Suboptimal Ciprofloxacin Dosing as a Potential Cause of Decreased Pseudomonas aeruginosa Susceptibility in Children with Cystic Fibrosis

STUDY 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. DESIGN: Pharmacodynamic analysis using Monte Carlo simulations of three previously published population pharmacokinetic models. SETTING: Pediatric hospital in Paris, France. PATIENTS: 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. MEASUREMENTS AND MAIN 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%. CONCLUSION: 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.