This study aimed to characterize pharmacokinetics of intravenous and oral ciprofloxacin in children to optimize dosing scheme.
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.
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.
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.
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Committee on Infectious Diseases (2006) The use of systemic fluoroquinolones. Pediatrics 118:1287–1292. https://doi.org/10.1542/peds.2006-1722
Schaad UB, Wedgwood J, Ruedeberg A, et al (1997) Ciprofloxacin as antipseudomonal treatment in patients with cystic fibrosis. Pediatr Infect Dis J 16:106–111; discussion 123–126. https://doi.org/10.1097/00006454-199701000-00032
Schaad UB, Stoupis C, Wedgwood J et al (1991) Clinical, radiologic and magnetic resonance monitoring for skeletal toxicity in pediatric patients with cystic fibrosis receiving a three-month course of ciprofloxacin. Pediatr Infect Dis J 10:723–729
Pradhan KM, Arora NK, Jena A et al (1992) (1995) Safety of ciprofloxacin therapy in children: magnetic resonance images, body fluid levels of fluoride and linear growth. Acta Paediatr Oslo Nor 84:555–560. https://doi.org/10.1111/j.1651-2227.1995.tb13694.x
Salam MA, Dhar U, Khan WA, Bennish ML (1998) Randomised comparison of ciprofloxacin suspension and pivmecillinam for childhood shigellosis. Lancet Lond Engl 352:522–527. https://doi.org/10.1016/S0140-6736(97)11457-X
Bethell DB, Hien TT, Phi LT et al (1996) Effects on growth of single short courses of fluoroquinolones. Arch Dis Child 74:44–46. https://doi.org/10.1136/adc.74.1.44
Drusano G, Labro MT, Cars O et al (1998) Pharmacokinetics and pharmacodynamics of fluoroquinolones. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis 4(Suppl 2):S27–S41
Forrest A, Nix DE, Ballow CH et al (1993) Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients. Antimicrob Agents Chemother 37:1073–1081. https://doi.org/10.1128/aac.37.5.1073
Zelenitsky SA, Ariano RE (2010) Support for higher ciprofloxacin AUC 24/MIC targets in treating Enterobacteriaceae bloodstream infection. J Antimicrob Chemother 65:1725–1732. https://doi.org/10.1093/jac/dkq211
Abdulla A, Rogouti O, Hunfeld NGM et al (2020) Population pharmacokinetics and target attainment of ciprofloxacin in critically ill patients. Eur J Clin Pharmacol 76:957–967. https://doi.org/10.1007/s00228-020-02873-5
Sassen SDT, Mathôt RAA, Pieters R et al (2019) Population pharmacokinetics and dynamics of Ciprofloxacin prophylaxis in pediatric ALL patients. Clin Infect Dis Off Publ Infect Dis Soc Am. https://doi.org/10.1093/cid/ciz1163
Roberts JA, Alobaid AS, Wallis SC et al (2019) Defining optimal dosing of ciprofloxacin in patients with septic shock. J Antimicrob Chemother 74:1662–1669. https://doi.org/10.1093/jac/dkz069
Schwartz GJ, Haycock GB, Edelmann CM, Spitzer A (1976) A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics 58:259–263
Zheng Y, Wang Z, Lui G et al (2019) Simultaneous quantification of levofloxacin, pefloxacin, ciprofloxacin and moxifloxacin in microvolumes of human plasma using high-performance liquid chromatography with ultraviolet detection. Biomed Chromatogr BMC 33:e4506. https://doi.org/10.1002/bmc.4506
Bioanalytical Method ValidationGuidance for Industry. https://www.fda.gov/media/70858/download. Accessed 31 Jul 2020
Anderson BJ, Holford NHG (2008) Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol 48:303–332. https://doi.org/10.1146/annurev.pharmtox.48.113006.094708
Sheiner LB, Beal SL (1981) Some suggestions for measuring predictive performance. J Pharmacokinet Biopharm 9:503–512. https://doi.org/10.1007/BF01060893
European committee on antimicrobial susceptibility testing Antimicrobial wild type distributions of microorganisms. https://mic.eucast.org/Eucast2/SearchController/search.jsp?action=performSearch&BeginIndex=0&Micdif=mic&NumberIndex=50&Antib=47&Specium=-1. Accessed Jan 2021
Schaefer HG, Stass H, Wedgwood J et al (1996) Pharmacokinetics of ciprofloxacin in pediatric cystic fibrosis patients. Antimicrob Agents Chemother 40:29–34. https://doi.org/10.1128/AAC.40.1.29
Payen S, Serreau R, Munck A et al (2003) Population pharmacokinetics of ciprofloxacin in pediatric and adolescent patients with acute infections. Antimicrob Agents Chemother 47:3170–3178. https://doi.org/10.1128/aac.47.10.3170-3178.2003
Rajagopalan P, Gastonguay MR (2003) Population pharmacokinetics of ciprofloxacin in pediatric patients. J Clin Pharmacol 43:698–710
Zhao W, Hill H, Le Guellec C et al (2014) Population pharmacokinetics of ciprofloxacin in neonates and young infants less than three months of age. Antimicrob Agents Chemother 58:6572–6580. https://doi.org/10.1128/AAC.03568-14
Facchin A, Bui S, Leroux S et al (2018) Variability of ciprofloxacin pharmacokinetics in children: impact on dose range in sickle cell patients. J Antimicrob Chemother 73:3423–3429. https://doi.org/10.1093/jac/dky328
Lubowitz H, Slatopolsky E, Shankel S et al (1967) Glomerular filtration rate. Determination in patients with chronic renal disease. JAMA 199:252–256. https://doi.org/10.1001/jama.199.4.252
Rapp M, Urien S, Foissac F et al (2020) Population pharmacokinetics of meropenem in critically ill children with different renal functions. Eur J Clin Pharmacol 76:61–71. https://doi.org/10.1007/s00228-019-02761-7
Béranger A, Oualha M, Urien S et al (2018) Population pharmacokinetic model to optimize cefotaxime dosing regimen in critically ill children. Clin Pharmacokinet 57:867–875. https://doi.org/10.1007/s40262-017-0602-9
Béranger A, Benaboud S, Urien S et al (2019) Piperacillin population pharmacokinetics and dosing regimen optimization in critically ill children with normal and augmented renal clearance. Clin Pharmacokinet 58:223–233. https://doi.org/10.1007/s40262-018-0682-1
Cook AM, Hatton-Kolpek J (2019) Augmented renal clearance. Pharmacotherapy 39:346–354. https://doi.org/10.1002/phar.2231
van Zanten ARH, Polderman KH, van Geijlswijk IM et al (2008) Ciprofloxacin pharmacokinetics in critically ill patients: a prospective cohort study. J Crit Care 23:422–430. https://doi.org/10.1016/j.jcrc.2007.11.011
Hodel M, Genné D (2009) Antibiotics: drug and food interactions. Rev Med Suisse 5:1979–1984
Thuo N, Ungphakorn W, Karisa J et al (2011) Dosing regimens of oral ciprofloxacin for children with severe malnutrition: a population pharmacokinetic study with Monte Carlo simulation. J Antimicrob Chemother 66:2336–2345. https://doi.org/10.1093/jac/dkr314
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Hirt, D., Oualha, M., Pasquiers, B. et al. Population pharmacokinetics of intravenous and oral ciprofloxacin in children to optimize dosing regimens. Eur J Clin Pharmacol (2021). https://doi.org/10.1007/s00228-021-03174-1
- Population pharmacokinetics
- Dose optimization