Aminoglycosides

Aminoglycosides are a class of antibiotics including gentamicin, tobramycin, amikacin, neomycin, plazomicin, and streptomycin. The class binds the 30S ribosomal subunit to inhibit bacterial protein synthesis. Unlike other medications with a similar mechanism of action, aminoglycosides are bactericidal. Aminoglycosides provide coverage against aerobic gram-negative pathogens, including Pseudomonas. Aminoglycosides can also be used synergistically with inhibitors of bacterial cell wall synthesis (e.g., β lactams) for gram-positive pathogens. Use is limited by serious side effects, including nephrotoxicity and ototoxicity.

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Chemistry and Pharmacodynamics

Chemical structure

  • Contains a hexose-ring nucleus
  • Glycosidic linkages to various amino sugars 
  • Gentamicin is the prototypical drug.
Chemical structure of gentamicin

Chemical structure of gentamicin:
a core hexose ring (2-deoxystreptamine in the center) with 2 amino sugar molecules attached

Image: “Gentamicin” by NEUROtiker. License: Public Domain

Mechanism of action

  • Aminoglycosides bind to the bacterial 30S ribosomal subunit.
  • Disruption of bacterial protein synthesis by:
    • Prevention of initiation complex formation
    • Misreading of mRNA → production of faulty protein → damage to the cell
    • Inhibition of translocation
  • The process is lethal for the bacterial cell → bactericidal (concentration-dependent killing)
  • The postantibiotic effect allows for continued suppression of bacterial growth.
  • Note: Aminoglycosides are transported across the cell membrane via an oxygen-dependent process (not effective against anaerobic bacteria).
Site of action for aminoglycosides

The site of action for aminoglycosides, which target the 30S ribosomal subunit
tRNA: transfer RNA
mRNA: messenger RNA

Image by Lecturio. License: CC BY-NC-SA 4.0

Pharmacokinetics

Absorption

  • Poor enteral absorption 
  • Usually given IV or IM

Distribution

  • Hydrophilic → volume of distribution ↑ with fluid overload (e.g., edema, ascites)
  • Crosses the placenta
  • Does not cross the blood-brain barrier
  • Poor penetration into:
    • Biliary tree
    • Respiratory secretions

Excretion

  • Clearance is correlated with renal function (↓ glomerular filtration → ↑ half-life).
  • Approximately 99% is unchanged in the urine.
  • Can be removed with hemodialysis

Indications

Antimicrobial coverage

  • Aerobic gram-negative bacteria, including:
    • Pseudomonas aeruginosa
    • Escherichia coli
    • Klebsiella pneumoniae
    • Haemophilus influenzae
    • Serratia marcescens
    • Francisella tularensis
    • Brucella
    • Yersinia
    • Campylobacter
  • Mycobacteria
  • Synergistic effect with β-lactam antibiotics against:
    • Staphylococcus
    • Streptococcus
    • Enterococcus

Types of infections

  • Usually used in combination therapy for:
    • Endocarditis
    • Nosocomial pneumonia
    • Osteomyelitis
    • Urinary tract infections (including pyelonephritis)
  • Used as monotherapy for:
    • Multidrug-resistant (MDR) urinary tract infections
    • Plague
    • Tularemia
  • Off-label:
    • Tobramycin: inhaled (for cystic fibrosis)
    • Amikacin and streptomycin: MDR Mycobacterium tuberculosis

Adverse Effects and Contraindications

Adverse effects

  • Nephrotoxicity → accumulation of aminoglycosides in the renal cortex
  • Ototoxicity (can be irreversible):
    • Amikacin: cochlear damage
    • Gentamicin, streptomycin, and tobramycin: vestibular damage
  • Neuromuscular blockade (rare)

Contraindications

  • Allergy to aminoglycosides
  • Pregnancy
  • Neuromuscular disorders (e.g., myasthenia gravis)

Drug interactions

  • Caution with nephrotoxic drugs: 
    • Amphotericin B
    • Vancomycin
    • NSAIDs
    • Radiocontrast dye  
  • Loop diuretics: ↑ risk of ototoxicity
  • ↑ Risk of neuromuscular blockade:
    • Vecuronium
    • Botulinum toxin
    • Mecamylamine

Monitoring

  • Serum drug levels (peak and trough levels)
  • Renal function 
  • Hearing function
  • Visual acuity

