"عسى ان تكون علما ينتفع به" Groups of antibiotics Streptomycin Kanamycin Cell membrane permiability Ototoxic Nephrotoxic Concentration dependant

1. Antibiotics Groups
Aminoglycosides

2. Members
1. Amikacin
2. Streptomycin
3. Dihydrostreptomycin
4. Gentamycin
5. Apramycin
6. Kananmycin
7. Neomycin
8. Paromycin
9. Tobramycin
10. Spectinomycin

3. History
 Aminogylcoside were first discovered at 1944 after the
isolation of streptomycin from a strain of Streptomyces
griseus.
 Over the next 20 years, other aminoglycosides were isolated
from streptomycetes (neomycin and kanamycin) and from
Micromonospora purpurea (gentamicin).
 Semi-synthetic derivatives have subsequently been produced,
including amikacin from kanamycin.

4. Pharmacokinetics
Absorption
 Aminoglycosides are not well absorbed from the
gastrointestinal tract.
 They are well absorbed after intramuscular or subcutaneous
injection.
 Their volumes of distribution are small

5. Cont. …
Tissue distribution
 Effective concentrations are achieved in synovial, pleural,
peritoneal and pericardial fluids.
 Intrauterine and intra-mammary administration is also
effective, but significant tissue residues result.
 Aminoglycosides do not bind significantly to plasma proteins.
 They are large polar molecules, they are poorly lipid-soluble;
– They do not readily enter cells.
– They don’t penetrate cellular barriers, this means that therapeutic
concentrations are not easily achieved in cerebrospinal or ocular
fluids.

6. Cont. …
Half life t 1/2
 Their half-lives in plasma are relatively short (1–2 h).
Elimination
 Elimination is entirely via the kidney.

7. Spectrum
 Bactericidal antibiotics.
 Concentration-dependent killing action.
 Mainly Gram negative aerobes.

8. Mechanism of Action
Cell entry
 Aminoglycosides are actively pumped into Gram-negative
cells through an oxygen-dependent interaction between the
negatively charged surface of the outer cell membrane and
the aminoglycosides cations.
 This results in altered bacterial cell membrane permeability.

9. Cont. …
Inside the cell
 The aminoglycosides bind to the 30S ribosomal subunit and
cause misreading of the messenger RNA, resulting in
disruption of bacterial protein synthesis.
 This further affects cell membrane permeability, allowing
more aminoglycosides uptake leading to more cell disruption
and finally cell death.

10. Cont. …
Note
 Different aminoglycosides have slightly different effects.
– Streptomycin and dihydrostrptomycin act at a single site on the
ribosome, but other aminoglycosides act at several sites.
 The action of aminoglycosides is bactericidal and dose-
dependent, and there is a significant post-antibiotic effect.

11. Combination
 While theoretically one would expect interaction with β-
lactam antibiotics to enhance penetration of aminoglycosides
into bacterial cells as a result of the interference with cell wall
synthesis, human efficacy and toxicity studies now dispute
that there is any therapeutic justification for this type of
combination.
 However, it would appear that some of the formulation types
used in animals, such as a combination of an aminoglycoside
and the procaine salt of benzylpenicillin, do provide enhanced
antibacterial activity.

12. Resistance
 Bacterial resistance to aminoglycosides is mediated through
bacterial enzymes:
1. Phosphotransferases
2. Acetyltransferases
3. Adenyltransferases
 They inactivate aminoglycosides and prevent their binding to
the ribosome.
 Genes encoding these enzymes are frequently located on
plasmids, facilitating rapid transfer of resistance to other
bacteria.

13. Safety
 All aminoglycosides display ototoxicity and nephrotoxicity.
– Streptomycin is the most ototoxic but the least nephrotoxic.
– Neomycin is the most nephrotoxic.
 Nephrotoxicity is associated with accumulation of
aminoglycosides in the renal proximal tubule cells, where the
drugs accumulate within the lysosomes and are released into
the cytoplasm, causing damage to cellular organelles and cell
death.

14. Cont. …
 For this reason, aminoglycosides tend to be reserved for more
serious infections because of their toxicity.
 The more toxic members such as neomycin are restricted to
topical or oral use.
 The less toxic aminoglycosides such as gentamycin are used
parenterally for treatment of Gram-negative sepsis.

15. Indications
 Aminoglycosides are used for treatment but not for
prophylaxis.
– An exception is the use of neomycin as a dry-cow treatment at the end
of lactation in dairy cows.
 No aminoglycosides are used as antimicrobial growth
promotants.

16. Cont. …
 Oral preparations:
– Neomycin and streptomycin preparations are available for treatment
of bacterial enteritis in calves.
 Ophthalmic preparations :
– Framycetin are used in sheep and cattle
 Neomycin preparations (some in combination with β-lactams)
are used in the treatment of bovine mastitis.
 Systemic use of streptomycin, neomycin, and spectinomycin is
often restricted in food-producing animals because of
widespread resistance and because of extended persistence
of residues in kidney tissues.

17. Dosage
 Once-daily dosing is effective because aminoglycosides
display concentration-dependent killing activity and a long
post-antibiotic effect.

18. Cont. …
 Risk factors for aminoglycosides toxicity include:
1. Prolonged therapy (>7−10 days)
2. More than once daily treatment
3. Acidosis and electrolyte disturbances
4. Age (neonates, geriatrics)
5. Pre-existing renal disease
 As toxicity to aminoglycosides is related to the trough
concentration of drug, once-daily high dose treatment is used
to allow drug concentration during the trough period to fall
below the threshold that causes toxicity.

19. Precaution
 In the case of animals with impaired renal function, this may
not apply as aminoglycosides are generally contraindicated or
administered with extended dosing intervals.