AMINOGLYCOSIDES

Aminoglycoside is category of traditional Gram-

negative antibacterial therapeutic agents that inhibit protein
synthesis and contain as a portion of the molecule an amino-
modified glycoside (sugar), the term can also refer more generally to
any organic molecule that contains aminosugar substructures.
Aminoglycoside antibiotics display bactericidal activity against gram-
negative aerobes and some anaerobic bacilli where resistance has
not yet arisen, but generally not against Gram-positive and
anaerobic Gram-negative

Figure 1. Structure of Sreptomycin

Members of Aminoglycosides
Streptomycin the first-in-class aminoglycoside antibiotic
derived from Streptomyces griseus, the earliest modern agent
used against tuberculosis, and an example that lacks the
common 2-deoxystreptamine moiety present in many other
class members. (Figure 1)
Other examples include the deoxystreptamine-containing
agents kanamycin, tobramycin,gentamicin, and neomycin .

Mechanism of Action:
They inhibit bacterial protein synthesis by binding irreversibly to the
bacterial 30S ribosomal subunit.
Aminoglycosides act primarily by impairing bacterial protein
synthesis through binding to prokaryotic ribosomes. Passage of these
highly polar molecules across the outer membrane of gram-negative
bacteria is a self-promoted uptake process involving the drug-
induced disruption of Mg2+ bridges between adjacent
lipopolysaccharide molecules. Penetration through porin channels is
 unlikely because of the large size of aminoglycosides (approximately
1.8 by 1.0 by 1.0 nm).(Figure 2)

Figure 2. Mchanism of action of aminoglycosides

Pharmacology:

Gastrointestinal absorption of these agents is unpredictable and always

low. neomycin is available only for oral and topical use. After intravenous
administration,
Aminoglycosides are freely distributed in the extracellular space but
penetrate poorly into the CSF, vitreous fluid of the eye, biliary tract,
prostate, and tracheobronchial secretions, even in the presence of
inflammation.

Spectrum of Activity
Aminoglycosides have bactericidal activity against aerobic gram-
negative bacilli (including Pseudomonas spp.), activity against M.
tuberculosis, and a relatively low incidence of bacterial resistance.
Aminoglycosides are highly potent, broad-spectrum antibiotics with
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Aminoglycosides are used for

Serious gram-negative bacillary infections (especially those due

to Pseudomonas aeruginosa)
Aminoglycosides are active against most gram-negative aerobic
and facultative anaerobic bacilli but lack activity against anaerobes
and most gram-positive bacteria, except for most staphylococci;
however, some gram-negative bacilli and methicillin-resistant
staphylococci are resistant.

Aminoglycosides that are active against P.

aeruginosa include tobramycin (particularly), gentamicin,
and amikacin. Streptomycin, neomycin, and kanamycin are not
active against P. aeruginosa.Gentamicin and tobramycin have
similar antimicrobial spectra against gram-negative bacilli,
buttobramycin is more active against P. aeruginosa,
and gentamicin is more active against Serratia
marcescens. Amikacin is frequently active against gentamicin-
and tobramycin-resistant pathogens.

Aminoglycosides are infrequently used alone, except when used for

plague and tularemia. They are usually used with a broad-
spectrum -lactam for severe infection suspected to be due to a
gram-negative bacillary species. However, because of increasing
aminoglycoside resistance, a fluoroquinolone can be substituted for
the aminoglycoside in initial empiric regimens, or if the pathogen is
found to be susceptible to the accompanying antibiotic, the
aminoglycoside can be stopped after 2 to 3 days unless an
aminoglycoside-sensitive P. aeruginosa is identified.

Gentamicin or, less commonly, streptomycin may be used with

other antibiotics to treat endocarditis due to streptococci or
enterococci. Enterococcal resistance to aminoglycosides has
become a common problem. Because treatment of enterococcal
 endocarditis requires prolonged use of a potentially nephrotoxic and
ototoxic aminoglycoside plus a bacterial cell wallactive drug (eg,
penicillin,vancomycin) to achieve bactericidal synergy, the choice of
aminoglycoside must be based on special in vitro susceptibility
testing. Susceptibility only to high levels of aminoglycosides in vitro
predicts synergy when low-dose aminoglycoside therapy is
combined with a cell wallactive drug. If the strain is susceptible to
high levels of gentamicin and streptomycin, gentamicin is preferred
because serum levels can be readily determined and toxicity is less.
High-level enterococcal resistance to gentamicin in vitro does not
rule out susceptibility of these strains to high levels ofstreptomycin;
in such cases, streptomycin should be used.

Few therapeutic options are available for endocarditis due to

enterococci that are resistant to high levels
of gentamicin and streptomycin; no synergistic cell wallactive
drug/aminoglycoside combination exists for endocarditis due to
such strains, but the combination of the cell wallactive
drugs ampicillin and ceftriaxone has recently been shown to be
effective and minimizes the risk of nephrotoxicity.
Streptomycin has limited uses because of resistance and toxicity. It
is used to treat tularemia and plague and, with other antibiotics, to
treat TB.

Because of toxicity, neomycin and kanamycin are limited to topical

use in small amounts. Neomycin is available for eye, ear, oral, and
rectal use and as a bladder irrigant. Oral neomycin is used topically
against intestinal flora to prepare the bowel before surgery and to
treat hepatic coma.
 Use Drug
Second-choice medications: for

tuberculosis (TB)
Streptomycin
streptococcal endocarditis (with B-
lactam)
enterococcal endocarditis ( with
penicillins )
Intestinal infections
Paromomycin
Ttt of hepatic encephalopathy
Ttt of amebiasis
prophylaxis GI surgery
Neomycin
prevention of hepatic encephalopathy &
hypercholesterolemia

Ttt of systemic infection Tobramycin

respiratory tract infection

Ttt of systemic infection

Gentamicin
life threatening infection
eye infection
Respiratory tract infection
Skin infection Amikacin
Urinary tract infection
Blood, abdomen or bones infection
septicemia
Lower respiratory tract infection Netilmicin
Urinary tract infection
peritonitis and endometritis

RESISTANCE MECHANISMS

The emergence of resistant strains has somewhat reduced the potential

of aminoglycosides in empiric therapies.
The main mechanisms which may affect all aminoglycosides are :
(i) A decreased uptake and/or accumulation of the drug in bacteria
(ii) The bacterial expression of enzymes which modify the antibiotic.

Adverse Effects
All aminoglycosides cause
Renal toxicity (often reversible)
Vestibular and auditory toxicity (often irreversible)
Prolongation of effects of neuromuscular blockers
Symptoms and signs of vestibular damage are vertigo and ataxia.
Risk factors for renal, vestibular, and auditory toxicity are
Frequent or very high doses
Very high blood levels of the drug
Long duration of therapy (particularly > 3 days)
Older age
A preexisting renal disorder
Coadministration of vancomycin, cyclosporine, or amphotericin B
For renal toxicity, coadministration of contrast agents
High doses given over a long period of time typically cause more concern
about renal toxicity, but even low doses given for a short time can
worsen renal function.