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

Abstract 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 T 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 T . 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.