In vitro pharmacokinetics/pharmacodynamics of the combination of avibactam and aztreonam against MDR organisms

Abstract

Objectives: The combination of aztreonam and avibactam has been proposed for the treatment of infections caused bymetallo-β-lactamase-producing Gram-negative organisms, given the stability of aztreonamagainst metallo-β-lactamases plus the broad coverage of avibactam against AmpC β-lactamases and ESBLs. This study aimed to evaluate the efficacy of the combination against four clinical isolates with defined but diverse β-lactamase profiles. Methods: The MICs of aztreonamwere determined without and with avibactam(1, 2, 4, 8 and 16 mg/L). Using the MIC values, the static time-kill kinetic studies were designed to encompass aztreonam concentrations of 0.25, 0.5, 1, 2 and 4 times the MIC at the respective avibactam concentrations from 0 to 8 mg/L. Aztreonam and avibactamconcentrations were determined by LC-MS/MS during the course of the time-kill kinetic studies to evaluate whether avibactam protects aztreonam from degradation. Results: Three of the four isolates had aztreonam MICs ≥128 mg/L in monotherapy. Dramatically increasing susceptibility associated with a decrease in aztreonam MIC was observed with increasing avibactam concentration. Against all isolates, the combinations resulted in greater killing with amuch lower dose requirement for aztreonam. The resulting changes in base-10 logarithmof cfu/mL at both the 10 h and 24 h references (versus 0 h) were synergistic. In contrast, a significantly higher concentration of aztreonam in the monotherapy was required to produce the same kill as that in the combination therapy, due to rapid aztreonam degradation in two isolates. Conclusions: The aztreonam/avibactam combination protects aztreonam from hydrolysis and provides synergy in antimicrobial activity against multiple β-lactamase-expressing strains with a wide MIC range.