title: 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 Fe(3+) 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 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.
  
  
  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 non-fermenters, though resistance was common in P. aeruginosa from cystic fibrosis. Raised MICs for some isolates were independent of β-lactamase.
authors.affiliation: Antibiotic Resistance Monitoring & Reference Laboratory, HPA Centre for Infections, 61 Colindale Avenue, London NW9 9EQ, UK. david.livermore@hpa.org.uk
authors.forename: David M
authors.initials: DM
authors.lastname: Livermore
authors.forename: Shazad
authors.initials: S
authors.lastname: Mushtaq
authors.forename: Marina
authors.initials: M
authors.lastname: Warner
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D019818:Clavulanic Acid / Q000494:pharmacology*; D003470:Culture Media / Q000737:chemistry; D024881:Drug Resistance, Bacterial; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D008997:Monobactams / Q000494:pharmacology*; D065093:beta-Lactamase Inhibitors
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D003470:Culture Media; D004791:Enzyme Inhibitors; D008997:Monobactams; D065093:beta-Lactamase Inhibitors; D019818:Clavulanic Acid