Aminoglycosides
Aminoglycosides
are a group of natural and semi-synthetic antibiotics having amino sugars
linked to an aminocyclitol ring by means of glycosidic bond.
History: Streptomycin was
the first member of Aminoglycoside antibiotics discovered in 1944 by Waksman
and his co-workers from a strain of Streptomyces griseus. Neomycin was next to
be isolated in
1949 followed by
Kanamycin in 1957 and Gentamicin in 1963.
Chemistry and source: The Aminoglycosides consist of two or more amino sugars joined to a
hexose (aminogyclitol) nucleus by means of glycosidec linkage.The presence of
amino group on the glycosides imparts alkaline nature to Aminoglycosides and
the hydro-oxyl groups on the sugars provide high water solubility (or poor
lipid solubility) to the drugs. If these hydro-oxyl groups are removed (e.g., in
case of Tobramycin), the drug becomes more active. Aminoglycosides prepared
from Streptomyces carry the suffix –mycin, whereas those derived from
Micromonospora have their names ending with –micin.
Mode of action: The
Aminoglycosides are bactericidal drugs that act by inhibiting protein synthesis
in susceptible bacteria, mainly gram negative organisms. Their antimicrobial
action is concentration dependent (they produce greater cidal effect at high
concentrations). Aminoglycosides diffuse across the aqueous porin channels of
gram negative bacteria to reach periplasmic space. Next, the Aminoglycosides
are carried from periplasmic space into bacterial cytoplasm. This
transportation occurs with the help of an oxygen-dependent process which is
linked to electron transport chain. Anaerobic environment inhibits the
oxygen-dependent transport system. Therefore anaerobes and facultative
anaerobes are inherently resistant to Aminoglycosides. Once inside the
bacterial cell, Aminoglycosides interact with bacterial ribosomes and inhibit
bacterial protein synthesis. Aminoglycosides can bind with both 30S and 50S
ribosomal subunits (more specifically they bind to 30S-50S ribosomal juncture),
although their binding with 30S subunit is stronger. Aminoglycosides impair the
bacterial protein synthesis through several mechanisms including:
(a) Interference with the formation of
initiation complex.
(b) Distortion of
mRNA condons resulting in misreading of the codons. This causes incorporation
of one or more incorrect amino acid(s) into the peptide chain and synthesis of
abnormal proteins.
(c) Promotion of premature termination of translation with detachment of
the ribosomal complex.
|
Classification
of Aminoglycosides |
|
|
Category |
Examples |
|
Narrow-spectrum
Aminoglycosides |
Streptomycin,
Dihydrostreptomycin |
|
Broad-spectrum
Aminoglycosides |
Neomycin,
Kanamycin |
|
Extended-spectrum
Aminoglycosides |
Gentamicin,
Tobramycin |
Antibacterial Spectrum: Aminoglycosides
are bactericidal in action and are more active against gram negative bacteria. Antibacterial spectrum of Aminoglycosides varies with the type of
antibiotic. Streptomycin and Dihydrostreptomycin have relatively narrow spectra
mainly gram-negative species. The broad-spectrum Aminoglycosides (e.g.,
Neomycin and Kanamycin) are active against many gram-negative and gram-positive
organisms but not pseudomonas. The extended-spectrum Aminoglycosides possess
antibacterial spectra similar to broad-spectrum antibiotics and are also active
against pseudomonas aeruginosa and a variety of aerobic bacteria. Anaerobic
bacteria are only moderately sensitive to Aminoglycosides.
Pharmacokinetics: Aminoglycosides are water
soluble and polar compounds and generally ionize in solution. They are not
absorbed orally and distribute only extracellularly. They are more active in
alkaline pH. Absorption of Aminoglycosides from GI tract
takes place only in the presence of inflammation or ulceration of GI tract or
in very young animals that are still on colostrum. This property is utilized in
bacterial cleansing of intestine prior to gastro-intestinal surgery.
Aminoglycosides are extensively distributed in ECF but they do not readily
enter into the cells (thus they are ineffective against intracellular
pathogens) due to their polar nature. Therefore they are largely excluded from
brain, CSF, eye and most body tissues except kidney and inner ear. In the renal
tubular cells and the endolymph and perilymph of the inner ear Aminoglycosides
accumulate in high concentrations via an active transport mechanism and these
may contribute to nephrotoxicty and ototoxicity respectively. In pregnant
animals Aminoglycosides may cross the placental barrier and reach fetal plasma
and amniotic fluid causing deafness in young ones. The neonates have relatively
more volume of ECF hence the plasma levels of Aminoglycosides remain
comparatively low and renal clearance becomes low. In contrast dehydration reduces
the volume of ECF with high plasma concentration of Aminoglycosides resulting
in increased renal clearance. The Aminoglycosides are not metabolized in the
body and are excreted largely unchanged in the urine by glomerular filtration.
