antibiotics (including amikacin, gentamicin, kanamycin, tobramycin,
and netilmicin) are used in the treatment of serious systemic
infections such as infective endocarditis and Gram negative
septicaemia. Streptomycin is used in the treatment of tuberculosis
Monitoring the serum concentrations of aminoglycoside antibiotics is an important part of treatment as their toxic: therapeutic ratio is very low. In addition, the pharmacokinetics of aminoglycosides vary considerably from person to person, making accurate prediction of initial dosage difficult. The sources of this variation are differences in renal function and tissue distribution.
The aminoglycosides are almost completely cleared unchanged from the body by renal excretion; clearance is therefore subject to variation when renal function varies. This is important for two reasons. Firstly, renal function is often impaired in patients with severe sepsis, in whom aminoglycosides are often indicated; furthermore, as the infection resolves improvement in renal function may further alter the pharmacokinetics of the antibiotic. Secondly, the aminoglycosides are themselves nephrotoxic and may therefore impair their own disposition. If this happens a vicious cycle of renal impairment with worsening toxicity may arise. Although the renal toxicity is usually reversible, accumulation of the aminoglycoside may lead to ototoxicity, which may be irreversible.
The distribution of the aminoglycosides to the tissues varies among patients because of a wide range of factors, including age, fever, body weight, anaemia, drug interactions, and overall severity of illness.
The variations in the clearance and apparent volume of distribution of gentamicin
result in variation in its initial half life from 0.4 h to 7.6 h in patients
with normal renal function.
In this chapter we apply to aminoglycosides the criteria which must be fulfilled in part or in full before the measurement of their plasma concentrations can be considered worth while.
Criteria for measurement
Is there difficulty in interpreting clinical evidence of the therapeutic or toxic effects?
Therapeutic responses to aminoglycosides may take several days to become clinically apparent. It is therefore important during the early phases of treatment to know that you are giving a dose which is likely to have an eventual therapeutic effect. To do this you need to measure the serum concentration, as there is a poor relation between dose and serum concentration but a good relation between serum concentration and the therapeutic effect. Furthermore, even when a therapeutic response starts to occur it can be difficult to know whether it is optimal. Again, measurement of the concentration will help.
As far as renal toxicity is concerned, it is impossible to distinguish clinically between renal impairment secondary to the illness and that secondary to a toxic effect of the aminoglycosides. However, diagnosing the cause of renal impairment is a secondary consideration, and measurement of the serum aminoglycoside concentration is used to prevent toxicity rather than to diagnose drug induced renal toxicity.
As we describe below, the problem of ototoxicity is more complicated.