The influences of renal function and maturation on vancomycin elimination in newborns and infants.

The purpose of this study was to describe the maturation of vancomycin (V) clearance and the influence of altered renal function in infants on vancomycin using population pharmacokinetic methods. A population pharmacokinetic model was developed using NONMEM from clinical data obtained from 374 newborns and infants < 2 years of age (median age = 27 days) from four institutions. A total of 1103 serum V concentrations were used in the model development, including 311 with elevated serum creatinine (CR) (> 0.8 mg/dl) and more than 104 evaluations in infants older than 2 months of age. The final model was evaluated against a second data set of 160 concentrations from 67 infants at one of the institutions and then used to develop dosing guidelines. The data were best described by a two-compartment model. Weight and CR greatly influenced vancomycin elimination, while postnatal age and prematurity (< 28 weeks) were significant but less important predictors of V elimination. For the typical study infant (age = 27 days, CR = 0.6, WT= 1.8 kg, gestational age = 33.5 weeks), this results in VdSS = 0.79 l/kg and Cl = 0.066 l/h/kg. The validation data set showed the model to be unbiased. Dosing guidelines from this model, based on serum creatinine and gestational age at birth, performed better than published guidelines based on postconceptional age. Vancomycin clearance is initially reduced in premature infants and increases with postnatal age. Most of the age-related changes could be predicted by the concomitant fall in serum creatinine. Dosing guidelines that incorporate these factors are more likely to produce therapeutic V concentrations in infants.

Vancomycin pharmacokinetics in infants: relationship to postconceptional age and serum creatinine.

Multidose pharmacokinetics of vancomycin were studied in 15 infants with gestational age less than 36 weeks and suspected or confirmed Staphylococcus epidermidis infections. Postconceptional age (PCA) at the time of the study ranged from 26 to 44 weeks. Vancomycin individual doses ranged from 6.7 to 10.6 mg/kg and were infused over 60 min. Five postinfusion samples were obtained in 13 infants, while 4 samples were obtained in 2 patients. Vancomycin pharmacokinetic parameters were determined by fitting the data to a two-compartment model using a weighted least-squares nonlinear regression method. Mean vancomycin body clearance (CL), volume of distribution (Vdss) and terminal elimination half-life were 1.37 ml/min, 0.58 liters and 5.6 h, respectively. When standardized for patient weight, the CL and Vdss values were 1.07 ml/min/kg and 0.48 liters/kg, respectively. The CL (ml/min/kg) was strongly inversely correlated with the serum creatinine (r = -0.82), while a weaker but significant association was noted with PCA (r = 0.41). These data suggest that in sick infants, in addition to the PCA, serum creatinine should be considered when determining the initial vancomycin dosing regimen.

Direct determination of tobramycin clearance in patients with mild-to-moderate cystic fibrosis.

Studies performed in patients with cystic fibrosis (CF) have suggested altered pharmacokinetic parameters for aminoglycosides. Specifically, increased plasma clearance (Cl) of aminoglycosides and increased apparent volume of distribution have been noted. In the present study, tobramycin Cl is determined by both serum concentration data and direct renal clearance (Clren). Tobramycin Clren appeared to be directly correlated to the measured creatinine clearance (Clcr) (r = 0.93, p less than 0.01). The tobramycin Cl, by both methods of determination, was not elevated in comparison to the Clcr or expected values for patients without the disease. These results appear to corroborate a recent study in which the renal and plasma Cl of gentamicin was measured in patients with mild-to-moderate CF and were not noted to be elevated. It is suggested that standard doses of tobramycin be used initially in patients with mild-to-moderate CF with dosage adjustment based on serum concentration data to achieve the desired goals.

Developmental pattern of gentamicin kinetics in very low birth weight (VLBW) sick infants.

Kinetic studies were carried out in 15 very low birth weight (VLBW) infants during three courses of gentamicin (G) therapy for suspected sepsis. All received two courses but only 6 required a third course. G dosage was 2.0 +/- 0.2 mg/kg/24 h for the first and second course and 2.5 mg/kg/12 h for the third course. G dosage was adjusted to maintain serum peak G concentration of 4-8 micrograms/ml and trough concentration of 0.5-2 micrograms/ml. On the third day of therapy, a 24-hour collection of urine for creatinine (C) and G concentrations was performed in 28 of 36 cases. G clearance and G elimination rate constant were calculated based on chronological age (CA) of less than or equal to 7 (I), 8-30 (II) and greater than or equal to 31 (III) days. The mean BW and GA were 1,002 +/- 206 g and 28.4 +/- 1.5 weeks, respectively. Mean CA for the starting of therapy for each course was the first day, 19 +/- 9 and 68 +/- 26 days of life, respectively. Mean serum G peak and trough concentrations were 5.9 +/- 1.1 and 1.6 +/- 0.6 micrograms/ml for the first; 5.7 +/- 1.2 and 1.3 +/- 0.6 micrograms/ml for the second; 5.1 +/- 0.8 and 1.1 +/- 0.6 micrograms/ml for the third course of therapy. Mean apparent volume of distribution of G were 0.53 +/- 0.10 liter/kg for the first and 0.50 +/- 0.11 liter/kg for the second and third courses. Mean clearances for the three CA groups were 6.4 +/- 1.9; 7.6 +/- 3.2; 24.1 +/- 8.0 ml/min/1.73 m2 for G and 6.4 +/- 2.2; 7.7 +/- 3.1; 23.3 +/- 8.8 for C with serum C of 1.3 +/- 0.4, 1.2 +/- 0.6 and 0.6 +/- 0.4 mg%, respectively. There were no statistically significant differences for serum C, G and C clearance between CA I and II but significant differences were found for the above between CA III vs. CA I and II (p less than 0.005). G clearance closely correlated with C clearance (r = 0.99, p less than 0.001). The elimination rate constant was significantly higher after 30 days of life when CA III is compared to CA I and II or combined (p less than 0.001). This study shows that during the first month of life, VLBW sick infants still have decreased renal function and poor G clearance, therefore, G should be given every 24 h and the dose be adjusted based on individual patient serum G levels.