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AMINOGLYCOSIDES
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Aminoglycosides (AGs) are a group of natural and semisynthetic antibiotics having

polybasic amino groups linked glycosidically to 2 or more amino sugar residues. These antibiotics
are derived from bacteria of geni Streptomyces or Micromonospora. AG derived from genus
Streptomyces are named with suffix –mycin;( eg: streptomycin) while those derived from genus
Micromonospora are named with suffix – micin. (eg: gentamicin)

Common properties of all aminoglocosides

1. all are bactericidal and more active at alkaline pH
2. they ionize in solution; are not absorbed orally; distribute only extracellularly; do not
penetrate brain or CSF
3. all are excreted unchanged in urine by glomerular filtration
4. all are used as sulfate salts, which are highly water soluble and solutions stable for months
5. they act by interfering with bacterial protein synthesis
6. all are primarily active against aerobic gram negative bacilli, but spectrum differs.
7. there is only partial cross resistance among them; an organism resisitant to one AG may still
respond to another
8. relatively narrow margin of safety
9. all exhibit ototoxicity and nephrotoxicity ; neomycin and framycetin are AG with high
systemic toxicity, therefore used only topically.
10. A post-antibiotic effect, i.e., residual bactericidal activity persisting after the serum concentration
has fallen below the minimum inhibitory concentration (MIC), also is characteristic of
aminoglycoside antibiotics; the duration of this effect also is concentration dependent. These
properties probably account for the efficacy of once-daily dosing regimens of aminoglycosides.
Classification:
1. Based on origin
-mycin (Streptomyces)- Aminoglycosides derived from the genus Streptomyces are named with the
suffix –mycin
Egs: Streptomycin, Neomycin ,Framycetin, Paromomycin, Ribostamycin, Kanamycin,Amikacin, Arbekacin,
Bekanamycin, Dibekacin, Tobramycin, Hygromycin B, Spectinomycin,

-micin(Micromonospora)- those derived from the genus Micromonospora are named with the suffix
-micin. Egs: Gentamicin,Netilmicin,Sisomicin,Isepamicin,Verdamicin,Astromicin

2. Based on spectrum of activity

Narrow-spectrum :streptomycin and dihydrostreptomycin, which are mainly active against
aerobic, gram-negative bacteria
Expanded-spectrum : Neomycin, framycetin (neomycin B), paromomycin (aminosidine), and
kanamycin have broader spectra than streptomycin that often include several gram-positive as well
as many gram-negative aerobic bacteria. Gentamicin, tobramycin, amikacin, sisomicin, and
netilmicin are AG with extended spectra that include Pseudomonas aeruginosa

Chemistry and Structure : The aminoglycosides consist of two or more amino sugars joined in
glycosidic linkage to a hexose nucleus, which usually is in a central position. This hexose, or aminocyclitol,
is either streptidine (found in streptomycin) or 2-deoxystreptamine (found in all other available
aminoglycosides). These compounds thus are (aminoglycosidic) aminocyclitols, although the simpler term
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aminoglycoside is used commonly to describe them. A related compound, spectinomycin, is an aminocyclitol

that does not contain amino sugar. The chemical structure of apramycin differs somewhat from that of
the typical aminoglycosides but is similar enough to be included in this class. The structure of
spectinomycin is unusual, but it is fairly comparable to other aminocyclitols with regard to its
mechanism of action and antibacterial spectrum

♦ Chemically, the aminoglycoside antibiotics are characterized by an aminocyclitol

group, with aminosugars attached to the aminocyclitol ring in glycosidic linkage.
♦ Because of minor differences in the position of substitutions on the molecules, there
may be several forms of a single aminoglycoside.
♦ For example, gentamicin is a complex of gentamicins C1 and C2, and neomycin is a
mixture of neomycins B, C, and fradiomycin.
♦ The amino groups contribute to the basic nature of this class of antibiotics, and the
hydroxyl groups on the sugar moieties to high aqueous solubility and poor lipid solubility.
♦ If these hydroxyl groups are removed (eg, tobramycin), antibiotic activity is
markedly increased.
♦ Differences in the substitutions on the basic ring structures within the various
aminoglycosides account for the relatively minor differences in antimicrobial spectra, patterns
of resistance, and toxicities.
♦ Aminoglycosides are typically quite stable. When the water solubility of an
aminoglycoside is marginal, it is usually the sulfate salt that is used for PO or parenteral
administration
♦ A post-antibiotic effect, i.e., residual bactericidal activity persisting after the serum
concentration has fallen below the minimum inhibitory concentration (MIC), also is
characteristic of aminoglycoside antibiotics; the duration of this effect also is concentration
dependent. These properties probably account for the efficacy of once-daily dosing regimens
of aminoglycosides.
Mechanism of Action:
Aminoglycosides are more effective against rapidly multiplying organisms, and they
affect and ultimately destroy bacteria by several mechanisms.

