterial wall, in susceptible species, produces an
osmotic imbalance that especially affects bacteria in their
growth phase (during which
the processes of the synthesis
of bacterial walls are very
important), which leads in the
end to the lysis of the bacterial
cell.

The peptidoglycan is a rigid layer of similar

composition in Gram-positive and Gramnegative bacteria. This layer is responsible
for the strength of the bacterial wall, and
represents up to 90% of the wall in the case
of Gram-positive bacteria and around 10%
of it in the case of Gram-negative ones. Its
synthesis during cellular growth involves a
cutting off, by the autolysins, of the unions
that connect small areas of the pre-existing
peptidoglycan as well as the insertion of
new portions of the peptidoglycan.

The action of transporters is necessary

for synthesis to occur, which allows the
precursors to pass through the plasmatic
membrane into the area where growth of
the cell wall is produced. The reaction of
transpeptidisation gives rise to a final
interlinking of the two chains of the peptidoglycan. The amoxicillin acts by inhibiting this reaction.

1.4

Pharmacokinetic properties

1.4.1 Absorption
For the drugs administered by
oral route to be effective, it is
important to know their degree
of absorption through the digestive tube. Amoxicillin is an acid
resistant penicillin and so does
not present any problems of
absorption at a gastrointestinal
level. Therefore, the concentrations reached at a systemic
level are effective. These concentrations are two times higher than other antibiotics in the
same family, like ampicillin,
which means that their therapeutic action is much more
rapid.

Figure 1: Concentrations of amoxicillin in the serum of broiler chickens treated

with a single oral dose of trihydrate ampicillin and trihydrate amoxicillin of 25
mg/kg (Lashev and Semerdziev, 1983).

The absorption of amoxicillin

by oral route is not generally
affected by the ingestion of
foodstuffs, and the maximum
plasmatic concentrations are
rapidly reached in the majority
of animal species between 1
and 2 hours after administering
this product.

1.4.2 Diffusion
Amoxicillin presents a low rate
of joining to plasmatic proteins
and diffuses rapidly in the
majority of body liquids and tissues. This diffusion extends to
the effusions of synovial membranes, to the liquids expectorated and to the lymphatic tis-

sue. The diffusion is even more

satisfactory in the liquids that
result from an inflammatory process.

The therapeutic action of amoxicillin is much more rapid than

that of other antibiotics in the
same family, because it reaches higher concentrations at a
systemic level.

1.4.3 Elimination
Amoxicillin is eliminated at high
concentrations through urine.
60% of an oral dose is recovered in an unaltered form and
75% of an intramuscular dose
is recovered in the urine six
hours after being administered.
The semi-life of elimination is
17 hours.
Although the principal elimination route of amoxicillin is
through the urine, it is also
excreted in small quantities in
milk and bile.

Figure 2: Concentrations of amoxicillin in serum of pigs after administration by

oral route of trihydrate amoxicillin at a dose of 10 mg/kg b.w. (Lashev, 1986).

The bioavailability of amoxicillin

by oral route is situated around
67% in chickens and 50% in
pigs. It reaches significant levels
in blood in an hour. It rapidly
becomes well distributed throughout the whole organism, with
very little joining to the plasmatic
proteins (17-20%).

Numerous
studies
have
demonstrated that the plasmatic levels of amoxicillin that are
obtained in chickens and pigs
treated by oral route by drinking water reach levels above
the MIC values (Minimum
Inhibitory Concentrations) des-

cribed for the microorganisms

involved in staphylococcal
arthritis and colibacillosis in
chickens and in streptococcal
meningitis in pigs.

1.5

In vitro activity

Amoxicillin is active against Gram-positive and Gram-negative bacteria. Some outstanding species
considered as sensitive to amoxicillin are:
Gram-positive bacteria

Gram-negative bacteria

Non-penicillinase producing Staphylococcus

(Staphylococcus aureus,
Staphylococcus sp, ...)
Streptococcus (Streptococcus suis,
Streptococcus pneumoniae, ...)
Corynebacterium (Corynebacterium sp, ...)
Clostridium (Clostridium perfringens,
Clostridium tetani, Clostridium sp, ...)
Actinomyces sp
Bacillus anthracis
Listeria monocytogenes
Erysipelothrix rhusiopathiae

Pasteurella sp
Mannheimia haemolytica
Haemophilus sp
Actinobacillus sp
Escherichia coli
Salmonella sp
Moraxella sp
Fusobacterium sp

On the other hand, the bacteria

which generally show resistance
to amoxicillin are the penicillinase producing Staphylococcus

1.6

and some of the Enterobacters

such
as:
Klebsiella
sp,
Enterobacter sp, Proteus sp and
Pseudomonas aeruginosa.

In vivo activity

Amoxicillin is a broad-spectrum
penicillin that is well absorbed
through the gastrointestinal
tract. Therefore, when administered by oral route it can be used
for intestinal infections as well as
for treating systemic infections.

3.12 g/ml) against Staphylococcus sp. and Streptococcus

sp. The majority of strains of
Escherichia coli are inhibited
by concentrations of amoxicillin
equal to or lower than 12.5
g/ml.

Its use in drinking water is

recommended and widely
used on large production farms
where it is extremely difficult to
treat each animal individually.

The efficacy of amoxicillin when

given by oral route is wellknown and has been extensively demonstrated in the scientific literature since its discovery in various animal species,
among them chickens and
pigs.

Amoxicillin is active at low concentrations (between 0.02 and