Is 4 MG/KG an adequate loading dose for genta-micin/tobramycin in critically ill surgical patients?

Introduction: Critically ill patients with gram-negative sepsis demonstrate increased volumes of distribution for aminoglycosides (AG), and many do not achieve initial therapeutic levels. We hypothesized that a higher loading dose for AG would increase the proportion of patients who reach therapeutic levels early in therapy when compared with historic controls with 3 mg/kg (1). Methods: This prospective SICU observational study was designed to determine the value of a 4 mg/kg loading dose for tobramycin(T) and gentamicin(G) or 16 mg/kg for amikacin(A )in reaching initial therapeutic serum AG levels (defined as > 8 meg/ml for G and T or > 32 meg/ml for A). The drug was infused over 30 minutes and serum levels obtained one hour (peak) and eight hours post-infusion for pharmacokinetics. Results: Forty seven patients had data available for analysis. Subjects were 58±17 years old, with median APACHE II scores of 14 (range 7 to 28). Baseline serum creatinine levels were 1.6±0.9 mg/dl, with a calculated creatinine clearance of 65±36 ml/min. Pharmacokinetic calculations yielded a 49% increase in the apparent Vd at 0.37±0.12 L/kg. The Kel was 0.13±0.06hr^-1 and the t1/2 was 6.8±3.5hrs. The one hour post-infusion aminoglycoside levels were therapeutic in 44 of 47 subjects (94%) vs 50% in historic controls (p<0.001). The median serum level for G and T was 10.5 meg/ml (range 5.6 to 18.3). As suspected, the Kel correlated with the calculated creatinine clearance (R = 0.64; P<0.001) and the APACHE II score correlated with the percent increase in apparent Vd (R = 0.29; P<0.05). Conclusions: The proposed 4mg/kg loading dose achieves initial therapeutic levels in critically ill patients with increased volumes of distribution. The apparent Vd in our population was increased by 49% and correlated with the severity of disease. Due to the variability of pharmacokinetics in these patients, increased loading doses and individualized dosing will achieve optimal AG levels.