Review article
Pharmacodynamics and dosing of aminoglycosides

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Pharmacokinetic properties

Aminoglycosides are very poorly absorbed when administered orally, and must be given parenterally for the treatment of systemic infections. The agents demonstrate remarkably similar kinetics, with similar elimination half-lives of generally 2 to 3 hours in normal subjects, and similar volumes of distribution (Table 1). When given by intravenous injection they demonstrate three-compartment first-order elimination, although two- and one-compartment models fit the time-concentration profiles

Pharmacodynamics

Pharmacodynamics refers to the dynamics of drug action (ie, inhibition and killing). More precisely it is the relationship between the fluctuating concentrations seen with dosing and the killing of bacteria. It is often referred to as “pharmacokinetics-pharmacodynamics.” In this article it is referred to as “pharmacodynamics.” Readers are directed to some more detailed reviews for further elaboration of aminoglycoside PD concepts and findings [7], [8].

Nephrotoxicity

Aminoglycosides are obligate nephrotoxins, and renal impairment is eventually detected in all patients if treated for long enough [21]. The toxicity occurs because of the accumulation of aminoglycosides within the proximal tubular epithelial cell in lysosomal phospholipid complexes, which eventually rupture and initiate cell death [22]. As a consequence, the local renin-angiotensin system is activated, leading to local vasoconstriction and a decrease in the glomerular filtration rate, so-called

The move to once-daily (extended-interval) dosing

Once-daily dosing of aminoglycosides was initially introduced for the treatment of urinary tract infection [42], [43], [44], [45]. The high and prolonged urinary levels justified this move. It was less obvious initially that this approach might be useful for the treatment of systemic infection, and there was considerable concern that giving the total daily dose as a single dose once-daily increases toxicity because of the high peaks. Nevertheless, the cumulative in vitro and animal data noted

Dosing by age

Because renal function varies with age, recommendations for starting doses should vary with age if the AUC24:MIC ratio is the PD target. Although once-daily dosing is now used widely for standard therapeutic situations, there is no consensus on doses. Doses used in prospective once-daily comparative studies outside the urinary tract have ranged from 3 to 5 mg/kg daily for gentamicin, 4 mg/kg for tobramycin, 3.8 to 6.6 mg/kg for netilmicin, and 11 to 20 mg/kg for amikacin. Only one of these

Dosing in special situations

In certain clinical situations the kinetics of aminoglycosides may differ from those seen in children and adults, the doses may be different or there may be special toxicity issues. These clinical situations are discussed later, with an emphasis on selection of starting doses. It is recommended that doses thereafter be based on monitoring, using one of the methods described later.

Renal impairment

The introduction of third- and fourth-generation cephalosporins, carbapenems, and monobactams has significantly reduced reliance on aminoglycosides in patients with significant renal impairment. Nevertheless, there are circumstances in these types of patients when aminoglycosides are considered a necessary part of the treatment, and hence it is important to have a safe approach to their use. Choices of approach are influenced in part by the need or otherwise to preserve residual renal function.

Monitoring

Conventionally, aminoglycosides have been monitored during therapy to reduce the likelihood of toxicity. The collection of peak and trough levels with 8-hourly dosing became standard practice worldwide, and laboratory assays became universally available and inexpensive as a result. This method of monitoring has a number of problems. It focuses on somewhat arbitrary targets for peak and trough based on values seen in adults with normal renal function and there is no real accounting for the

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