2. Aminoglycosides
The first aminoglycoside, the antibiotic streptomycin,
was discovered in 1944 by American biochemists Selman
Waksman, Albert Schatz, and Elizabeth Bugie, who isolated
the compound from Streptomyces griseus, a strain of soil
bacteria
.
The aminoglycosides are first-line therapy for a limited
number of very specific, often historically prominent
infections, such as plague, tularemia, and tuberculosis; they
also are frequently used to treat infections caused by aerobic
gram-negative bacteria
Aminoglycosides are used for the treatment of serious
infections due to aerobic gram-negative bacilli
4. Mechanism Of Action
The aminoglycoside antibiotics are rapidly bactericidal. Bacterial
killing is concentration-dependent, but residual bactericidal
activity persists even after the serum concentration has fallen
below the minimum inhibitory concentration. These properties
account for the efficacy of once-daily dosing regimens.
Driven by the membrane electrical potential aminoglycosides
diffuse through aqueous channels formed by porin proteins in the
outer membrane of gram-negative bacteria and enter the
periplasmic space
Aminoglycosides
5. Mechanism Of Action
This rate-limiting process can be blocked or inhibited by a
reduction in pH or anaerobic conditions, as in an abscess.
Once inside the cell, aminoglycosides bind to polysomes and
interfere with protein synthesis by causing misreading and
premature termination of mRNA translation
The resulting aberrant proteins may be inserted into the cell
membrane, altering permeability and further stimulating
aminoglycoside transport.
Aminoglycosides
6. Microbial Resistance To The Aminoglycosides
Resistance to aminoglycosides occurs via: 1) efflux pumps, 2)
decreased uptake, and/or 3) modification and inactivation by
plasmid-associated synthesis of enzymes.
Each of these enzymes has its own aminoglycoside specificity;
therefore, cross-resistance cannot be presumed.
[Note: Amikacin is less vulnerable to these enzymes than other
antibiotics in this group.]
Aminoglycosides
7. Antibacterial Spectrum Of The Aminoglycosides
The antibacterial activity of most aminoglycosides is directed
primarily against aerobic gram-negative bacilli
including those that may be multidrug resistant, such as
Pseudomonas aeruginosa, Klebsiella pneumoniae, and
Enterobacter sp.
Additionally, aminoglycosides are often combined with a β-
lactam antibiotic to employ a synergistic effect, particularly in the
treatment of Enterococcus faecalis and Enterococcus faecium
infective endocarditis.
Aminoglycosides
8. Absorption, Distribution, Dosing, And Elimination Of The
Aminoglycosides
Absorption
The highly polar, polycationic structure of the aminoglycosides
prevents adequate absorption after oral administration.
The aminoglycosides are highly polar and, thus, poorly absorbed from
the gastrointestinal (GI) tract.
The aminoglycosides are highly polar and, thus, poorly absorbed from
the gastrointestinal (GI) tract.
Aminoglycosides are absorbed rapidly after intramuscular injection.
Aminoglycosides
9. Distribution
All the aminoglycosides have similar pharmacokinetic properties.
These polar drugs do not penetrate into most cells, central nervous
system (CNS), and the eye.
Except for streptomycin, there is negligible binding of
aminoglycosides to plasma proteins.
The volume of distribution of these drugs approximates the volume of
extracellular fluid.
Concentrations of aminoglycosides in secretions and tissues are low
[Note: Due to low distribution into fatty tissue, the aminoglycosides are
dosed based on lean body mass, not actual body weight.]
Aminoglycosides
10. Dosing
Current practice is to administer the total daily dose as a single injection,
which is associated with less toxicity and equal efficacy as multiple-dose
regimens
Once-daily regimens are safer with equal efficacy, cost less, and are
administered more easily. with creatinine clearances of <20–25 mL/min, where
dosing every 48 hours is more appropriate
Whether once-daily or multiple-daily dosing is used, the dose must be
adjusted for patients with creatinine clearances of <80–100 mL/min, and
plasma concentrations must be monitored
For twice- or thrice-daily dosing regimens, both peak (30 minutes after
dosing) and trough (immediately before the next dose) plasma concentrations
are determined.
Aminoglycosides
11. Elimination
More than 90% of the parenteral aminoglycosides are excreted
unchanged in the urine
The aminoglycosides are excreted almost entirely by glomerular
filtration, and urine concentrations of 50–200 µg/mL are
achieved.
The plasma half-lives of the aminoglycosides vary between 2 and
3 hours in patients with normal renal function.
Aminoglycosides
12. Adverse Effects Of The Aminoglycosides
All aminoglycosides can produce reversible and irreversible vestibular,
cochlear, and renal toxicity.
Ototoxicity
Ototoxicity (vestibular and auditory) is directly related to high peak plasma
levels and the duration of treatment
Nephrotoxicity
Approximately 8–26% of patients who receive an aminoglycoside for more
than several days will develop mild renal impairment that almost always is
reversible
It manifests as tubular damage resulting in loss of urinary concentrating power,
low g.f.r., nitrogen retention, albuminuria and casts.
Aminoglycosides
13. Neuromuscular paralysis
This adverse effect is associated with a rapid increase in
concentrations (for example, high doses infused over a short
period.) or concurrent administration with neuromuscular
blockers.
Allergic reactions:
Contact dermatitis is a common reaction to topically applied
neomycin
Aminoglycosides
14. Precautions And Interactions
1.Avoid aminoglycosides during pregnancy: risk of foetal
ototoxicity.
2. Avoid concurrent use of other ototoxic drugs, e.g. high ceiling
diuretics, minocycline.
3. Avoid concurrent use of other nephrotoxic drugs, e.g.
amphotericin B, vancomycin, cyclosporine and cisplatin.
4. Cautious use in patients past middle age and in those with
kidney damage.
5. Cautious use of muscle relaxants in patients receiving an
aminoglycoside.
6. Do not mix aminog lycoside with any drug in the same
syringe/infusion bottle.
Aminoglycosides
15. Streptomycin
Streptomycin is used for the treatment of certain unusual infections
usually in combination with other antimicrobial agents
Because it is less active than other members of the class against aerobic
gram-negative rods, it has fallen into disuse.
Pharmacokinetics
Streptomycin is highly ionized. It is neither absorbed nor destroyed in
the g.i.t. However, absorption from injection site in muscles is rapid.
It is distributed only extracellularly: volume of distribution (0.3 L/kg)
is nearly equal to the extracellular fluid volume
Streptomycin is not metabolized-excreted unchanged in urine.
Glomerular filtration is the main channel:.
.
Aminoglycosides
16. Adverse effects
About 1/5 patients given streptomycin 1 g BD i.m. experience
vestibular disturbances. Auditory disturbances are less common.
Streptomycin has the lowest nephrotoxicity among
aminoglycosides; probably because it is not concentrated in the
renal cortex.
Hypersensitivity reactions are rare; rashes, eosinophilia,
fever and exfoliative dermatitis have been noted. .-naphylaxis is
very rare.
Uses
Tuberculosis, Plague, Tularemia
Aminoglycosides
