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J Clin Pharmacol. 2016 Aug;56(8):909-35. doi: 10.1002/jcph.705. Epub 2016 Mar 31.

Pharmacometric Approaches to Personalize Use of Primarily Renally Eliminated Antibiotics in Preterm and Term Neonates.

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Division of Paediatric Pharmacology and Pharmacometrics, University of Basel Children's Hospital, Basel, Switzerland.
Institute of Pharmacology, Clinical Pharmacology and Toxicology, Medical Faculty, University of Belgrade, Belgrade, Serbia.
Division of Clinical Pharmacology, Service of Biomedicine, Department of Laboratory, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
Department of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
Department of Development and Regeneration, KU Leuven, Belgium.
Intensive Care and Department of Surgery, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
Division of Clinical Pharmacology, Children's National Health System, Washington, DC, USA.
Quantitative Solutions LP, Menlo Park, CA, USA.


Sepsis remains a major cause of mortality and morbidity in neonates, and, as a consequence, antibiotics are the most frequently prescribed drugs in this vulnerable patient population. Growth and dynamic maturation processes during the first weeks of life result in large inter- and intrasubject variability in the pharmacokinetics (PK) and pharmacodynamics (PD) of antibiotics. In this review we (1) summarize the available population PK data and models for primarily renally eliminated antibiotics, (2) discuss quantitative approaches to account for effects of growth and maturation processes on drug exposure and response, (3) evaluate current dose recommendations, and (4) identify opportunities to further optimize and personalize dosing strategies of these antibiotics in preterm and term neonates. Although population PK models have been developed for several of these drugs, exposure-response relationships of primarily renally eliminated antibiotics in these fragile infants are not well understood, monitoring strategies remain inconsistent, and consensus on optimal, personalized dosing of these drugs in these patients is absent. Tailored PK/PD studies and models are useful to better understand relationships between drug exposures and microbiological or clinical outcomes. Pharmacometric modeling and simulation approaches facilitate quantitative evaluation and optimization of treatment strategies. National and international collaborations and platforms are essential to standardize and harmonize not only studies and models but also monitoring and dosing strategies. Simple bedside decision tools assist clinical pharmacologists and neonatologists in their efforts to fine-tune and personalize the use of primarily renally eliminated antibiotics in term and preterm neonates.


antibiotic stewardship; infectious diseases; neonatology; pharmacodynamics; pharmacokinetics; pharmacometrics; population pharmacokinetics

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