♦ Their main site of action is the membrane-associated bacterial ribosome through which they
interfere with protein synthesis. To reach the ribosome, they must first cross the bacterial cell
wall and then the cell membrane. The primary intracellular site of action of the aminoglycosides is
the 30S ribosomal subunit, which consists of 21 proteins and a single 16S molecule of RNA. At least
three of these ribosomal proteins, and perhaps the 16S ribosomal RNA as well, contribute to the
streptomycin-binding site, and alterations of these molecules markedly affect the binding and
subsequent action of streptomycin
♦ Because of the polarity of these compounds, a specialized transport process is required. The first
concentration-dependent step requires binding of the aminoglycoside to anionic components
in the cell membrane. The subsequent steps are energy-dependent and involve the transport of
the polar, highly charged aminoglycoside across the cytoplasmic membrane, followed by
interaction with the ribosomes.
♦
♦ The driving force for this transfer is probably the membrane potential. These processes are
much more efficient if the energy used is aerobically generated
♦
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♦ Several features of these mechanisms are of clinical significance:

♦
♦ 1) The antibacterial activity of the AGs depends on an effective concentration of antibiotic
outside the cell. 2) Anaerobic bacteria and induced mutants are generally resistant because
they lack appropriate transport systems. 3) With low oxygen tension, as in hypoxic tissues,
transfer into bacteria is diminished. 4) Divalent cations, eg, Ca and Mg, can interfere with
transport into bacteria because they can combine with the specific anionic sites and exclude
the cationic aminoglycosides. 5) Transport of aminoglycosides across bacterial cell
membranes is facilitated by an alkaline pH; a low pH may increase membrane resistance
>100-fold. 6) Changes in osmolarity also can alter the uptake of aminoglycosides. 7) Some
aminoglycosides are transported more efficiently than others, and thus tend to have greater
antibacterial activity.

Antibacterial Spectrum

 Streptomycin and dihydrostreptomycin have relatively narrow spectra, and bacterial resistance is
becoming prevalent. However, some staphylococci and a number of gram-negative bacilli are still
susceptible, among which are strains of Actinomyces bovis , Pasteurella spp , E coli , Salmonella spp ,
Campylobacter fetus , Leptospira spp , and Brucella spp . Mycobacterium tuberculosis is also sensitive
to streptomycin
 Neomycin, framycetin, and kanamycin have broader spectra than streptomycin, and their clinical use is
most often directed against gram-negative species such as E coli and Salmonella , Klebsiella ,
Enterobacter , Proteus , and Acinetobacter spp
 The antibacterial activity of gentamicin, tobramycin, kanamycin, netilmicin, and amikacin is directed
primarily against aerobic gram-negative bacilli. These aminoglycosides with broader spectra that
include P aeruginosa are often highly effective against a wide variety of aerobic bacteria. Anaerobic
bacteria and fungi are not appreciably affected; streptococci are usually only moderately sensitive or
quite resistant
 Kanamycin, like streptomycin, has a more limited spectrum compared with other aminoglycosides; in
particular, it should not be used to treat infections caused by Serratia or P. aeruginosa.
 Aminoglycosides have little activity against anaerobic microorganisms or facultative bacteria
under anaerobic conditions.
 Their action against most gram-positive bacteria is limited, and they should not be used as single agents
to treat infections caused by gram-positive bacteria.
 In combination with a cell wall-active agent, such as a penicillin or vancomycin, an aminoglycoside
(streptomycin and gentamicin have been tested most extensively) produces a synergistic bactericidal
effect in vitro against enterococci, streptococci, and staphylococci.
 The aerobic gram-negative bacilli vary in their susceptibility to the aminoglycosides Tobramycin and
gentamicin exhibit similar activity against most gram-negative bacilli, although tobramycin usually is
more active against P. aeruginosa and some Proteus spp.
 Many gram-negative bacilli that are resistant to gentamicin because of plasmid-mediated inactivating
enzymes also will be resistant to tobramycin.
 Amikacin and, in some instances, netilmicin retain their activity against gentamicin-resistant strains
because they are a poor substrate for many of the aminoglycoside-inactivating enzymes.
 AG are commonly used to control local and systemic infections caused by susceptible aerobic bacteria
(generally gram-negative) because of their effectiveness. Examples include septicemia;
tracheobronchitis; pneumonia; osteoarthritis; and infections of the urinary tract, GI tract, and skin and
wounds. Several aminoglycosides are used topically in the ears and eyes.
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 The treatment interval should be increased in neonates (especially puppies and foals), in renal failure,
and in obese animals.
 Doses may be increased in animals with edema, hydrothorax, or ascites, provided their renal function is
unimpaired

