Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

AMINOGLYCOSIDES AND AMINOCYCLITOLS
the peptide and thus inhibition of ribosomal protein
synthesis. The extent and type of misreading vary
because different aminoglycosides interact with different
proteins. Streptomycin acts at a single site but other
aminoglycosides act at several.
Other actions of aminoglycosides include interference
with the cellular electron transport system, induction of
RNA breakdown, inhibition of translation, effects on
DNA metabolism and damage to cell membranes.
Mechanisms of resistance
Resistance to aminoglycosides, often plasmid-mediated,
can develop rapidly. The mechanisms involved
include:
● mutation of the organisms, resulting in altered
ribosomes that no longer bind the drug
● reduced permeability of the bacteria to the drug
● inactivation of the drug by bacterial enzymes.
Bacteria may acquire the ability to produce enzymes
(phosphotransferases, acetyltransferases, adenyltransferases)
that modify aminoglycosides at exposed
hydroxyl or amino groups to prevent ribosomal binding.
This is the principal type of resistance among Gramnegative
enteric bacteria, is usually plasmid-controlled
and is very important clinically and epidemiologically.
Bacterial strains with reduced permeability, and consequently
two- to fourfold increases in MIC, may be
selected during treatment with an aminoglycoside and
show cross-resistance to all other drugs within the
group. This may only be important in neutropenic
patients.
Deletion or alteration of receptor protein on 30S subunits
because of chromosomal mutation is less important
than plasmid-mediated resistance, except for streptomycin,
where a single-step mutation imparting high-level
resistance can occur readily even during treatment.
Antibacterial spectrum (Fig. 8.14)
● Predominantly active against Gram-negative aerobic
bacteria.
● Staphylococcus are usually susceptible to aminoglycosides
but most other Gram-positive aerobes are
Gram positive
aerobes
Obligate
anaerobes
Gram negative
aerobes
Penicillinaseproducing
Staphylococcus
Fig. 8.14 Antibacterial spectrum for aminoglycosides.
not; β-hemolytic Streptococcus are reasonably susceptible
to gentamicin but not to neomycin, streptomycin
or kanamycin. Resistance may emerge during
treatment.
● Some Mycobacterium and Mycoplasma are
susceptible.
● In potency, the spectrum of activity and stability to
enzymes of plasmid-mediated resistance is: amikacin
> tobramycin ≥ gentamicin > neomycin = kanamycin
> streptomycin.
● Streptomycin is the most active against Mycobacterium
and the least active against other microbes.
Pharmacokinetics
● Aminoglycosides are not significantly absorbed from
the gut, so must be given parenterally to treat systemic
infections.
● All have poor tissue penetration (including CNS and
eye) as they are highly hydrophilic.
● They are eliminated almost exclusively by glomerular
filtration.
● Half-lives are short in plasma (40–60 min) but much
longer (>30 h) for tissue-bound drug.
● Aminoglycosides have a prolonged postantibiotic
effect; so plasma concentrations do not need to continuously
exceed the MIC of the target organism.
Once-daily dosing is now recommended to reduce
toxicity.
● The bactericidal action of aminoglycosides is
enhanced in an alkaline medium and may be reduced
by acidity secondary to tissue damage.
● All aminoglycosides bind to and are inactivated by
pus.
Adverse effects
Adverse effects of the aminoglycosides may be enhanced
by concurrent administration of diuretics, which may
deplete extracellular fluid and increase circulating aminoglycoside
concentrations.
Nephrotoxicity
All aminoglycosides can cause renal toxicity to some
degree. They bind to the brush border of proximal renal
tubular cells, accumulate in lysosomes and inhibit lysosomal
phospholipase. Toxicity correlates with the degree
of tubular reabsorption of the drug and the degree to
which phospholipid metabolism in proximal tubular
cells is inhibited. Therefore gentamicin, which undergoes
the greatest reabsorption and interferes most
potently with phospholipid metabolism, has the greatest
nephrotoxic potential. Amikacin is the least nephrotoxic.
Toxicity is cumulative and transport of the drug
into proximal tubular cells is a saturable process.
Hence giving the total daily dose in a single injection is
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