Aminoglycosides

 Aminoglycosides are a group of natural and

semisynthetic antibiotics having polybasic
aminogroups linked glycosidically to two or
more aminosugar (streptidine, 2-deoxy
streptamine, garosamine) residues
 Unlike penicillin, which was a chance
discovery, aminoglycosides are products of
deliberate search for drugs effective against
gram negative bacteria
 Aminoglycosides include:
– Streptomycin (Streptomyces griseum)
– Neomycin (S. fradiae)
– Kanamycin (S. kanamyceticus)
– Tobramycin (S. tenebrarius)
– Amikacin (semisynthetic derivative of
kanamycin)
– Gentamicin (Micromonospora purpurae)
– Sisomicin (similar to C1a component of
gentamicin)
– Netilmicin (semisynthetic derivative of
sisomicin)
 Chemical structure

Aminoglycosides have a hexose ring

(aminocyclitol ring), either streptidine
(in streptomycin) or 2-
deoxystreptamine (other
aminoglycosides), to which various
(two or more) amino sugars are
attached by glycosidic linkage. That’s
why they are called aminoglycosides
 Common properties
 Polycations
 Highly polar (water soluble)
 Stable in solution. They are used as sulphate
salts, which are highly water soluble. Solutions
are stable for months
 More active in alkaline than in acid pH
 All are bactericidal
 Common toxicity profile like ototoxicity &
nephrotoxicity
 Poor oral absorption
 Volume of distribution approximately the
extracellular space (0.26 L/kg)
 Tissue distribution variable (poor CNS
penetration)
 Negligible metabolism
 Ranally eliminated (filtered, with a small
amount of proximal reabsorption)
 Elimination t½ 2-3 hours (if renal function is
normal)
 Can cross placenta (teratogenic)
 Have concentration dependent killing property
 Exhibit post antibiotic effect
 They act by interfering with bacterial protein
synthesis
 All are active primarily against aerobic gram
negative bacilli. No activity against anaerobic
microorganism or facultative bacteria. Limited
activity against gram positive bacteria,
observed only when combined with β-lactams
or glycopeptides. Streptococci highly resistant
 There is only partial cross resistance among
them. An organism resistant to one
aminoglycoside may still respond to another.
Resistance – 1st  kanamycin, then 
gentamicin, then  tobramycin. Amikacin is
less vulnerable to those enzyme because it is
developed as poor substrate of these enzymes
 They have relatively narrow margin of safety
 Antibacterial activity
 Antibacterial activity directed against aerobic
gram-negative bacilli, including Pseudomonas
aeruginosa
 No activity against anaerobic microorganism or
facultative bacteria
 Limited activity against gram-positive bacteria.
To achieve an additive or synergistic effect
aminoglycosides are often combined with a β-
lactams antibiotic or glycopeptides or a drug
active against anaerobic bacteria
 Streptococci highly resistant (used in blood
agar to isolate)
 Mechanism of action
 Aminoglycosides are irreversible inhibitors of
protein synthesis, but the precise mechanism
for bactericidal activity is not known
 The initial event is passive diffusion via porin
channels across the outer cell membrane
 Aminoglycosides then enters the bacterial cell
cytoplasm via O2 dependent active transport
system.
– The transmembrane electrochemical gradient
supplies the energy for this process &
transport is coupled to a proton pump
 – Low extracellular pH & anaerobic conditions
inhibit transport by reducing the gradient
– Transport may be enhanced by cell wall-
active drugs such as penicillin or vancomycin
 Inside the cell, aminoglycosides irreversibly
binds with the specific receptor protein on the
30S subunit ribosomal protein
 Protein synthesis is inhibited by
aminoglycosides in at least three ways
– Aminoglycosides interfere with the normal
activity of the “initiation complex” of peptide
formation
 – They induce *misreading of mRNA
template, which causes incorporation of
incorrect amino acid into the peptide,
resulting in a nonfunctional or toxic
protein
– Amino acid attachment results the
breakup of polysomes into nonfunctional
monosomes which is incapable of
protein synthesis
 These activities occur more or less
simultaneously, & the overall effect is
irreversible & lethal for the cell
 Mechanisms of resistance:
– Three principal mechanisms have been
established:
 Production of a transferase
(aminoglycosidase) enzyme or enzymes
inactivates the aminoglycoside by
adenylation, acetylation, or
phosphorylation (bind with the amino
group of the drug). Each of these enzymes
has its own aminoglycoside specificit;
therefore, cross resistance is not an
invariable rule. This is the principal type of
resistance encountered clinically.
