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

Abstract

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. MICs were determined on Mueller-Hinton agar supplemented with 2,2'-bipyridyl to chelate Fe(3+) and induce TonB-mediated uptake. 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 metallo- or 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. BAL30376 overcomes most AmpC-, ESBL- and carbapenemase-mediated resistance in Enterobacteriaceae, though strains with KPC carbapenemases are resistant. It was active against many problem non-fermenters, though resistance was common in P. aeruginosa from cystic fibrosis. Raised MICs for some isolates were independent of β-lactamase.