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:
a core hexose ring (2-deoxystreptamine in the center) with 2 amino sugar molecules attached
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).
The site of action for aminoglycosides, which target the 30S ribosomal subunit
tRNA: transfer RNA
mRNA: messenger RNA
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:
| Drug class | Mechanism of action | Coverage | Adverse effects |
|---|---|---|---|
| Amphenicols |
|
|
|
| Lincosamides |
|
|
|
| Macrolides |
|
|
|
| Oxazolidinones |
| Gram-positive cocci:
|
|
VRE: vancomycin-resistant Enterococcus
Antibiotic sensitivity:
Chart comparing the microbial coverage of different antibiotics for gram-positive cocci, gram-negative bacilli, and anaerobes.
References
- 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/
- 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/
- 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/
- 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/
- Leis JA, Rutka JA, Gold WL. (2015). Aminoglycoside-induced ototoxicity. CMAJ; 187(1):E52. https://pubmed.ncbi.nlm.nih.gov/25225217/
- Selimoglu E. (2007). Aminoglycoside-induced ototoxicity. Curr Pharm Des; 13(1):119–26. https://pubmed.ncbi.nlm.nih.gov/17266591/
- 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/
- Drew, R.H. (2020). Aminoglycosides. Bloom, A. (Ed.), UpToDate. Retrieved July 2, 2021, from https://www.uptodate.com/contents/aminoglycosides
- Block, M., Blanchard, D.L. (2020). Aminoglycosides. StatPearls. Retrieved July 2, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK541105/
- 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
