Pharmacokinetic/Pharmacodynamic Analysis of Extended/Two-Step Infusion Ceftazidime/Avibactam in Children With Gram-Negative Bacterial Infections

Purpose

To simulate the pharmacokinetic/pharmacodynamic (PK/PD) exposure of ceftazidime/avibactam (CZA) in children with gram-negative bacterial infections, and explore the appropriateness of the CZA standard dosing regimen (STD), further optimize the dosing regimen by extended/two-step infusion.

Methods

Monte Carlo simulations were performed to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) of CZA with varying weight in two age groups (≥6–12 and ≥12–18 years old, respectively), utilizing PK parameters and PD data (from the EUCAST as well as the published data on US children). The simulated dosing regimens included STD and extended/two-step infusion.

Findings

When the PK/PD target for ceftazidime was set at 50% of time that free drug concentrations remain above the minimum inhibitory concentration of the pathogen during the dosing interval (50% fT > MIC), the CZA STD achieved PTAs of ≥90% at susceptibility breakpoint (MIC = 8 mg/L) for children in weighed 15–30 kg (≥6–12years old) and 35–45 kg (≥12–18 years old). However, when the PK/PD target for ceftazidime was set at 100% fT > MIC, none could achieve PTAs of ≥90%. The CFR results showed that the STD couldn't provide CFRs ≥90% in all children, but extended infusion or two-step infusion could achieve the target CFRs in all children based on the MIC distribution of US children, and improve the CFRs based on EUCAST's MIC distribution. Compared with extended infusion, two-step infusion could reduce total infusion time in partial patients.

Implications

The current STD of CZA may not adequately meet the therapeutic requirements in children, thus it is recommended to optimize the dosing regimen by extended/two-step infusion or increasing the daily dose, guided by therapeutic drug monitoring.