- Aminoglycosides are bactericidal drugs that function by binding irreversibly to the 30S subunit of the ribosome and inhibit protein synthesis.
- Firstly, the drug enters the cell by diffusing across the membrane. Secondly, it is actively transported across the cell membrane into the cytoplasm by an oxygen dependent process. Transport is coupled to a proton pump. This means that low ECF pH (forces the bacterial proton pump to work against a concentration gradient) and anaerobic conditions (low oxygen levels) make aminoglycosides less effective.
- Aminoglycosides are very effective against aerobic Gram-ve bacteria, e.g. E.coli, Proteus, Klebsiella, Enterobacter, Serratia and other Gram-ve rods.
- Importantly, aminoglycosides demonstrate synergistic activity with other cell wall inhibiting drugs (penicillins, vancomycin). Using a β-lactam antibiotic together with gentamicin will extend its spectrum to include Gram +ve bacteria.
- Therefore, clinical indications are as follows:
- Gram-ve sepsis (may be helpful as a second agent due to synergism)
- It is not helpful in the following situations:
- Pneumonia/lung abscess (decreased oxygen tension in the infected lung, and the infected tissue has lower pH)
- Staph/strep infections as a single agent (due to inability to penetrate the cell wall)
- Resistance is usually plasmid mediated, and has the following mechanisms:
- Production of transferase enzyme that inactivates aminoglycosides
- Reduced entry of aminoglycoside into the cell
- Alteration of ribosomal binding site
- Aminoglycosides have interesting properties that may make single injection preferable to two or three divided doses. They are:
- Concentration dependent killing – increased concentration will kill increased proportion of bacteria at an increased rate.
- Significant post-antibiotic effect – antibacterial activity persists beyond the time by which measurable drug is present. This may last several hours.
- Also note that toxicity is both time and concentration dependent. Toxicity is unlikely to occur unless a certain threshold concentration has been reached. Hence, at therapeutic concentrations, the time above the threshold is less with single doses than with multiple ones.
- Other benefits include lower nursing cost and allowing outpatient treatment.
- IM or IV. There are very poorly absorbed PO, everything just ends up in the poo.
- They are very polar drugs and do not enter cells readily. Gentamicin is largely excluded from the CNS and eye.
- Rate of excretion is directly related to creatinine clearance and therefore gentamicin levels should be measured/renal function should be monitored.
- All aminoglycosides are ototoxic and nephrotoxic.
- The ototoxicity usually manifests as tinnitus and high frequency hearing loss initially, then vestibular damage (ataxia and vertigo)
- Note that ototoxicity of gentamicin is irreversible and mainly manifests as vestibular dysfunction.
- Nephrotoxicity is usually mild and reversible.
- Toxicity is potentiated by high drug concentration, longer duration of use, elderly and renal insufficiency.
- Avoid the use of gentamicin with loop diuretics (e.g. frusemide or ethacrynic acid, as they are ototoxic) and with other nephrotoxics (e.g. vancomycin and amphotericin)