Impact of a high loading dose of amikacin in patients with severe sepsis or septic shock

Background: The therapeutic effect of aminoglycosides is highest and optimal when the peak plasma concentration (C-max)/minimal inhibitory concentration (MIC) ratio is between 8 and 10. The French guidelines recommend to use high doses of aminoglycosides for empiric antibiotic therapy in patients suffering from severe sepsis or septic shock. In clinical practice, the recommended target is an amikacin Cmax between 60 and 80 mg/L, which corresponds to approximately 8 times the MIC breakpoint, as defined by the European Committee on Antimicrobial Susceptibility Testing. The aim of this study was to assess the incidence and impact on mortality of an amikacin concentration between 60 and 80 mg/L in patients suffering from severe sepsis or septic shock. Methods: This was a prospective observational cohort study conducted in two intensive care units (ICU). Patients receiving amikacin at a loading dose of 30 mg/kg for severe sepsis or septic shock were enrolled in the cohort. The target Cmax for amikacin was between 60 and 80 mg/L, as recommended by French guidelines (i.e. C-max/MIC breakpoint = 8-10). Results: Over the study period, the amikacin C-max was < 60 mg/L, between 60 and 80 mg/L, and > 80 mg/L in 20 (18.2%), 46 (41.8%) and 44 (40%) of the 110 selected patients, respectively. Mortality rate was 40, 28.3 and 56.8% in the groups of patients with C-max < 60 mg/L, 60 mg/L < Cmax < 80 mg/L and C-max > 80 mg/L, respectively. Following multivariate analysis, mortality rate was significantly lower in the group of patients with amikacin C-max between 60 and 80 mg/L than in the group of patients with amikacin C-max > 80 mg/L (P = 0.004). The multivariate analysis also revealed that the factors independently associated with a higher in-ICU mortality rate were age (P = 0.02) and norepinephrine dose (P = 0.0001). Conclusions: With a loading dose of 30 mg/kg of amikacin, concentration was potentially suboptimal (C-max < 60 mg/L) in only 18.2% of patients. The pharmacodynamic target (60 mg/L < C-max < 80 mg/L) recommended by French guidelines was reached in 41.8% of patients and was associated with reduced in-ICU mortality. But amikacin overexposure (i. e. C-max > 80 mg/L) was frequent and potentially associated with increased mortality.