title: Activity of BAL30072 alone or combined with β-lactamase inhibitors or with meropenem against carbapenem-resistant Enterobacteriaceae and non-fermenters.
abstract: OBJECTIVE
  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.
authors: Antimicrobial Resistance & Healthcare-Associated Infection Unit, HPA-Colindale, London NW9 5EQ, UK.
authors: Shazad
authors: S
authors: Mushtaq
authors: Neil
authors: N
authors: Woodford
authors: Russell
authors: R
authors: Hope
authors: Rachael
authors: R
authors: Adkin
authors: David M
authors: DM
authors: Livermore
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics; D004357:Drug Synergism; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000302:isolation & purification; D004756:Enterobacteriaceae Infections / Q000382:microbiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006761:Hospitals; D006801:Humans; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D008997:Monobactams / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013844:Thiazoles / Q000494:pharmacology*; D013845:Thienamycins / Q000494:pharmacology*; D006113:United Kingdom; D018440:beta-Lactam Resistance; D001618:beta-Lactamases / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; C552042:BAL 30072; D001426:Bacterial Proteins; D004269:DNA, Bacterial; D004791:Enzyme Inhibitors; D008997:Monobactams; D013844:Thiazoles; D013845:Thienamycins; D001618:beta-Lactamases; C063912:carbapenemase; D000077731:Meropenem
keywords: KPC carbapenemases; NDM carbapenemases; OXA carbapenemases; VIM carbapenemases; monosulfactam