D Hirt1,2,3, M Oualha4,5, B Pasquiers4, S Blanot6, R Rubinstazjn7, C Glorion8, S El Messaoudi4, D Drummond9, V Lopez10, J Toubiana11, A Béranger4,5, Sana Boujaafar4,12, Yi Zheng4,12, Carmen Capito13, S Winter14, P L Léger15, R Berthaud16,17,18, Inès Gana4,12, F Foissac4,17,18, J M Tréluyer4,12,17,18, N Bouazza4,17,18, S Benaboud4,12. 1. EA7323, Evaluation des Thérapeutiques et Pharmacologie Périnatale et Pédiatrique, Université de Paris, 89 rue d'Assas, 75014, Paris, France. deborah.hirt@aphp.fr. 2. Service de Pharmacologie Clinique, AP-HP, Hôpital Cochin, 27 rue du Faubourg Saint Jacques, 75014, Paris, France. deborah.hirt@aphp.fr. 3. INSERM, U1018, Hôpital de Bicêtre, 78 Rue du Général Leclerc, 94270, Le Kremlin-Bicêtre, France. deborah.hirt@aphp.fr. 4. EA7323, Evaluation des Thérapeutiques et Pharmacologie Périnatale et Pédiatrique, Université de Paris, 89 rue d'Assas, 75014, Paris, France. 5. Service de Réanimation et Surveillance Continue Médico-Chirurgicales Pédiatriques, Hôpital Necker Enfants Malades, 149 Rue de Sèvres, 75015, Paris, France. 6. Service de Neurochirurgie, Hôpital Necker Enfants Malades, 149 Rue de Sèvres, 75015, Paris, France. 7. Service de Réanimation Chirurgicale Pédiatrique, Hôpital Necker Enfants Malades, 149 Rue de Sèvres, 75015, Paris, France. 8. Service de Chirurgie Orthopédique et Traumatologie Pédiatrique, Hôpital Necker Enfants Malades, 149 Rue de Sèvres, 75015, Paris, France. 9. Service de Pneumologie Pédiatrique, Hôpital Necker Enfants Malades, 149 Rue de Sèvres, 75015, Paris, France. 10. Service de Réanimation Cardiaque Pédiatrique, Hôpital Necker Enfants Malades, 149 Rue de Sèvres, 75015, Paris, France. 11. Service de Pédiatrie Générale - Équipe Mobile D'infectiologie, Hôpital Necker Enfants Malades, AP-HP, Université de Paris, 149 Rue de Sèvres, 75015, Paris, France. 12. Service de Pharmacologie Clinique, AP-HP, Hôpital Cochin, 27 rue du Faubourg Saint Jacques, 75014, Paris, France. 13. Service de Chirurgie Viscérale et Urologique Pédiatriques, Hôpital Necker Enfants Malades, 149 Rue de Sèvres, 75015, Paris, France. 14. Service d'hématologie, Immunologie et Rhumatologie Pédiatrique Hôpital Necker Enfants Malades, 149 Rue de Sèvres, 75015, Paris, France. 15. Service de Réanimation Pédiatrique, Hôpital Armand Trousseau, 26 Avenue du Dr Arnold Netter, 75012, Paris, France. 16. Service de Néphrologie Pédiatrique, Hôpital Necker Enfants Malades, 149 Rue de Sèvres, 75015, Paris, France. 17. Unite de Recherche Clinique Paris Descartes Necker Cochin, AP-HP, 89 rue d'Assas, 75014, Paris, France. 18. CIC-1419 Inserm, Cochin-Necker, 149 Rue de Sèvres, 75015, Paris, France.
