A model-based evaluation of the pharmacokinetics-pharmacodynamics (PKPD) of avibactam in combination with ceftazidime.

BACKGROUND

The emergence of β-lactamase-producing bacteria limits the effectiveness of β-lactam (BL) antibiotics, and the combination with a β-lactamase inhibitor (BLI) aims to counteract this resistance. However, existing guidelines primarily focus on optimizing the dosing of BLs and do not adequately address the interaction between BLs and BLIs, leading to uncertain pharmacokinetic/pharmacodynamic (PK/PD) targets and potentially suboptimal dosing strategies.

OBJECTIVES

To investigate optimal PK/PD targets and dosing strategies for avibactam (BLI) combined with ceftazidime (BL) using mechanism-based PKPD models.

METHODS

PK models for ceftazidime and avibactam were integrated with mechanism-based PKPD models for Gram-negative bacteria. Simulations explored dose regimens in mice and humans, evaluating PK/PD indices and computing the PTA for diverse dosing strategies and infusion modes.

RESULTS

AUC/MIC was the most predictive index for avibactam against Enterobacteriaceae in both mice and humans, regardless of infusion mode. Against , > C predicted efficacy in mice, while AUC/MIC and Cmax/MIC were more predictive in humans, particularly for continuous infusion regimens. Higher PTAs were achieved with increased avibactam doses relative to ceftazidime, particularly with 1:1 and 2:1 ceftazidime:avibactam ratios. Continuous infusion improved PTA against but had limited impact on Enterobacteriaceae.

CONCLUSION

The PK/PD indices predictive of avibactam efficacy varied by species (mice and humans), bacterial strains, and mode of infusion. Dosing simulations suggest that increasing avibactam relative to ceftazidime and using continuous infusion regimens may enhance bacterial killing. These findings highlight the importance of refining dosing strategies for both components of the combination therapy.