Activity of BAL30072 alone or combined with β-lactamase inhibitors or with meropenem against carbapenem-resistant Enterobacteriaceae and non-fermenters

摘要

Objectives: We investigated the activity of BAL30072, a dihydroxypyridone monosulfactam, against carbapenem- resistant Enterobacteriaceae and non-fermenters (i) alone, (ii) combined with BAL29880 (to inhibit AmpC) and/or clavulanate [to inhibit extended-spectrum β-lactamases (ESBLs)] and (iii) combined 1:1 with meropenem. Methods: Isolates were from multiple UK hospitals. MICs were determined by CLSI agar dilution. Carbapenemases were identified by PCR and sequencing. Results: BAL30072 inhibited 69% of the carbapenem-resistant Enterobacteriaceae at ≤4 mg/L, including 60%- 87% with OXA-48, IMP, NDM and VIM enzymes or combinations of impermeability with AmpC or ESBL, and 40% with KPC enzymes. The proportions susceptible exceeded 90% for BAL30072+BAL29880+clavulanate, except for isolates with KPC carbapenemases, where members of the international sequence type (ST) 258 Klebsiella pneumoniae clone remained resistant. At 4 mg/L, BAL30072 was active against all OprD-deficient Pseudomonas aeruginosa, against 8/12 with efflux-type β-lactam resistance and 19/25 with metallo-carbapenemases; these proportions were little increased if inhibitors were added. Most Acinetobacter baumannii with OXA or NDM carbapenemases were susceptible to BAL30072 alone at ≤4 mg/L, but those with OXA-58 were resistant, probably for reasons other than their β-lactamase. Addition of meropenem to BAL30072 increased activity against some individual isolates, but with little clear relationship to the resistance mechanism, except for consistent potentiation against OprD-deficient P. aeruginosa. Conclusions: BAL30072 had good activity against many diverse carbapenem resistance types. Adding clavulanate and/or BAL29880 extended activity against carbapenem-resistant Enterobacteriaceae, but not non-fermenters. Adding meropenem resulted in small increases in activity against individual isolates. Resistance remained common in the K. pneumoniae ST258 KPC clone, even with both inhibitors or meropenem added.