Mechanism of Resistance

Several mechanisms of aminoglycoside resistance:

  • Production of inactivating enzymes:
    • Acetyltransferases
    • Phosphotransferases
    • Nucleotidyltransferases
  • Alterations at ribosomal binding sites (methylation)
  • Efflux systems and ↓ cell permeability

Comparison of Antibiotics

The following table compares antibiotics, which inhibit bacterial protein synthesis:

Table: Comparison of several classes of bacterial protein synthesis inhibitor antibiotics
Drug classMechanism of actionCoverageAdverse effects
Amphenicols
  • Bind to the 50S subunit
  • Prevent transpeptidation
  • Gram positives
  • Gram negatives
  • Atypicals
  • GI upset
  • Optic neuritis
  • Aplastic anemia
  • Gray baby syndrome
Lincosamides
  • Bind to the 50S subunit
  • Prevent transpeptidation
  • Gram-positive cocci:
    • MSSA
    • MRSA
    • Streptococcus
  • Anaerobes
  • GI upset
  • Allergic reactions
  • Pseudomembranous colitis
Macrolides
  • Bind to the 50S subunit
  • Prevent transpeptidation
  • Gram positives
  • Gram negatives
  • Atypicals
  • Mycobacterium avium complex
  • GI upset
  • QT prolongation
  • Hepatotoxicity
  • Myasthenia gravis exacerbation
Oxazolidinones
  • Bind to the 23S rRNA of the 50S subunit
  • Prevent initiation complex formation
Gram-positive cocci:
  • MSSA
  • MRSA
  • VRE
  • Streptococcus
  • Myelosuppression
  • Neuropathy
  • Lactic acidosis
  • Serotonin syndrome
rRNA: ribosomal RNA
VRE: vancomycin-resistant Enterococcus
Antibiotic sensitivity chart

Antibiotic sensitivity:
Chart comparing the microbial coverage of different antibiotics for gram-positive cocci, gram-negative bacilli, and anaerobes.

Image by Lecturio. License: CC BY-NC-SA 4.0

References

  1. Avent ML, Rogers BA, Cheng AC, Paterson DL. (2011). Current use of aminoglycosides: indications, pharmacokinetics, and monitoring for toxicity. Intern Med J. 41(6):441–9. https://pubmed.ncbi.nlm.nih.gov/21309997/
  2. Pagkalis S, Mantadakis E, Mavros MN, Ammari C, Falagas ME. (2011). Pharmacological considerations for the proper clinical use of aminoglycosides. Drugs; 71(17):2277–94. https://pubmed.ncbi.nlm.nih.gov/22085385/
  3. Krause KM, Serio AW, Kane TR, Connolly LE. (2016). Aminoglycosides: An Overview. Cold Spring Harb Perspect Med; 6(6) https://pubmed.ncbi.nlm.nih.gov/27252397/
  4. LeBras M, Chow I, Mabasa VH, Ensom MH. (2016). Systematic Review of Efficacy, Pharmacokinetics, and Administration of Intraventricular Aminoglycosides in Adults. Neurocrit Care; 25(3):492–507. https://pubmed.ncbi.nlm.nih.gov/27043949/
  5. Leis JA, Rutka JA, Gold WL. (2015). Aminoglycoside-induced ototoxicity. CMAJ; 187(1):E52. https://pubmed.ncbi.nlm.nih.gov/25225217/
  6. Selimoglu E. (2007). Aminoglycoside-induced ototoxicity. Curr Pharm Des; 13(1):119–26. https://pubmed.ncbi.nlm.nih.gov/17266591/
  7. Lopez-Novoa JM, Quiros Y, Vicente L, Morales AI, Lopez-Hernandez FJ. (2011). New insights into the mechanism of aminoglycoside nephrotoxicity: an integrative point of view. Kidney Int; 79(1):33–45. https://pubmed.ncbi.nlm.nih.gov/20861826/
  8. Drew, R.H. (2020). Aminoglycosides. Bloom, A. (Ed.), UpToDate. Retrieved July 2, 2021, from https://www.uptodate.com/contents/aminoglycosides
  9. Block, M., Blanchard, D.L. (2020). Aminoglycosides. StatPearls. Retrieved July 2, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK541105/
  10. Werth, B.J. (2020). Aminoglycosides. MSD Manual Professional Version. Retrieved July 2, 2021, from  https://www.msdmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-drugs/aminoglycosides

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