Population Pharmacokinetics and Dosing of Amoxicillin in (Pre)term Neonates

Abstract

Amoxicillin plasma concentrations, pharmacokinetic parameters, and the influence of demographic, anthropometric, and clinical covariates were investigated in 150 neonates. Gestational age (GA) ranged from 25 to 42 weeks and mean postnatal age (PNA) was 0.8 days. Amoxicillin concentrations were measured with reversed-phase HPLC in surplus plasma from routine assays of coadministered gentamicin. Mean total body clearance corrected for body weight (CL/W) was 0.096 +/- 0.036 L/kg(-1)h(-1), mean elimination half-life (t(1/2)) was 5.2 +/- 1.9 hours, and mean volume of distribution corrected for body weight (V/W) was 0.65 +/- 0.13 L/kg. Multiple regression equations were calculated for the prediction of CL/W amoxicillin. CL/W gentamicin, V/W gentamicin, and GA were significant predictors of CL/W amoxicillin. Amoxicillin peak and trough concentrations after the second dose and the time the concentration exceeds the minimum inhibitory concentration (T>MIC), reached with the current dosage regimen, were evaluated. Toxic plasma concentrations were reached in several patients. Therefore, the authors have proposed a lower dosage regimen, based on GA, population pharmacokinetic parameters, bacterial susceptibility (T>MIC), and possible toxicity: 15 mg/kg per 8 hours and 20 mg/kg per 8 hours for neonates with GA < or = 34 and GA>34 weeks, respectively. Simulation with this new dosage regimen indicated that satisfactory plasma concentrations were reached in all 150 neonates. Therefore, use of therapeutic drug monitoring and pharmacokinetic calculations for dosage adjustment is generally not necessary.

Clinical pharmacokinetics of penicillins in the neonate: a review of the literature

“…The most recent study looked at the effects of postnatal age and found that the Cl was greater in neonates >9 days old (3.0 ml min −1 kg −1 ) [17] than had been shown in previous studies in neonates of a similar gestation (1.6 ml min −1 kg −1 ) [15]. Similarly, the t ½ was considerably shorter (3 h vs. 5.2 h).…”

“…In one study, the authors recommended a dose of 15 mg kg −1 8 h −1 for GA <34 weeks and 20 mg kg −1 8 h −1 for GA >34 weeks [15]. The authors of the second study suggested that preterm infants with GA <32 weeks in the first week of life should receive a maximum amoxicillin dose of 25 mg kg −1 12 h −1 [13].…”

“…Two studies looked at the PK and dosing of amoxicillin in neonates [13,15]. In one study, the authors recommended a dose of 15 mg kg −1 8 h −1 for GA <34 weeks and 20 mg kg −1 8 h −1 for GA >34 weeks [15].…”

“…There have been a total of six amoxicillin PK studies in neonates [13][14][15][16][17][18] (Table 3). Preterm infants (<32 weeks GA) have a longer t ½ (6.7 h) [13] than term neonates (3.7 h) [13,18].…”

Intravenous antibiotic durations for common bacterial infections in children: When is enough enough?

“…Even in neonates, several studies have demonstrated that therapeutic serum levels are easily reached with oral dosing of amoxicillin in term and preterm neonates. 8,9 For the remainder of this review, the published recommendations and available evidence behind the duration of IV therapy are summarized for 4 bacterial infections in children in which IV antibiotic therapy often continues after clinical recovery: meningitis, bacteremia, UTI, and acute osteomyelitis. We conclude by proposing additional considerations for IV antibiotic durations, especially in situations where guidelines and/or evidence are either nonexistent, dated, conflicting, or contrary to evidence from published studies.…”