The effect of sepsis upon gentamicin pharmacokinetics in neonates.
OBJECTIVE
To investigate the effect of sepsis upon the volume of distribution (Vd) of gentamicin in neonates.


METHODS
A retrospective chart review was conducted of neonates admitted to Dunedin Hospital who had gentamicin concentrations performed between 1st January 2000 and 30th October 2003. Data from 277 neonates, including a total of 576 gentamicin concentrations, were included in the pharmacokinetic analysis. Fifteen (5.4%) of the neonates had confirmed sepsis. Pharmacokinetic analyses were performed with NONMEM using a one compartment first order elimination model. Duration of infusion (D) was included as a parameter in the model. Covariates included sepsis (SEP), chronological age, gestational age (GA), birth weight, current weight, gender, Apgar score at 1 (AP1) and 5 (AP2) minutes, plasma C-reactive protein and serum creatinine.


RESULTS
The initial model provided a mean estimates of clearance (CL) of 0.0460 l kg(-1) h(-1), volume of distribution (Vd) of 0.483 l kg(-1) and D of 0.748 h. The magnitudes of interpatient variability, expressed as CV%, were 29.2% for CL, 20.8% for Vd and 71.5% for D. The magnitude of residual variability in gentamicin concentrations was 88.0%. The final pharmacokinetic model was: CL = (0.0177 + 0.00147.(GA-20) + 0.000635.AP2) l kg(-1) h(-1), Vd = (0.483 +0.0656. sepsis) l kg(-1), D = 0.672 h. The interpatient variability (CV%) was 22.8% for CL, 22.8% for Vd and 97.7% for D. The magnitude of residual variability in gentamicin concentrations was 83.3%.


CONCLUSIONS
The 14% increase in Vd in septic neonates implies that larger doses may be required to achieve peak therapeutic concentrations in the presence of sepsis. D is an important parameter in neonatal pharmacokinetic models.
Lingvall
M
M
University of Uppsala, Uppsala, Sweden.
Reith
D
D
Broadbent
R
R
D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001424:Bacterial Infections / Q000188:drug therapy*; D005260:Female; D005839:Gentamicins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D007231:Infant, Newborn; D007262:Infusions, Intravenous; D008297:Male; D008954:Models, Biological; D012189:Retrospective Studies; D018805:Sepsis / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D005839:Gentamicins