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Meropenem Pharmacokinetics, Pharmacodynamics, and Monte Carlo Simulation in the Neonate

Bradley, John S. MD*†‡; Sauberan, Jason B. PharmD†‡; Ambrose, Paul G. PharmD§; Bhavnani, Sujata M. PharmD, MS§; Rasmussen, Maynard R. MD†‡; Capparelli, Edmund V. PharmD‡

Pediatric Infectious Disease Journal: September 2008 - Volume 27 - Issue 9 - pp 794-799
doi: 10.1097/INF.0b013e318170f8d2
Original Studies

Background: Hospitalized neonates are exposed to antibiotic-resistant bacterial pathogens and develop nosocomial infections. Limited data are available regarding the neonatal pharmacokinetics of meropenem, a broad spectrum carbapenem antibiotic.

Methods: Neonates <2 months of age received a single dose of meropenem at 10 or 20 mg/kg. Meropenem serum concentrations were measured at specified times during the 24 hours postinfusion. Population pharmacokinetics (PPK) were evaluated using NONMEM. Using Monte Carlo simulation (MCS), the probability of pharmacokinetic-pharmacodynamic target attainment was evaluated by computer modeling from predictions extrapolated from PPK data, using “virtual” dosing regimens of 10, 20, and 40 mg/kg administered every 8 or 12 hours against community- and hospital-acquired pathogens.

Results: Thirty-seven neonates were enrolled, 22 were born at <36 weeks (range, 23–41 weeks) gestational age. Meropenem clearance was greater in neonates with older chronologic ages and in those born at later gestational ages. Serum creatinine and postconceptional age (PCA) were the best overall predictors of meropenem elimination: CL (L/h/kg) = 0.041 + 0.040/SCr + 0.003 × (PCA-35). MCS demonstrated that in infants during the first 2 weeks of life, a dosage of 20 mg/kg/dose every 8 hours achieved the desired PD target in 95% of preterm neonates and 91% of term neonates against Pseudomonas aeruginosa isolated from patients managed in adult and pediatric intensive care units in the United States.

Conclusions: MCS based on PPK determinations demonstrated that a meropenem dose of 20 mg/kg every 8 hours should provide adequate therapy for most nosocomial Gram-negative pathogens.

From the *Children's Hospital and Health Center; †Sharp Mary Birch Hospital for Women and Children; ‡University of California, San Diego, CA; and §Institute for Clinical Pharmacodynamics, Ordway Research Institute, Albany, NY.

Accepted for publication February 27, 2008.

This study was supported by a grant from AstraZeneca Pharmaceuticals, LP, and by NICHD grant 5 U10 HD031318-14 for Pediatric Pharmacology Research Units.

Address for correspondence: John S. Bradley, MD, Division of Infectious diseases, Children's Hospital and Health Center, 3020 Children's Way, MC 5041, San Diego, CA 92123. E-mail: jbradley@chsd.org.

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© 2008 Lippincott Williams & Wilkins, Inc.