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Clinical therapeutics

Ceftazidime dosage recommendations in burn patients: from a population pharmacokinetic approach to clinical practice via Monte Carlo simulations.


PMID 24094465

Abstract

Ceftazidime dosage regimen recommendations based on pharmacokinetic/pharmacodynamic approaches are not available for burn patients. The goal of this study was to propose a continuous dosage regimen of ceftazidime in burn patients, taking into account different MICs and pharmacokinetic covariates. The population pharmacokinetic analysis was conducted by using software dedicated to the analysis of nonlinear mixed effects models. The population pharmacokinetic model was first developed and validated in 70 adult burn patients. Taking into account various MICs of pathogens, 3 Monte Carlo simulation trials were conducted by using target concentration intervals (10-100, 20-100, and 40-100 mg/L). The recommended dosages were defined as the minimum dose leading to the highest percentage of patients whose ceftazidime concentrations were included in the target interval. Serum creatinine and age were identified as covariates of ceftazidime clearance. Age was also involved in volume of distribution. The simulations showed that a dose of 6 g/d did not allow achievement of the target interval in most patients. Regardless of dosage regimen, age, and serum creatinine, the mean percentage of patients reaching the 10- to 100-mg/L and the 20- to 100-mg/L target intervals were 99.4% (0.3%) and 96.1% (0.8%), respectively. For the 40- to 100-mg/L target interval, this percentage was only 76.4% (2.1%) (range, 65%-80%). Age and serum creatinine level can be used at the bedside to determine the initial doses of ceftazidime. These Monte Carlo simulations highlight the need of a reappraisal of ceftazidime's use in burn patients. Doses between 3 and 16 g/d are proposed, taking into account the pathogens' MICs. However, for sepsis caused by a pathogen with an MIC ≥ 8 mg/L, an insufficient percentage of burn patients will reach the therapeutic target with the recommended dosages.