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

3. 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

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
Agents: Gentamicin, Tobramycin, Amikacin, Streptomycin
MOA: binds to 30s ribosomal subunit; inhibits protein synthesis, bactericidal
Dose dependent killing
Post antibiotic effect

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
Amikacin shows less resistance—only 1 locus that may be inactivated by enzymes
Gentamicin and tobramycin—6 loci that may be inactivated by enzymes
Agents: Gentamicin, Tobramycin, Amikacin, Streptomycin
MOA: binds to 30s ribosomal subunit; inhibits protein synthesis, bactericidal
Dose dependent killing
Post antibiotic effect

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. 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)

10. 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
Agents: Gentamicin, Tobramycin, Amikacin, Streptomycin
MOA: binds to 30s ribosomal subunit; inhibits protein synthesis, bactericidal
Dose dependent killing
Post antibiotic effect

11. 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
Agents: Gentamicin, Tobramycin, Amikacin, Streptomycin
MOA: binds to 30s ribosomal subunit; inhibits protein synthesis, bactericidal
Dose dependent killing
Post antibiotic effect

12. 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
Agents: Gentamicin, Tobramycin, Amikacin, Streptomycin
MOA: binds to 30s ribosomal subunit; inhibits protein synthesis, bactericidal
Dose dependent killing
Post antibiotic effect

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
Agents: Gentamicin, Tobramycin, Amikacin, Streptomycin
MOA: binds to 30s ribosomal subunit; inhibits protein synthesis, bactericidal
Dose dependent killing
Post antibiotic effect

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. 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

16. 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

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

18. 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

19. Aminoglycosides Dosing and Monitoring
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 hours post infusion
Trough <2 mcg/mL
AE- nephrotoxicity (esp in elderly, renal dysfunction, dehydration, hypotension, liver dz, use of vanc, cephalosporins, clindamycin, piperacillin, foscarnet, furosemide), ototoxicity (high frequency), neuromuscular paralysis
Once daily may be less toxic