Distribution of piperacillin-tazobactam into cerebrospinal, peritoneal, and pleural fluid in children aged 0-18 years

Piperacillin-tazobactam is increasingly used to treat serious infections in children; however, data on its penetration into body fluids remain limited. We aimed to evaluate drug penetration into these sites and identify effective dosing regimens.

Free piperacillin-tazobactam concentrations were measured in serum, cerebrospinal fluid (CSF), peritoneal, and pleural fluid. A population pharmacokinetic model was developed to determine the penetration (AUC_{0 - ∞,  target site}/AUC_{0 - ∞,  serum}) into the relevant sites. Simulations evaluated intermittent (q8h, q6h, q4h) and continuous infusions to achieve 50% fT_>MIC in serum, peritoneal, and pleural fluid, and 100% fT_>MIC in CSF.

103 children (median age 7.0 y; range 0-17.3) were included. Using the final four-compartment model, the median penetration from serum into CSF, peritoneal, and pleural fluid was 0.02, 1.00, and 0.85 for piperacillin, and 0.07, 1.48, and 1.05 for tazobactam, respectively. Simulations demonstrated: in serum, for a minimum inhibitory concentration (MIC) of 16 mg/L, 100 mg/kg q8h was only sufficient in children <3 months and ≥12 y, while children 2-12 y and 3 months- <2 y required q6h and q4h or continuous infusions, respectively; q8h achieved a ≥90% probability of target attainment for an MIC ≤ 16 mg/L in peritoneal and pleural fluid; for CSF, a ≥90% probability of target attainment was achieved only at an MIC ≤ 0.25 mg/L.

Piperacillin-tazobactam has high penetration in peritoneal and pleural fluid, achieving therapeutic concentrations with 100 mg/kg q8h dosing in all ages. The low CSF penetration is insufficient for Gram-negative meningitis (MIC > 0.25 mg/L). Children aged 3 months to <2 y require more frequent dosing to reach serum targets.