Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 8 ANTIBACTERIAL DRUGS
pharyngeal and/or laryngeal edema, vomiting and
colic.
● A drug-related systemic allergic reaction may also
occur with deposition of immune complexes in
tissues and activation of complement. Clinical consequences
include lymphadenopathy, neuropathy,
vasculitis, nephritis, arthritis, urticaria and fever.
● Various hematological perturbations may follow
drug-induced antibody production, namely hemolytic
anemia, thrombocytopenia or rarely
neutropenia.
● Cutaneous reactions may be caused by immune
complex deposition or delayed hypersensitivity.
Allergy to antibacterial agents will only occur if there
has been previous exposure to that drug or a related
substance (including earlier doses in the current regimen).
However, certain anaphylactoid substances in formulations
may not require previous exposure to elicit hypersensitivity
reactions and these reactions will probably
recur every time the drug or related substance is administered.
It might not be feasible to confirm this clinically,
though, because of concerns of discomfort or danger to
the patient.
Treatment of drug hypersensitivity involves discontinuation
of the drug and, if anaphylaxis is present,
treatment with adrenaline (epinephrine), corticosteroid,
antihistamine and intravenous fluids as warranted.
Factors affecting the success of
antibacterial therapy
Bacterial susceptibility
Various factors need to be considered in susceptibility
testing. The minimum inhibitory concentration (MIC)
is the concentration of drug that must be attained at
the infection site to achieve inhibition of bacterial
replication.
In general, if bacteria are not susceptible to a drug in
vitro they will be resistant in vivo. (Exceptions exist:
resistance may be overcome by high concentrations
achieved in urine or with topical application of some
agents.) If a pathogen is sensitive to a drug in vitro the
drug may be effective in vivo, depending on a variety of
pharmacological, host and bacterial factors.
Distribution to the site of infection
(pharmacokinetic phase)
To be effective, an antibacterial agent must be distributed
to the site of infection and come into contact with
the infecting organism in adequate concentrations of the
active drug form.
For most, but not all, tissues antibacterial drug distribution
is perfusion limited.This means that, in tissues
with adequate blood supply, free (unbound) drug concentrations
achieved in plasma are directly related to or
equal to the concentration in the extracellular (interstitial)
space. However, drug distribution to the CNS,
eye, epithelial lining of the lung (bronchial secretions),
prostate and mammary gland is permeability limited, as
the lipid membrane forms a barrier to drug diffusion
(Table 8.1). Contrary to popular belief, most antibacterial
drugs reach therapeutically adequate concentrations
in bone and synovial fluid, although some drugs
achieve higher concentrations in bone than do others.
Bacteria that locate intracellularly (Bartonella, Brucella,
Chlamydophila, Mycobacterium, Rickettsia) will
not be affected by antibacterial agents that remain in
the extracellular space. Staphylococcus is facultatively
intracellular and may sometimes resist treatment because
of intracellular survival. Drugs that accumulate in
leukocytes and other cells include fluoroquinolones,
lincosamides and macrolides but aminoglycosides and
β-lactams do not achieve effective intracellular
concentrations.
An infectious/inflammatory process often adversely
affects the distribution of a drug in vivo. An exception
is inflammation of the meninges (meningitis), which
reduces the normal barrier between blood and cerebrospinal
fluid (CSF), so that antibacterial agents that normally
cannot cross this barrier reach the CSF. This
breakdown of barriers by inflammation does not occur
to an appreciable extent with the blood–prostate barrier
and blood–bronchus barrier.
Effective antibacterial concentrations may not be
achieved in poorly vascularized tissues, e.g. the extremities
during shock, sequestered bone fragments or heart
valves.
Favorable environmental conditions
Local factors that restrict access of antibacterial agents
to the site of infection include abscess formation, pus
and necrotic debris (inactivates aminoglycosides and
sulfonamides) and edema fluid. The presence of foreign
material in an infected site markedly reduces the likelihood
of effective antibacterial therapy; in an attempt to
phagocytose and destroy the foreign body, phagocytes
degranulate, depleting intracellular bactericidal substances.
These phagocytes are then relatively inefficient
in killing bacterial pathogens. In addition, foreign material
in a wound can protect bacteria from antibacterial
drugs and phagocytosis as the bacteria can form a
biofilm (glycocalyx) at the site of infection.
Unfavorable environmental conditions may slow
bacterial growth, thus rendering them less susceptible
to antibacterials like the penicillins and cephalosporins
that act by inhibiting cell wall synthesis and require
actively dividing cells to exert their bactericidal
effects.
These factors highlight the importance of creating an
environment conducive to wound healing and anti-
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