Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

PRINCIPLES OF ANTIBACTERIAL THERAPY
Table 8.1
Physicochemical properties of antibacterial drugs and effects on tissue distribution
Polar (hydrophilic) drugs of low lipophilicity Drugs of moderate to high lipophilicity Highly lipophilic molecules
with low ionization
Acids Bases Weak acids Weak bases Amphoteric
β-Lactamase inhibitors
Cephalosporins
Penicillins
Aminoglycosides
– amikacin
– gentamicin
– neomycin
– streptomycin
– tobramycin
Polymyxins
Spectinomycin
Sulfonamides
Lincosamides
– clindamycin
– lincomycin
Macrolides
– azithromycin
– clarithromycin
– erythromycin
– spiramycin
– tilmicosin
– tylosin
Trimethoprim
Tetracyclines
(except doxycycline,
minocycline)
Chloramphenicol
Fluoroquinolones
– ciprofloxacin
– enrofloxacin
– marbofloxacin
– norfloxacin
– orfloxacin
Lipophilic tetracyclines
(doxycycline,
minocycline)
Metronidazole
Rifampicin
These drugs: These drugs: These drugs:
• Do not readily penetrate ‘natural body
barriers’ so that effective concentrations
are not always achieved in CSF, milk and
other transcellular fluids
• Adequate concentrations may be
achieved in joints, pleural and peritoneal
fluids
• Penetration may be assisted by acute
inflammation
• Weak acids (cephalosporins, penicillins)
may diffuse into prostate in small
concentrations but easily diffuse back to
plasma
• Cross cellular membranes more readily than polar
molecules so enter transcellular fluids to a greater extent
• Weak bases will be ion-trapped (concentrated) in fluids
that are more acidic than plasma, e.g. prostatic fluid, milk,
intracellular fluid if lipophilic enough to penetrate (e.g.
erythromycin)
• Penetration into CSF and ocular fluids is affected by
plasma protein binding as well as lipophilicity –
sulfonamides and trimethoprim penetrate effectively
whereas lincosamides, macrolides and tetracyclines do
not, probably due to efflux pumps
• Azalides (azithromycin, clarithromycin) have prolonged
half-life due to extensive uptake to, and slow release from,
tissues. They penetrate phagosomes and phagolysomes
well and have extensive tissue distribution as a result of
their concentration in macrophages and neutrophils
• Tetracyclines do not achieve high concentrations in
prostate
• Cross cellular
barriers very readily
• Penetrate into
difficult transcellular
fluids such as
prostatic fluid and
bronchial secretions
• However,
chloramphenicol
and tetracyclines
don’t reach high
concentrations in
prostate
• All penetrate CSF
except tetracyclines
and rifampicin which
do not, probably due
to efflux pumps
• All penetrate into
intracellular fluids
Modified from Watson ADJ, Maddison JE, Elliott J 1998 Antibacterial drugs. In: Gorman NT (ed.) Canine medicine and therapeutics, 3rd edn.
Blackwell, Oxford: 53-72.
bacterial action, including appropriate surgical drainage
and wound cleansing.
Lowered pH and oxygen tension can also adversely
affect activity of various antibacterial agents. For
example, the lethal action of penicillins depends on
autolytic enzyme activity in bacteria that is impaired by
low pH. Penicillins in general are not much affected by
an acidic environment but activity is diminished in the
presence of hemoglobin. Low pH also results in marked
loss of activity of erythromycin, clindamycin and fluoroquinolones.
An anaerobic environment decreases the
effectiveness of aminoglycosides, whereas metronidazole
has no activity against aerobic bacteria.
Environmental conditions can be manipulated to
enhance antibacterial activity. For example, in lower
urinary tract infections it is desirable for urine to be
acidic when using tetracyclines and alkaline when using
aminoglycosides.
The ability of a molecule to penetrate membranes
increases with decreasing electrostatic charge; thus antibacterial
drugs that are weak acids work best in an
acidic environment and those that are weak bases work
best in an alkaline environment.
High lipid solubility (see Table 8.1) will facilitate
penetration of antibacterial drugs generally, including
into devitalized tissue and phagocytic cells.
Client compliance
As with all drug therapy, antibacterials will not be effective
unless administered correctly to the patient. As discussed
in Chapter 1, it is important to maximize the
likelihood that a client will administer drugs at the right
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