45 aminoglycosides

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45 aminoglycosides

  1. 1. AMINOGLYCOSIDES Anita Q. Sangalang, MD, FPOGS FACULTY OF PHARMACY UNIVERSITY OF SANTO TOMAS
  2. 2. AMINOGLYCOSIDES MODES OF ANTIBACTERIAL ACTION  Treatment of microbial infection with antibiotics • Multiple daily dosing • Maintain serum concentration level above the minimum inhibitory concentration (MIC)
  3. 3. AMINOGLYCOSIDESMODES OF ANTIBACTERIAL ACTIONCONCENTRATION DEPENDENT Some drugs and aminoglycosides • As the plasma level is increased above the MIC, the drug kills an increasing proportion of bacteria at a more rapid rate
  4. 4. AMINOGLYCOSIDESMODES OF ANTIBACTERIAL ACTIONTIME DEPENDENT Any antibiotics, including penicillin and cephalosporins • Directly related to time above MIC • Independent of concentration once the MIC is reached
  5. 5. AMINOGLYCOSIDESMODES OF ANTIBACTERIAL ACTIONPOSTANTIBIOTIC EFFECT Aminoglycosides’ killing action continues when the plasma levels have declined below measurable levels
  6. 6. AMINOGLYCOSIDESMODES OF ANTIBACTERIAL ACTIONPOSTANTIBIOTIC EFFECT Greater efficacy when administered as a single large dose than when given as multiple smaller doses
  7. 7. AMINOGLYCOSIDESMODES OF ANTIBACTERIAL ACTION Toxicity (in contrast to antibacterial activity) depends on a critical plasma concentration and on that time such a level is exceeded Time above such threshold is shorter with single large dose Basis for once-daily dosing protocols
  8. 8. AMINOGLYCOSIDES PHARMACOKINETICS  Structurally related amino sugars attached by glycosidic linkages  Polar compounds  Not absorbed orally
  9. 9. AMINOGLYCOSIDES PHARMACOKINETICS  Given intramuscularly or intravenously for systemic effects  Limited tissue penetration  Do not readily cross the blood-brain barrier
  10. 10. AMINOGLYCOSIDES PHARMACOKINETICS  Major mode of excretion • Glomerular filtration  Plasma levels are affected by changes in renal function
  11. 11. AMINOGLYCOSIDESPHARMACOKINETICS Excretion is directly proportional to creatinine clearance With normal renal function, elimination half-life is 2-3 h
  12. 12. AMINOGLYCOSIDESPHARMACOKINETICS Dosage adjustment must be made in renal insufficiency to avoid toxic accumulation Monitoring plasma levels is needed for safe and effective dosage selection and adjustment
  13. 13. AMINOGLYCOSIDESPHARMACOKINETICS For traditional dosing regimens • 2 or 3 times daily • Peak serum levels • Measured at 30-60 minutes after administration • Trough serum levels • Measured just before the next dose
  14. 14. AMINOGLYCOSIDESMECHANISM OF ACTION Bactericidal (irreversible) inhibitors of protein synthesis Penetration of bacterial cell wall is partly dependent on O2-dependent active transport
  15. 15. AMINOGLYCOSIDES MECHANISM OF ACTION  Minimal activity against strict anaerobes  Transport is enhanced by cell wall synthesis inhibitors • Antimicrobial synergism
  16. 16. AMINOGLYCOSIDESMECHANISM OF ACTION Bind to 30S ribosomal unit Interfere with protein synthesis 1. Block formation of initiation complex 2. Cause misreading of the code on the mRNA template 3. Inhibit translocation
  17. 17. AMINOGLYCOSIDES MECHANISMS OF RESISTANCE  Resistant due to failure to penetrate into the cell • Streptococci, including S. pneumoniae • Enterococci
