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Aminoglycosides

Aminoglycosides. Mark Johnson, Pharm.D., BCPS Associate Professor and Director of Postgraduate Education. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mmed&part=A688. Aminoglycosides Origins.

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Aminoglycosides

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  1. Aminoglycosides Mark Johnson, Pharm.D., BCPS Associate Professor and Director of Postgraduate Education

  2. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mmed&part=A688http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mmed&part=A688

  3. AminoglycosidesOrigins • Streptomycin was isolated from Streptomyces griseus and neomycin was isolated from Streptomyces fradiae in the 1940’s • Gentamicin isolated from Micromonospora in 1963 • Others later developed amikacin, netilmicin tobramycin http://www.aafp.org/afp/981115ap/gonzalez.html

  4. Aminoglycosides • Mechanism of Action • Crosses outer bacterial membrane by passive diffusion via porin channels, then binds to 30s ribosomal subunit and thus inhibits protein synthesis • Prevent the formation of an initiation complex of peptide formation • Cause misreading of the messenger RNA message, leading to the production of nonsense peptides • Increase membrane leakage

  5. Aminoglycosides • Mechanism of resistance: • Transferase enzyme inactivates aminoglycoside (main mechansim) • Impaired entry of aminoglycoside into the cell (genotypic or phenotypic) • Receptor protein on 30S ribosomal subunit may be deleted or altered • Resistance depending on aminoglycoside • Amikacinshows less resistance—only 1 locus that may be inactivated by enzymes • Gentamicin and tobramycin—6 loci that may be inactivated by enzymes

  6. Aminoglycosides • Spectrum of activity: • Broad gram negative coverage including Pseudomonas, Enterobacter, Serratia, Proteus, Acinetobacter, Klebsiella, others • Almost always used in combination with another antibiotic such a beta-lactam to extend coverage, provide synergy, and because may not be effective alone outside of the urinary tract (due to tissue hypoxia, WBC debris , local acidosis, etc.)

  7. Aminoglycosides • Spectrum of activity: • Synergistic with beta lactams against gram positive cocci • Enterococcus faecalis endocarditis—bacteriocidal combo (ampicillin or penicillin + gentamicin or streptomycin) • Staphylococcus aureus endocarditis—quicker killing (naficillin + gentamicin) • Negligible anaerobic coverage

  8. Aminoglycosides • Spectrum of activity: • Concentration-Dependent Killing (Dose-Dependent Killing) • Increasing concentrations kill an increasing proportion of bacteria and a more rapid rate • Postantibiotic Effect • Antibacterial activity persists despite unmeasurable drug concentrations • May last for several hours, and varies with type of bacteria

  9. AminoglycosidesClinical Uses • Serious, life-threatening gram-negative infection • Complicated skin, bone or soft tissue infection • Complicated urinary tract infection • Sepsis • Peritonitis and other severe intra-abdominal infections • Severe pelvic inflammatory disease • Endocarditis • Mycobacterium infection • Neonatal sepsis • Ocular infections (topical) • Otitisexterna (topical) http://www.aafp.org/afp/981115ap/gonzalez.html

  10. AminoglycosidesAgents • Gentamicin (Garamycin) • Most widely used • Effective for both gram-positive (although resistance occurs) and gram-negatives • Almost always used in combination with another antibiotic (beta-lactam) • IV, IM • Topical • Ophthalmic

  11. AminoglycosidesAgents • Tobramycin (Nebcin) • Similar coverage overall to gentamicin, except better Pseudomonas coverage • More expensive than gentamicin • Also comes as a solution for inhalation for cystic fibrosis (TOBI 300mg in 5ml sodium chloride solution) • IV, IM • Ophthalmic

  12. AminoglycosidesAgents • Amikacin (Amikin) • Used for resistant bacteria • Dosed differently than gentamicin or tobramycin • IV, IM • Streptomycin • 2nd line for tuberculosis in combination with other agents • Used in combination with penicillin or ampicillin for Enterococcusfaecalisendocarditis or Viridans streptococcusendocarditis, although some resistance has emerged • IM

  13. Aminoglycosides • Other Agents: • Neomycin (Mycifradin) • Limited to topical and oral use (bowel prep for surgery 1gm PO every 6-8h for 1-2 days with erythromycin) • Resistance exists especially to Pseudomonas and Streptococci • Kanamycin (Kantrex) • Similar to neomycin • IV, irrigation • Paromomycin (Humatin) • For intestinal amebiasis, hepatic coma • Oral • Netilmicin (Netromycin) (not in US) • Similar to gentamicin and tobramycin, but may be more active against resistant strains • IV, IM

  14. Other • Spectinomycin (Trobicin)—Not in US • Aminocyclitrol antibiotic structurally related to aminoglycosides (lacks amino sugars and glycosidic bonds) • Active in vitro against gram positive and gram negatives • Used clinically as alternative treatment for drug-resistant gonorrhea or gonorrhea in penicillin-allergic patients • IM

  15. AminoglycosidesAdverse Effects • Nephrotoxicity • Reversible, non-oliguruic renal failure (acute tubular necrosis) • ?Relationship to elevated troughs • Risk factors • Elderly, Renal dysfunction, Dehydration, Hypotension, Liver disease, Concomitant use of other nephrotoxins, > 5 days of therapy (limit therapy to 2 weeks if possible) • Monitoring: renal casts, urine output, SCr • Once daily dosing—renal tubular cells have time between dosing intervals to decrease intracellular levels • Somewhat depends on aminoglycoside: • Most nephrotoxic: neomycin, tobramycin, gentamicin • But still treat all similarly with monitoring

  16. AminoglycosidesAdverse Effects • Ototoxicity • Both vestibular and cochlear • Vestibular: 2/3 of ototoxicity; manifests as vertigo, ataxia, loss of balance, tinnitus • Cochlear: 1/3 of ototoxicty; manifests as high frequency hearing loss, deafness is unusual • Often irreversible • Relationship to peak levels • Neomycin, kanamycin, amikacin are most ototoxic

  17. AminoglycosidesAdverse Effects—Other • Neuromuscular blockade at very high doses given too fast resulting in respiratory paralysis • Hypersensitivity (rare)

  18. AminoglycosidesLab Test Interactions • Some penicillins (extended spectrum penicillins) my accelerate degradation of aminoglycosides in vitro • Leads to decreased aminoglycoside concentrations • Separate timing of administration of antibiotics

  19. AminoglycosidesDosing and Monitoring • Dosing • Levels are based on disease state • Traditional dosing vs. once daily • Peak – 30 minutes after infusion • 4 – 10 mcg/mL for gentamicin and tobramycin • 15 – 30 mcg/mL for amikacin • Troughs – 30 minutes before infusion • <2 mcg/mL for gentamicin and tobramycin • <10 mcg/mL for amikacin • Once Daily dosing - Random levels 10- 12 hours post infusion • Trough <2 mcg/mL

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