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

Objectives: The combination of aztreonam and avibactam has been proposed for the treatment of infections caused bymetallo-beta-lactamase-producing Gram-negative organisms, given the stability of aztreonam against metallo-beta-lactamases plus the broad coverage of avibactam against AmpC beta-lactamases and ESBLs. This study aimed to evaluate the efficacy of the combination against four clinical isolates with defined but diverse beta-lactamase profiles. Methods: The MICs of aztreonam were 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 avibactam concentrations 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 a much lower dose requirement for aztreonam. The resulting changes in base-10 logarithm of 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 beta-lactamase-expressing strains with a wide MIC range.