They possess a significant post-antibiotic effect. Therefore, despite their
short half-lives (2-4 hours) a single injection of the total daily dose of
Aminoglycosides may be effective (i.e., they are repeated after 12-24 hours).
Clinical
uses: Aminoglycosides
are widely used in veterinary medicine to treat local and systemic infections
caused by susceptible bacteria, generally gram negative bacteria. They may be
infused into uterus (intrauterine) to treat endometritis and into udder
(intramammary) to treat mastitis. Some Aminoglycosides are also administered topically
in the eyes and ears (provided that the tympanic membrane is intact). In
veterinary medicine, Streptomycin is primarily used in combination with
Penicillins for the treatment of conditions like shipping fever
(pasteurelosis), foot rot, mastitis and coliform infections. Neomycin is used
orally or in enema form to reduce the number of ammonia producing bacteria in the
treatment of hepatic encephalopathy. It may be used topically for skin, eye and
ear infections. Neomycin is never used parentrally due to its enhanced systemic
toxicity. Kanamycin is orally used to treat gram negative enteric infections in
domestic animals. Gentamicin is the most widely used Aminoglycoside in human as
well in veterinary medicine. It can be used for the treatment of bacterial
infections of respiratory tract, urinary tract, GIT, bones, soft tissues and
skin. It is administered through intramammary and intrauterine routes to treat
mastitis and metritis respectively. It may be used topically for skin, eye and
ear infections.
Side effects/Adverse effects: All Aminoglycosides have potential to
produce toxic effects but the relative tendency differs. Nephrotoxicity,
ototoxicity and neuromuscular blockade are important adverse effects observed
with Aminoglycosides.
1. Nephrotoxicity: Nephrotoxicity
with Aminoglycosides occurs as a result of excessive accumulation of
antibiotics in the proximal tubular cells of kidneys. As Aminoglycosides are
positively charged agents, they get attracted to negatively charged
phospholipids of the renal membrane followed by their transport inside the tubular
cells via pinocytosis. This transport is directly related to the membrane content
of phosphatidly inositol (which is high in renal cortex and cochlear tissues).
The Aminoglycosides can inhibit various essential enzymes like phospholipases.
Inhibition of phospholipase results in reduced synthesis of prostaglandins
(that are crucial for optimal renal microcirculation) thereby leading to
nephrotoxicity. Manifestations of nephrotoxicity include presence of enzymes of
brush border in urine,
2. Ototoxicity: Aminoglycosides
get accumulated into perilymph and endolymph of the inner ear in dose and time
dependent manner. Ototoxicity is greater when the plasma concentration of drug
is persistently high. Ototoxicity once
occur is usually irreversible and result from progressive destruction of
vestibular or cochlear sensory cells. Vestibular injury leads to nystagmus
(involuntary, rhythmical movement of the eye), inco-ordination, vertigo, head
tilt, ataxia (abnormal gait) and loss of righting reflex (inability to retrieve
normal posture) in animals. Hearing impairment or deafness may be produced by
permanent damage and loss of hair cells in the organ of Corti. Aminoglycosides
should not be instilled into ear unless the tympanic membrane is intact because
direct administration of Aminoglycosides into the inner ear could cause
potential damage. Among Aminoglycosides, Streptomycin is the most ototoxic.
3. Neuromuscular blockade: All Aminoglycosides have the potential to
produce neuromuscular blockade. The effect is produced mainly by interference
with the release of acetylcholine from motor nerve endings, probably by
antagonism of Ca+2 that is normally required for exocytosis [normally
the Ach is stored in storage vesicles (after its synthesis), when an action
potential is propagated across the length of pre-synaptic neuron, it opens the
calcium channels (located on the outer surface of that neuron) thereby leading
to exocytosis of storage vesicle causing the release of Ach to synaptic cleft.
There the Ach binds to NM receptors to trigger the signalling
pathway required for muscular contraction]. However, concomitant administration
of neuromuscular blocking agents and general anaesthetics with Aminoglycosides
may substantially increase the risk of neuromuscular blockade.
Contraindications and precautions: Patients suffering from pre-existing renal disorders should avoid
the use of Aminoglycosides. Aminoglycosides may impair neuromuscular
transmission and so are not given to patients with myasthenia gravis. They
cause adverse effects on fetus so their use during pregnancy is not recommended
unless considered mandatory.
Drug interactions: Concurrent use of Aminoglycosides with loop diuretics (e.g., Frusemide) may aggravate the nephrotoxic effects of Aminoglysosides. Risk of neuromuscular blockade and respiratory muscle paralysis increases when Aminoglysosides are used with inhalant anesthetics or neuromuscular blocking drugs. Aminoglycosides show synergistic antibacterial effect with β-lactam antibiotics.
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