Aminoglycosides

Key examples

• Gentamicin
• Amikacin

 

Common indications

• Severe infections, particularly those caused by Gram-negative aerobes (including Pseudomonas aeruginosa):
• Severe sepsis, including where the source is unidentified.
• Pyelonephritis and complicated urinary tract infection.
• Biliary and other intra-abdominal sepsis.
• Endocarditis.
• Aminoglycosides lack activity against streptococci and anaerobes (see Mechanisms of action), so should be combined with penicillin and/or metronidazole when the organism is unknown.

 

Mechanisms of action

• Aminoglycosides bind irreversibly to bacterial ribosomes (30S subunit) and inhibit protein synthesis. They are bactericidal (i.e. they kill bacteria), although this effect is likely to be due to additional mechanisms that are incompletely understood. Their spectrum of action includes Gram-negative aerobic bacteria, staphylococci and mycobacteria (for example, streptomycin was one of the first effective treatments for tuberculosis).
• Aminoglycosides enter bacterial cells via an oxygen-dependent transport system. Streptococci and anaerobic bacteria do not have this transport system, so have innate aminoglycoside resistance. Other bacteria acquire resistance through reduced cell membrane permeability to aminoglycosides or acquisition of enzymes that modify aminoglycosides to prevent them from reaching the ribosomes. As penicillins weaken bacterial cell walls, they may enhance aminoglycoside activity by increasing bacterial uptake.

 

Important adverse effects

• The most important adverse effects are nephrotoxicity and ototoxicity. 
• Aminoglycosides accumulate in renal tubular epithelial cells and cochlear and vestibular hair cells where they trigger apoptosis and cell death. 
• Nephrotoxicity presents as reduced urine output and rising serum creatinine and urea and is potentially reversible. 
• Ototoxicity is often not noticed until after resolution of the acute infection, when the patient may complain of hearing loss, tinnitus (cochlear damage) and/or vertigo (vestibular damage). Ototoxicity may be irreversible.

 

Warnings

• Aminoglycosides are renally excreted. 
• Monitoring of plasma drug concentrations with careful dose adjustment is essential to prevent renal, cochlear and vestibular damage, particularly in neonates and the elderly who are most susceptible and in patients with renal impairment. 
• Aminoglycosides can impair neuromuscular transmission so should not be given to people with myasthenia gravis unless absolutely necessary.

 

Important interactions

• Ototoxicity is more likely if aminoglycosides are co-prescribed with loop diuretics (e.g. furosemide) or vancomycin.
• Nephrotoxicity is more likely if aminoglycosides are co-prescribed with ciclosporin, platinum chemotherapy, cephalosporins or vancomycin. 

Monitoring 

• For efficacy, monitor symptoms and signs (e.g. pyrexia) and blood inflammatory markers (e.g. C-reactive protein) to ensure resolution of infection. 
• For safety, renal function should be measured before (to guide dosing) and during (to detect toxicity) parenteral aminoglycoside therapy. 
• The plasma drug concentration is usually measured 18–24 hours after the first dose (trough level). The next dose should only be administered if these have fallen to a safe level with a low risk of toxicity (e.g. gentamicin <1 mg/mL). 
• If the plasma concentration is too high, the next dose should be withheld until repeat levels indicate that it is safe to give.