We showed that, MDV3100 because of PK alterations, a loading dose of �� 25 mg/kg of amikacin is necessary to achieve therapeutic peak concentrations in patients with severe sepsis or septic shock. Antimicrobials PKs in ICU patients are significantly different from those in healthy volunteers or less severely ill patients [14,31,32]. Increased cardiac index and interstitial fluid shifts in sepsis result in a larger volume of distribution (Vd), which may reduce plasma antibiotic levels [33]. Decreased protein binding can result in higher free-drug concentrations, and organ dysfunction may decrease drug metabolism and clearance [33]. Finally, infections, especially when acquired in the ICU, are often caused by more-resistant pathogens [34]. For aminoglycosides, peak concentration is determined by the administered dose and by the Vd [30].

The Vd of amikacin is between 0.2 and 0.3 L/kg in healthy volunteers and in patients with mild infections [12,20,35]. In our study, the median Vd was 0.41 L/kg, corresponding to a >60% increase when compared with normal ranges. These results confirm data from previous studies. In 200 adult and pediatric ICU patients with severe gram-negative infections, the Vd of amikacin varied from 0.17 to 0.98 L/kg, with a mean of 0.37 L/Kg [16]. A mean Vd of 0.47 L/kg was reported in 30 ICU patients [17]. In patients with postoperative septic shock, the Vd was 0.41 �� 0.08 L/kg, a significantly higher value than that in controls (0.25 �� 0.01 L/kg) [36]. The variability of Vd in sepsis patients is probably multifactorial and depends on the degree of inflammation, vascular permeability, and fluid extravasation [12,32,37].

Doses of 15 and 20 mg/kg produced means of 33.5 �� 14.8 and 33.8 �� 4.7 ��g/ml, respectively, in adult ICU patients [15,16]. However, the peak obtained with these regimens was largely below the desired concentration of 64 ��g/ml, suggesting that higher doses of amikacin should be administered to achieve optimal peak levels. Moreover, previous studies on amikacin dose in ICU patients had limited patient samples [17,36,38], were retrospective [10,39], or had exclusion criteria, such as septic shock [15], APACHE II score >35 [40], liver cirrhosis [17], or acute renal failure [15-17,40], making it difficult to extrapolate the results to a general septic ICU population.

Our study is the first to provide data on sepsis patients with several comorbidities, high disease severity, and multiple organ dysfunctions, Cilengitide with an ICU mortality rate of nearly 40%. This cohort of 74 patients was relatively large and representative of a typical ICU population. Most of the infections were secondary to gram-negative infections, with 20% being caused by difficult-to-treat bacteria known to be associated with high mortality rates [41].