Pharmacokinetics

 The aminoglycosides are highly polar cations and therefore are very poorly absorbed from
the gastrointestinal tract. Less than 1% of a dose is absorbed after either oral or rectal administration.
The drugs are not inactivated in the intestine and are eliminated quantitatively in the feces.
 Long-term oral or rectal administration of aminoglycosides may result in accumulation to
toxic concentrations in patients with renal impairment. Absorption of gentamicin from the
gastrointestinal tract may be increased by gastrointestinal disease (e.g., ulcers or inflammatory bowel
disease).
 All the AGs are absorbed rapidly from intramuscular sites of injection. Peak concentrations
in plasma occur after 30 to 90 minutes and are similar to those observed 30 minutes after completion of
an intravenous infusion of an equal dose over a 30-minute period.
 Because of their polar nature, the aminoglycosides do not penetrate into most cells, the
central nervous system (CNS), and the eye. Except for streptomycin, there is negligible binding of
aminoglycosides to plasma albumin. Concentrations of AGs in secretions and tissues are low. High
concentrations are found only in the renal cortex and the endolymph and perilymph of the inner ear;
the high concentration in these sites likely contribute to the nephrotoxicity and ototoxicity caused by
these drugs
 The aminoglycosides are excreted almost entirely by glomerular filtration, and urine
concentrations of 50 to 200 µ g/ml are achieved. A large fraction of a parenterally administered dose is
excreted unchanged during the first 24 hours, with most of this appearing in the first 12 hours
Mechanisms of Bacterial Resistance:
may be plasmid-mediated or due to mutation

1. Impaired transport across the cell membrane is one mechanism of nonplasmid mediated
resistance. Because the transport process is active and oxygen-dependent, anaerobic bacteria (eg,
Bacteroides fragilis and Clostridium perfringens ) and- facultative anaerobes (eg, enterobacteria
and Staphylococcus aureus ) are more resistant to the aminoglycosides when in an anaerobic
environment.
Resistance due to impaired transport can be induced by exposure to sublethal concentrations of
these antibiotics. Examples of this form include streptomycin resistance among strains of
Pseudomonas aeruginosa , low-level aminoglycoside resistance among enterococci, and gentamicin
resistance in Streptococcus faecalis
2. Impaired ribosomal binding may not be a clinically important form of resistance. Examples
include Escherichia coli strains in which a single-step mutation prevents the binding of
streptomycin to the ribosome. The same mechanism has been described in Pseudomonas
aeruginosa
3. Enzymatic modification of aminoglycosides may be plasmid-encoded and chromosomally
mediated. The enzymes are found in both gram-negative and gram-positive bacteria. There are 3
major types of enzymes involved, with several subclasses in each case.
The main groups are acetylating enzymes (acetyltransferases), adenylating enzymes
(nucleotidyltransferases), and phosphorylating enzymes (phosphotransferases). The susceptibility
of the aminoglycosides to specific enzymatic attack is quite variable, and the substrate profiles
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differ for each subclass. This explains the common incidence of cross-resistance yet the frequent
differences in susceptibility patterns. Chemical alteration of an aminoglycoside may render it
relatively stable to enzymatic hydrolysis (eg, kanamycin modified to amikacin is relatively resistant
to inactivating enzymes).
Several other mechanisms of resistance are recognized: 1) Increasing the concentration of divalent
cations (especially Ca2+ and Mg2+) in the media increases resistance in Pseudomonas aeruginosa . 2)
Mutants of P aeruginosa produce an excess of outer cell membrane protein, called H1, that confers
relative resistance to gentamicin. 3) A low pH, as found in acidic urine or in abscess cavities, leads
to persistent viability of microorganisms even with relatively high concentrations of
aminoglycosides

