A model-based analysis of pharmacokinetic-pharmacodynamic (PK/PD) indices of avibactam against Pseudomonas aeruginosa.

Objective: The aim of the present work was to use a semi-mechanistic pharmacokinetic-pharmacodynamic (PK/PD) model developed from in vitro time-kill measurements with P. aeruginosa to compare different pharmacodynamic indices derived from simulated human avibactam exposures, with respect to their degree of correlation with the modelled bacterial responses.

Methods: A mathematical model of the effect of ceftazidime-avibactam on the growth dynamics of P. aeruginosa was used to simulate bacterial responses to modelled human exposures from fractionated avibactam dosing regimens with a fixed ceftazidime dosing regimen (2 or 8 g q8h as a 2-h infusion). The relatedness of the 24-h change in bacterial density and avibactam exposure parameters was evaluated to determine exposure parameter that closely correlated with bacterial growth/killing responses.

Results: Frequent dosing was associated with higher efficacy, resulting in a reduction of avibactam daily dose. The best-fit PD index of avibactam determined from the simulation was fT > C of 1 mg/L avibactam and q8h was the longest dosing interval able to achieve 2-log kill: 41-87% (3.3 h to 7.0 h out of 8-h interval, respectively). The avibactam exposure magnitude required to achieve a 2-log kill in the simulations was dependent on the susceptibility of the bacterial isolate to ceftazidime.

Conclusions: Avibactam activity in combination with ceftazidime against multidrug resistant P. aeruginosa correlated with fT > C. Setting a threshold avibactam concentration to 1 mg/L, superimposed over a simulated human-like exposure of ceftazidime, achieved at least 2-log kill for the clinical dose of 500 mg q8h avibactam as a 2-h infusion, depending on the minimum inhibitory concentration of ceftazidime alone.