Developmental Population Pharmacokinetics-Pharmacodynamics of Meropenem in Chinese Neonates and Young Infants: Dosing Recommendations for Late-Onset Sepsis

Abstract

The pharmacokinetic (PK) studies of meropenem in Chinese newborns with late-onset sepsis (LOS) are still lacking. Causative pathogens of LOS and their susceptibility patterns in China differ from the data abroad. We, therefore, conducted a developmental population pharmacokinetic–pharmacodynamic analysis in Chinese newborns with the goal to optimize meropenem dosing regimens for LOS therapy. An opportunistic sampling strategy was used to collect meropenem samples, followed by model building and validation. A Monte Carlo simulation was performed to show the probability of target attainment (PTA) for various dosages. The information from 78 newborns (postmenstrual age: 27.4–46.1 weeks) was compiled and had a good fit to a 1-compartment model that had first order elimination. The median (range) values of estimated weight–normalized volume of distribution (V)and clearance (CL) were 0.60 (0.51–0.69) L/kg and 0.16 (0.04–0.51) L/h/kg, respectively. Covariate analysis revealed that postnatal age (PNA), gestational age (GA) and current weight (CW) were the most important factors in describing meropenem PK. Simulation results showed for LOS with a minimal inhibitory concentration (MIC) of 8 mg/L, the doses of 30 mg/kg 3 times daily (TID) as a 1-h infusion for newborns with GA ≤ 37 weeks and 40 mg/kg TID as a 3-h infusion for those with GA > 37 weeks were optimal, with PTA of 71.71% and 75.08%, respectively. In conclusion, we proposed an evidence-based dosing regimen of meropenem for LOS in Chinese newborns by using the population pharmacokinetic–pharmacodynamic analysis, based on domestic common pathogens and their susceptibility patterns.

Meropenem Disposition in Neonatal and Pediatric Extracorporeal Membrane Oxygenation and Continuous Renal Replacement Therapy

“…This was in line with several studies with critically ill neonatal and pediatric patients [12,14,16,17,20,34], whereas other studies found a two-compartment model to ensure the best fit [13,15,19,21,35]. Reported values for CL and Vd normalized to BW in studies with critically ill pediatric patients were in the range 0.057-0.63 L/h/kg and 0.46-2.04 L/kg, respectively [13,[15][16][17][19][20][21]34,35]. Our BW-normalized values of CL and Vd were 0.138 L/h/kg and 0.51 L/kg, respectively, which was in the reported range.…”

“…We found a one-compartment model to provide the best description of meropenem distribution. This was in line with several studies with critically ill neonatal and pediatric patients [12,14,16,17,20,34], whereas other studies found a two-compartment model to ensure the best fit [13,15,19,21,35]. Reported values for CL and Vd normalized to BW in studies with critically ill pediatric patients were in the range 0.057-0.63 L/h/kg and 0.46-2.04 L/kg, respectively [13,[15][16][17][19][20][21]34,35].…”

Meropenem Clearance in a Child With End-stage Renal Disease Undergoing Prolonged Intermittent Renal Replacement Therapy: A Case Report and Literature Review

“…This finding was opposite to our previous studies. 19,20 However, the observations are understandable in patients undergoing PIRRT, as many factors such as dialysis membrane, setting of blood flow and dialysis rate could also alter the elimination of meropenem. 11 Other factors, such as the frequency of dosing regimens and the addition of extracorporeal membrane oxygenation, may also change the clearance of meropenem in patients undergoing renal replacement.…”

Optimal use of β-lactams in neonates: machine learning-based clinical decision support system

“…Information on neonates receiving antibacterial treatments from previous neonatal studies was used to establish a virtual neonate dataset. 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 The dataset included information on 2569 neonates. The mean (SD) values of current weight (CW) and postmenstrual age (PMA) were 2463 (1023) [range 450–9370] g and 36.9 (4.43) [range 28.4–48.0] weeks.…”