Indications:

The common infectious conditions for which AGs are used as antiinfectious agents are bacteremia
,septicemia, bone and joint infections, enteritis (Neomycin sulfate: for enteritis caused by
Escherichia coli), respiratory tract infections, skin and soft tissue infections, urinary tract
infections.

Side Effects and Toxicity

These effects may vary with the aminoglycoside and dose or interval used, but all members of the
group are potentially toxic. All aminoglycosides have the potential to produce reversible and irreversible
vestibular, cochlear, and renal toxicity. These side effects complicate the use of these compounds and make
their proper administration difficult

1. Ototoxicity : AGs can result in ototoxicity, which manifests as auditory or vestibular

dysfunction. Ototoxicity has been linked to mutations in a mitochondrial ribosomal RNA gene,
indicating that a genetic predisposition exists for this side effect. : Aminoglycosides
concentrate in the perilymph of the inner ear. The damage to the ciliated cells
can result in deafness and vestibular nerve injury may also result as well
Vestibular injury leads to nystagmus, incoordination, and loss of the righting r.eflex. The lesion is
often irreversible, although physiologic adaptation can occur. Cats are particularly sensitive
to the toxic vestibular effects. Cochlear damage is manifested by hearing impairment
produced by permanent damage and loss of the hair cells in the organ of Corti. High-
frequency hearing is impaired first, and deafness may not be complete, depending on the
dosage used. Such an impediment could be of enormous importance (eg, in guide dogs), and
aminoglycosides should not be administered to such animals except under extenuating
circumstances.
Aminoglycosides should not be instilled into the ear unless the tympanic membrane is
intact, because diffusion of the drug into the inner ear could cause damage.
Several risk factors may predispose to vestibular and cochlear damage by aminoglycosides
(in addition to those for nephrotoxicity), including preexisting acoustical or vestibular
impairment and previous treatment with potentially ototoxic drugs or loop-acting diuretics
(eg, furosemide, ethacrynic acid). The ototoxic potential is highest for gentamicin,
sisomicin, and neomycin, and lowest for netilmicin
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2. Nephrotoxicity: The nephrotoxic potential varies among individual aminoglycosides. The

relative toxicity correlates with the concentration of drug found in the renal cortex in experimental
animals. Neomycin, which concentrates to the greatest degree, is highly nephrotoxic in human
beings and should not be administered systemically. Streptomycin does not concentrate in the renal
cortex and is the least nephrotoxic . It manifests as tubular damage resulting in loss of urinary
concentrating power, low GFR, nitrogen retention, albuminuria and catss. AGs interefer with
production of Prostaglandins in kidney which is usually related to reduced GFR. Aminoglycosides
accumulate in proximal tubular epithelial cells, where they are sequestered in lysosomes and
interact with ribosomes, mitochondria, and other intracellular constituents to cause cell
injury . Persistence of aminoglycosides in plasma and thus urine is likely to predispose the
tubular cells to toxicity Nonoliguric renal failure is the usual observation; it is generally
reversible, although recovery may be prolonged. Any failure in glomerular filtration results
in excessively high concentrations of aminoglycoside, which in turn result in further renal
damage.
Renal function should be monitored during therapy. Polyuria, decreased urine osmolality,
enzymuria, proteinuria, cylindruria, and increased fractional sodium excretion are indicative
of aminoglycoside nephrotoxicity. Later, BUN and creatinine concentrations may be
increased. Early changes or evidence of nephrotoxicity can be detected in 3-5 days, with
more overt signs in 7-10 days.
Several factors predispose to aminoglycoside nephrotoxicosis, including age (with young
[especially the newborn and old animals being sensitive), compromised renal function, total
dose, duration of treatment, dehydration and hypovolemia, aciduria, acidosis, severe sepsis
or endotoxemia, concurrent administration of other nephrotoxic drugs such as NSAIDS,
furosemide, , methoxyflurane, amphotericin B, cis-platinum, and some cephalosporins
In renal insufficiency, generally the interval between doses is prolonged (rather than
reducing the dose) to minimize toxicity
The risk of aminoglycoside-induced nephrotoxicity can be reduced by maintaining patient
hydration and an alkaline urine pH, dosing once daily, and avoiding nephroactive drugs (eg,
NSAID, diuretics

