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Antibiotic Groups - Aminoglycosides

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"عسى ان تكون علما ينتفع به"
Groups of antibiotics
Cell membrane permiability
Concentration dependant

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Antibiotic Groups - Aminoglycosides

  1. 1. Antibiotics Groups Aminoglycosides
  2. 2. Members 1. Amikacin 2. Streptomycin 3. Dihydrostreptomycin 4. Gentamycin 5. Apramycin 6. Kananmycin 7. Neomycin 8. Paromycin 9. Tobramycin 10. Spectinomycin
  3. 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. 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. 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. 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. 7. Spectrum  Bactericidal antibiotics.  Concentration-dependent killing action.  Mainly Gram negative aerobes.
  8. 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. 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. 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. 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. 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. 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. 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. 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. 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. 17. Dosage  Once-daily dosing is effective because aminoglycosides display concentration-dependent killing activity and a long post-antibiotic effect.
  18. 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. 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.