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

Abstract

ABSTRACTSecondary to the stability of aztreonam against metallo-β-lactamases, coupled with avibatam's neutralizing activity against often coproduced extended-spectrum β-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-β-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 14Enterobacteriaceaeand 13Pseudomonas aeruginosaisolates, of which 25 produced metallo-β-lactamases. Additionally, sixP. aeruginosaisolates 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 theEnterobacteriaceaebacterial isolates (aztreonam MIC, ≤32 μg/ml;fT>MIC, ≥38%) and minimal activity against the remaining isolates (aztreonam MIC, ≥128 μg/ml;fT>MIC, 0%). Alternatively, aztreonam-avibactam therapy resulted in the reduction of all 14Enterobacteriaceaeisolates (aztreonam-avibactam MICs, ≤16 μg/ml;fT>MIC, ≥65%) and no difference between the 375- and 600-mg doses of avibactam was noted. Similar pharmacodynamically predictable activity againstP. aeruginosawas noted in studies with neutropenic and immunocompetent mice, with activity occurring when the MICs were ≤16 μg/ml and variable efficacy noted when the MICs were ≥32 μg/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-β-lactamase-producing Gram-negative pathogens that coproduce ESBLs or AmpC.