Pharmacodynamic Evaluation of Ampicillin-sulbactam in Pediatric Patients Using Plasma and Urine Data

<jats:sec> <jats:title>Background:</jats:title> <jats:p>We aimed to develop population pharmacokinetic (PK) models of ampicillin and sulbactam using pooled data analysis and to optimize dosing regimens of ampicillin-sulbactam (combination ratio of 2:1) in pediatric patients.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>Population PK models of ampicillin and sulbactam were separately developed by simultaneously fitting plasma and urine data from pediatric patients in 14 published studies. Based on these models, we estimated the probability of attaining a pharmacodynamic (PD) target [50% of time that free drug concentrations above the minimum inhibitory concentration, 50% <jats:italic toggle="yes">f</jats:italic>T > minimum inhibitory concentration (MIC)] against MIC<jats:sub>90</jats:sub> [MIC that blocked the growth of 90% of the strains] of common bacteria in community-acquired pneumonia.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>The analysis included 54 pediatric patients (0.083–16.42 years of age, 4.0–77.0 kg of body weight). A total of 284 plasma concentrations and 90 urinary excretions from 0 to 6 hours after administration were used for population PK modeling. The data were adequately described by 2-compartment models for ampicillin and sulbactam. Age was not a statistically significant covariate in the PK of either drug. The PK/PD breakpoint MICs for 45 mg/kg 3 times daily and 75 mg/kg 4 times daily (q.i.d.) were 0.25 and 1 μg/mL, respectively. For empiric therapy of community-acquired pneumonia, because MIC<jats:sub>90</jats:sub> values for the main target pathogens is high (MIC<jats:sub>90</jats:sub> = 2 μg/mL for <jats:italic toggle="yes">Streptococcus pneumoniae</jats:italic> and MIC<jats:sub>90</jats:sub> = 4 μg/mL for <jats:italic toggle="yes">Haemophilus influenzae</jats:italic>), 75 mg/kg q.i.d. (Food and Drug Administration–approved maximum dosage in United States) might be better than 45 mg/kg 3 times daily (within approved dosage in Japan) to cover many pathogens.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>From the results of this PK/PD approach, 75 mg/kg q.i.d. (Food and Drug Administration–approved maximum dosage) should be recommended in the empiric therapy of community-acquired pneumonia.</jats:p> </jats:sec>