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Antimicrobial Agents and Chemotherapy, September 2009, p. 3871-3879, Vol. 53, No. 9
0066-4804/09/$08.00+0     doi:10.1128/AAC.00351-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Meropenem Pharmacokinetics in the Newborn

John N. van den Anker,^1,2,3,4 Pavla Pokorna,⁵ Martina Kinzig-Schippers,⁶ Jirina Martinkova,⁷ Ronald de Groot,⁸ G. L. Drusano,^9* and Fritz Sorgel^6,10

Departments of Pediatrics,¹ Pharmacology & Physiology, The George Washington University School of Medicine and Health Sciences, Washington, DC,² Division of Pediatric Clinical Pharmacology, Children's National Medical Center, Washington, DC,³ Department of Pediatrics, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands,⁴ Department of Pediatrics, Charles University, Prague, Czech Republic,⁵ Institute of Biomedical and Pharmaceutical Research, Heroldsberg, Germany,⁶ Department of Pharmacology, University of Hradec Kralove, Hradec Kralove, Czech Republic,⁷ Department of Pediatrics, University Children's Hospital Nijmegen, Nijmegen, The Netherlands,⁸ Ordway Research Institute, Albany, New York,⁹ Department of Pharmacology, University of Duisburg—Essen, Essen, Germany,¹⁰

Received 14 March 2009/ Returned for modification 12 May 2009/ Accepted 24 June 2009

We studied meropenem in 23 pre-term (gestational age, 29 to 36 weeks) and 15 full-term (gestational age, 37 to 42 weeks) neonates. Meropenem doses of 10, 20, and 40 mg/kg were administered as single doses (30-min intravenous infusion) on a random basis. Blood was obtained for determining the meropenem concentration nine times. Each child required other antimicrobials for proven/suspected bacterial infections. Samples were assayed by high-performance liquid chromatography analysis. Population pharmacokinetic parameter values were obtained by employing the BigNPAG program. Model building was performed by the likelihood ratio test. The final model included estimated creatinine clearance (CL_cr) (Schwartz formula) and weight (Wt) in the calculation of clearance (meropenem clearance = 0.00112 x CL_cr + 0.0925 x Wt + 0.156 liter/hr). The overall fit of the model to the data was good (observed = 1.037 x predicted – 0.096; r² = 0.977). Given the distributions of estimated creatinine clearance and weight between pre-term and full-term neonates, meropenem clearance was substantially higher in the full-term group. A Monte Carlo simulation was performed using the creatinine clearance and weight distributions for pre-term and full-term populations separately, examining 20- and 40-mg/kg doses, 8- and 12-h dosing intervals, and 0.5-h and 4-h infusion times. The 8-h interval produced robust target attainments (both populations). If more resistant organisms were to be treated (MIC of 4 to 8 mg/liter), the 40-mg/kg dose and a prolonged infusion was favored. Treating clinicians need to balance dose choices for optimizing target attainment against potential toxicity. These findings require validation in clinical circumstances.

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* Corresponding author. Mailing address: Ordway Research Institute, 150 New Scotland Avenue, Albany, NY 12208. Phone: (518) 641-6410. Fax: (518) 641-6304. E-mail: gdrusano{at}ordwayresearch.org

Published ahead of print on 6 July 2009.

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Antimicrobial Agents and Chemotherapy, September 2009, p. 3871-3879, Vol. 53, No. 9
0066-4804/09/$08.00+0     doi:10.1128/AAC.00351-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.