protein synthesis inhibitors inhibitors

1. Antibacterial chemotherapy
Protein synthesis inhibitors

3. Aminoglycosides
• The aminoglycosides include streptomycin,
neomycin, kanamycin, amikacin, gentamicin,
tobramycin, sisomicin, netilmicin, and others.
They are used most widely against gram-
negative enteric bacteria, especially in
bacteremia and sepsis, in combination with
vancomycin or a penicillin for endocarditis,
and for treatment of tuberculosis.

4. Mechanism of action
• Aminoglycosides are irreversible inhibitors of
protein synthesis and are bactericidal drugs. The
initial event is passive diffusion via porin channels
across the outer membrane. Drug is then actively
transported across the cell membrane into the
cytoplasm by an oxygen-dependent process. Low
extracellular pH and anaerobic conditions inhibit
transport by reducing the gradient. Transport
may be enhanced by cell wall-active drugs such
as penicillin or vancomycin; this enhancement
may be the basis of the synergism of these
antibiotics with aminoglycosides.

5. • Inside the cell, aminoglycosides bind to specific 30S-
subunit ribosomal proteins (S12 in the case of
streptomycin). Protein synthesis is inhibited by
aminoglycosides in at least three ways
• (1) interference with the initiation complex of peptide
formation
• (2) misreading of mRNA, which causes incorporation of
incorrect amino acids into the peptide and results in a
nonfunctional or toxic protein
• (3) breakup of polysomes into nonfunctional
monosomes.

6. • Three principal mechanisms have been established:
• (1) production of a transferase enzyme or enzymes
inactivates the aminoglycoside by adenylylation,
acetylation, or phosphorylation. This is the principal
type of resistance encountered clinically.
• (2) There is impaired entry of aminoglycoside into the
cell. This may be genotypic, ie, resulting from mutation
or deletion of a porin protein or proteins involved in
transport and maintenance of the electrochemical
gradient; or phenotypic, eg, resulting from growth
conditions under which the oxygen-dependent
transport process described above is not functional.

7. • (3) The receptor protein on the 30S ribosomal
subunit may be deleted or altered as a result
of a mutation.

8. Antibacterial spectrum
• The aminoglycosides are effective against many aerobic
Gram-negative and some Gram-positive organisms.
They are most widely used against Gram-negative
enteric organisms and in sepsis. They may be given
together with a penicillin in streptococcocal infections
and those caused by Listeria spp. and P. aeruginosa.
Gentamicin is the aminoglycoside most commonly
used, although tobramycin is the preferred member of
this group for P. aeruginosa infections. Amikacin has
the widest antimicrobial spectrum and can be effective
in infections with organisms resistant to gentamicin
and tobramycin.

9. Pharmacokinetics
• The aminoglycosides are polycations and therefore
highly polar. They are not absorbed from the
gastrointestinal tract and are usually given
intramuscularly or intravenously. They cross the
placenta but do not cross the blood-brain barrier,
although high concentrations can be attained in joint
and pleural fluids. The plasma half-life is 2-3 h.
Elimination is virtually entirely by glomerular filtration
in the kidney, 50-60% of a dose being excreted
unchanged within 24 h. If renal function is impaired,
accumulation occurs rapidly, with a resultant increase
in those toxic effects (such as ototoxicity and
nephrotoxicity) that are dose related.

10. Therapeutic uses
• Urinary Tract Infections
• In the seriously ill patient with pyelonephritis,
an aminoglycoside alone or in combination
with a beta-lactam antibiotic offers broad and
effective initial coverage

11. • Pneumonia
• Aminoglycosides are ineffective for the treatment of
pneumonia due to anaerobes or S. pneumoniae, which
are common causes of community-acquired
pneumonia. They should not be considered as effective
single-drug therapy for any aerobic gram-positive cocci
(including S. aureus or streptococci), the
microorganisms commonly responsible for suppurative
pneumonia or lung abscess. An aminoglycoside in
combination with a beta-lactam antibiotic is
recommended as standard therapy for hospital-
acquired pneumonia in which a multiple-drug-resistant
gram-negative aerobe is a likely causative agent

12. • Amikacin is the preferred agent for the initial
treatment of serious nosocomial gram-
negative bacillary infections in hospitals where
resistance to gentamicin and tobramycin has
become a significant problem.

