Population Pharmacokinetic Analysis of Cefoperazone-Sulbactam in Pediatric Patients: Simultaneous Analysis of Plasma and Urine Data for Optimal Dosing Regimens

BACKGROUND: This study aimed to develop population pharmacokinetic (PK) models of cefoperazone and sulbactam through simultaneous analysis of plasma and urine data in pediatric patients and to optimize dosing regimens based on PK/pharmacodynamic (PD) simulation. METHODS: Population PK models of cefoperazone and sulbactam were separately developed by simultaneously fitting plasma and urine data from pediatric patients described in 9 published articles. Probabilities of attaining the bactericidal target of 70% of free time above minimum inhibitory concentration (70% fT > MIC) for cefoperazone against clinical isolates of common bacteria were estimated based on the final model. RESULTS: Seventy-eight pediatric patients were the subjects for PK modeling (0.83-14.6 years old and 6-51.6 kg of body weight). A total of 439 plasma concentrations and 138 urinary excretions up to 7 hours after administration were used for population PK modeling. The data were adequately described by 2-compartment models for cefoperazone and sulbactam. Age was not a statistically significant covariate in the PK of both drugs. For empiric therapy of community-acquired pneumonia, the PK/PD breakpoint of 0.5-hour infusion of 20 mg/kg (cefoperazone-sulbactam dose ratio of 1:1) 4 times daily was 0.13 μg/mL and could cover MIC 90 of Streptococcus pneumoniae (MIC 90 = 0.125 μg/mL) and Haemophilus influenzae (MIC 90 = 0.125 μg/mL). However, since MIC 90 values for nosocomial pathogens are high (MIC 90 = 2 μg/mL for Staphylococcus aureus and MIC 90 = 4 μg/mL for Morganella morganii ), a 4-hour infusion of 60 mg/kg (cefoperazone-sulbactam dose ratio of 2:1) 4 times daily might be better to cover many pathogens. CONCLUSIONS: This study described population PK models of cefoperazone and sulbactam detailing the excretion process with urine data in pediatric patients and developed optimal dosing regimens of cefoperazone-sulbactam including extended infusion in consideration with pathogens, based on PK/PD simulation.