Download PHL 424 6th SF

PHL 424
Antimicrobials
6th Lecture
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
Inhibitors of bacterial protein synthesis,
Aminoglycosides
 Aminoglycosides are a group of bactericidal
antibiotics originally obtained from various
streptomyces species and sharing chemical,
antimicrobial, pharmacologic and toxic
characteristics
 The group includes streptomycin, neomycin,
kanamycin, amikacin, gentamicin, tobramycin
and others
 Streptomycin is the oldest and best-studied
of the aminoglycosides
 Gentamicin, tobramycin and amikacin are the
most widely employed aminoglycosides at
present
 Neomycin and kanamycin are now largely limited to topical or oral use
 The severe nephrotoxicity associated with neomycin precludes parenteral administration,
and its current use is limited to topical application for skin infections or oral administration
to prepare the bowel prior to surgery
Inhibitors of bacterial protein synthesis,
Aminoglycosides, MOA
 Aminoglycosides diffuse through aqueous channels formed by porin proteins in the outer
membrane of G-ve bacteria to enter the periplasmic space. Their transport across the
cytoplasmic membrane is energy- and oxygen-dependent (membrane electrical potential is
required to drive permeation of these antibiotics)
 This transport is rate-limiting and can be inhibited by divalent cations (e.g., Ca2+ & Mg2+), a
reduction in pH and anaerobic conditions. The last two conditions impair the ability of the
bacteria to maintain the membrane potential, which is the driving force necessary for
transport. Thus the antimicrobial activity of aminoglycosides is reduced markedly in the
anaerobic environment of an abscess for example
Inhibitors of bacterial protein synthesis,
Aminoglycosides, MOA
 Once inside the cell, aminoglycoside binds to the 30S ribosomal subunit and interferes
with initiation of protein synthesis by fixing the 30S-50S ribosomal complex at the start
codon (AUG) of mRNA, leading to accumulation of abnormal initiation complexes, socalled streptomycin monosomes, blocking further translation of the message
Inhibitors of bacterial protein synthesis,
Aminoglycosides, MOA
 Aminoglycoside binding to the 30S subunit also causes misreading of mRNA, leading to:
 premature termination of translation with detachment of the ribosomal complex and incompletely
synthesized protein (B)
 incorporation of incorrect amino acids (indicated by the X), resulting in the production of
abnormal or nonfunctional proteins (C)
 The resulting aberrant proteins may be inserted into the cell membrane, leading to altered
permeability and further stimulation of aminoglycoside transport. This leads to leakage of small
ions, followed by larger molecules and, eventually, by proteins from the bacterial cell. This
progressive disruption of the cell envelope, as well as other vital cell processes, may help to
explain the lethal action of aminoglycosides
Inhibitors of bacterial protein synthesis,
Aminoglycosides, contd.
 Antimicrobial actions:
 These antibiotics are rapidly bactericidal
Bacterial killing is concentration-dependent:
 The higher the concentration, the greater is the rate at which bacteria are killed
A post-antibiotic effect (residual bactericidal activity persisting after the serum
concentration has fallen below the MIC) is characteristic of such antibiotics; the
duration of this effect also is concentration dependent
 These properties probably account for the efficacy of once-daily dosing regimens
 Their antibacterial activity is directed primarily against aerobic G-ve bacilli
 They have little activity against anaerobic microorganisms
 Their action against most G+ve bacteria is limited, and they should not be used
as single agents to treat infections caused by such bacteria
In combination with a cell wall-active agent, such as a penicillin or vancomycin,
an aminoglycoside produces a synergistic bactericidal effect in vitro against
enterococci, streptococci and staphylococci
The aminoglycosides synergize with β-lactam antibiotics because of the latter's
action on cell wall synthesis, which enhances diffusion of the aminoglycosides
into the bacterium
Inhibitors of bacterial protein synthesis,
Aminoglycosides, contd.
 Resistance mechanisms:
