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Antimicrob Agents Chemother. 2018 Apr 26;62(5). pii: e02238-17. doi: 10.1128/AAC.02238-17. Print 2018 May.

Pharmacokinetics of Penicillin G in Preterm and Term Neonates.

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Pediatric Intensive Care Unit, Tartu University Hospital, Tartu, Estonia.
UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.
Paediatric Infectious Diseases Research Group, Institute for Infection and Immunity, St. George's University of London, London, United Kingdom.
Institute of Chemistry, University of Tartu, Tartu, Estonia.
Clinic of Haematology and Oncology, North Estonia Medical Centre, Tallinn, Estonia.
Institute of Computer Science, University of Tartu, Tartu, Estonia.
Department of Microbiology, University of Tartu, Tartu, Estonia
Department of Microbiology, University of Tartu, Tartu, Estonia.


Group B streptococci are common causative agents of early-onset neonatal sepsis (EOS). Pharmacokinetic (PK) data for penicillin G have been described for extremely preterm neonates but have been poorly described for late-preterm and term neonates. Thus, evidence-based dosing recommendations are lacking. We describe the PK of penicillin G in neonates with a gestational age (GA) of ≥32 weeks and a postnatal age of <72 h. Penicillin G was administered intravenously at a dose of 25,000 or 50,000 IU/kg of body weight every 12 h (q12h). At steady state, PK blood samples were collected prior to and at 5 min, 1 h, 3 h, 8 h, and 12 h after injection. Noncompartmental PK analysis was performed with WinNonlin software. With those data in combination with data from neonates with a GA of ≤28 weeks, we developed a population PK model using NONMEM software and performed probability of target attainment (PTA) simulations. In total, 16 neonates with a GA of ≥32 weeks were included in noncompartmental analysis. The median volume of distribution (V) was 0.50 liters/kg (interquartile range, 0.42 to 0.57 liters/kg), the median clearance (CL) was 0.21 liters/h (interquartile range, 0.16 to 0.29 liters/kg), and the median half-life was 3.6 h (interquartile range, 3.2 to 4.3 h). In the population PK analysis that included 35 neonates, a two-compartment model best described the data. The final parameter estimates were 10.3 liters/70 kg and 29.8 liters/70 kg for V of the central and peripheral compartments, respectively, and 13.2 liters/h/70 kg for CL. Considering the fraction of unbound penicillin G to be 40%, the PTA of an unbound drug concentration that exceeds the MIC for 40% of the dosing interval was >90% for MICs of ≤2 mg/liter with doses of 25,000 IU/kg q12h. In neonates, regardless of GA, the PK parameters of penicillin G were similar. The dose of 25,000 IU/kg q12h is suggested for treatment of group B streptococcal EOS diagnosed within the first 72 h of life. (This study was registered with the EU Clinical Trials Register under EudraCT number 2012-002836-97.).


early-onset sepsis; group B streptococcus; late-preterm neonate; noncompartmental analysis; population pharmacokinetics; term neonate

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