Activity of BAL30376 (monobactam BAL19764+BAL29880+clavulanate) versus Gram-negative bacteria with characterized resistance mechanisms

Abstract

Background: BAL30376 combines the siderophore monobactam BAL19764 (Syn/PTX 2416) with the bridged monobactam BAL29880 to inhibit AmpC enzymes and with clavulanate to inhibit extended-spectrum β-lactamases (ESBLs). We tested BAL30376 and its components versus isolates and laboratory strains of Enterobacteriaceae and non-fermenters. Methods: MICs were determined on Mueller-Hinton agar supplemented with 2,2′-bipyridyl to chelate Fe3 + and induce TonB-mediated uptake. Results: Unprotected BAL19764 had MICs≤1 mg/L for most cephalosporin-susceptible Enterobacteriaceae, but values for a few isolates ranged up to 8 mg/L; its MICs were substantially raised for isolates with AmpC β-lactamases and ESBLs. Those of BAL30376 were ≤1 mg/L for 84% of ESBL producers and ≤4 mg/L for 85% of AmpC producers, excluding isolates with exceptional impermeability. Laboratory transformants with metalloor OXA-48 carbapenemases were susceptible to unprotected BAL19764, but many clinical isolates with these enzymes were resistant, probably having additional mechanisms; BAL30376, by contrast, was active at 4 mg/L versus 31/35 metallo-β-lactamase producers and 14/19 with OXA-48, although those with KPC carbapenemases were resistant. AmpC-mediated resistance to BAL19764 in Pseudomonas aeruginosa was overcome by BAL30376, as was that due to PER-1 enzyme; but MICs >16 mg/L were frequent for cystic fibrosis isolates. Many Burkholderia cepacia and carbapenemase-producing Acinetobacter baumannii were susceptible to BAL19764 and BAL30376 at ≤4 mg/L, but others were highly resistant, with MICs≥128 mg/L. Conclusions: BAL30376 overcomes most AmpC-, ESBL- and carbapenemase-mediated resistance in Enterobacteriaceae, though strains with KPC carbapenemases are resistant. It was active against many problem nonfermenters, though resistance was common in P. aeruginosa from cystic fibrosis. Raised MICs for some isolates were independent of β-lactamase. © The Author 2010. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.