1. Inactivation of the drug by microbial enzymes such as phosphotransferases,
adenyltransferases and acetyltransferases
 Each of these enzymes has its own aminoglycoside specificity; therefore,
cross-resistance is not an invariable rule
 Amikacin is less vulnerable to these enzymes than are the other antibiotics of
this group
2. Failure of the antibiotic to penetrate intracellularly: Decrease in the active transport
of the drug
3. Altering the 30S ribosome binding site of the drug  Low affinity of the drug for the
bacterial ribosome
 Any organism resistant to one aminoglycoside is not resistant to all
Inhibitors of bacterial protein synthesis,
Aminoglycosides, contd.
 Pharmacokinetics
 The highly polar, polycationic structure of these drugs prevents adequate absorption
after oral administration. Therefore, all aminoglycosides (except neomycin) must be
given parenterally to achieve adequate serum levels
 All aminoglycosides are absorbed rapidly from intramuscular sites of injection
 Because of their polar nature, they do not penetrate into most cells, the CNS and the
eye
 The elimination of aminoglycosides depends almost entirely on the kidney
 The half-lives of aminoglycosides in plasma are similar (2-3 h in patients with normal
renal function)
 The half-life for tissue-bound aminoglycoside has been estimated to range from 30 to
700 h
Aminoglycosides, contd.
 Therapeutic Uses:
 Aminoglycosides exert bactericidal effect on dividing and
non-dividing microorganisms
 They are in general active against aerobic G-ve bacteria
including Pseudomonas aeruginosa
 Aminoglycosides are used in combination with a blactam for the therapy of serious G-ve microbial
infections (e.g., P. aeruginosa, Enterobacter, urinary
tract infections, bacteremia, infected burns, pneumonia)
 Streptomycin (or gentamicin) is the drug of choice for the
treatment of tularemia
 Streptomycin and gentamicin are effective agents for the
treatment of all forms of plague
 Treatment of tuberculosis, streptomycin always should
be used in combination with at least one or two other
drugs to which the causative strain is susceptible
 Neomycin and framycetin, whilst too toxic for systemic
use, are effective for topical treatment of the conjunctiva
or external ear
 Their oral use is restricted to their action against GIT
infections as amebiasis (mostly neomycin)
Inhibitors of bacterial protein synthesis,
Aminoglycosides, contd.
 Side effects:
 All aminoglycosides have the potential to produce reversible and irreversible
ototoxicity and renal toxicity
Toxicity correlates with the total amount of drug administered. Consequently, toxicity
is more likely to be encountered with longer courses of therapy (more than 5 days),
at higher doses, in the elderly and in the setting of renal insufficiency
The relative incidence of ototoxicity appears to be equal for all aminoglycosides
Ototoxicity can manifest itself either as auditory damage, resulting in tinnitus and
high-frequency hearing loss initially, or as vestibular damage, evident by vertigo,
ataxia, and loss of balance
Neomycin, which concentrates to the greatest degree in kidney, 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
Concurrent use with loop diuretics (eg, furosemide, ethacrynic acid) or other
nephrotoxic antimicrobial agents (vancomycin, amphotericin) can potentiate
nephrotoxicity and should be avoided
Inhibitors of bacterial protein synthesis,
Aminoglycosides, contd.
 Side effects:
 They produce a curare-like effect with neuromuscular blocking effect that
results in respiratory paralysis. The mechanism responsible is a decrease in
both the release of ACh from prejunctional nerve endings and the sensitivity of
the postsynaptic site


Patients with myasthenia gravis are particularly at risk

This paralysis is usually reversible by calcium gluconate or neostigmine
Hypersensitivity occurs infrequently
Because of their toxicity with prolonged administration, aminoglycosides should not be
used for more than a few days unless deemed essential for a successful or improved
outcome
Once the microorganism is isolated and its sensitivities to antibiotics are determined, the
aminoglycoside should be discontinued if the infecting microorganism is sensitive to less
toxic antibiotics