The Aminoglycosides
Active against gram negative
bacteria.
Hydrophilic compounds, do not cross
membranes, do not distribute well.
All given by injection, or locally
applied.
Not metabolized.
Excreted by the kidneys.
Ototoxic and nephrotoxic.
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The aminoglycosides consist of two or more
amino sugars
joined in glycosidic linkage to a hexose
nucleus, which usually
is in a central position
a hexose is a
glycosidic linkage is a type of covalent bond that joins a monosaccharide with six
carbohydrate (sugar) molecule to another group carbon atoms 2
• The polycationic aminoglycoside chemical structure results in a
binding both to the anionic outer bacterial membrane and to
anionic phospholipids in the cell membranes of mammalian
renal proximal tubular cells.
• The former contributes to the bactericidal effects of these
compounds, while the latter binding accounts for their toxicity.
Because of their hydrophilicity, the transport of
aminoglycosides across the hydrophobic lipid bilayer of
eukaryotic cell membranes is impeded
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MECHANISM OF ANTIBACTERIAL ACTION
• The antibacterial actions of the aminoglycosides involve
two possibly synergistic effects.
• First, the positively charged aminoglycoside binds to negatively
charged sites on the outer bacterial membrane, thereby
disrupting membrane integrity.
• It is likely that the aminoglycoside-induced bacterial outer
membrane degradation accounts for the rapid concentration
dependent bactericidal effect of these compounds.
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MECHANISM OF ANTIBACTERIAL ACTION
• Second, aminoglycosides bind to various sites on bacterial 30S ribosomal
subunits, disrupting the initiation of protein synthesis and inducing errors
in the translation of messenger RNA to peptides.
• They also bind to sites on bacterial 50S ribosomal subunits, although the
significance of this binding is uncertain.
• In addition, they have a post antibiotic effect; that is, they continue to
suppress bacterial regrowth even after removal of the antibiotic from the
bacterial microenvironment.
• It is likely that ribosome disruption accounts for this postantibiotic
activity.
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• The postantibiotic effect is characterized by prolonged
suppression of bacterial regrowth after the initially high
aminoglycoside concentration has fallen to a subinhibitory level.
• Perhaps resumption of bacterial ribosomal function requires the
time-consuming synthesis of new ribosomes after their
disruption by aminoglycosides.
• The postantibiotic effect explains why aminoglycosides can be
given in single daily doses despite their short half-life
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• Penetration of aminoglycosides through the outer bacterial
membrane occurs both by outer membrane disruption and by
diffusion through outer membrane porins.
• Penetration through the inner bacterial membrane occurs in two
phases.
• The first requires that the cytosol have a negative electron potential
and therefore be inhibited by the presence of a low pH.
• The second phase depends on aerobic bacterial metabolism and
therefore will be inhibited by low oxygen tension
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• The latter two observations are of considerable clinical relevance,
since
• both a low pH and a low oxygen tension
frequently occur in bacterial abscesses.
• Administration of B-lactam antibiotics will reverse the negative
effects of both low pH and low oxygen tension on the ability of
aminoglycosides to penetrate into bacteria;
• this ability accounts in part for the synergism that occurs between
aminoglycoside and B-lactam antibiotic drugs.
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The Aminoglycosides
Used to treat infections caused by
aerobic gram-negative bacteria and
rapidly bactericidal.
They inhibit protein synthesis by binding
to the 30S ribosomal subunit
and alter protein synthesis.
Streptomycin: 1947.
Used only in TB.
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The Aminoglycosides
Gentamicin.
Tobramycin.
Amikacin.
Netilmicin
Neomycin:
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The Aminoglycosides
Gentamicin:
Widely used in hospitals.
Good for Staphylococcus and Gram-
negative organisms.
Short T
1/2.
Toxic,blood level monitoring is
required.
Incompatible with other drugs, so
given separately.
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The Aminoglycosides
Neomycin:
Very toxic, not given systemically.
Given to sterilize the bowel before
surgery.
Also locally as drops or ointment in ear,
nose, eye, or skin infections.
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Tetracyclines
Wide spectrum of activity (Gram
positive and negative bacteria),
but resistance develops very
rapidly.
Bacteriostatic, only stop
bacterial growth, do not kill
bacteria. So, we depend on the
presence of a good patient’s
immune system.
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Tetracyclines
Disrupt function of 30S or 50S
ribosomal subunits to reversibly
inhibit protein synthesis.
Orally absorbed, but absorption
affected by food, and dairy
products.
Widely distributed in the body.
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A transfer RNA is an adaptor
molecule composed of RNA,
typically 76 to 90 nucleotides
in length that serves as the
physical link between the
mRNA and the amino acid
sequence of proteins
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Tetracyclines
Rarely used nowadays, EXCEPT:
Doxycycline: given once daily for
acne.
Adverse Effects:
Nausea, vomiting, diarrhea.
Changes in normal flora leading to
diarrhea and candida infection.
Bone deposits in children, appears
on teeth
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