title: Use of Monte Carlo simulation to assess the pharmacodynamics of beta-lactams against Pseudomonas aeruginosa infections in children: a report from the OPTAMA program.
abstract: BACKGROUND
  Assessing the likelihood of achieving bactericidal pharmacodynamic exposures against Pseudomonas aeruginosa with intravenous antimicrobial regimens would provide insights into the selection of empiric therapy in the pediatric population.
  
  
  OBJECTIVE
  The objective of this study was to use pharmacodynamic modeling to determine the likelihood of various pediatric antibiotic regimens achieving bactericidal exposures against P aeruginosa in children.
  
  
  METHODS
  Minimum inhibitory concentrations (MICs) were determined for meropenem (20 and 40 mg/kg q8h), imipenem (15 and 25 mg/kg q6h), ceftazidime (50 mg/kg q8h), cefepime (50 mg/kg q8h), and piperacillin/tazobactam (75 mg/kg q6h) against P aeruginosa isolates from 2 pediatric institutions. A 5000-patient Monte Carlo simulation was performed to predict attainment of pharmacodynamic targets against P aeruginosa for each of these regimens in a population of 10-year-olds. Optimal regimens were defined as those that had a > or =90% likelihood of attaining target exposures.
  
  
  RESULTS
  At institution 1, high-dose imipenem, high-dose meropenem, and ceftazidime achieved bactericidal pharmacodynamic exposures (likelihood of target attainment: 94%, 92%, and 92%, respectively). No other regimen was associated with a high probability of attaining bactericidal exposure (low-dose imipenem, 87%; cefepime, 85%; low-dose meropenem, 84%; piperacillin/tazobactam, 60%). At institution 2, no regimen was associated with a high likelihood of attaining bactericidal exposure; the calculated probabilities were cefepime, 78%; ceftazidime, 65%; high-dose meropenem, 58%; high-dose imipenem, 57%; low-dose imipenem, 54%; low-dose meropenem, 47%; and piperacillin/tazobactam, 47%. A lack of agreement between attainment of bactericidal exposures and percent susceptibility was apparent for many of the regimens.
  
  
  CONCLUSIONS
  Few regimens demonstrated a high likelihood of achieving bactericidal exposures against P aeruginosa at these institutions. Importantly, percent susceptibility overestimated attainment of the bactericidal target for some regimens, suggesting that further study is necessary in pediatric patients. The findings of this study highlight differences in target attainment and MIC distributions between institutions, emphasizing the importance of using institution-specific data when selecting empiric antimicrobial therapy.
authors.affiliation: University of Connecticut, School of Pharmacy, Storrs, Connecticut, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Ellis
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Kuti
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007223:Infant; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D009010:Monte Carlo Method; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000302:isolation & purification; D047090:beta-Lactams / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D047090:beta-Lactams