Human Simulated Studies of Aztreonam and Aztreonam-Avibactam To Evaluate Activity against Challenging Gram-Negative Organisms, Including Metallo-β-Lactamase Producers

Secondary to the stability of aztreonam against metallo-beta-lactamases, coupled with avibatam's neutralizing activity against often coproduced extended-spectrum beta-lactamases (ESBLs) or AmpC enzymes, the combination of aztreonam and avibactam has been proposed as a principal candidate for the treatment of infections with metallo-beta-lactamase-producing Gram-negative organisms. Using the neutropenic-mouse thigh infection model, we evaluated the efficacy of human simulated doses of aztreonam-avibactam and aztreonam against 14 Enterobacteriaceae and 13 Pseudomonas aeruginosa isolates, of which 25 produced metallo-beta-lactamases. Additionally, six P. aeruginosa isolates were also evaluated in immunocompetent animals. A humanized aztreonam dose of 2 g every 6 h (1-h infusion) was evaluated alone and in combination with avibactam at 375 or 600 mg every 6 h (1-h infusion), targeting the percentage of the dosing interval in which free-drug concentrations remained above the MIC (fT> MIC). Efficacy was evaluated as the change in bacterial density after 24 h compared with the bacterial density at the initiation of dosing. Aztreonam monotherapy resulted in reductions of two of the Enterobacteriaceae bacterial isolates (aztreonam MIC, <= 32 mu g/ml; fT> MIC, >= 38%) and minimal activity against the remaining isolates (aztreonam MIC, >= 128 mu g/ml; fT> MIC, 0%). Alternatively, aztreonam-avibactam therapy resulted in the reduction of all 14 Enterobacteriaceae isolates (aztreonam-avibactam MICs, <= 16 mu g/ml; fT> MIC, >= 65%) and no difference between the 375- and 600-mg doses of avibactam was noted. Similar pharmacodynamically predictable activity against P.aeruginosa was noted in studies with neutropenic and immunocompetent mice, with activity occurring when the MICs were <= 16 mu g/ml and variable efficacy noted when the MICs were >= 32 mu g/ml. Again, no difference in efficacy between the 375- and 600-mg doses of avibactam was observed. Aztreonam-avibactam represents an attractive treatment option for infections with metallo-beta-lactamase-producing Gram-negative pathogens that coproduce ESBLs or AmpC.