13. • Netilmicin is useful for the treatment of
serious infections owing to susceptible
Enterobacteriaceae and other aerobic gram-
negative bacilli. It is effective against certain
gentamicin-resistant pathogens, with the
exception of enterococci

14. • Meningitis
• If therapy with an aminoglycoside is
necessary, in adults, 5 mg of a preservative-
free formulation of gentamicin (or equivalent
dose of another aminoglycoside) is
administered directly intrathecally or
intraventricularly once daily

15. • Peritonitis Associated with Peritoneal Dialysis
• Patients who develop peritonitis as a result of
peritoneal dialysis may be treated with
aminoglycoside diluted into the dialysis fluid
to a concentration of 4-8 mg/L for gentamicin,
netilmicin, or tobramycin or 6-12 mg/L for
amikacin.

16. • Bacterial Endocarditis
• "Synergistic" or low-dose gentamicin (3 mg/kg
per day in three divided doses) in combination
with a penicillin or vancomycin has been
recommended in certain circumstances for
treatment of infections due to gram-positive
organisms, primarily bacterial endocarditis.

17. • Sepsis
• Inclusion of an aminoglycoside in an empirical
regimen is commonly recommended for the
febrile patient with granulocytopenia and for
sepsis when P. aeruginosa is a potential
pathogen.
• Topical Applications
• Gentamicin is absorbed slowly when it is applied
topically in an ointment and somewhat more
rapidly when it is applied as a cream.

18. • Neomycin has been used widely for topical
application in a variety of infections of the skin
and mucous membranes caused by
microorganisms susceptible to the drug. These
include infections associated with burns,
wounds, ulcers, and infected dermatoses.
However, such treatment does not eradicate
bacteria from the lesions.

19. • Tularemia
• Streptomycin (or gentamicin) is the drug of
choice for the treatment of tularemia.
• Plague
• Streptomycin is effective agent for the
treatment of all forms of plague. The
recommended dose is 2 g/day in two divided
doses for 10 days.

20. • Tuberculosis
• Streptomycin is a second-line agent for the
treatment of active tuberculosis, and
streptomycin always should be used in
combination with at least one or two other
drugs to which the causative strain is
susceptible.

21. Unwanted effects
• The ototoxicity involves progressive damage to, and
eventually destruction of, the sensory cells in the
cochlea and vestibular organ of the ear. The result,
usually irreversible, may manifest as vertigo, ataxia and
loss of balance in the case of vestibular damage, and
auditory disturbances or deafness in the case of
cochlear damage. Any aminoglycoside may produce
both types of effect, but streptomycin and gentamicin
are more likely to interfere with vestibular function,
whereas neomycin and amikacin mostly affect hearing.
Ototoxicity is potentiated by the concomitant use of
other ototoxic drugs

22. • The nephrotoxicity consists of damage to the kidney
tubules, and function recovers if the use of the drugs is
stopped. Nephrotoxicity is more likely to occur in
patients with pre-existing renal disease or in conditions
in which urine volume is reduced, and concomitant use
of other nephrotoxic agents (e.g. first-generation
cephalosporins) increases the risk. As the elimination
of these drugs is almost entirely renal, their
nephrotoxic action can impair their own excretion, and
a vicious cycle may develop. Plasma concentrations
should be monitored regularly and the dose adjusted
accordingly.

23. • A rare but serious toxic reaction is paralysis
caused by neuromuscular blockade. This is
usually seen only if the agents are given
concurrently with neuromuscular-blocking
agents. It results from inhibition of the Ca2+
uptake necessary for the exocytotic release of
acetylcholine.
• Hypersensitivity reactions, primarily skin rashes,
occur in 6-8% of patients when neomycin is
applied topically.