Aminoglycosides

Aminoglycoside antibiotics such as streptomycin and gentamicin are commonly used throughout the world due to their low costs, high effectiveness, and low rate of true resistance. They are active against a wide range of gram-negative bacteria, as well as against Staphylococcus aureus , Pseudomonas aeruginosa and Mycobacterium tuberculosis. Aminoglycosides are used primarily for the treatment of life-threatening infections such as peritonitis, bacteremia, pneumonia, endocarditis as well as urinary tract infections, cystic fibrosis and tuberculosis. However, their use is severely hampered by the risk of serious side effects such as nephrotoxicity and ototoxicity, leading to kidney failure and hearing loss.

Aminoglycosides are biologically inert molecules, which are not metabolized by the organism. Most of the compound is secreted in the urine, but up to 10% of the antibiotic binds to megalin and accumulates to high concentrations in the cells lining the proximal tubules of the kidney (Figure 3). Accumulation of aminoglycosides in the lysosomes of these cells results in cell death and impairment of renal function. Similarly, accumulation of aminoglycosides takes place in the vestibular and cochlea sensory cells of the inner ear, leading to cell death and subsequent vestibular damage and hearing loss.

Nephrotoxicity currently occurs in around 5-15% of individuals treated with aminoglycosides, depending on the dosing regiment and type of drug used. The severity of the nephrotoxicity ranges from mild to acute renal failure, and it invariably results in loss of proteins, vitamins and salts from the body. It is a potentially life-threatening complication requiring urgent medical attention, and monitoring of kidney function is part of aminoglycoside treatment regiments. Although nephrotoxicity may be reversible following discontinuation of treatment it continues to have great impact on the clinical use of aminoglycosides.

Aminoglycosides accumulate in the kidney during the cause of the treatment, limiting the overall duration of treatment periods as well as the total amount of drugs that can be administered. Accumulation in the kidney also depends on the plasma concentration (=concentration in the ultra filtrate exposed to the proximal tubules cells). Uptake in the kidney increases with plasma concentration up to a point where the uptake pathway becomes saturated. The bactericidal activity of aminoglycosides is likewise concentration dependent but shows no saturation. As a consequence, improvement in clinical benefit as well as a reduction in the risk of nephrotoxicity has been achieved by changing the dosing regiment from two or three daily injections to one daily injection with the same amount of drug. The once daily injection achieves a higher peak plasma concentration with better bactericidal effect than the more moderate average plasma concentrations achieved with multiple daily administrations. At the same time, the higher peak concentration does not adversely affect the kidney due to saturation of the uptake pathway, while the lower average plasma concentration reduces the overall risk of nephrotoxicity due to slower renal accumulation. Due to inter-individual variations in renal clearance rates and the importance of preventing build up of high plasma concentrations, once-daily administrations still require monitoring of plasma concentrations during treatment, and dosing effectively becomes adjusted based on individual pharmacokinetic parameters.

Accumulation of aminoglycosides in vestibular and cochlear sensory cells of the inner ear also leads to cell death resulting in progressive hearing loss and vestibular dysfunction. In contrast to aminoglycoside mediated nephrotoxicity, effects on the cochlear and vestibular systems are largely irreversible. The effects are therefore cumulative with multiple rounds of treatment. The incidence of ototoxicity varies greatly dependent on the treatment regiment and the drugs used, ranging from 10-20% in the acute setting, to up to 80% in patients receiving chronic therapy for tuberculosis. Deafness affects around 0.5-8% of treated individuals. Vestibular toxicity affects around 3%.