In vitro and in vivo activities of the diazabicyclooctane OP0595 against AmpC-derepressed Pseudomonas aeruginosa

Pseudomonas aeruginosa is a common cause for healthcare-associated infections, which have been historically treated by antipseudomonal beta-lactam agents in the clinical setting. However, P. aeruginosa has evolved to overcome these beta-lactam agents via multiple endogenous resistance mechanisms, including derepression of the chromosomal cephalosporinase (AmpC). In this article, we investigated the effective concentration of OP0595 for combination with piperacillin, cefepime or meropenem in in vitro susceptibility tests, and the antibacterial activity of cefepime in combination with OP0595 in both in vitro time-kill studies and in vivo murine thigh infection model study with AmpC-derepressed P. aeruginosa. The sufficient combinational concentration of OP0595 was a 4 mu g ml(-1) with all these three beta-lactam agents. OP0595 increased the antibacterial activity of cefepime in both in vitro and in vivo studies against all strains tested. Taken together, OP0595 is the diazabicyclooctane serine p-lactamase inhibitor with activity against AmpC-derepressed P. aeruginosa and its combinational use with a beta-lactam agent will provide a new approach for the treatment of P. aeruginosa infections.