Commonly occurs in hospital setting.
 There is impaired entry of aminoglycoside
into the cell. This may be genotypic, i.e.,
resulting from mutation or deletion of a
porin protein or proteins involved in
transport & maintenance of the
electrochemical gradient; or phenotypic,
e.g. resulting from growth conditions
under which the oxygen-dependent
transport process is not functional
 The receptor protein on the 30S ribosomal
subunit may be deleted or altered as a
result of a mutation. So there is low affinity
for ribosome
 Resistance:
–First Kanamycin,
–then Gentamycin &
–then Tobramycin
 Netilmicin & Amikacin are less
vulnerable to these enzymes
because it is developed as a poor
substrate of these enzymes
 Once daily administration of Aminoglycosides:
– Traditionally, aminoglycosides have been
administered in two or three equally divided
daily dose for patients with normal renal
function.
– However, once-daily aminoglycoside dosing
called extended interval aminoglycoside dose
(EIAD) may be preferred in certain clinical
situations
– Once daily administration recommended:
 Gram negative bacilli infection: urinary,
abdominal, pelvic, lower respiratory tract
& soft tissue
– Once daily administration may be more
effective:
 Mild to moderate renal insufficiency (Ccr
>40 ml/min)
 Fever in neutropenic patient (in a setting of
low incidence of P. aeruginosa infection)
– Aminoglycosides have concentration
dependent killing – i.e., increasing
concentrations kill an increasing proportion
of bacteria & at a more rapid rate
– They also have a significant postantibiotic
effect, such that the antibacterial activity
persists beyond the time during which
measurable drug is present. The
– postantibiotic effect of aminoglycosides can
reach several hours.
– Because of these properties, a given total
amount of aminoglycoside may have better
efficacy when administered as a single large
dose than when administered as multiple
smaller doses
– There is no difference in incidence &
intensity of any of the adverse effects in
EIAD
– A trough concentration above 2μg/mL is
predictive of toxicity. At clinically relevant
doses, the time above this threshold will be
greater with multiple smaller doses of drug
– than with a single large dose
– Single daily dose of aminoglycoside is just as
safe, effective & no more (& often less) toxic
than multiple smaller doses. Therefore many
authorities now recommend that
aminoglycosides be administered as a single
daily dose in many clinical situations with
the following exceptions:
 Severe renal insufficiency
 Severe burn
 Ascitis
 Severe sepsis syndrome
 The efficacy of once daily aminoglycoside
dosing in combination therapy of
 enterococcal, streptococcal &
staphylococcal endocarditis remains to be
defined
 Myocardial disease
 Pregnancy
 Neonates/children
 Hemodialysis
 Concomitant nephrotoxic drugs
 Culture document predominant P.
aeruginosa infection in neutropenic patient
 The standard low-dose, thrice daily
administration is still recommended
 Once-daily dosing has potential practical
advantages:
– Determination of serum concentrations is
probably unnecessary unless aminoglycoside
is given for more than 3 days
– A drug administered once a day rather than 3
times a day saves time
– Less nursing time is required to give a drug
once a day instead of 3 times a day
– Once a day dosing lends itself to outpatient
therapy
 Clinical uses:
– Gentamicin (preferred among
aminoglycosides). If it is resistant then
Tobramycin (similar to gentamicin. Slightly
more active against P aeruginosa), Amikacin,
Netilmicin (less ototoxic, less active against P
aeruginosa)
 For blind therapy of serious undiagnosed
infection usually with penicillin or
metronidazole
 Urinary tract infection (effective but used
only in seriously ill pyolonephritis)
 Pneumonias (community acquired
pneumonia is susceptible to beta lactam,
however combination is required in
hospital acquired pneumonia)
 Meningitis (ceftriaxone preferred, but
required in Pseudomonas)
 Peritonitis (peritoneal dialysis)
 Sepsis (anti-pseudomonal Penicillin with
Gentamicin or Amikacin or Tobramycin or
Netilmicin)
 Penicillin-aminoglycoside combinations
also are used to achieve bactericidal
activity in treatment of enterococcal
endocarditis & to shorten duration of
therapy for viridans streptococcal &
staphylococcal endocarditis
 Topical (slowly as ointment, but rapid as
cream)
 Streptomycin:
– Bacterial endocarditis (with Benzyl penicillin)
– Tularemia (tetracycline is preferred)
– Plague (tetracycline & chloramphenicol)
– Tuberculosis (one of the combination in
MDRTB) 2nd line agent I/M or I/V
 Neomycin: broad spectrum. Too toxic for
parenteral use
– Topical administration in ulcers, wounds &
burns
– Used orally to reduce intestinal load of
Enterobacteriaceae (preferred one is Lactulose)
– Bowel preparation along with erythromycin
base to reduce incidence of wound infection
after elective colorectal surgery
 Unwanted effects:
– All aminoglycosides are ototoxic &
nephrotoxic
– Ototoxicity & nephrotoxicity are more likely
to be encountered when
 Therapy is continued for more than 5 days
 At higher doses
 In the elderly
 In the setting of renal insufficiency
– Concurrent use with loop diuretics
(frusemide, ethacrynic acid) or other
nephrotoxic antimicrobial agents (e.g.
