Assuming a three- to fourfold factor for converting doses of amikacin to gentamicin and tobramycin, it has been suggested that higher doses should be used for these two aminoglycosides in patients with septic shock [18,42]. However, a dose >7 mg/kg has not been prospectively validated for these drugs. Our data demonstrate than that, with 25 mg/kg of amikacin, the target peak concentration (>64 ��g/ml) was achieved in 70% of patients. An even higher dose may be necessary in some patients for whom the peak concentration remains below the desired level. Simulation with a standard regimen (15 mg/kg) of amikacin resulted in insufficient peak concentrations in >90% of patients, confirming the need to increase amikacin doses to ensure that adequate peak levels are achieved in sepsis patients.

A relation between the intensity of the septic process and the expansion of the Vd can be assumed. Marik et al. [16,43] and Lugo-Goytia et al. [39] demonstrated an association between sepsis severity, estimated by the APACHE II score, and aminoglycoside Vd. Vd was also reported to be correlated with oxygen extraction ratio, serum albumin levels, and adrenergic support in another study [17]. We did not find any relation between Vd and any demographic, clinical, hemodynamic, or biologic variable. Our population was analyzed in the early phase of the septic process, and this may explain the difference from previous studies, which were conducted in the steady state. The considerable interindividual variability observed in critically ill patients may also limit the a priori prediction of PK abnormalities and the optimal dose that should be administered to sepsis patients.

Optimizing aminoglycoside therapy should, therefore, be achieved by tight serum-concentration monitoring (peak and trough) and rapid dose adjustment [44] according to pathogen MIC. This strategy requires pathogen MIC measurement and a Cmin <5 ��g/ml to optimize the subsequent doses and to avoid drug accumulation.Physiologic alterations associated with increased BMI affect the aminoglycoside PK. This is due to the variable penetration of these drugs into adipose tissue. Previous studies have validated dosing weight correction factors to normalize predictions of Vss in morbidly obese subjects [23] as well as in overweight/underweight patients [24] in a non-ICU population.

Also, IBW seems to fit the pharmacokinetics of these antimicrobials better than the total body weight (TBW) to calculate the aminoglycoside regimen [45,46]; however, some uncertainty exists in this area [47]. Our results suggest that using a DW-based regimen could result in a relative underdosing of aminoglycoside in critically ill sepsis patients when compared with a TBW-based regimen. Brefeldin_A Thus, if using IBW, a loading dose even higher than 25 mg/kg should be considered in this patient population to obtain adequate amikacin peak concentrations.