3. Neuromuscular blockade: All AGs, when administered in doses that result in high
plasma levels, have been associated with muscle weakness and respiratory arrest attributable
to neuromuscular blockade. The effect is more pronounced when aminoglycosides are used
with other drugs that cause neuromuscular blockade (skeletal muscle relaxants,
Neuormuscular blocking agents/curare like drugs: d-tubocurarine) with gas anesthetics.
Neomycin, streptomycin, kanamycin, amikacin, gentamicin, and tobramycin are listed
in order of most to least potent for these neuromuscular effects.
The effect is due to the chelation of calcium and competitive inhibition of the prejunctional
release of acetylcholine in most instances (there are some differences among
aminoglycosides). The blockade is antagonized by calcium gluconate and somewhat less
consistently by neostigmine

4. Other forms of toxicity and side effects include CNS disturbances,convulsions,

collapse after rapid IV administration, superinfection when used topically or PO, a
malabsorption syndrome due to allocation of intestinal villous function when used PO in
neonates, occasional hypersensitivity reactions, contact dermatitis, cardiovascular
depression, and inhibition of some WBC functions (eg, neutrophil migration and chemotaxis
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and Cardiovascular depression may be aggravated by aminoglycosides when administered

to animals under halothane anesthesia. High concentrations of carbenicillin, ticarcillin, and
piperacillin inactivate aminoglycosides both in vitro and in vivo in the presence of renal
failure

Drug interactions
1. Aminoglycosides, two or more concurrently(concurrent administration may increase the risk
of ototoxicity, nephrotoxicity, or neuromuscular blockade)
2. Calcium/(intravenous calcium supplementation may decrease nephrotoxicity associated
with aminoglycosides
3. Calcium channel blocker : an increased risk of neuromuscular blockade may occur with
concomitant administration with an aminoglycoside
4. Halothane anesthesia-half-life of elimination increases; a longergentamicin dosing interval
after anesthesia may help correct for the changes, but serious consideration should be given
to choice of another antimicrobial
5. Iron, supplemental-the risk of auditory and renal toxicity might be increased
whenaminoglycosides are administered with iron supplements
6. NSAIDs, loop diuretics, can potentiate the nephrotoxicity.
7. Neuromuscular blocking agents or drugs with neuromuscular blocking activity ,concurrent use with
aminoglycosides can increase the risk of neuromuscular blockade, particularly during anesthesia
Edrophonium reversed any remaining neuromuscular block during recovery; calcium
supplementation can also help reverse neuromuscular blockade
8. BUN, serum creatinine, serum transaminases, and alkaline phosphatase values may be increased by
AG therapy . Proteinuria is a significant laboratory finding

Streptomycin :
was the earliest oldest aminoglycoside obtained from Streptomyces griseus. It is active against
mycobacteria, Leptospira, francisellatularensis, and Yersinia pestis, but only some mycoplasma,
gram negative organisms, and Staphylococcus species. Streptomycin is used for the treatment of
certain unusual infections generally in combination with other antimicrobial agents. Because it
generally is less active than other members of the class against aerobic gram-negative rods, it has
fallen into disuse. It is administered by deep IM or IV . IM injection may be painful, with a hot,
tender mass developing at the site of injection Dihydrostreptomycin is chemically very similar to
streptomycin. The introduction of newer aminoglycosides has eclipsed the significance of
dihydrostreptomycin and streptomycin in the face of increasing bacterial resistance.

