Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

PENICILLINS
Gram positive
aerobes
Obligate
anaerobes
b-LACTAM ANTIBIOTICS
PENICILLINS
Gram negative
aerobes
Penicillinaseproducing
Staphylococcus
Excellent activity against most, although not necessarily all,
pathogens in this quadrant
Good activity against many pathogens in this quadrant but
some important pathogens may be resistant
Moderate activity against pathogens in this quadrant–
unpredictable resistance patterns
No useful activity against most pathogens in this quadrant,
although there may be some individual exceptions–refer to
individual drug information
Fig. 8.1 Antimicrobial spectrum chart and key.
Mechanism of action
Penicillin G is derived from various Penicillium molds.
Discovery of the penicillin nucleus, 6-aminopenicillanic
acid, led to production of various semisynthetic penicillins.
Those penicillins have been synthesized in an
attempt to improve the spectrum, activity and stability
of the parent compound. Many of the newer penicillins
are modifications of ampicillin. For example, substitution
of a carboxy group for the amino group of ampicillin
on the acyl side chain produced carbenicillin and
ticarcillin.
Bacteria differ from animal cells by possessing a rigid
outer layer, the cell wall. The bacterial cell possesses an
unusually high internal osmotic pressure. Injury to the
cell wall or inhibition of its synthesis may result in cell
lysis. The peptidoglycan component of the cell wall is
essential to the integrity of the bacterial envelope. It
consists of alternating units of N-acetylglucosamine and
N-acetylmuramic acid, crosslinked by short strands of
peptides. Almost all bacteria have cell membranebinding
proteins called penicillin-binding proteins
(PBP). The PBPs are enzymes (transpeptidases, carboxypeptidases,
endopeptidases) involved in the terminal
stages of assembling the cell wall by crosslinking the
peptidoglycan layer and reshaping the cell wall during
growth and division. Binding of transpeptidase PBPs
causes inhibition of peptidoglycan synthesis. The final
step in the action of β-lactams probably involves inactivation
of an inhibitor of autolytic enzymes in the
cell wall.
Penicillins are structural analogs of D-alanyl-Dalanine
and bind with high affinity to those PBPs
involved in cell wall synthesis. However, other PBPs act
as β-lactamases and thus inactivate penicillins and cephalosporins.
Bacteria have 3–6 PBPs and different PBPs
possess different affinities for different drugs. The antibacterial
activity of each β-lactam is dependent on its
ability to bind one of the PBPs that form or maintain
cell wall structure while avoiding destructive PBPs. PBPs
are under chromosomal control and mutations can alter
their number and affinity for different β-lactam drugs.
The antibacterial spectrum of any penicillin depends
primarily on its stability against bacterial β-lactamases
but also its ability to reach the PBP on the cell membrane
and its binding affinity for the target PBP.
Differences in susceptibility of Gram-positive and
Gram-negative bacteria to penicillins result from structural
differences in cell walls, differences in receptor
sites (PBPs) and binding affinity for the target PBP, the
relative amount of peptidoglycan present (Grampositive
bacteria possess far more) and to the different
types of β-lactamase produced by bacteria. In Gramnegative
bacteria the outer portion of the cell wall is a
lipopolysaccharide and lipoprotein bilayer membrane,
which may hinder the passage of drugs through the cell
wall. All penicillins tend to be ionized at physiological
pH so will not diffuse through the lipid bilayer of the
Gram-negative outer membrane. The large hydrophobic
groups on the narrow-spectrum penicillins (e.g. penicillin
G) hinder their passage through the porins in most
Gram-negative outer membranes. Substitution with
more hydrophilic amino groups (e.g. ampicillin, amoxicillin)
in place of the benzyl group allows the molecule
to penetrate this barrier and so broadens the spectrum
of activity. In contrast, Gram-positive organisms have a
thin outer layer exterior to the peptidoglycan layer,
which β-lactams can rapidly penetrate.
Penicillins affect growing cells and have little influence
on those that are dormant, so they should not be
administered with bacteriostatic agents. The antibacterial
action of penicillin is greatest during the periods of
rapid bacterial multiplication. Penicillins (and cephalosporins)
are time-dependent killers; thus the time for
which plasma concentrations remain above MIC is the
best predictor of treatment success and frequent dosing
or depot formulations are therefore required.
Mechanisms of resistance
Resistance to β-lactams is mediated by induced β-
lactamase production or by intrinsic means. β-
lactamases are a diverse group of enzymes that hydrolyze
the cyclic amide bond of the β-lactam ring and render it
inactive. They were isolated from bacteria before β-
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