AMINOGLYCOSIDE

ANTIBIOTICS
 INTRODUCTION
• These drugs are used primarily to treat infections caused by aerobic gram-negative bacteria;
streptomycin is an important agent for the treatment of tuberculosis.
• The aminoglycoside group includes gentamicin, tobramycin, amikacin, netilmicin, kanamycin,
streptomycin, and neomycin.
• These agents contain amino sugars linked to an aminocyclitol ring by glycosidic bonds.
• They are polycations, and their polarity is responsible in part for pharmacokinetic properties shared
by all members of the group.
• For example, none is absorbed adequately after oral administration, inadequate concentrations are
found in cerebrospinal fluid (CSF), and all are excreted relatively rapidly by the normal kidney.
• In contrast to most inhibitors of microbial protein synthesis, which are bacteriostatic, the
aminoglycosides are bactericidal inhibitors of protein synthesis.
• Because of their use is which associated with serious toxicities, they have been replaced to some
extent by safer antibiotics, such as the third and fourth-generation of cephalosporins, the
fluoroquinolones, and the carbapenems.
 HISTORY AND SOURCE
• Aminoglycosides are natural products or semisynthetic derivatives of compounds produced by a
variety of soil actinomycetes.
• Streptomycin was first isolated from a strain of Streptomyces griseus.
• Gentamicin and netilmicin are broad-spectrum antibiotics derived from species of the actinomycete
Micromonospora.
• The difference in spelling (-micin) compared with the other aminoglycoside antibiotics (-mycin)
reflects this difference in origin.
• Tobramycin is one of several components of an aminoglycoside complex (nebramycin) that is
produced by S. tenebrarius (1967).
• It is most similar in antimicrobial activity and toxicity to gentamicin.
• In contrast to the other aminoglycosides, amikacin, a derivative of kanamycin, and netilmicin, a
derivative of sisomicin, are semisynthetic products.
• Other aminoglycoside antibiotics have been developed (e.g., arbekacin, isepamicin, and sisomicin),
but they have not been introduced into clinical practice in the United States because numerous potent,
less toxic alternatives (e.g., broad-spectrum b-lactam antibiotics and quinolones) are available
 MECHANISM OF ACTION
• Susceptible gram-negative organisms allow aminoglycosides to diffuse through porin
channels in their outer membranes.
• These organisms also have an oxygen-dependent system that transports the drug across
the cytoplasmic membrane. The antibiotic then binds to the 30s ribosomal subunit prior
to ribosome formation.
• There, it interferes with assembly of the functional ribosomal apparatus and/or can cause
the 30s subunit of the completed ribosome to misread the genetic code.
• Polysomes become depleted, because the aminoglycosides interrupt the process of
polysome disaggregation and assembly.
• [Note: the aminoglycosides synergize with î²-lactam antibiotics because of the latter's
action on cell wall synthesis, which enhances diffusion of the aminoglycosides into the
bacterium.]
 ANTIBACTERIAL SPECTRUM
• The aminoglycosides are effective in the empirical treatment of infections suspected of
being due to aerobic gram-negative bacilli, including Pseudomonas aeruginosa.

• To achieve an additive or synergistic effect, aminoglycosides are often combined with a

• All aminoglycosides are bactericidal.

• The exact mechanism of their lethality is unknown because other antibiotics that affect
protein synthesis are generally bacteriostatic.
 RESISTANCE
• Resistance can be caused by
1. Decreased uptake of drug when the oxygen-dependent transport system for
aminoglycosides or porin channels are absent.
2. Plasmid-associated synthesis of enzymes (for example, acetyl transferases,
nucleotidyltransferases, and phosphotransferases) that modify and inactivate
aminoglycoside antibiotics.
• Each of these enzymes has its own aminoglycoside specificity; therefore, cross-resistance
is not an invariable rule.
• Mutations affecting proteins in the bacterial ribosome, the target for these drugs, can
confer marked resistance to their action.
• However, most commonly resistance is due to acquisition of plasmids or transposon-
encoding genes for aminoglycoside-metabolizing enzymes or from impaired transport of
drug into the cell.
• Thus there can be cross-resistance between members of the class.
 PHARMACOKINETICS
Administration: The highly polar, polycationic structure of the aminoglycosides prevents
adequate absorption after oral administration. Therefore, all aminoglycosides must be given
parenterally to achieve adequate serum levels.

• The bactericidal effect of aminoglycosides is concentration and time dependent; that is, the
greater the concentration of drug, the greater the rate at which the organisms die.

Distribution: All the aminoglycosides have similar pharmacokinetic properties. Levels

• High concentrations accumulate in the renal cortex and in the endolymph and perilymph
of the inner ear, which may account for their nephrotoxic and ototoxic potential.

• All aminoglycosides cross the placental barrier and may accumulate in fetal plasma and
amniotic fluid (the fluid surrounding a fetus within the amnion).

Elimination: Metabolism of the aminoglycosides does not occur in the host.

• All are rapidly excreted into the urine, predominantly by glomerular filtration.

• Accumulation occurs in patients with renal failure and requires dose modification.
PHARMACOKINETICS
OF
AMINOGLYCOSIDE
 ADVERSE EFFECTS
• It is important to monitor plasma levels of gentamicin, tobramycin, and amikacin to avoid
concentrations that cause dose-related toxicities.
• Patient factors, such as old age, previous exposure to aminoglycosides, and liver disease,
tend to predispose patients to adverse reactions.
• The elderly are particularly susceptible to nephrotoxicity and ototoxicity.
1. Ototoxicity: It (vestibular and cochlear) is directly related to high peak plasma levels
and the duration of treatment. The antibiotic accumulates in the endolymph and
perilymph of the inner ear, and toxicity correlates with the number of destroyed hair
cells in the organ of Corti.
• Deafness may be irreversible and has been known to affect fetuses in utero. Patients
simultaneously receiving another ototoxic drug, such as cisplatin or the loop diuretics,
furosemide, bumetanide, or ethacrynic acid, are particularly at risk.
• Vertigo and loss of balance (especially in patients receiving streptomycin) may also occur,
because these drugs affect the vestibular apparatus.
2. Nephrotoxicity: Retention of the aminoglycosides by the proximal tubular cells
disrupts calcium-mediated transport processes, and this results in kidney damage
ranging from mild, reversible renal impairment to severe, acute tubular necrosis, which
can be irreversible.
3. Neuromuscular paralysis: This side effect most often occurs after direct
intraperitoneal or intrapleural application of large doses of aminoglycosides. The
mechanism responsible is a decrease in both the release of acetylcholine from
prejunctional nerve endings and the sensitivity of the postsynaptic site. Patients
with myasthenia gravis are particularly at risk. Prompt administration of calcium
gluconate or neostigmine can reverse the block.
4. Allergic reactions: Contact dermatitis is a common reaction to topically applied
neomycin.
ADVERSE EFFECTS
OF
AMINOGLYCOSIDE
 THERAPEUTIC USES
• Bacterial Endocarditis
• Tularemia
• Plague
• Tuberculosis
• Urinary Tract Infections
• Pneumonia
• Meningitis
• Peritoneal Dialysis-Associated Peritonitis
• Sepsis
• Nosocomial gram-negative bacillary infections
 Pharmacist is a linker between patient and registered
general physician. So, It’s Pharmacist’s duty to take right
decision in perfect pattern.