  18. 18. AMINOGLYCOSIDESMECHANISMS OF RESISTANCE Plasmid-mediated formation of inactivating enzymes • Primary mechanism of resistance • Varying susceptibility to the enzyme
  19. 19. AMINOGLYCOSIDESMECHANISMS OF RESISTANCE Plasmid-mediated formation of inactivating enzymes • Group transferases • Catalyze the acetylation of amine functions • Transfer of phosphoryl or adenyl groups to the O2 atoms of hydroxyl groups on the aminoglycoside
  20. 20. AMINOGLYCOSIDESMECHANISMS OF RESISTANCE Plasmid-mediated formation of inactivating enzymes • Transferases produced by enterococci can inactivate • Amikacin • Gentamicin • Tobramycin • Not streptomycin
  21. 21. AMINOGLYCOSIDESMECHANISMS OF RESISTANCE Plasmid-mediated formation of inactivating enzymes • Netilmicin is less susceptible and is active against more strains of organisms
  22. 22. AMINOGLYCOSIDESCLINICAL USESGENTAMICIN, TOBRAMYCIN, and AMIKACIN Serious infections caused by aerobic gram (-) bacteria • E. coli Enterobacter • Klebsiella Proteus • Providencia Pseudomonas • Serratia
  23. 23. AMINOGLYCOSIDESCLINICAL USESGENTAMICIN, TOBRAMYCIN, and AMIKACIN Used for the following but is not the drug of choice • H. influenzae • M. catarrhalis • Shigella species
  24. 24. AMINOGLYCOSIDES CLINICAL USES ANTIBACTERIAL SYNERGY  Not effective for gram (+) cocci when used alone  Combination of aminoglycoside and cell wall synthesis inhibitors
  25. 25. AMINOGLYCOSIDESCLINICAL USESANTIBACTERIAL SYNERGY Combined with penicillin in the treatment • Pseudomonal • Listerial • Enterococcal infections
  26. 26. AMINOGLYCOSIDESCLINICAL USESSTREPTOMYCIN Tuberculosis Plague Tularemia Multi-drug-resistant (MDR) strains of M. tb resistant to streptomycin maybe susceptible to amikacin
  27. 27. AMINOGLYCOSIDES CLINICAL USES NEOMYCIN  Used topically  Locally • In the GIT • Eliminate bacterial flora
  28. 28. AMINOGLYCOSIDES CLINICAL USES NETILMICIN  Reserved for serious infections resistant to other aminoglycosides
  29. 29. AMINOGLYCOSIDESCLINICAL USESSPECTINOMYCIN Aminocylitol related to aminoglycosides Back-up drug Intramuscular as single dose for gonorrhea
  30. 30. AMINOGLYCOSIDES TOXICITY B. OTOTOXICITY  Auditory or vestibular damage (or both) maybe irreversible • Auditory impairment • Amikacin and kanamycin • Vestibular dysfunction • Gentamicin and tobramycin
  31. 31. AMINOGLYCOSIDESTOXICITYB. OTOTOXICITY Risk is proportionate to the plasma levels • High if dosage is not modified in renal dysfunction Increased with the use of loop diuretics Contraindicated in pregnancy
  32. 32. AMINOGLYCOSIDES TOXICITY B. NEPHROTOXICITY  Acute tubular necrosis  Reversible  Most nephrotoxic • Gentamicin and tobramycin
  33. 33. AMINOGLYCOSIDES TOXICITY B. NEPHROTOXICITY  More common in elderly patients  Patients concurrently receiving • Amphotericin B • Cephalosporins • Vancomycin
  34. 34. AMINOGLYCOSIDESTOXICITYB. NEUROMUSCULAR BLOCKADE Rare Curare-like block may occur at high doses • Respiratory paralysis Reversible
  35. 35. AMINOGLYCOSIDES TOXICITY B. NEUROMUSCULAR BLOCKADE  Treatment • Calcium • Neostigmine • Ventilatory support
  36. 36. AMINOGLYCOSIDES TOXICITY B. SKIN REACTIONS  Neomycin • Allergic skin reactions like contact dermatitis

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