title: Population pharmacokinetics of ciprofloxacin in neonates and young infants less than three months of age.
abstract: Ciprofloxacin is used in neonates with suspected or documented Gram-negative serious infections. Currently, its use is off-label partly because of lack of pharmacokinetic studies. Within the FP7 EU project TINN (Treat Infection in NeoNates), our aim was to evaluate the population pharmacokinetics of ciprofloxacin in neonates and young infants <3 months of age and define the appropriate dose in order to optimize ciprofloxacin treatment in this vulnerable population. Blood samples were collected from neonates treated with ciprofloxacin and concentrations were quantified by high-pressure liquid chromatography-mass spectrometry. Population pharmacokinetic analysis was performed using NONMEM software. The data from 60 newborn infants (postmenstrual age [PMA] range, 24.9 to 47.9 weeks) were available for population pharmacokinetic analysis. A two-compartment model with first-order elimination showed the best fit with the data. A covariate analysis identified that gestational age, postnatal age, current weight, serum creatinine concentration, and use of inotropes had a significant impact on ciprofloxacin pharmacokinetics. Monte Carlo simulation demonstrated that 90% of hypothetical newborns with a PMA of <34 weeks treated with 7.5 mg/kg twice daily and 84% of newborns with a PMA ≥34 weeks and young infants receiving 12.5 mg/kg twice daily would reach the AUC/MIC target of 125, using the standard EUCAST MIC susceptibility breakpoint of 0.5 mg/liter. The associated risks of overdose for the proposed dosing regimen were <8%. The population pharmacokinetics of ciprofloxacin was evaluated in neonates and young infants <3 months old, and a dosing regimen was established based on simulation.
authors.affiliation: Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, Jinan, China Department of Paediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, APHP, Paris, France Clinical Investigation Center CIC1426, INSERM, Paris, France EA7323, Université Paris Diderot-Université Paris Descartes, Paris, France.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Women's and Children's Health, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom Neonatal Unit, Liverpool Women's Hospital, Liverpool, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Hill
authors.affiliation: EA4245, Faculté de Médecine, Université François Rabelais, Tours, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Le Guellec
authors.affiliation: Department of Medical Microbiology, Royal Liverpool University Hospital, Liverpool, United Kingdom.
authors.forename: Tim
authors.initials: T
authors.lastname: Neal
authors.affiliation: Paediatric Intensive Care, Alder Hey Children's Hospital, Liverpool, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Mahoney
authors.affiliation: Paediatric Intensive Care, Alder Hey Children's Hospital, Liverpool, United Kingdom.
authors.forename: Stephane
authors.initials: S
authors.lastname: Paulus
authors.affiliation: CNRS UMR5558, Laboratoire de Biométrie et Biologie Evolutive, Université de Lyon, EPICIME-CIC 1407-INSERM-Hospices Civils de Lyon, Lyon, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Castellan
authors.affiliation: CNRS UMR5558, Laboratoire de Biométrie et Biologie Evolutive, Université de Lyon, EPICIME-CIC 1407-INSERM-Hospices Civils de Lyon, Lyon, France.
authors.forename: Behrouz
authors.initials: B
authors.lastname: Kassai
authors.affiliation: Intensive Care, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands Division of Pediatric Clinical Pharmacology, Children's National Medical Center, Washington, DC, USA Departments of Pediatrics, Pharmacology, and Physiology, George Washington University, School of Medicine and Health Sciences, Washington, DC, USA Department of Paediatric Pharmacology, University Children's Hospital Basel, Basel, Switzerland.
authors.forename: Johannes N
authors.initials: JN
authors.lastname: van den Anker
authors.affiliation: Division of Clinical Pharmacology and Therapeutic Innovation, Children's Mercy Hospital, Kansas City, Missouri, USA Department of Pediatrics, University of Missouri-Kansas City, Kansas City, Missouri, USA.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Kearns
authors.affiliation: Department of Women's and Children's Health, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom Neonatal Unit, Liverpool Women's Hospital, Liverpool, United Kingdom.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Turner
authors.affiliation: Department of Paediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, APHP, Paris, France Clinical Investigation Center CIC1426, INSERM, Paris, France EA7323, Université Paris Diderot-Université Paris Descartes, Paris, France evelyne.jacqz-aigrain@rdb.aphp.fr.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Jacqz-Aigrain
mesh_terms: D000900:Anti-Bacterial Agents / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001835:Body Weight; D002316:Cardiotonic Agents / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D002939:Ciprofloxacin / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D005865:Gestational Age; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015931:Intensive Care, Neonatal; D008297:Male; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D056687:Off-Label Use; D011446:Prospective Studies
chemical_list: D000900:Anti-Bacterial Agents; D002316:Cardiotonic Agents; D002939:Ciprofloxacin; D003404:Creatinine