title: Safety study of Ciprofloxacin in newborn mice.
abstract: Ciprofloxacin, a broad-spectrum antimicrobial agent belonging to the fluoroquinolone family, is prescribed off-label in infants less than one year of age. Ciprofloxacin is included in the European Medicines Agency priority list of off-patent medicinal products requiring evaluation in neonates. This evaluation is undergoing within the TINN (Treat Infections in Neonates) FP7 EU project. As part of the TINN project, the present preclinical study was designed to assess the potential adverse effects of Ciprofloxacin on neurodevelopment, liver and joints in mice. Newborn mice received subcutaneous Ciprofloxacin at 10, 30 and 100 mg/kg/day from 2 to 12 postnatal days. Peak plasma levels of Ciprofloxacin were in the range of levels measured in human neonates. We examined vital functions in vivo, including cardiorespiratory parameters and temperature, psychomotor development, exploratory behavior, arthro-, nephro- and hepato-toxic effects. We found no effect of Ciprofloxacin at 10 and 30 mg/kg/day. In contrast, administration at 100 mg/kg/day delayed weight gain, impaired cardiorespiratory and psychomotor development, caused inflammatory infiltrates in the connective tissues surrounding the knee joint, and moderately increased extramedullary hematopoiesis. The present study pleads for careful watching of cardiorespiratory and motor development in neonates treated with Ciprofloxacin, in addition to the standard surveillance of arthrotoxicity.
authors.affiliation: Inserm, U1141, Robert Debré Hospital, APHP, 75019, Paris, France; Denis Diderot-Paris 7 University, Robert Debré Hospital, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bourgeois
authors.affiliation: Inserm, U1141, Robert Debré Hospital, APHP, 75019, Paris, France; Denis Diderot-Paris 7 University, Robert Debré Hospital, Paris, France; Department of Developmental Biology, Robert Debré Hospital, APHP, Paris, France.
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Delezoide
authors.affiliation: Inserm, Clinical Investigation Center CIC 1426, Robert Debré Hospital, APHP, Paris, France; Department of Pediatric Pharmacology and Pharmacogenetics, Robert Debré Hospital, APHP, Paris, France.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Inserm, U1141, Robert Debré Hospital, APHP, 75019, Paris, France; Denis Diderot-Paris 7 University, Robert Debré Hospital, Paris, France; Department of Developmental Biology, Robert Debré Hospital, APHP, Paris, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Guimiot
authors.affiliation: Inserm, U1141, Robert Debré Hospital, APHP, 75019, Paris, France; Denis Diderot-Paris 7 University, Robert Debré Hospital, Paris, France; Department of Pathology, Lariboisière Hospital, APHP, 75010, Paris, France.
authors.forename: Homa
authors.initials: H
authors.lastname: Adle-Biassette
authors.affiliation: Inserm, U1141, Robert Debré Hospital, APHP, 75019, Paris, France; Denis Diderot-Paris 7 University, Robert Debré Hospital, Paris, France; PhenoPups SAS, Evry, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Durand
authors.affiliation: Inserm, U1141, Robert Debré Hospital, APHP, 75019, Paris, France; Denis Diderot-Paris 7 University, Robert Debré Hospital, Paris, France.
authors.forename: Maud
authors.initials: M
authors.lastname: Ringot
authors.affiliation: Inserm, U1141, Robert Debré Hospital, APHP, 75019, Paris, France; Denis Diderot-Paris 7 University, Robert Debré Hospital, Paris, France.
authors.forename: Jorge
authors.initials: J
authors.lastname: Gallego
authors.affiliation: Department of Pharmacy, Robert Debré Hospital, APHP, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Storme
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 Clinical Pharmacology and Clinical Trials, Louis Pradel Hospital, EPICIME, Lyon, France; CNRS, UMR, 5558, Lyon, France; Lyon-1 University, Lyon, France; Inserm, Clinical Investigation Center CIC1407, Louis Pradel Hospital, Lyon, France.
authors.forename: Behrouz
authors.initials: B
authors.lastname: Kassaï
authors.affiliation: Department of Women's and Children's Health, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Turner
authors.affiliation: Denis Diderot-Paris 7 University, Robert Debré Hospital, Paris, France; Inserm, Clinical Investigation Center CIC 1426, Robert Debré Hospital, APHP, Paris, France; Department of Pediatric Pharmacology and Pharmacogenetics, Robert Debré Hospital, APHP, Paris, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Jacqz-Aigrain
authors.affiliation: Inserm, U1141, Robert Debré Hospital, APHP, 75019, Paris, France; Denis Diderot-Paris 7 University, Robert Debré Hospital, Paris, France. Electronic address: boris.matrot@inserm.fr.
authors.forename: Boris
authors.initials: B
authors.lastname: Matrot
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D001522:Behavior, Animal / Q000187:drug effects; D002939:Ciprofloxacin / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007596:Joints / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009420:Nervous System / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D012119:Respiration / Q000187:drug effects; D018570:Risk Assessment; D013045:Species Specificity; D015430:Weight Gain / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin
keywords: Arthrotoxicity; Fluoroquinolone; Hepatotoxicity; Neonate; Nephrotoxicity; Neurodevelopment