3. Introduction
• First isolated from soil organisms in 1944
• Susceptible aerobic Gram Negative Bacteria
• Narrow margin of safety
• Within the therapeutic dose range
– Produces characteristic lesions in kidney, cochlea,
and vestibular apparatus
4. Antibacterial Activity
• Aerobic G-ve bacteria ( Citrobacter, Enterobacter, E. coli,
proteus, Pseudomonas, Enterococci and Staph aureus *)
• Lack activity against most anaerobic or facultative bacteria
and activity against G+ve# organisms is limited
• # Strept pyogenes is highly resistant
• Anti-tubercular Drugs– Streptomycin and Amikacin
6. Aminoglycosides Transport
• Transport across the cell membrane is by active transport via-
polyamine carrier system.
• Chloramphenicol is known to block this transport system.
• Antimicrobial activity is reduced in an:
• anaerobic environment and
• at low pH
7. Structure and chemical characteristics
• Classification
– Micromonospora actinomyctes
• Gentamicin (gentamicin and netilmicin)
– Streptomyces spp.
• Streptomycin (streptomycin and dihydrostreptomycin)
• Kanamycin (kanamycin, amikacin, and tobramycin)
• Neomycin (neomycin) groups
8. Pharmacokinetics
• Water soluble weak bases
• Polycations ( highly charged )
• Poorly absorbed from GIT ( parenteral or topical )
• No distribution to most cells , including CNS
• Only 10 % bind of the drug bind to plasma protein
• No significant metabolic breakdown
• Excreted unchanged in urine ( glomerular filtration)
9. Synergy & Caution with Beta Lactams
Synergy
The β-lactams inhibit cell wall synthesis and thereby increase the
permeability of the aminoglycosides.
Caution !
It should be remembered that penicillin and aminoglycoside
antibiotics must never be physically mixed, because both are
chemically inactivated to a significant degree on mixing.
10. Mechanism of action
• -cidal, inhibiting protein synthesis
– 30S ribosomal subunit
• Most effective on growing organisms
11. Mechanism of action
• cidal, inhibiting protein synthesis
– Irreversibly binds to 30S ribosomal subunit
• Causes distortion and malfunction of ribosome
• Blocks initiation translation
– Causes misreading of mRNA
– Not effective against anaerobes, enterococci and
streptococci
12. Antibacterial Spectrum
• Most bacterial species are sensitive
– aminoglycoside concentration varies widely among species.
• Intracellular concentration is dependent upon a
transport system located in the cell membrane
– Oxygen-dependent system ordinarily transports
polyamines and is absent in anaerobes
• Therefore, only clinically useful against organisms
growing in aerobic conditions.
13. Antibacterial Spectrum
• Antibacterial spectrum:
– Gram negatives:
• Pseudomonas,
• Proteus,
• Serratia,
• E. coli,
• Klebsiella
– Neomycin
• S. aureus and Proteus
• Pseudomonas and Strep are resistant
15. Resistance
• Decreased uptake, decreased binding affinity,
enzymes (plasmids).
– Streptomycin is now largely useless
• Secondary agent for tuberculosis
• Combination with tetracycline for treating brucellosis
and plague
– Kanamycin & gentamicin – face the same fate
– Amikacin
16. Pharmacokinetics
• Polycationic nature
– Very water soluble and poorly lipid soluble
• Poor oral absorption
– Oral administration only for intestinal infection
– Otherwise parenteral administration
• All are given as water soluble sulfate salts
– Infusion
– IM injected dose is rapidly absorbed
• Strong tissue binding residual amounts can be found at the injection site
for long periods of time
17. Distribution
• Minimally protein bound ( 10% )
– Do not penetrate into the CNS or eye
– May cross the placenta
• Therapeutic concentrations are produced only in ECF.
• Relatively high concentrations of the drugs have
been found in kidney, the cochlea, and vestibular
apparatus.
– Elimination half life from these tissues is much longer than
that from plasma
18. Elimination
• > 90% of injected drug is eliminated from the
kidney via glomerular filtration
– Renal dysfunction - dosage adjustment
• Lowering the dose
• Increasing the interval
• Both
– Therapeutic drug monitoring
19. Streptomycin
• Tularemia, brucellosis, plague
• Gram-negative bacillary infections of the
urinary tract
• Streptomycin was formerly the mainstay of
antituberculous therapy but is now rarely used
in the developed world.
20.
21. Gentamicin
• Gentamicin is the most commonly used,
covering Gram-negative aerobes, e.g. Enteric
organisms (E.coli, Klebsiella, S. faecalis,
Pseudomonas and Proteus spp.)
• It is also used in antibiotic combination
against Staphylococcus aureus.
• It is not active against aerobic Streptococci.
22. Gentamicin
• In addition to treating known sensitive
organisms, it is used often blindly with other
antibiotics in severe infections of unknown
cause.
23. Other Aminoglycosides
• Amikacin, netilmicin and tobramycin are used
the same manner as gentamicin
• Tobramycin is more active against
Pseudomonas and for some gentamicin-
resistant organisms.
