AMINOGLYCOSIDES

Aminoglycosides
 Streptomycin
 Neomycin
 Kanamycin
 Amikacin
 Gentamicin
 Tobramycin
 Sisomycin
 Netilmicin

Aminoglycosides
 Are amino sugars bound by glycosidic
bridges to a hexose nucleus
 They are used widely against gram-
negative enteric bacteria (bacteremia and
sepsis, in combination with vancomycin or
a penicillin for endocarditis for the
treatment of tuberculosis)

Aminoglycosides
 Have a hexose ring, either streptidine or 2-
deoxystreptamine to which various amino
sugars are attached by glycosidic linkages
 They are water-soluble
 Stable in solution
 More active at alkaline than at acidic pH
Mechanism of Action
 Irreversible inhibitors of protein synthesis
 Generally bactericidal and their efficacy in
several cases can be greatly enhanced by
the concomitant use of cell wall inhibiting
β-lactams and glycopeptides
 Activity: primarily directed toward gram-

negative bacilli and mycobacteria


Protein synthesis is inhibited by
aminoglycosides in 3 ways
1. Interference with the initiation complex of
peptide formation
2. Misreading of mRNA, which causes

incorporation of incorrect amino acids into

the peptide, resulting in a nonfunctional or
toxic protein
3. Breakup of polysomes into nonfunctional

monosomes
* Occurs more or less simultaneously, overall

effect is irreversible and lethal for the cell

Mechanism of Resistance
 Ribosomal mutations
 Reduced intracellular transport
 Plasmid-mediated aminoglycosides-
modifying enzymes (acethyltransferases,
aenyltransferases and
phosphotransferases)
Pharmacokinetics
 Poorly absorbed orally
 Do not penetrate well into the CNS,
bronchial secretions or certain microbial
cells but are effective intracellularly in the
treatment of tuberculosis, plaque,
brucellosis, and tularemia
 Administered in high parenteral doses
 Normal elimination half-lives are 2-3 hrs.
which can be extended to 24-100 hrs. in
end-stage renal disease
 Excreted primarily by glomerular filtration
General therapeutic uses
 Parental aminoglycosides currently
available include amikacin, gantamicin,
kanamycin, netilmicin, streptomycin and
tobramycin
 Kanamycin and neomycin are available for
oral use for gastointestinal infections
 Aminoglycosides are indicated for
infections caused by gram-negative
aerobic bacteria
 Often combined with a penicillin or
cephalosporin for various infections
Adverse effects
 Renal toxicity and both auditory and
vestibular ototoxicity
 Nephrotoxicity is caused by inhibition ofan
intracellular lysosomal phospholipase in
the renal proximal tubules resulting in
aminoglycoside accumulation and
subsequent reduced glomerular filtration,
reduces water and Na transport, reduced
mitochondrial respiration and reduced
protein synthesis resulting in renal
necrosis
Other adverse effects
 Neuromuscular blockade of the curare type
 Rare blood dyscrasias
 Headache
 Dizziness
 Urticarial and peripheral neuropathy
Drug interactions
 Nephrotoxicity of aminglycosides is
increased by vancomycin, cephalosporin
and methoxyflurane
 Loop diuretics increase auditory toxicity
A.Streptomycin
 Produced by Streptomyces griseus
 Mainly used as a second-line agent for
treatment of tuberculosis
 Given intramuscularly or intravenously
 Used only in combination with other agents
to prevent emergence of resistance
 Given intramuscularly in combination with
an oral tetracycline
 Most serious toxic effect is disturbance of
vestibular function-vertigo and loss of
balance
B. Gentamicin
 Isolated from Micromonospora purpurea
 Effective against both gram-negative
organism
 Inhibits in vitro many strains of staphylococci
and coliforms and other gram-negative
bacteria
 Active alone, but also as a synergistic
companion with β-lactam antibiotics
 In combination with vancomycin or a
penicillin produces a potent bactericidal
effect, which in part is due to enhanced
uptake of drug that occurs with inhibition of
cell wall synthesis
 Given intarvenously or intramuscularly
 Neither intrathecal nor intraventicular
 Adverse reaction: nephrotoxicity is usually
irreversible and mild, ototoxicity which
tends to be irreversible

C. Tobramycin
 Has an antibacterial spectrum similar to
that gentamicin
 Given intramuscularly or intravenously
 Adverse reaction: ototoxic and nephrotoxic

D. Amikacin
 Semisynthetic derivative of kanamycin
 Less toxic
 Given intramuscularly
 Adverse reaction: nephrotoxic and ototoxic
E. Neomycin and
Kanamycin
 Active against gram-negative and gram-
positive bacteria and some mycobacteria
 Poorly absorbed from the GIT
 Limited to topical and oral use
 Neomycin is too toxic for parenteral use
 Adverse reaction: nephrotoxicity and
ototoxicity
 Auditory function is affected more than
vestibular
 Deafness has occurred
end