Abstract
PURPOSE: This study aimed to characterize pharmacokinetics of intravenous and oral ciprofloxacin in children to optimize dosing scheme. METHODS: Children treated with ciprofloxacin were included. Pharmacokinetics were described using non-linear mixed-effect modelling and validated with an external dataset. Monte Carlo simulations investigated dosing regimens to achieve a target AUC0-24 h/MIC ratio ≥ 125. RESULTS: A total of 189 children (492 concentrations) were included. A two-compartment model with first-order absorption and elimination best described the data. An allometric model was used to describe bodyweight (BW) influence, and effects of estimated glomerular filtration rate (eGFR) and age were significant on ciprofloxacin clearance. CONCLUSION: The recommended IV dose of 10 mg/kg q8h, not exceeding 400 mg q8h, would achieve AUC0-24 h to successfully treat bacteria with MICs ≤ 0.25 (e.g. Salmonella, Escherichia coli, Proteus, Haemophilus, Enterobacter, and Klebsiella). A dose increase to 600 mg q8h in children > 40 kg and to 15 mg/kg q8h (max 400 mg q8h, max 600 mg q8h if augmented renal clearance, i.e., eGFR > 200 mL/min/1.73 m2) in children < 40 kg would be needed for the strains with highest MIC (16% of Pseudomonas aeruginosa and 47% of Staphylococcus aureus). The oral recommended dose of 20 mg/kg q12h (not exceeding 750 mg) would cover bacteria with MICs ≤ 0.125 but may be insufficient for bacteria with higher MIC and a dose increase according bodyweight and eGFR would be needed. These doses should be prospectively confirmed, and a therapeutic drug monitoring could be used to refine them individually.
PURPOSE: This study aimed to characterize pharmacokinetics of intravenous and oral ciprofloxacin in children to optimize dosing scheme. METHODS: Children treated with ciprofloxacin were included. Pharmacokinetics were described using non-linear mixed-effect modelling and validated with an external dataset. Monte Carlo simulations investigated dosing regimens to achieve a target AUC0-24 h/MIC ratio ≥ 125. RESULTS: A total of 189 children (492 concentrations) were included. A two-compartment model with first-order absorption and elimination best described the data. An allometric model was used to describe bodyweight (BW) influence, and effects of estimated glomerular filtration rate (eGFR) and age were significant on ciprofloxacin clearance. CONCLUSION: The recommended IV dose of 10 mg/kg q8h, not exceeding 400 mg q8h, would achieve AUC0-24 h to successfully treat bacteria with MICs ≤ 0.25 (e.g. Salmonella, Escherichia coli, Proteus, Haemophilus, Enterobacter, and Klebsiella). A dose increase to 600 mg q8h in children > 40 kg and to 15 mg/kg q8h (max 400 mg q8h, max 600 mg q8h if augmented renal clearance, i.e., eGFR > 200 mL/min/1.73 m2) in children < 40 kg would be needed for the strains with highest MIC (16% of Pseudomonas aeruginosa and 47% of Staphylococcus aureus). The oral recommended dose of 20 mg/kg q12h (not exceeding 750 mg) would cover bacteria with MICs ≤ 0.125 but may be insufficient for bacteria with higher MIC and a dose increase according bodyweight and eGFR would be needed. These doses should be prospectively confirmed, and a therapeutic drug monitoring could be used to refine them individually.
Authors: Jason A Roberts; Abdulaziz S Alobaid; Steven C Wallis; Anders Perner; Jeffrey Lipman; Fredrik Sjövall Journal: J Antimicrob Chemother Date: 2019-06-01 Impact factor: 5.790
Authors: D B Bethell; T T Hien; L T Phi; N P Day; H Vinh; N M Duong; N V Len; L V Chuong; N J White Journal: Arch Dis Child Date: 1996-01 Impact factor: 3.791
Authors: A Forrest; D E Nix; C H Ballow; T F Goss; M C Birmingham; J J Schentag Journal: Antimicrob Agents Chemother Date: 1993-05 Impact factor: 5.191
Authors: Alan Abdulla; Omar Rogouti; Nicole G M Hunfeld; Henrik Endeman; Annemieke Dijkstra; Teun van Gelder; Anouk E Muller; Brenda C M de Winter; Birgit C P Koch Journal: Eur J Clin Pharmacol Date: 2020-04-19 Impact factor: 2.953