vancomycin or amphotericin) can potentiate
nephrotoxicity & should be avoided if
possible
– It is important to monitor plasma levels of
gentamicin, tobramycin, netilmicin &
amikacin to avoid concentrations that cause
dose-related toxicities
– When the drugs are administered two or
three times daily, both peak & trough levels
are measured
– Peak levels are defined as those obtained
thirty minutes to one hour after infusion
– Trough levels are obtained immediately
before the next dose
– When once daily dosing is employed, only
the trough concentrations are monitored
 Ototoxicity (irreversible):
– Is directly related to high peak plasma levels
& the duration of treatment
– Progressive accumulation of drug in
perilymph & endolymph of the inner ear
– Half-lives in otic fluid is six times longer than
plasma
– Toxicity depends on the Area Under the
Curve (AUC)
– Damage of the hair cells begins at central
part of cochlea (high-frequency)
– Toxicity correlates with the number of
– destroyed hair cells in the organ of Corti
– Deafness may be irreversible & has been known
to affect fetuses in utero
– Aminoglycoside ear drops can cause ototoxicity
when instilled in patients with perforated
eardrum; are contraindicated in them
– Clinical feature of cochlear damage
 Tinnitus & high frequency hearing loss
initially
 Conversation is not interfered at early stage
 Delayed diagnosis as people can continue for
some days with normal conversation that is of
low frequency
– Clinical features of vestibular damage
 Intense headache, vertigo, ataxia, loss of
balance (specially in patients receiving
streptomycin), mental past pointing
– Streptomycin & Gentamicin produce
predominantly vestibular effects
– Amikacin, Kanamycin & Neomycin
primarily affect auditory function
– Tobramycin affects both
– Patients simultaneously receiving another
ototoxic drug, such as the loop diuretics
frusemide, bumetanide, or ethacrynic acid or
cisplatin, are particularly at risk
 Nephrotoxicity (reversible)
– Accumulation & retention of aminoglycoside in
proximal tubular cells
– These cells have the capacity to regenerate. That’s
why the effects are reversible
– Related to inhibition of intracellular
phospholipases
– Disrupt calcium-mediated transport processes, &
this results in kidney damage ranging from mild,
reversible renal impairment to severe, acute
tubular necrosis, which can be irreversible
– Aminoglycosides interfere with the production of
prostaglandins in the kidney & this is causally
related to reduced GFR
– However, the exact biochemical processes
that lead to the toxicity remain to be
elucidated
– Associated factors: hypotension,
dehydration, duration of therapy,
concomitant liver disease, advanced age,
other nephrotoxins
– Nephrotoxicity results in rising serum
creatinine levels or reduced creatinine
clearance, although the earliest indication
often is an increase in trough serum
aminoglycoside concentrations
– Reduced excretion of drug may lead to
ototoxicity later
 – Order of nephrotoxicity
 Neomycin is highest toxic
 Streptomycin is the least toxic
 Tobramycin & Gentamicin are in between
& equal
 Neuromuscular paralysis:
– In very high doses, aminoglycosides can
produce a curare-like effect with
neuromuscular blockade that results in
respiratory paralysis
– The mechanism responsible is a decrease in
both the release of acetylcholine (results from
inhibition of calcium uptake necessary for the
exocytotic release of acetylcholine) from
– prejunctional nerve endings & the sensitivity
of the postsynaptic site
– This side effect most often occurs after the
direct intraperitoneal or intrapleural
application of large doses of aminoglycosides
– Only observed when given concurrently with
other neuromuscular blocking drugs or along
with anesthesia
– Neomycin is particularly criminal with this
ability
– Patients with myasthenia gravis are
particularly at risk
 – Prompt administration of calcium gluconate
or neostigmine can reverse the block
 Allergic reactions:
– Hypersensitivity occurs infrequently
– Contact dermatitis is a common reaction to
topically applied neomycin
 Other:
– Bone marrow depression, hemolytic anemia
& bleeding due to antagonism of factor V
– Teratogenicity: risk of 8th cranial nerve
damage to fetus
– GIT: nausea, vomiting, loose motion
 Precautions & interactions of Aminoglycosides
– Avoid aminoglycosides during pregnancy: risk of
fetal ototoxicity
– Avoid concurrent use of other nephrotoxic drugs, e.g.
