Population pharmacokinetics of continuous-infusion ceftazidime in febrile neutropenic children undergoing HSCT: implications for target attainment for empirical treatment against Pseudomonas aeruginosa.
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ABSTRACT: OBJECTIVES:To conduct a population pharmacokinetic analysis of continuous-infusion ceftazidime in a retrospective cohort of paediatric HSCT patients who were empirically treated for febrile neutropenia (FN) and who underwent therapeutic drug monitoring of ceftazidime steady-state plasma concentrations (Css) for optimization of drug exposure. METHODS:A non-parametric approach with Pmetrics was used for pharmacokinetic analysis and covariate evaluation. Monte Carlo simulations were performed to calculate the PTA of the pharmacodynamic determinant of efficacy (Css/MIC ?4) against Pseudomonas aeruginosa with continuous-infusion ceftazidime dosages of 1-6?g daily. The Css safety threshold was arbitrarily placed at 100?mg/L and advisable dosages were used. RESULTS:A total of 46 patients with 70 ceftazidime Css values were included. Estimated glomerular filtration rate (eGFR) and body surface area were the covariates associated with drug clearance. At the EUCAST clinical breakpoint of 8?mg/L, simulations showed that continuous-infusion ceftazidime dosages of 4-6?g daily attained optimal PTAs (>90%) across most of 16 different clinical scenarios based on four classes of eGFR (50-145, 145.1-200, 200.1-286 and 286.1-422?mL/min/1.73?m2) and body surface area (0.30-0.64, 0.65-0.88, 0.89-1.34 and 1.35-1.84?m2). In patients with body surface area 0.30-0.64?m2 and eGFR ?200?mL/min/1.73?m2 the advisable dose of 3?g daily allowed only suboptimal PTAs (<75%). The cumulative fraction of response against MIC distribution of P. aeruginosa was >87%. CONCLUSIONS:Continuous-infusion ceftazidime dosages ranging from 3 to 6?g daily according to different classes of eGFR and body surface area may allow optimized empirical treatment of P. aeruginosa infections in paediatric HSCT patients with FN.
SUBMITTER: Cojutti PG
PROVIDER: S-EPMC6524490 | biostudies-literature | 2019 Jun
REPOSITORIES: biostudies-literature
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