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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 • 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 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 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 • Amikacin shows less resistance—only 1 locus that may be inactivated by enzymes • Gentamicin and tobramycin—6 loci that may be inactivated by enzymes 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.) 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 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 Aminoglycosides Clinical 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) Otitis externa (topical) http://www.aafp.org/afp/981115ap/gonzalez.html Aminoglycosides Agents • 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 Aminoglycosides Agents • 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 Aminoglycosides Agents • 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 Enterococcus faecalis endocarditis or Viridans streptococcus endocarditis, although some resistance has emerged – IM 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 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 Aminoglycosides Adverse 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 Aminoglycosides Adverse 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 Aminoglycosides Adverse Effects—Other • Neuromuscular blockade at very high doses given too fast resulting in respiratory paralysis • Hypersensitivity (rare) Aminoglycosides Lab 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 Aminoglycosides Dosing 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