AMINOGLYCOSIDES

I. Pharmacology

  1. Creates fissures in outer cell membrane of bacteria, followed by uptake of the antibiotic molecule into the bacterial cell (this occurs much less avidly in anaerobes, accounting for the inefficacy of aminoglycosides in anaerobic infections)
  2. Highly polar molecules, so don't penetrate intracellularly very well, except for renal tubular cells
  3. Poorly absorbed from GI tract
  4. After parenteral administration, don't penetrate well into CSF, vitreous fluid, prostate, or brain
  5. Excreted by glomerular filtration; most have t-1/2 of about 2h in pts with normal renal function
  6. Half-life in renal cortex is about 100h, hence the propensity to nephrotoxicity (usually reversible; tubular necrosis; u/a shows dark-brown, fine, or granulated casts)--risk of this is increased with:
    1. Preexisting renal disease
    2. Age
    3. Volume depletion
    4. Duration of therapy
    5. Concommitant use of:
      1. Radiographic contrast media
      2. Diuretics (cause decrease in effective circulating volume)
      3. ACE inhibitors
      4. NSAIDs
      5. Amphotericin
      6. Cisplatin
      7. Other nephrotoxic drugs
      8. Allopurinol (J. Gen. Int. Med. 13:735, 1998--JW)
  7. Also can cause ototoxicity (vestibular and auditory; usually irreversible) and, rarely, neuromuscular blockade and hypersensitivity reactions

II. Individual agents

  1. Streptomycin--the first
  2. Neomycin--too toxic for systemic use
  3. Gentamicin--most commonly used of all the aminoglycosides
  4. Amikacin and Tobramycin--only slight pharmacologic differences from Gentamicin
  5. Netilmicin

III. Clinical use

  1. Antimicrobial spectra
    1. Broad coverage of aerobic gram-negative rods
    2. Also cover most strains of staphylococcus
    3. Intermediate coverage of enterococcus
      1. All enterococci have low-level resistance to aminoglycosides b/c of their anerobic metabolism
      2. Some high-level resistance has been seen as of 1998
      3. Concommitant use of a beta-lactam drug can facilitate aminoglycoside penetration into bacterial cells
    4. Cover some mycobacteria
    5. Tobramycin has greater in vitro against Pseudomonas aeruginosa than other aminoglycosides; this is of unclear clinical significance
  1. Used to treat sepsis, skin, bone, soft tissue, urinary tract, peritoneal and other intra-abdominal, pelvic, and endocardial infections; also topically for ocular infections and otitis externa.
  1. Usually used in combination with other antibiotics, e.g. beta-lactams, to cover gram-positives and/or avoid development of resistant organisms
  1. Resistance issues
    1. Most resistance due to inactivation by intracellular bacterial enzymes
    2. "Adaptive resistance"--seen sometimes with pseudomonas aeruginosa--decreased intracellular uptake of antibiotic; may not be demonstrated on in vitro sensitivity testing
    3. Amikacin may be less associated with bacterial resistance than other aminoglycosides--for this reason, may be preferable in nosocomial infections with gram-negative rods
  1. Dosing timing--single as opposed to multiple daily doses may result in equal or better antimicrobial efficacy with less toxicity
    1. Single daily dosing not considered appropriate for pediatric pts or pts with cystic fibrosis, burns, enterococcal infections, or endocarditis
    2. The followin doses are for Q24h if CrCl > 60ml/min; Q36h if CrCl 40-59 ml/min; Q48h for CrCl 20-39ml/min; not recc'd for CrCl < 20ml/min (See also "Estimated Creatinine Clearance")
      1. Amikacin 15 mg/kd/dose over 60min
      2. Gentamicin 5-7 mg/kg/dose over 60min
      3. Netilmicin 5-7 mg/kg/dose over 60min
      4. Tobramycin 5-7 mg/kg/dose over 60min
    3. Check serum drug levels 12h after start of dose and adjust dosing interval according to results
      1. For amikacin, shoot for < 8ug/ml for Q24h dosing, 9-15 for Q36h, 16-26 for Q48h
      2. For gentamicin, netilmicin, and tobramycin, shoot for < 3ug/ml for Q24h dosing, 3-5 for Q36h, 5-7 for Q48h
    4. For obese pts, adjust dose using "dosing weight" calculated as ideal body weight + (total body weight - ideal body weight) x 0.4
  1. Dosing in endocarditis (assuming normal renal function)
    1. For Strep or Enterococcal, gentamicin 1mg/kg up to 80mg IV or IM Q8h (shoot for trough levels < 2) or Streptomycin 7.5mg/kg up to 500mg IM Q12h (shoot for trough levels < 5)
    2. For Staph, gentamicin 1mg/kg up to 80mg IV or IM Q8h (shoot for trough levels < 2)

(Source: AFP 58:1811, 1998)