Aminoglycosides
Bactericidal antimicrobials that prevent protein synthesis by irreversible binding to the 30S ribosomal subunit, preventing mRNA transcription.
- As they are large, polar molecules, they must be actively transported into the cell
- This occurs with an oxygen dependent transporter
Therefore they are not effective against anaerobes.
- This occurs with an oxygen dependent transporter
- Transport is inhibited by increased Ca2+, Mg2+, low pH, and low O2
- Aminoglycoside killing is dependent on the peak concentration over MIC
Typically peak concentration must be 8-10x MIC.- Exposure to aminoglycosides causes bacteria to down-regulate aminoglycoside uptake, and therefore increases MIC
This effect disappears after ~24 hours, and is one justification for daily dosing of aminoglycosides. Additional justifications include:- Allows larger single doses to be used, increasing bactericidal effect
- Aminoglycosides exhibit a post-antibiotic effect
Ongoing bactericidal activity even after concentration falls.
- Exposure to aminoglycosides causes bacteria to down-regulate aminoglycoside uptake, and therefore increases MIC
| Property | Gentamicin |
|---|---|
| Uses/Spectrum | Gram negative including pseudomonas, limited gram positive (staph, limited strep), synergistic effects with β-lactams and vancomycin. |
| Route of Administration | IV only. |
| Dosing | 4-7mg.kg-1. |
| Distribution | 70% protein bound. Very small VD of 0.2L.kg-1, which may result in significant pharmacokinetic changes with oedema. |
| Metabolism | Not metabolised. |
| Elimination | Eliminated unchanged, elimination t1/2 prolonged up to 70 hours in renal impairment. |
| CNS | Ototoxicity due to accumulation in perilymph, and is usually permanent. Increased risk with concomitant frusemide use. |
| MSK | Muscle weakness. |
| Renal | Nephrotoxicity due to accumulation in the renal cortex, typically reversible. |
| Toxic Effects | Narrow therapeutic index, requires monitoring and dose reduction in renal impairment. |
References
- Peck TE, Hill SA. Pharmacology for Anaesthesia and Intensive Care. 4th Ed. Cambridge University Press. 2014.
- Stubbings W, Bostock J, Ingham E, Chopra I Mechanisms of the post-antibiotic effects induced by rifampicin and gentamicin in Escherichia coli. J Antimicrob Chemother. 2006 Aug;58(2):444-8.
- Deranged Physiology - Kill Characteristics of Antibiotic Agents