• Tobramycin and netilmicin are less ototoxic
and less nephrotoxic
• Neomycin is used orally for decontamination
of GI tract.
24. Adverse Effects
• Their undesirable side effects: severe ototoxicity and
nephrotoxicity and neuromuscular paralysis
25. Adverse effects
• Dose related!!!!
• Concentration x Time dependence
– Proximal tubular cell damage
– Destruction of sensory cells in cochlea
– Destruction of sensory cells in vestibular
apparatus
– Neuromuscular paralysis
27. Nephrotoxicity
• 5 % ~ 10 %, Dose-related, prolonged therapy(>10 days)
- AMA, 1986; Gambertoglio et al, 1983
• Pathophysiology
– More polycationic like gentamicin and neomycin, enter
proximal tubular cells by pinocytosis.
• Inhibit lysosomal enzymes, the vesicles accumulate and take on a
whorl-like appearance( cytosegresomes )
• Excessive numbers of these apparently kill the cells, producing
severe toxicity.
28. • Proximal tubular necrosis, may not see clinically
– Acute nonoliguric renal failure
– Proximal tubular damage causes the whole nephron to fail
➔ increased serum aminoglycoside concentrations.
– Proximal renal tubular cells regenerate
AMA, 1986; Gambertoglio et al, 1983
• Nephrotoxicity is not limited to proximal tubular toxicity but
also may involve the medullar region (Henle loop and
collecting duct) of the nephron.
Critical Care Medicine. 30(6):1242-5, 2002 Jun
29. Risk Factor
• Advanced age
• Sepsis, Shock
• Prolonged aminoglycoside usage
• Underlying renal insufficiency
• Coadministration of other nephrotoxic agents
• Dehydration
• Decreased albumin or poor nutritional status
• Pneumonia
• Hypercalcemia
• Leukemia
• Rapidly fatal illness
• Liver or kidney disease
• Pleural effusion, ascites
• Reduced aminoglycoside clearance
• Elevated initial steady-state concentration
- Schneider et al, 1996; Bertino et al, 1993
31. • Based on dose-response data
• Gentamicin > Tobramycin & amikacin > Netilmicin
• - Anon, 1978; Schentag, 1979; Zaske, 1986
• Number of free amino groups & relative
nephrotoxicity
• - Bennett (1983)
32. Initial Presentation
• Proteinuria and cylindruria (casts in urine), Cre
elevation
– After 5 ~ 7 days of therapy
– Pre-existing renal pathology is a serious predisposing
factor
33. How to Treat ??
• Supportive !!
• Discontinuation !!
• Dialysis !?
34. How to Minimize Nephrotoxicity
• Peak and trough levels
• Renal function tests
• Serum creatinine levels
• Abnormal urinary sediment
• Leukocyturia
• Elevated levels of beta-2 microglobulins excreted in
the urine
Knoben & Anderson, 1988; AMA, 1986
Gambertoglio et al, 1983
• Once-daily Dose ???
37. Ototoxicity: cochlear and vestibular
apparatus
• Progressively damage the sensory cells of the
cochlea and vestibular apparatus
– Killed sensory cells do not regenerate
• Loss of hearing, vertigo, ataxia, and loss of balance
• Concentration & Duration
– High concentration within a short duration
– Long durations of therapy at lower concentrations
39. Cochlear Damage
• Varying degrees of hearing loss
– High frequency tones
• Tinnitus
• Sense of fullness or aching in the ears
Minor, 1998; Matzke & Kovarik, 1988; Lietman, 1985
42. Risk factors for ototoxicity
• Impaired renal function
• Intrinsic ototoxic potential of the drug
• Combination with other ototoxic drugs
• Total dose and duration of therapy
• Prior exposure to aminoglycosides
• Prolonged exposure of inner-ear tissues to the
aminoglycoside
Minor, 1998; Bendush, 1982
43. How to avoid ototoxicity ??
• Renal, auditory, and vestibular function
– Assessed before, during, and following therapy
• Aminoglycoside serum concentrations
Franke et al, 1983
• Avoiding prolonged therapy and ototoxic agents
• Maintain hydration, urine output, and normal serum
electrolytes
Lesar, 1989
• Recommend : stop the aminoglycoside at the first
sign of vestibulotoxicity
46. Neuromuscular paralysis
• Inhibit Ca++ into nerve on depolarization
– required for exocytotic ACh release
– Ca++ injections can improve release
• Weakness at doses on top end of range if any
renal problem
• Respiratory paralysis if use for lavage of
peritoneal or pleural cavity!
49. PreventAll These Side Effects ??
• Not Using Aminoglycoside !!
– There are antibiotics with equal or better
sensitivity profiles than aminoglycosides against
GNRs and Pseudomonas.
» The Am J Surg Vol.180(6) Dec. 2000 pp 512-516
• Once Daily Dose !!
– Nephrotoxicity
• Monitoring !!
