Suboptimal ciprofloxacin dosing as a potential cause of decreased Pseudomonas aeruginosa susceptibility in children with cystic fibrosis.
OBJECTIVE
To assess the probability of achieving ciprofloxacin pharmacodynamic targets with currently recommended dosages in order to investigate the risk of ciprofloxacin underexposure in children with cystic fibrosis.


METHODS
Pharmacodynamic analysis using Monte Carlo simulations of three previously published population pharmacokinetic models.


METHODS
Pediatric hospital in Paris, France.


METHODS
A total of 120 pediatric outpatients with cystic fibrosis followed over a 2-year period (2007-2008), whose ages and body weights were within the range of the values observed in the three published studies.


RESULTS
The ciprofloxacin dosage regimens used for the simulations were those currently recommended for the treatment of pulmonary infections caused by Pseudomonas aeruginosa susceptible to ciprofloxacin: 10 mg/kg 3 times/day intravenously and 20 mg/kg twice/day orally. Pharmacodynamic targets for ciprofloxacin were defined as a 24-hour area under the plasma concentration-time curve (AUC):minimum inhibitory concentration (MIC) ratio of less than 110 for resistance acquisition and greater than 125 for bacterial eradication. For a P. aeruginosa isolate with an MIC close to the clinical breakpoint, the probability of the AUC:MIC ratio to be less than 110 achieved values of 74-100%, depending on the model used, whereas the probability to achieve an AUC:MIC ratio greater than 125 decreased to 0-22%.


CONCLUSIONS
These results provide a pharmacologic hypothesis-that the current dosing recommendations of ciprofloxacin for cystic fibrosis children may be suboptimal-to explain the decrease in the susceptibility of P. aeruginosa to ciprofloxacin observed in children with cystic fibrosis. These results need to be confirmed in prospective pharmacokinetic-pharmacodynamic studies performed in children with cystic fibrosis in order to determine whether higher doses, with or without therapeutic drug monitoring, or a lower clinical breakpoint could be considered in this population.
Université Paris Descartes, Paris, France.
Emmanuelle
E
Guillot
Isabelle
I
Sermet
Agnès
A
Ferroni
Stéphanie
S
Chhun
Gérard
G
Pons
Jean-Ralph
JR
Zahar
Vincent
V
Jullien
D000293:Adolescent; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002648:Child; D002939:Ciprofloxacin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003198:Computer Simulation; D003550:Cystic Fibrosis / Q000150:complications / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial; D006801:Humans; D009010:Monte Carlo Method; D011552:Pseudomonas Infections / Q000150:complications / Q000188:drug therapy*; D011550:Pseudomonas aeruginosa / Q000187:drug effects*
D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin