Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 8 ANTIBACTERIAL DRUGS
lactam antibiotics were developed commercially and
therefore have intrinsic activity in the bacteria.
The β-lactamases are generally secreted extracellularly
in large amounts by Gram-positive bacteria; relatively
small quantities are strategically produced in the
periplasmic space in Gram-negative bacteria. Bacteria
that produce β-lactamases include Enterobacter,
Escherichia, Klebsiella, Proteus, Pseudomonas and
Staphylococcus,
Different bacteria produce different types of β-lactamase.
Staphylococcal β-lactamase is called penicillinase.
Production of β-lactamases is widespread among
common Gram-negative primary and opportunistic
pathogens.
In Gram-positive bacteria, especially Staphylococcus,
resistance to penicillin G is mediated mainly by production
of penicillinases that are plasmid mediated and
excreted extracellularly as inducible exoenzymes. Penicillinase
is induced during treatment, which may explain
treatment failure in a patient with a strain of Staphylococcus
intermedius that is sensitive to penicillin in
vitro.
The inherent resistance to penicillin G of many Gramnegative
bacteria results from low bacterial permeability,
lack of PBPs and various β-lactamase enzymes. In
Gram-negative bacteria, β-lactamase may be chromosomally
mediated or plasmid-mediated and may be
inducible or constitutive (i.e. part of the normal makeup
of the organism). Plasmid-mediated β-lactamase
causes high-level resistance whereas those that are chromosomally
mediated are present at low levels and only
sometimes contribute to resistance. Resistance may also
occur by production of an impermeable outer membrane
through mutations in the porin structure. Pseudomonas,
for example, is innately resistant to most
penicillins because the porins in its outer membrane are
small and very difficult for many drugs to pass
through.
Efforts to overcome bacterial resistance caused by β-
lactamase production proceed along two lines. One
seeks to modify the β-lactam nucleus so that the antibiotic
is stable in the presence of penicillinase; cloxacillin
is an example of this. The other searches for substances
that inhibit β-lactamase and can be coupled with the
penicillin (or cephalosporin) to protect the drug from
destruction by β-lactamases; clavulanic acid and sulbactam,
two products of this approach, are discussed later
in this chapter.
Pharmacokinetics
Penicillins in general:
● are able to achieve concentrations adequate to kill or
inhibit susceptible bacteria in most tissue fluids,
though high doses may be required to obtain adequate
concentrations in joint, pleural and peritoneal
cavities
● are generally excluded from CNS, prostate and
eye
● are charged at physiological pH and lipid insoluble,
so do not readily enter living cells
● show enhanced entry across biological membranes
and through blood–brain and blood–CSF barriers in
the presence of inflammation (this does not apply to
the prostate or blood–bronchus barrier)
● may reach concentrations in inflamed tissues that
exceed plasma concentrations
● undergo minimal hepatic metabolism, except for
ampicillin
● are eliminated by glomerular filtration and renal
tubular secretion: 60–100% of drug is excreted in
urine unchanged, resulting in very high concentrations
in urine. Urine:plasma ratios are of the order
of 200–300:1
● cross the placenta slowly
● are not all stable in gastric acid; some have to be
given parenterally
● may have their systemic availability after oral administration
delayed and/or reduced by ingesta (e.g.
with cloxacillin and ampicillin but less so with
amoxicillin)
● have a time-dependent mode of bacterial killing, so
that plasma concentrations should be maintained
above the MIC of the pathogen for as long as possible
throughout the dosing interval.
Adverse effects
● Penicillins in general have a very wide therapeutic
ratio as mammalian cells do not possess a cell wall.
Most toxic effects are related to hypersensitivity,
usually immediate in onset. This may manifest as
local reactions at the site of injection (swelling,
edema, pain) or systemic reactions such as urticaria
and skin rashes or anaphylaxis and collapse. Hypersensitivity
reactions have been recorded in most
domestic species and can be fatal. They are much less
common after oral administration. If an animal is
allergic to one form of penicillin it will react to other
forms.
● Penicillins can induce gastrointestinal superinfection
in many species in which fermentation in the cecum
is an important part of the digestive process. Thus
penicillins should never be given to guinea-pigs,
ferrets, rabbits and hamsters by any route.
● Many of the acute reactions to penicillins reported
in animals are in fact due to the toxic effects of the
potassium or procaine with which the penicillin has
been combined. Potassium penicillin G should be
injected slowly. At high doses, procaine injected IM
can cause nervous excitement (ataxia, excitability,
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