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 (Cmax)/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 Cmaxbetween 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 Cmaxfor amikacin was between 60 and 80 mg/L, as recommended by French guidelines (i.e. Cmax/MIC breakpoint = 8-10).


RESULTS
Over the study period, the amikacin Cmaxwas <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 Cmax< 60 mg/L, 60 mg/L < Cmax< 80 mg/L and Cmax> 80 mg/L, respectively. Following multivariate analysis, mortality rate was significantly lower in the group of patients with amikacin Cmaxbetween 60 and 80 mg/L than in the group of patients with amikacin Cmax> 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 (Cmax< 60 mg/L) in only 18.2% of patients. The pharmacodynamic target (60 mg/L < Cmax< 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. Cmax> 80 mg/L) was frequent and potentially associated with increased mortality.
Réanimation polyvalente, Hôpital Felix Guyon, Centre Hospitalier Universitaire Felix Guyon, Allée des Topazes, Bellepierre, 97405, Saint Denis, France. nicolas.allou@hotmail.fr.
Nicolas
N
Allou
Département d'Anesthésie Réanimation, AP-HP, Centre Hospitalier Universitaire Bichat-Claude-Bernard, 46, rue Henri-Huchard, 75018, Paris, France.
Astrid
A
Bouteau
Réanimation polyvalente, Hôpital Felix Guyon, Centre Hospitalier Universitaire Felix Guyon, Allée des Topazes, Bellepierre, 97405, Saint Denis, France.
Jérôme
J
Allyn
Département d'Anesthésie Réanimation, AP-HP, Centre Hospitalier Universitaire Bichat-Claude-Bernard, 46, rue Henri-Huchard, 75018, Paris, France.
Aurélie
A
Snauwaert
Réanimation polyvalente, Hôpital Felix Guyon, Centre Hospitalier Universitaire Felix Guyon, Allée des Topazes, Bellepierre, 97405, Saint Denis, France.
Dorothée
D
Valance
Réanimation polyvalente, Hôpital Felix Guyon, Centre Hospitalier Universitaire Felix Guyon, Allée des Topazes, Bellepierre, 97405, Saint Denis, France.
Julien
J
Jabot
Réanimation polyvalente, Hôpital Felix Guyon, Centre Hospitalier Universitaire Felix Guyon, Allée des Topazes, Bellepierre, 97405, Saint Denis, France.
Bruno
B
Bouchet
Réanimation polyvalente, Hôpital Felix Guyon, Centre Hospitalier Universitaire Felix Guyon, Allée des Topazes, Bellepierre, 97405, Saint Denis, France.
Richard
R
Galliot
Réanimation polyvalente, Hôpital Felix Guyon, Centre Hospitalier Universitaire Felix Guyon, Allée des Topazes, Bellepierre, 97405, Saint Denis, France.
Laure
L
Corradi
Département d'Anesthésie Réanimation, AP-HP, Centre Hospitalier Universitaire Bichat-Claude-Bernard, 46, rue Henri-Huchard, 75018, Paris, France.
Philippe
P
Montravers
Département d'Anesthésie Réanimation, AP-HP, Centre Hospitalier Universitaire Bichat-Claude-Bernard, 46, rue Henri-Huchard, 75018, Paris, France.
Pascal
P
Augustin
Amikacin; Pharmacokinetics/pharmacodynamics; Severe sepsis/septic shock