Activity of OP0595-β-lactam combination against Gram-negative bacteria with extended-spectrum, AmpC and carbapenem-hydrolysing β-lactama

Background: OP0595 is a diazabicyclooctane that (i) acts as a PBP2-ctive antibacterial, (ii) inhibits Class A and C β-lactamases and (iii), like mecillinam, gives β-lactamase-independent potentiation of β-lactams targeting other PBPs. We tested its behaviour against β-lactam-resistant Enterobacteriaceae and non-fermenters. Methods: Organisms were UK clinical isolates; MICs were determined by CLSI agar dilution for OP0595 alone or combined at 1–4 mg/L with aztreonam, biapenem, cefepime or piperacillin. Results: MICs of OP0595 for Escherichia coli, Enterobacter, Citrobacter and Klebsiella spp. were mostly 1–4 mg/L but values >4 mg/L were seen for minorities of isolates irrespective of other resistances, and for 50%–60% of those with ertapenem resistance involving porin loss plus ESBL or AmpC activity. OP0595 MICs for Serratia, Proteeae and non-fermenters mostly were >4 mg/L. When its MIC was ≤4 mg/L, OP0595's antibacterial activity dominated combination activity. For ‘OP0595-resistant’ (MIC >4 mg/L) isolates with Class A or C β-lactamases OP0595 achieved strong potentiation of substrate β-lactams, contingent on β-lactamase inhibition. β-Lactamase-independent potentiation was evident with aztreonam, cefepime and piperacillin—less so for biapenem—for many OP0595-resistant Enterobacteriaceae with Class B carbapenemases, which are not inhibited by OP0595. OP0595 acted solely as a β-lactamase inhibitor for non-fermenters. Conclusions: OP0595 inhibited Enterobacteriaceae, not non-fermenters; its combinations had broad activity versus Enterobacteriaceae, largely contingent on OP0595's antibacterial activity but also on inhibition of Class A and C β-lactamases and on the β-lactam-enhancer effect, which allowed activity against many OP0595-resistant metallo-β-lactamase-producing Enterobacteriaceae. For non-fermenters OP0595 acted only as a β-lactamase inhibitor.