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
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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
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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)
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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