NSAIDs, Amphotericin B, Vancomycin, Cyclosporine,
Cisplatin
– Cautious use of other ototoxic drugs like vancomycin,
minocycline & furosemide, though clinical evidence
of potentiated ototoxicity is meagre
– Cautious use in patients > 60 years age & in those
with kidney damage
– Cautious use of muscle relaxants in patients receiving
an aminoglycoside
– Do not mix aminoglycoside with any drug in the
same syringe/infusion bottle
 Streptomycin
 Isolated from a strain of streptomyces griseus
 Antibacterial spectrum & mechanism of
resistance are typical of that of other
aminoglycosides
 Clinical uses:
– Mycobacterial infections: mainly as second
line agent for treatment of TB. It should be
used only in combination with other agents
to prevent emergence of resistance
– Nontubercular infections: in plague,
tularemia, & sometimes bruellosis,
streptomycin given in combination with
tetracycline
 Gentamicin
 Isolated from Micromonospora purpurea
 Antibacterial activity:
– Inhibits in vitro many strains of
staphylococci & coliform & other gram-
negative bacteria
– It is active alone, but also as a synergistic
companion with β-lactam antibiotics, against
pseudomonas, proteus, enterobacter,
klebsiella, serratia, stenotrophomonas &
other gram-negative rods
– It has no activity against anaerobes
(bacteroides)
 Clinical uses:
– I/M or I/V administration:
 For severe infections (e.g. sepsis &
pneumonia) caused by gram-negative
bacteria that are likely to be resistant to
other drugs, especially pseudomonas,
enterobacter, serratia, proteus,
acinetobacter, & klebsiella. It usually is
used in combination with a second agent,
as an aminoglycoside alone may not be
effective for infections outside the urinary
tract
 – Aminoglycosides should not be used for
single agent therapy of pneumonia because
penetration of infected lung tissue is poor &
local conditions of low pH & low oxygen
tension contribute to poor activity
 Topical administration:
– Creams, ointments, & solutions containing
0.1-0.3% gentamicin sulfate have been used
for the treatment of infected burns, wounds,
or skin lesions & the prevention of I/V
catheter infections
– 10 mg can be injected S.C. for treatment of
ocular infections
 Intrathecal administration:
– Meningitis caused by gram-negative bacteria
has been treated by the intrathecal injection
of gentamicin sulfate
– However, neither intrathecal nor
intraventricular (toxic) gentamicin was
beneficial in neonates with meningitis
– Moreover, the availability of third-generation
cephalosporins for gram-negative meningitis
has rendered this therapy obsolete in most
cases
 Amikacin
 Semisynthetic derivative of kanamycin
 Less toxic than the parent molecule
 Resistant to many enzymes that inactivate
gentamicin & tobramycin, & it therefore can be
used against some microorganisms resistant to
the latter drugs
 Many gram-negative enteric bacteria, including
many strains of proteus, pseudomonas,
enterobacter, & serratia, are inhibited by
amikacin in vitro
 Strains of MDRTB including streptomycin-
resistant strains, are usually susceptible to
amikacin
 Neomycin & Kanamycin
 Paromomycin is also a member of this group
 Antibacterial activity & resistance:
– Active against gram-positive & gram-
negative bacteria & some mycobacteria
– Pseudomonas & streptococci are generally
resistant
– The wide spread use of these drugs in bowel
preparation for elective surgery has resulted
in the selection of resistant organisms &
some outbreaks of enterocolitis in hospitals
 Clinical use:
– Limited to topical & oral use
– Topical administration:
 Used on infected surfaces or injected into
  joints, the pleural cavity, tissue spaces, or
abscess cavities where infection is present
 Ointments, often formulated as a
neomycin-polymyxin-bacitracin
combination, can be applied to infected
skin lesions or in the nares for suppression
of staphylococci but they are largely
ineffective
– Oral administration:
 In preparation for elective bowel surgery,
often combined with erythromycin base.
This reduces aerobic bowel flora with little
effect on anaerobes
 In hepatic coma (supplemented by
lactulose)