Aminoglycosides (gentamicin, tobramycin, and amikacin) are bactericidal antibiotics that are active against aerobic Gram-negative and Gram-positive organisms. Clinically these agents are utilized for serious Gram-negative infections, as well as in combination with betalactams for Gram-positive synergy. This chapter discusses how to dose aminoglycosides for serious Gram-negative infections.

When designing dosing regimens, one must consider the pharmacodynamics of the agent in question. For aminoglycosides, this means understanding how these agents exert their bactericidal effects. Aminoglycosides display concentration-dependent killing (Table 149.1), which simply means that the higher the peak concentration increases above the minimum inhibitory concentration (MIC), the better the killing effectiveness. Time-dependent agents are the opposite. Their killing effectiveness is solely dependent on the amount of time the drug concentration remains above the MIC and not the degree to which they are over the MIC. To take advantage of this, time-dependent drug doses are administered multiple times during the day to keep the serum concentrations above the MIC as much as possible.

Multiple studies have shown a dose-response relationship with aminoglycosides, both clinically and experimentally. A series of papers were published in the mid 1980s that show initial “therapeutic” peaks were important predictors of successful treatment outcomes with aminoglycosides. The last paper in this series, published by Moore et al. (1987), discussed the importance of the peak:MIC ratio. Maximum peak:MIC ratio, defined as >10, was one of two statistically significant variables shown to be a predictor of a favorable outcome (the other was a favorable underlying prognosis). These studies were done with initial doses of gentamicin 2 mg/kg, and amikacin 8 mg/kg.

Subsequent studies have utilized higher doses of aminoglycosides for the therapy of these serious infections. A study of a dose 3 mg/kg, based on either an ideal or adjusted body weight, of gentamicin or tobramycin was evaluated in critically ill surgical patients. This
study showed that the increased dose resulted in a higher initial peak (8.1 μg/mL), but this was achieved in only 50% of patients. A dose of nearly 4 mg/kg was extrapolated from study data to achieve a peak 10 μg/mL and can be reliably used. Postinfusion levels can be obtained, and even experienced providers will consult an ICU PharmD for discussion of the next dose.