Evaluation of gentamicin first-dose pharmacokinetics in septic critically ill patients: pilot study

Introduction

Aminoglycosides, especially gentamicin, are extensively used for treatment of severe infections. A dose of 7 mg/kg is recommended to achieve a high peak serum concentration. However, its accumulation is associated with adverse reactions, notably renal injury. Knowledge of gentamicin pharmacokinetics in critically ill patients is therefore crucial to therapeutic success and prevention of toxicity.

Methods

Patients' demographic and clinical data were collected. We studied gentamicin pharmacokinetic data from patients treated between January 2006 and June 2008 in two ICUs. Patients were eligible if the gentamicin dose was selected to achieve high serum levels (target concentration of 16 to 24 μg/ml) and if pharmacokinetic data from such patients, specifically peak and trough levels, were measured after the first dose. The Sawchuk and Zaske one-compartment pharmacokinetic model [1] was used to calculate the gentamicin volume of distribution (Vd), maximum concentration (Cmax) and clearance.

Results

We studied 32 patients with a mean age of 63 years (24 men). Mean Sequential Organ Failure Assessment score was 7.65 and the mean Charlson comorbidities score was 3.54. The median Vd was 0.41 l/kg (IQR 0.36 to 0.46 l/kg). Only four patients had a Vd equal to or less than 0.26 l/kg, usually found in the healthy population. We found no correlation between Vd and age, Charlson comorbidities score, Sequential Organ Failure Assessment score, and creatinine serum level (r² = 0.016, 0.18, 0.037, and 0.067, respectively). The presence of mechanical ventilation and septic shock had no influence on Vd (P = 0.59 and P = 0.14, respectively). Women had a significantly higher mean Vd/kg (0.51 vs. 0.39 l/kg, P = 0.002) and, therefore, lower Cmax (15.2 vs. 18.5 μg/ml, P = 0.016). In a logistic regression model, only sex (female: OR = 0.032; 95% CI = 0.03 to 0.387) and the dose/kg (per mg/kg: OR = 3.21; 95% CI = 1.17 to 8.79) were significantly associated with the achievement of Cmax above 16 μg/ml.

Conclusion

The gentamicin Vd cannot be predicted by age, the presence of renal failure or any studied comorbidities. Therefore, in order to obtain adequate therapeutic levels as soon as possible, a high first gentamicin dose (that is, at least 7 mg/kg) should be given to all patients. In women, even higher doses may be needed.