Clinical strategies: general renal impairment

Aminoglycosides are almost completely cleared through the kidneys via glomerular filtration and we can use measures of this, such as creatinine clearance (CrCl), to predict clearance and adjust dosing where necessary.

Last week, you saw how the Cockcroft—Gault equation is used to calculate CrCl and this is used to inform dosing. The next few steps will build on what you learnt about aminoglycoside PK and dosing in week 2 and provide further information on aminoglycoside use in patients with renal impairment.

What impacts renal function?

Renal function can be affected by:

• Increasing age – Glomerular filtration rate (GFR) gradually declines over adulthood
• High blood pressure – Damages nephrons over time
• Medicines – Some medicines can reduce blood flow (e.g. blood pressure medicines) or damage the kidney tissues (e.g. aminoglycosides)
• Dehydration – Reduces perfusion of the kidneys and the function declines
• Infection – Sepsis can reduce blood pressure and reduce kidney perfusion

PK changes associated with renal function

As renal function deteriorates, GFR declines, thus aminoglycoside clearance also reduces. For example, the half-life of gentamicin in healthy adults is usually 2 hours, but this can increase to 4 hours in mild renal impairment and up to 40 to 60 hours in renal failure. The increased length of time required to clear the dose of aminoglycoside, results in higher concentrations in the body for prolonged periods of time. This increases the risk of adverse effects and kidney toxicity due to aminoglycoside accumulation in the renal proximal tubular cells. Read more about aminoglycoside-induced nephrotoxicity in the paper linked at the bottom of this page.

Dosing strategies

Two strategies can be used to reduce the risk of harm from aminoglycosides in renal impairment:

1. Increased dosing interval: High-dose aminoglycosides are generally given every 24-hours. Increasing the dosing interval allows more time for each dose to clear and avoid accumulation. For example, maintaining a high dose of amikacin (15 mg/kg once daily) but increasing the dosing interval to 36-hourly if CrCl is 40-59 mL/min, or 48-hourly if CrCl is 20-30 mL/min.
2. Reducing the dose: This can avoid sustaining toxic concentrations of aminoglycosides over prolonged periods, but care must be taken if high peaks are needed for efficacy. For example, the daily dose of gentamicin can be reduced from 5-7 mg/kg once daily (healthy adults) to 3-5 mg/kg (CrCl 31-59 mL/min) and a maximum of 3 mg/kg once daily (CrCl 20-30 mL/min).

For those patients with a CrCl below 20 mL/min, the safest strategy is to give a single dose, then undertake therapeutic drug monitoring (TDM), and only give the next dose once the gentamicin has cleared sufficiently (e.g. for gentamicin the serum concentrations should be below 1 mg/L).

In the next step, we will look at the changes that are made to aminoglycoside dosing in patients who are receiving haemodialysis.