Gentamicin :

obtained from Micromonospora purpurea. Gentamicin is an important agent for the treatment of
many serious gram-negative bacillary infections. It is the aminoglycoside of first choice because of
its low cost and reliable activity against all but the most resistant gram-negative aerobes.
Gentamicin preparations are available for parenteral, ophthalmic, and topical administration.
Gentamicin, tobramycin, amikacin, and netilmicin can be used interchangeably for the treatment of
most of the following infections. For most indications, gentamicin is the preferred agent because of
long experience with its use and its relatively low cost. Many different types of infections can be
treated successfully with these aminoglycosides; however, owing to their toxicities, prolonged use
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should be restricted to the therapy of life-threatening infections and those for which a less toxic
agent is contraindicated or less effective.

Neomycin:

obtained from Streptomyces fradiae, became available for use a few years after streptomycin.
Neomycin has been effective against many gram-negative organisms and Staphylococcus aureus.
However, the use of neomycin is limited by a relatively high risk of toxicity with systemic use;

Tobramycin :

obtained from Streptomyces tenebrarius . The antimicrobial activity, pharmacokinetic properties,

and toxicity profile of tobramycin are very similar to those of gentamicin. Tobramycin may be
given either intramuscularly or intravenously. Dosages and serum concentrations are identical with
those for gentamicin. Tobramycin also is available in ophthalmic ointments and solutions.
Indications for the use of tobramycin are the same as those for gentamicin. The superior activity of
tobramycin against P. aeruginosa makes it the preferred aminoglycoside for treatment of serious
infections caused by this organism. It usually should be used concurrently with an antipseudomonal
β -lactam antibiotic

Framycetin:

obtained from S. lavendulae, is very similar to neomycin. It is used topically on eye, skin, ear as it is toxic
for systemic administration.

Sisomicin:

obtained from Micromonospora inyoensis . is chemically and pharmacokinetically similar to gentamicin..

but more potent on Pseudomonas, few other gram negative bacilli It can be used interrchangably with
gentamicin, howver is susceptible to AG inactivating enzymes.

Amikacin :

It is a semisynthetic derivative of kanamycin, the first less toxic alternative to older

aminoglycosides. Because amikacin has the broadest spectrum of activity of the
aminoglycosides, including superior activity against pathogens such as Pseudomonas,proteus,
Staph. species and kanamycin-resistant Enterobacteriaceae, it eclipsed the use of kanamycin, a
drug with a very similar pharmacokinetic profile. Amikacin is considered effective against strains
not susceptible to other AGs because it resists some aminoglycoside inactivating enzymes

Kanamycin:

The use of kanamycin has declined markedly because its spectrum of activity is limited compared
with other aminoglycosides, and it is among the most toxic.
Kanamycin has been employed to treat tuberculosis in combination with other effective drugs. It has
no therapeutic advantage over streptomycin or amikacin and probably is more toxic
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Netilmicin :

Netilmicin is the latest of the AGs to be marketed. It is similar to gentamicin and tobramycin in its
pharmacokinetic properties and dosage. Its antibacterial activity is broad against aerobic gram-
negative bacilli. Like amikacin, it is not metabolized by the majority of the aminoglycoside-
inactivating enzymes, and it therefore may be active against certain bacteria that are resistant to
gentamicin.

AMINOCYCLITOLS

Apramycin

is an aminocyclitol antibiotic with a chemical structure very similar to that of the aminoglycosides but
different enough to leave it unaffected by many aminoglycoside inactivating enzymes. At low
concentrations, apramycin is more effective in inhibiting bacterial protein synthesis than
amikacin,gentamicin, or streptomycin. Apramycin is active against Staphylococcus aureus, many gram-
negative organisms, and some mycoplasma strains. Apramycin has been reported to be effective in vitro
against E. coli and Salmonella species that are resistant to streptomycin and neomycin

Spectinomycin

is related to the aminoglycosides in structure, but its use is confined to the treatment of gonorrhoea
in patients allergic to penicillin, or in those whose infections are caused by penicillin-resistant
gonococci
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Gentamicin 3-6 mg/kg, IM or SC, SID- BID

Kanamycin12-15 mg/kg, IM or SC, SID-BID
Streptomycin/dihydrostreptomycin7.5-12.5 mg/kg, IM or SC, BID
Amikacin5-7.5 mg/kg, IM or SC, BID
Netilmicin3-6 mg/kg, IM or SC, SID- BID Neomycin15 mg/kg, PO, SID- BID0.5-1 g/quarter,
intramammary, SID